WO2021250635A1 - Sels d'acide de compositions à base d'acide fluoroquinolone carboxylique et procédés de fabrication et d'utilisation associés - Google Patents

Sels d'acide de compositions à base d'acide fluoroquinolone carboxylique et procédés de fabrication et d'utilisation associés Download PDF

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WO2021250635A1
WO2021250635A1 PCT/IB2021/055177 IB2021055177W WO2021250635A1 WO 2021250635 A1 WO2021250635 A1 WO 2021250635A1 IB 2021055177 W IB2021055177 W IB 2021055177W WO 2021250635 A1 WO2021250635 A1 WO 2021250635A1
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Prior art keywords
formulation
besifloxacin
weight
poloxamer
purified water
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PCT/IB2021/055177
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English (en)
Inventor
Sumana GHOSH
Anamika BHATTACHARYYA
Himanshi SINGH
Suresh SADHASIVAM
Mau SINHA
Mukesh Kumar Garg
Kalpna GARKHAL
Mukesh Kumar
Pragati KHARE
Swati Gupta
Shiladitya Sengupta
Charles G. Chavdarian
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Vyome Therapeutics Inc.
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Publication of WO2021250635A1 publication Critical patent/WO2021250635A1/fr

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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
    • A61K9/0043—Nose
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present disclosure is in the field of pharmaceutical and chemical sciences.
  • the present disclosure generally relates to the synthesis of therapeutic agents, processes for preparing said agents, compositions comprising said therapeutic agents and their uses.
  • the disclosure relates to medicinally important acid salts of fluoroquinolone carboxylic acid based chemical molecules [compounds of formula I], method of preparing said molecules, compositions, and the use of such molecules as therapeutic agents.
  • the said acid salts of fluoroquinolone carboxylic acid based chemical molecules are useful in treating infections such as ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna and combinations thereof.
  • BACKGROUND Otitis inflammation of the ear
  • BACKGROUND Otitis inflammation of the ear
  • BACKGROUND Otitis inflammation of the ear
  • otitis externa infections and inflammation in the external auditory canal
  • otitis media infections and inflammatory response comprising the middle ear cavity and ossicles
  • otitis interna or labyrinthitis or neuronitis infections in internal ear
  • Acute otitis externa also known as swimmer’s ear is typically caused by growth of bacteria (Pseudomonas spp. and Staphylococcus spp. being the most common) in external auditory canal,.,.
  • otitis externa Other bacteria like Proteus spp., Escherichia coli are also reported in some cases of otitis externa.
  • Fungal external otitis otomycosis
  • otitis externa otomycosis
  • Symptoms of otitis externa include pain (otalgia) due to external auditory canal edema and erythema and purulent discharge.
  • otitis externa is associated with hearing loss and perforations of the tympanic membrane.
  • Malignant otitis externa or chronic otitis externa is a rare complication of the spread of otitis externa into the mastoid and/or temporal bone.
  • Otitis media also known as tympanitis
  • Otitis media comprises a spectrum of diseases in the middle ear mainly acute otitis media, otitis media with effusion and chronic suppurative otitis media.
  • the pathogenesis of otitis media is multifactorial and several factors influence the progression of otitis media including allergies, inflamed or enlarged adenoids, colds, and respiratory infections by viruses and bacteria.
  • Onset of otitis media occurs generally due to dysfunction or blocking of the eustachian tube, caused by bacterial colonization of nasopharynx (mainly Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae).
  • nasopharynx mainly Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae.
  • Staphylococcus aureus and Streptococcus pyogenes are also reported. These allow normally produced fluids to build up in the middle ear.
  • trapped fluid can become infected by a virus or bacteria leading to progression of acute otitis media. This establishes an acute inflammatory cycle in the middle ear, bacterial persistence in the middle ear through biofilm formation, and finally severe chronic ear disease.
