WO2009027762A2 - Formes posologiques liquides d'antibiotiques fluoroquinolone ou sel de ceux-ci pour administration ophtalmique, otique et nasale - Google Patents

Formes posologiques liquides d'antibiotiques fluoroquinolone ou sel de ceux-ci pour administration ophtalmique, otique et nasale Download PDF

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WO2009027762A2
WO2009027762A2 PCT/IB2007/002878 IB2007002878W WO2009027762A2 WO 2009027762 A2 WO2009027762 A2 WO 2009027762A2 IB 2007002878 W IB2007002878 W IB 2007002878W WO 2009027762 A2 WO2009027762 A2 WO 2009027762A2
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pharmaceutically acceptable
stable solution
solution according
ophthalmic
otic
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PCT/IB2007/002878
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WO2009027762A3 (fr
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Chandrashekhar Mainde
Girish Shantilal Achliya
Suresh Parasmal Bora
Rajendra Nandlal Nagori
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Wockhardt Research Centre
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the present invention relates to stable solutions suitable for ophthalmic, otic, or nasal administration that include fluoroquinolone antibiotic or salts thereof and amino acid, optionally in combination with one or more drugs for the treatment of bacterial infections.
  • the invention further provides stable solutions suitable for ophthalmic, otic, or nasal administration that include nadifloxacin and pharmaceutically acceptable salts thereof.
  • the invention also relates to processes for the preparation of the stable solutions.
  • Fluoroquinolone antibiotics are widely used in the management of infectious diseases. Their potent and broad spectrum of activity, efficacy and relative safety make them useful. They act by inhibiting the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae.
  • the antibiotics representing fluoroquinolone class are, but not limited to, nadifloxacin, ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, gatifloxacin and moxifloxacin and salts thereof.
  • Nadifloxacin is chemically, 9-fluoro-6,7-dihydro-8-(4-hydroxy-l-pyperidinyl)-5-methyl- l-oxo-lH,5H-benzo(I,j)quinolizine-2-carboxylic acid of Formula I provided below.
  • Nadifloxacin is a synthetic quinolone with potent broad-spectrum anti-bacterial activity. Nadifloxacin inhibits the enzyme DNA gyrase that is involved in bacterial DNA synthesis and replication, thus inhibiting the bacterial multiplication.
  • RS-nadifloxacin and S-nadifloxacin exhibit strong antibacterial activity against Gram-positive, Gram-negative and anaerobic bacteria, resistant Gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant Staphylococcus aureus, coagulase negative staphylococci, such as methicillin-resistant Staphylococcus epidermidis (MRSE), enterococci, betahemolytic streptococci and viridans group of streptococci, mycobacteria and newly emerging nosocomial pathogens such as Chryseobacterium meninges epticum, and Gram-negative pathogens such as E.coli, Klebsiella, Proteus, Serratia, Citrobacter and Pseudomonas.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidi
  • S-(-)-nadifloxacin in particular exhibits potent antibacterial activity against glycopeptide intermediate S. aureus (GISA), vancomycin intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA).
  • GISA glycopeptide intermediate S. aureus
  • VISA vancomycin intermediate S. aureus
  • VRSA vancomycin-resistant S. aureus
  • Nadifloxacin is also active against quinolone-resistant Staphylococci.
  • Nadifloxacin is marketed in the form of cream for topical application for the treatment of acne vulgaris, folliculitis and sycosis vulgaris. It is also indicated for the treatment of topical bacterial infections with susceptible bacteria.
  • quinolone antibiotics to treat infections is known art in the field of ophthalmic pharmaceutical compositions and methods of treatment.
  • Several quinolone antibacterial agents available in the market include gatifloxacin (available as Zymar®), Levofloxacin (available as Quixin® or Iquix®), Ciprofloxacin (available as Ciloxan®), Ofloxacin (available as Ocuflox®), Lomefloxacin (available as Lomeflox®), Moxifloxacin (available as Vigamox®) and Norfloxacin (available as Chibroxin®).
  • U.S. Patent No. 4,844,902 discloses a topically applicable formulation comprising by weight about 0.01 to 30% of an anti-bacterially active compound, 0.01 to 10% of a corticosteroid and a carrier.
  • U.S. Patent No. 6,333,045 discloses liquid pharmaceutical compositions of gatifloxacin or salt thereof and disodium edetate.
  • U.S. Patent No. 6,716,830 discloses ophthalmic dosage forms of moxifioxacin or salts thereof in a concentration of 0.1% to 1% (w/w) and pharmaceutically acceptable vehicle.
  • U.S. Patent No. 6,359,016 relates to topical suspension formulations containing ciprofloxacin and dexamethasone.
  • U.S. Patent No 4,399,134 discloses processes for the preparation of nadifloxacin or salts thereof and antibacterially effective pharmaceutical compositions of nadifloxacin.
  • Typical dosage forms include tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injectable preparations (solutions, suspensions, etc).
  • U.S. Patent No 6,884,768 discloses solid oral pharmaceutical compositions that includes nadifloxacin, an absorbefacient and taurine compounds.
  • U.S. Patent Application 20060183698 describes topical ophthalmic formulation that includes serum electrolytes; an antimicrobial compound and an anti-inflammatory or steroidal compound.
  • antimicrobial agents include nadifloxacin.
  • U.S. Patent Application 20040176337 discloses topical . compositions of benzoquinolizine-2-carboxylic acid antimicrobial drug.
  • U.S. Patent Application 20040176321 discloses injectable pharmaceutical composition for intravenous delivery of an active agent that includes RS-( ⁇ )-nadifloxacin; S-(-)- nadifloxacin and hydrates thereof; or S ⁇ (-)-nadifloxacin arginine and salts thereof.
  • PCT Publication WO 04/00360 describes pharmaceutical compositions of several active ingredients including nadifloxacin for topical use for treatment of dermatosis.
  • European Patent EP 275,515 and U.S. Patent No. 4,923,862 disclose aqueous pharmaceutical compositions of levofloxacin and ofloxacin or salts thereof.
  • PCT application WO 02/39993 discloses a stable pharmaceutical preparation of a combination drug, comprising an anti-infective agent, selected from the group consisting of quinolone derivatives, amino-glycoside derivatives and their pharmaceutically acceptable salts; an ant-inflammatory agent which is a corticosteroid; a complexation enhancing polymer; a solubilizer exhibiting an inclusion phenomena; pharmaceutically acceptable excipients within a suitable carrier system.
  • quinolone antibiotic compositions are generally effective in treating ophthalmic infections, and have distinct advantages over prior ophthalmic antibiotic compositions, particularly those having relatively limited spectrum of antimicrobial activity, such as: neomycin, polymyxin B, gentamicin and tobramycin, which are primarily useful against gram negative pathogens; and bacitracin, gramicidin, and erythromycin, which are primarily active against gram positive pathogens.
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or a salt thereof, one or more pharmaceutically acceptable amino acid and pharmaceutically acceptable vehicle therefor.
  • Embodiments of the solution dosage form may include one or more of the following features.
  • the te ⁇ n "fluoroquinolone antibiotic or a salt thereof referred to throughout in this invention includes, but not limited to, nadifloxacin, ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, gatifloxacin and moxifioxacin or salts or single enantiomers thereof.
  • amino acid in relation to an amino acid herein means that having no undesired or detrimental effect on the health of the subject being treated.
  • amino acid in suitable amount provides increased solubility of fluoroquinolone antibiotic, lowered potential to induce phlebitogenicity, fulfilling the abnormal toxicity regulatory requirements and stability when stored for an extended period at specified temperature and humidity ranges.
  • the amino acid can be used in concentration of 0.1% to 4.0% (w/v).
  • the amino acid may be selected from one or more of arginine, histidine, arginine acetate, arginine-glutamate, arginine monohydrochloride, histidine acetate, histidine acetate dihydrate, histidine monohydrochloride, histidine monohydrochloride monohydrate, lysine, lysine acetate, lysine monohydrochloride, ornithine, tryptophan, L-arginine, L- histidine, L-arginine acetate, L-arginine-L-glutamate, L-arginine monohydrochloride, L- histidine acetate, L-histidine acetate dihydrate, L-histidine monohydrochloride, L- histidine monohydrochloride monohydrate, L-Lysine, L-Lysine acetate, L-Lysine monohydrochloride and/or a salts thereof and/or D or DL form of these amino acids or
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising nadifloxacin or a pharmaceutically acceptable salt thereof at a concentration of 0.01% to 1% (w/v), arginine at a concentration of 0.1% to 4.0% (w/v), and pharmaceutically acceptable vehicle therefor.