  • acute otitis media is seen in both adults and children, it is primarily common in the paediatric population. Symptoms of acute otitis media include moderate-to-severe bulging of the tympanic membrane, onset of ear pain and/or acute ear discharge. Sometimes recurrent acute otitis media in children are prevalent where several episodes of acute otitis media persist for many consecutive months. Such episodes are associated with ear pain and fever along with middle ear effusion. In some cases, symptoms of acute otitis media disappear with proper treatment, but the middle ear effusion may remain behind the tympanic membrane. This leads to otitis media with effusion. The trapped fluid may cause temporary and mild hearing loss.
  • tympanostomy tube insertion It is the primary indication for tympanostomy tube insertion, which is the most commonly performed operation on children to drain out the excess fluid accumulated in middle ear.
  • acute otitis media or otitis media with effusion can progress to chronic suppurative otitis media, characterized by the persistent infection and inflammation of the middle ear and mastoid air cells.
  • This condition typically involves perforation of the tympanic membrane, with intermittent or continuous otorrhea.
  • mucin prevents the transmission of sound waves from the middle ear to the inner ear, leading to conductive hearing loss.
  • Pseudomonas aeruginosa and Staphylococcus aureus are the predominant bacterial pathogens implicated in chronic suppurative otitis media.
  • Proetus mirabilis, Klebsiella spp., Escherichia coli, and Enterobacter spp. are also associated with chronic suppurative otitis media in some cases.
  • bacterial biofilms are formed that prevent action of antibiotics and elicit severe inflammatory responses, which might contribute to the chronicity of otitis media.
  • Otitis media is associated with host inflammation due to host response against pathogens that depends on a complex interplay of innate and adaptive immune mechanisms.
  • the innate immune system detects microbial infection and uses pattern recognition receptors to recognize the molecular signature of pathogens.
  • pattern recognition receptors include toll-like receptors, cytoplasmic nucleotide-binding oligomerization domain (NOD)-like receptors etc.
  • NOD cytoplasmic nucleotide-binding oligomerization domain
  • Different cytokines are involved in the early and late stages of inflammation including IL-1, IL-6, TNF- ⁇ and IL-8.
  • the conventional treatment approaches for treating otitis externa include the application of topical drugs, including antibiotics, corticosteroids, and acetic acid or a combination, and dry ear precautions.
  • use of acetic acid solution in otitis can lead to trauma in the ear canal, thereby increasing risk of an infection by the decreased barrier of the epithelium.
  • Oral antibiotics are generally prescribed for acute otitis media.
  • topical antibiotics are preferred for effective drug delivery at the site of action.
  • drug needs to be employed periodically to treat ear infection and otitis. Therefore, there is a need to develop formulations to provide a safe, effective treatment using sustained drug delivery methods.
  • the present disclosure aims in developing formulations with the aforesaid properties.
  • FIG. 1 shows SEM images showing effect of drug (16 ⁇ g/ml) on matured biofilms (72 h) of S. aureus ATCC 6538P the anti-biofilm property of the active compounds; and
  • Figure 2 shows comparison of cytokine secretion from THP-1 cells induced with TLR-2 agonist (Pam3CSK4) in the absence or presence of Formula 3.
  • the word “comprise”, or variations such as “comprises” or “comprising” or “containing” or “has” or “having” wherever used, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
  • composition has been interchangeably used with term “formulation”, and are intended to convey the ordinary meaning as understood by a person skilled in the art.
  • the term “managing” or “management” includes, treating or healing of a disease condition or disorder or ill effects or side effects.
  • management refers to decreasing the risk of death due to a disease or disorder, delaying the onset of a disease or disorder, inhibiting the progression of a disease or disorder, partial or complete cure of a disease or disorder and/or adverse effect attributable to the said disease or disorder, obtaining a desired pharmacologic and/or physiologic effect (the effect may be prophylactic in terms of completely or partially preventing a disorder or disease or condition, or a symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease or disorder and/or adverse effect attributable to the disease or disorder), or relieving a disease or disorder (i.e.
  • E is a salt
  • X is N or CR 8
  • R 2 is H, SH or alkyl
  • R 3 is H or halo
  • R8 is H, C1-C6alkyl, C1-C6alkoxy or halo
  • A is absent or a linker, wherein the linker is a bond or the linker is selected from the group consisting of: unsubstituted piperazinyl; 3-methylamino piperidine; pyrrolidinyl [3,4-b]piperidine; piperind- 4-ol; 1-H-benzoimidazol-2-yl; (1-H-benzoimidazol-2-yl)-amino; 2-Amino-1-H- benzoimidazolyl; 5,6-mono and di-substituted 1-H-benzoimidazol-2-yl
  • the present disclosure provides a formulation comprising a compound selected from: wherein ‘E’ is a salt; wherein ‘E’ is a salt; wherein ‘E’ is a salt; and combinations thereof.
  • the salt is selected from a group comprising inorganic salt or organic salt or their combination.
  • the inorganic salt is selected from a group comprising hydrobromate, sulfate, bisulfate or phosphate nitrate.
  • the organic salts like monoacid salt, diacid salt and alpha and beta hydroxy acid salt or any combination thereof.
  • the monoacid is selected from a group comprising acetate, phenylacetate, trifluoroacetate, propionate, stearate, palmitate, laurate, oleate, benzoate, 2-acetoxybenzoate, naphthalate, napthylate, fumarate, methanesulfonate, ethanedisulfonate, isethionate, p-toluenesulfonate, benezenesulfonate, laurylsulfonate, glucoheptonate, sulfanilate, lactobionate, valerate, salicylate, mandelate, lactate, glycolate or any combination thereof.
  • the diacid is selected from a group comprising oxalate, maleate, glutamate, 2-hydroxyglutamate, succinate, adipate, or any combination thereof.
  • the hydroxy diacid is selected from a group comprising alpha and beta hydroxy diacid comprising malate, tartarate, citrate or any combination thereof.
  • the salts are selected from a group comprising hydrochloride, mesylate, besylate, tosylate and combinations thereof. The present disclosure provides a formulation comprising a compound selected from:
  • composition comprising a compound selected from:
  • composition comprising a compound selected from:
  • a formulation comprising a therapeutically effective amount of compound of formula I thereof optionally along with excipient(s).
  • the excipient is selected from a group comprising gelling agent, isotonicity agent, suspending agent and solubiliser, dispersing agent, buffering agent, antioxidants, pH adjusting agent, penetration enhancers, surfactants, mineral oil, fatty acids, fatty alcohols, preservative, granulating agent, binding agent, lubricating agent, disintegrating agent, chelating agents, sweetening agent, glidant, anti-adherent, anti-static agent, gum, coating agent, coloring agent, flavoring agent, plasticizer, preservative, suspending agent, emulsifier, plant cellulosic material, spheronization agent, viscosity modifying agents and solvent, and combinations thereof.
  • the formulation comprising a compound of the present invention is in a form selected from a group comprising an in situ gel, an aqueous suspension, a solution, or combinations thereof.
  • the gelling agent is a thermosensitive gelling agent.
  • the thermosensitive gelling agent is selected from a group comprising poloxamer, phospholipon 90 h, polyvinyl alcohol.
  • the viscosity modifying agent is selected from a group comprising polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose and hydroxypropyl methylcellulose combinations thereof.
  • the isotonicity agent is selected from a group comprising sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, ammonium sulfate, glycerin, mannitol, sorbitol and other sugar alcohols combinations thereof.
  • isotonicity agent is composed of cations and anions, wherein said cations are selected from a group comprising sodium, potassium or ammonium cations and anions are selected from a group comprising chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions.
  • the suspending agent and solubiliser is selected from a group comprising povidone K90, povidone, fatty acid esters, fatty acid alcohols, glycerin, ethoxy alcohols, hydrogenated castor oils and its derivatives, sorbitan esters combinations thereof.
  • the buffering agent is selected from a group comprising tromethamine, boric acid, sodium borate, sodium acetate, acetic acid alkali or alkaline earth metal carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate, tromethamine (TRIS) and combinations thereof.
  • the antioxidant is selected from a group comprising sodium bisulphite, potassium metabisulphite and combinations thereof.
  • the pH adjusting agent is selected from a group comprising sodium hydroxide, hydrochloric acid, citric acid monohydrate, Sulfuric acid, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts, combinations, mixtures and combinations thereof.