  • Embodiments of the solution dosage form may include one or more of the following features.
  • the term "nadifloxacin or a pharmaceutically acceptable salt thereof referred to throughout in this invention means racemic nadifloxacin and its salts, its single enantiomer such as R-Nadifloxacin or S-nadifloxacin or salts thereof with organic or inorganic bases.
  • (S)-Nadifloxacin salts with amino acids such as arginine salt is also covered in this invention.
  • nadifloxacin or its salt to be formulated in the solution pharmaceutical composition of the present invention varies according to the degree of infection of a particular subject, but normally, nadifloxacin is formulated within the range of 0.01 to 1.0% (w/v), preferably 0.1 to 0.8% (w/v), more preferably 0.2 to 0.5% (w/v).
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising nadifloxacin or a pharmaceutically acceptable salt thereof at a concentration of 0.01 % to 1% (w/v), wherein the solution does not show any precipitation during the entire period of shelf life.
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising nadifloxacin or a pharmaceutically acceptable salt thereof at a concentration of 0.01% to 1% (w/v), wherein the solution does not show any precipitation during the entire period of shelf life and the amount of total related substances after six months of storage at 25°C/60%RH or at 45°C/75%RH is 2.0 % (w/w) or less.
  • Nadifloxacin solution dosage form is tested for stability using specified temperature and humidity ranges. Accelerated stability studies are performed by subjecting the samples at 40°C/75% Relative Humidity for 6 months. Total relative substances of the sample are tested; the different impurity values obtained indicated that there is no any precipitation and the formulation is stable at accelerated storage conditions.
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising nadifloxacin or a pharmaceutically acceptable salt thereof at a concentration of 0.01% to 1% (w/v), a pharmaceutically effective amount of hydroxypropyl- ⁇ -cyclodextrin, and pharmaceutically acceptable vehicle therefor.
  • Hydroxypropyl- ⁇ -cyclodextrin acts as a solubility enhancer component, helps to stabilize the solution and further helps to enhance the penetration of the drug into the corneal tissue.
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising nadifloxacin or a pharmaceutically acceptable salt thereof at a concentration of 0.01% to 1% (w/v), arginine at a concentration of 0.1% to 4.0% (w/v), a pharmaceutically effective amount of hydroxypropyl- ⁇ -cyclodextrin, and pharmaceutically acceptable vehicle therefor.
  • a process for the preparation of a stable solution comprising: a) mixing water, nadifloxacin or a pharmaceutically acceptable salt thereof, arginine and hydroxypropyl- ⁇ -cyclodextrin; b) filtering the solution; and c) filling in suitable containers.
  • a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or salt thereof, at least one amino acid, a steroid and pharmaceutically acceptable vehicle therefor.
  • the suitable steroidal drug comprises one or more of beclomethasone, betamethasone, budesonide, dexamethasone, clobetasol, clobetasone, fiumethasone, fluorometholone, hydrocortisone, prednisolone, triamcinolone loteprednol, niethylprednisolone, medrysone and the like.
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising nadifloxacin or a pharmaceutically acceptable salt thereof at a concentration of 0.01% to 1% (w/v), arginine at a concentration of 0.1% to 4.0% (w/v), a pharmaceutically effective amount of hydroxypropyl- ⁇ -cyclodextrin, a steroid, and pharmaceutically acceptable vehicle therefor.
  • a stable solution suitable for ophthalmic, otic or nasal administration comprising nadifloxacin or a pharmaceutically acceptable salt thereof at a concentration of 0.01% to 1% (w/v), arginine at a concentration of 0.1% to 4.0% (w/v), a pharmaceutically effective amount of hydroxypropyl- ⁇ -cyclodextrin, dexamethasone, and pharmaceutically acceptable vehicle therefor.
  • a process for the preparation of a stable solution comprising: a) mixing water, nadifloxacin or a pharmaceutically acceptable salt thereof, arginine, hydroxypropyl- ⁇ -cyclodextrin and dexamethasone; b) filtering the solution; and c) filling in suitable containers.
  • a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or salt thereof, at least one amino acid, an anti-inflammatory or anti-allergic agent and pharmaceutically acceptable vehicle therefor.