  • the penetration enhancer is selected from a group comprising propylene glycol, isopropyl myristate, fatty acid esters, fatty acid alcohols, glycerin, ethoxy alcohols, hydrogenated castor oils and its derivatives, sorbitan esters and combinations thereof.
  • the preservative is selected from a group comprising quaternary ammonium derivatives, benzethonium chloride, organomercury compounds, methyl benzoate, propyl benzoate, p-hydroxy-benzoates and salts thereof, betaphenylethyl alcohol, benzyl alcohol, phenylethyl alcohol and phenoxyethanol and combinations thereof.
  • the quaternary ammonium derivative is selected from a group comprising benzalkonium chloride, benzylammonium chloride, cetylmethyl ammonium bromide, cetylpyridinium chloride and combinations thereof.
  • the organomercury compound is selected from a group comprising thimerosal, phenylmercury acetate, phenylmercury nitrate and combinations thereof.
  • the formulation according to the invention can also include mixtures of the preservatives and combinations thereof.
  • the surfactant is selected from a group comprising polysorbate 20, polysorbate 80, thonzonium bromide, tweens, spans, polyoxysorbates, fatty-acid glycerol-polyethylene glycol esters or a mixture thereof.
  • surfactants are used at a concentration between about 1.0% weight to about 8.5% weight, preferably from about 2.0% weight to about 7.5% weight, more preferably from about 3.0% weight to about 7.0% weight.
  • solubility agents such as octoxynol 40, tyloxapol, pluronics and combinations thereof.
  • the chelating agents are selected from a group comprising citric acid, ethylene diaminetetraacetic acid (EDTA), EDTA sodium salts, and ethylene glycol-bis(.beta.-aminoethyl ether) N,N,N',N'-tetraacetic abis ((EGTA).
  • the concentration of gelling agent in the above said formulation ranges from about 0.1% weight to 30 % weight.
  • the concentration of isotonicity agent in the above said formulation ranges from about 0.5 % weight to 50 % weight.
  • the concentration of suspending agent in the above said formulation ranges from about 0.01 % weight to 30 % weight. In an embodiment of the present disclosure, the concentration of buffering agent in the above said formulation ranges from about 0.01% weight to 10% weight. In an embodiment of the present disclosure, the concentration of antioxidant in the above said formulation ranges from about 0.01% weight to 5% weight. In an embodiment of the present disclosure, the concentration of solubiliser in the above said formulation ranges from about 0.1% weight to 99% weight. In an embodiment of the present disclosure, the concentration of dispersing agent in the above said formulation ranges from about 0.1% weight to 70% weight. In an embodiment of the present disclosure, the concentration of pH adjusting agent in the above said formulation ranges from about 0.001% weight to 5% weight.
  • the concentration of penetration enhancer in the above said formulation ranges from about 0.01% weight to 99% weight.
  • the concentration of surfactants in the above said formulation ranges from about 0.01% weight to 50% weight.
  • the concentration of mineral oil in the above said formulation ranges from about 0.1% weight to 80% weight.
  • the concentration of fatty acids in the above said formulation ranges from about 0.1% weight to 70% weight.
  • the concentration of fatty alcohols in the above said formulation ranges from about 0.1% weight to 50% weight.
  • the concentration of preservative in the above said formulation ranges from about 0.01% weight to 5% weight.
  • the solvent is incorporated into the mixture of components up to the quantity sufficient to prepare a formulation.
  • the in-situ gel formulation comprises: about 0.9% by weight of sodium chloride, about 15% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2.18% by weight of besifloxacin hydrochloride, about 1% by weight of tween 80, sodium hydroxide and purified water (quantity sufficient to).
  • the in-situ gel formulation particularly comprises: about 0.9% by weight of sodium chloride, about 15% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2.18% by weight of besifloxacin hydrochloride, about 0.2 % by weight of povidone, sodium hydroxide, and purified water (quantity sufficient to).
  • the in-situ gel formulation particularly comprises: about 0.9% by weight of sodium chloride, about 15% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2.18% by weight of besifloxacin hydrochloride, about 1% by weight of tween 80, about 0.2 % by weight of povidone, sodium hydroxide, and purified water (quantity sufficient to).