  • the suitable anti-inflammatory or anti-allergic agent drug comprises one or more of diclofenac, ketorolac, flurbiprofen, indomethacin, suprofen, ibuprofen, ketorolac tromethamine, emedastine, levocabastine, azelastine, olopatadine, ketotifen, cromolyn, or lodoxamide and the like.
  • a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or salt thereof, at least one amino acid, an anti-fungal agent and pharmaceutically acceptable vehicle therefor.
  • An antifungal agent is any agent that prevents the growth of or kills a fungal organism.
  • antifungal agents can be agents that interpolate fungal cell wall components or act as cell wall inhibitors.
  • Suitable anti-fungal agent comprises one or more from butenafme, naftifine, terbinafine imidazoles: bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole and the like.
  • a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or salt thereof, at least one amino acid, a macrolide and pharmaceutically acceptable vehicle therefor.
  • the macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached.
  • Suitable macrolide comprises one or more from erythromycin, azithromycin, roxithromycin, clarithromycin and the like.
  • a process for the preparation of a stable solution comprising: a) mixing water, one or more fluoroquinolone antibiotics or salt thereof and amino acid; b) optionally, adding another active agent, wherein the active agent is selected from the therapeutic categories of steroids, anti-inflammatory /anti-allergic agents, anti- fungals, and macrolides; c) filtering the solution; and d) filling in suitable containers.
  • fluoroquinolones can be formulated into a stable dosage fo ⁇ n with the help of addition of a suitable amount of a pharmaceutically acceptable amino acid.
  • the stable solution is suitable for the treatment of ocular, otic and nasal infections.
  • the invention provides a stable dosage form of fluoroquinolone or salt thereof, optionally in combination with one or more drugs selected from the group comprising steroids, anti-inflammatory/anti-allergics, anti-fungal or macro lide for the treatment of ophthalmic, otic or nasal bacterial infections.
  • a stable ophthalmic solution composition may be expected to have better patient compliance and acceptance.
  • nadifioxacin can be formulated in to a solution dosage form that is suitable for the treatment of ocular, otic and nasal infections.
  • Ophthalmic dosage forms of nadifioxacin are not known in the art.
  • the present inventors have found that the low resistance of microbes to nadifioxacin, effectiveness in treating Methicillin- Resistant Staphylococcus Aureus (MRSA) infections and no cross-resistance with other quinolones makes nadifioxacin an ideal candidate for the treatment of bacterial infections of ophthalmic, otic and nasal origin.
  • MRSA Methicillin- Resistant Staphylococcus Aureus
  • nadifioxacin is effective in low dosages and is relatively well tolerable.
  • a second drug can be administered in co- therapy with fluoroquinolone antibiotic.
  • the second agent can be a steroid, anti-inflammatory/anti-allergics, anti-fungal or macrolide.
  • Formulations containing steroids are useful for topical application to the eye, ear, nose or skin. Steroids are insoluble in water and thus are generally available in suspended form or are dissolved in oil or solvents when used in the formulation.
  • a clear, stable solution composition is the most preferred formulation for administration to the eye.
  • the stable solution dosage form for the ophthalmic, otic or nasal use, as part of present invention can be present in a single use or multi-use container.
  • 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.
  • physical properties e.g., osmolality and pH
  • compositions are typically administered to the affected ophthalmic, otic or nasal tissues by topically applying one to four drops of a sterile solution, 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 ophthalmic, otic and nasal compositions of the present invention will typically have a pH in the range of 4.5 to 8.0.
  • the ophthalmic compositions must 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 (“m ⁇ sm/kg”), but will preferably be about 300 m ⁇ sm/kg.
  • the pharmaceutically acceptable vehicle may include water.
  • composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include complexing agent, one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • a complexing agent is capable of solubilizing the active agent in pharmaceutically acceptable vehicle by forming an inclusion complex.
  • the complexing agents selected in the present invention may be a cyclodextrin and its derivatives, which can be well tolerated when, administered by ophthalmic route for e.g. alpha-, beta- or gamma- cyclodextrins or derivatives thereof.
  • Ophthalmic, otic and nasal pharmaceutical products are typically packaged in multidose form. 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. Typically such preservatives are employed at a level of from 0.001% to 1.0% (w/v).
  • 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 help 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), and cyclodextrin especially HP- ⁇ -CD, or other agents known to those skilled in the art.
  • co-solvents are employed at a level of from 0.01% to 5% (w/v).
  • HP- ⁇ -CD has a tendency to form inclusion complex with many drugs including nadifloxacin. This complex offers several advantages, such as reduced irritation, increased tolerability and efficacy. The dose of nadifloxacin 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 know to those skilled in the art. Such agents are typically employed at a level of from 0,01% to 2% (w/v).
  • Nadifloxacin solution dosage form is tested for stability using accelerated stability tests as well as for initial time studies. Accelerated stability studies are performed by subjecting the samples at 40°C/75% Relative Humidity for 3 months and 6 months. The relative impurities (known and unknown) of the sample are tested by using HPLC analysis method. The different impurity values obtained indicated that the formulation is stable at accelerated storage conditions. The stability results are provided in Tables 2 and 3.
  • the single highest known impurity is nothing but the known impurity having maximum value selected from all known impurity peak areas.
  • the single highest unknown impurity is unknown impurity having maximum value selected from all unknown impurity peak areas. Sum of peak areas of single highest known impurity and single highest unknown impurity is represented as total.
  • stable in the present context encompasses the solution that does not show any precipitation during the entire period of shelf life.
  • Table 1 provides composition of batches of the present invention.
  • Nadifloxacin, amino acid and HP- ⁇ -CD were dissolved in water for injection.
  • a solution of polyvinyl alcohol and benzalkonium chloride in water for injection.
  • a solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using IN HCl between 5.5 to 7.5.
  • the solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg.
  • the resultant solution was filtered using 0.22 ⁇ membrane filters and filled in desired containers under laminar flow.
  • Table 2 provides composition of batches of the present invention.
  • Ciprofloxacin, amino acid and HP- ⁇ - CD were dissolved in water for injection.
  • a solution of polyvinyl alcohol and benzalkonium chloride in water for injection.
  • a solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using IN HCl between 4.5 to 7.0.
  • the solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg.
  • the resultant solution was filtered using 0.22 ⁇ membrane filters and filled in desired containers under laminar flow.
  • Table 3 provides composition of batches of the present invention.
  • Diclofenac sodium, amino acid and HP- ⁇ -CD was dissolved in water for injection.
  • a solution of polyvinyl alcohol and benzalkonium chloride in water for injection was added to this and the pH of the resultant solution was adjusted using IN HCl between 4.5 to 7.5.
  • the solution was then adjusted to required osmolality using a solution of glycerin in water for injection. Osmolality of solution was adjusted to 250-350 m ⁇ sm/kg.
  • the resultant solution was filtered using 0.22 ⁇ membrane filters and filled in desired containers under laminar flow.
  • Table 4 provides composition of batches of the present invention.
  • Gatifloxacin, amino acid and HP- ⁇ - CD were dissolved in water for injection.
  • a solution of polyvinyl alcohol and benzalkonium chloride in water for injection.
  • a solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using IN HCl to 6.0.
  • the solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 m ⁇ sm/kg.
  • the resultant solution was filtered using 0.22 ⁇ membrane filters and filled in desired containers under laminar flow.
  • Table 5 provides composition of batches of the present invention.
  • Nadifloxacin, diclofenac sodium, amino acid and HP- ⁇ -CD were dissolved in water for injection.
  • a solution of polyvinyl alcohol and benzalkonium chloride in water for injection.
  • a solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using IN HCl to 7.0.
  • the solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg.
  • the resultant solution was filtered using 0.22 ⁇ membrane Filters and filled in desired containers under laminar flow. Table 6 provides composition of batches of the present invention.
  • Nadifloxacin, naphazoline hydrochloride, amino acid and HP- ⁇ - CD were dissolved in water for injection.
  • a solution of polyvinyl alcohol and benzalkonium chloride in water for injection was added to this and the pH of the resultant solution was adjusted using IN HCl between 5.5 to 7.5.
  • the solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 m ⁇ sm/kg.
  • the resultant solution was filtered using 0.22 ⁇ membrane filters and filled in desired containers under laminar flow.
  • Table 7 provides composition of batches of the present invention.
  • Nadifloxacin, dexamethasone, amino acid and HP- ⁇ - CD were dissolved in water for injection.
  • a solution of polyvinyl alcohol and benzalkonium chloride in water for injection.