  • the components/ ingredients of the composition are adjusted to constitute 100 wt% composition.
  • the present disclosure provides a method for preparing in situ gel formulation, wherein the said process comprising the steps of: a. mixing the excipients to form a main phase; b.
  • the aqueous suspension formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.2% by weight of poloxamer, about 0.5% by weight of carbomer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin hydrochloride, Sodium hydroxide (pH 6-6.5); and purified water (quantity sufficient to).
  • the formulation comprises: about 0.9% by weight of sodium chloride, about 15% by weight of poloxamer, about 2.18% by weight of besifloxacin hydrochloride, sodium hydroxide; hydrochloric acid; and purified water (quantity sufficient to).
  • the formulation comprises: about 0.9% by weight of sodium chloride, about 15% by weight of poloxamer, about 2.18% by weight of besifloxacin hydrochloride, about 5% by weight of glycerin, sodium hydroxide, hydrochloric acid; and purified water (quantity sufficient to), wherein the pH of the suspension is ranging from 7 to 8, preferably pH of the suspension is about 7.59.
  • the formulation comprises: about 0.9% by weight of sodium chloride, about 15% by weight of poloxamer, about 2.18% by weight of besifloxacin hydrochloride, about 2.5% by weight of glycerin, sodium hydroxide, hydrochloric acid; and purified water (quantity sufficient to), wherein the pH of the suspension is ranging from 5 to 6, preferably pH of the suspension is about 5.4.
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.1% by weight of disodium edetate, about 0.2% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin hydrochloride, sodium hydroxide; and purified water (quantity sufficient to), wherein the pH of the suspension is ranging from 6 to 7.
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.1% by weight of disodium edetate, about 5% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin hydrochloride, sodium hydroxide; and purified water (quantity sufficient to), wherein the pH of the suspension is ranging from 6 to 7.
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.1% by weight of disodium edetate, about 10% by weight of Poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of Besifloxacin Hydrochloride, Sodium hydroxide; and purified water (quantity sufficient to), wherein the pH of the suspension is ranging from 6 to 7.
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.1% by weight of disodium edetate, about 15% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin hydrochloride, sodium hydroxide; and purified water (quantity sufficient to), wherein the pH of the suspension is ranging from 6 to 7.
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.2% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin or besifloxacin hydrochloride aqueous suspension, about 1% by weight of tween 80, sodium hydroxide; and purified water (quantity sufficient to).
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.2% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin or besifloxacin hydrochloride aqueous suspension, about 1% by weight of tween 80, about 0.2% by weight of povidone, sodium hydroxide; and purified water (quantity sufficient to).
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.2% by weight of Poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin or besifloxacin hydrochloride aqueous suspension, about 1% by weight of tween 80, about 0.2% by weight of povidone, about 1% by weight of tween 20, sodium hydroxide; and purified water (quantity sufficient to).
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.15% by weight of lecithin, about 15% by weight of poloxamer, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin hydrochloride, sodium hydroxide; and purified water (quantity sufficient to), wherein the pH of the suspension is ranging from 6 to 7.
  • the formulation comprises: about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.15% by weight of lecithin, about 15% by weight of poloxamer, about 2.5 % by weight of glycerin, about 3.5 % by weight of isopropyl myristate about 2% by weight of besifloxacin hydrochloride, sodium hydroxide; and mineral oil (quantity sufficient to), wherein the pH of the suspension is ranging from 6 to 7.
  • the formulation comprises: about 0.9% by weight of sodium chloride, about 15% by weight of poloxamer, about 2.18% by weight of besifloxacin hydrochloride, about 2.5 % by weight of glycerin, sodium hydroxide, hydrochloric acid; and water (quantity sufficient to), wherein the pH of the suspension is ranging from 6 to 7.
  • the present disclosure provides a compound selected from: ; Formula 2 wherein ‘E’ is a salt; Formula 3; or wherein ‘E’ is a salt; Formula 4 wherein ‘E’ is a salt; and combinations thereof.
  • the present disclosure provides a compound selected from: .
  • the present disclosure provides a compound selected from: .