  • a solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using IN HCl between 5.5 to 7.5. Osmolality of solution was adjusted to 250-350 m ⁇ sm/kg.
  • the resultant solution was filtered using 0.22 ⁇ membrane filters and filled in desired containers under laminar flow.
  • Tables 8 and 9 provide the stability data for the nadifloxacin solution dosage form prepared as per the Formula given in Table 1.

Abstract

La présente invention porte sur des solutions stables pour administration ophtalmique, otique ou nasale. Les solutions contiennent un antibiotique fluoroquinolone ou des sels de celui-ci et un acide aminé, facultativement en combinaison avec un ou plusieurs médicaments pour le traitement d'infections bactériennes. L'invention porte en outre sur des solutions stables pour administration ophtalmique, otique ou nasale qui contiennent de la nadifloxacine et des sels pharmaceutiquement acceptables de celle-ci. L'invention porte également sur des procédés de préparation desdites solutions stables.
PCT/IB2007/002878 2007-08-24 2007-10-02 Formes posologiques liquides d'antibiotiques fluoroquinolone ou sel de ceux-ci pour administration ophtalmique, otique et nasale WO2009027762A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2502616A1 (fr) * 2011-03-21 2012-09-26 Matthew Krayenbuhl Composition pharmaceutique nasale
CN104546696A (zh) * 2013-10-28 2015-04-29 南京长澳医药科技有限公司 一种s-(-)-那氟沙星-l-精氨酸单剂量滴眼液及其制备工艺
WO2018189575A1 (fr) * 2017-04-14 2018-10-18 Wockhardt Limited Compositions antibactériennes
RU2796503C2 (ru) * 2017-04-14 2023-05-24 Вокхардт Лимитед Антибактериальные композиции

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040176321A1 (en) * 2002-12-31 2004-09-09 Wockhardt Limited Compositions of benzoquinolizine carboxylic acid antibiotic drugs
US20040176337A1 (en) * 2002-12-31 2004-09-09 Wockhardt Limited Benzoquinolizine-2-carboxylic acid-containing compositions
US20050065164A1 (en) * 2001-04-25 2005-03-24 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US7164023B2 (en) * 2003-09-04 2007-01-16 Wockhardt Limited Benzoquinolizine-2-carboxylic acid arginine salt tetrahydrate
US7247642B2 (en) * 1999-05-07 2007-07-24 Wockhardt Limited Antibacterial optically pure benzoquinolizine carboxylic acids, processes, compositions and methods of treatment

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7247642B2 (en) * 1999-05-07 2007-07-24 Wockhardt Limited Antibacterial optically pure benzoquinolizine carboxylic acids, processes, compositions and methods of treatment
US20050065164A1 (en) * 2001-04-25 2005-03-24 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US20040176321A1 (en) * 2002-12-31 2004-09-09 Wockhardt Limited Compositions of benzoquinolizine carboxylic acid antibiotic drugs
US20040176337A1 (en) * 2002-12-31 2004-09-09 Wockhardt Limited Benzoquinolizine-2-carboxylic acid-containing compositions
US7164023B2 (en) * 2003-09-04 2007-01-16 Wockhardt Limited Benzoquinolizine-2-carboxylic acid arginine salt tetrahydrate

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2502616A1 (fr) * 2011-03-21 2012-09-26 Matthew Krayenbuhl Composition pharmaceutique nasale
WO2012127407A1 (fr) * 2011-03-21 2012-09-27 Dos Santos, Antonio Composition pharmaceutique pour une utilisation en administration nasale contenant un corticoïde et une quinolone ou de l'acide fusidique
US9636350B2 (en) 2011-03-21 2017-05-02 Matthew Krayenbuhl Pharmaceutical composition for use in nasal administration containing corticoid, and a quinolone or fusidic acid
CN104546696A (zh) * 2013-10-28 2015-04-29 南京长澳医药科技有限公司 一种s-(-)-那氟沙星-l-精氨酸单剂量滴眼液及其制备工艺
WO2018189575A1 (fr) * 2017-04-14 2018-10-18 Wockhardt Limited Compositions antibactériennes
CN109089413A (zh) * 2017-04-14 2018-12-25 沃克哈特有限公司 抗菌组合物
RU2796503C2 (ru) * 2017-04-14 2023-05-24 Вокхардт Лимитед Антибактериальные композиции

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