  • the present disclosure provides a compound selected from:
  • the present disclosure provides a formulation for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna which comprises the compound of formula I optionally along with excipient(s).
  • the present disclosure provides a formulation for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna which comprises the compound of formula I-A optionally along with excipient(s).
  • the present disclosure provides a formulation comprising besifloxacin or besifloxacin salt and hydroxyethyl cellulose.
  • the besifloxacin salt is besifloxacin.HCl.
  • the present disclosure provides a formulation comprising besifloxacin or besifloxacin. salt and hydroxyethyl cellulose.
  • the besifloxacin salt is besifloxacin.HCl.
  • the present disclosure provides a formulation for the treatment of otitis media, which comprises the compound of formula I optionally along with excipient(s).
  • a formulation comprising compound of formula I for the manufacture of a medicament for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna by suitable mode of administration.
  • a formulation comprising compound of formula I-A for the manufacture of a medicament for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna by suitable mode of administration.
  • the formulation is administered to a subject through modes selected from a group comprising, but not limited to, topical administration, otic administration, intratympanic administration, and combinations thereof.
  • a formulation comprising compound of formula I for the manufacture of a medicament for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna by suitable administration of compound of formula I.
  • a formulation comprising compound of formula I-A for the manufacture of a medicament for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna by suitable administration of compound of formula I-A.
  • a formulation comprising compound of formula I for the manufacture of a medicament for the treatment of otitis externa by topical administration.
  • a method for treatment and/or prevention and/or management of otitis media comprising administering to an individual a medicament comprising a compound of formula I.
  • a method for treatment and/or prevention and/or management of otitis media comprising administering to an individual a formulation comprising a compound of formula I optionally along with excipient(s).
  • a method for treatment and/or prevention of otitis media comprising administering to an individual a formulation comprising a compound of formula I.
  • a method for treatment and/or prevention and/or management of otitis media comprising administering to an individual a formulation comprising a compound of formula I-A optionally along with excipient(s).
  • a method for treatment and/or prevention of otitis media comprising administering to an individual a formulation comprising a compound of formula I-A.
  • a method for treating or preventing a middle ear infection and sequelae thereof by transmembrane administration of a medicament thereto comprising: applying a transmembrane carrier formulation to the outer surface of the tympanic membrane, said transmembrane carrier formulation comprising a compound of formula I-A useful in treating or preventing infections of the middle ear and sequelae thereof.
  • a method of treating an otic disease or condition associated with a microbial infection comprising administering into the middle ear of a patient in need thereof in situ gel formulation comprising about 0.9% by weight of sodium chloride, about 15% by weight of Poloxamer, about 2.5 % by weight of glycerin, about 2.18% by weight of Besifloxacin Hydrochloride, about 1% by weight of Tween 80, Sodium hydroxide; and Purified water (q.s.), wherein the composition is administered into the infected ear of patient, wherein the otic disease or condition is otitis media.
  • a method of treating an otic disease or condition associated with a microbial infection comprising administering into the middle ear of a patient in need thereof, an in situ gel formulation comprising about 0.9% by weight of sodium chloride, about 15% by weight of Poloxamer, about 2.5 % by weight of glycerin, about 2.18% by weight of Besifloxacin Hydrochloride, about 0.2 % by weight of povidone, Sodium hydroxide; and purified water (q.s.), wherein the formulation is administered into the infected ear of patient.
  • a method of treating an otic disease or condition associated with a microbial infection comprising administering into the middle ear of a patient in need thereof, an in situ gel formulation comprising about 0.9% by weight of sodium chloride, about 15% by weight of Poloxamer, about 2.5 % by weight of glycerin, about 2.18% by weight of Besifloxacin Hydrochloride, about 1% by weight of Tween 80, about 0.2 % by weight of povidone, Sodium hydroxide; and purified water (q.s.), wherein the formulation is administered into the infected ear of patient.
  • a method of treating an otic disease or condition associated with a microbial infection comprising administering into the middle ear of a patient in need thereof, an aqueous suspension formulation comprising about 0.25% by weight of hydroxyethyl cellulose, about 0.9% by weight of sodium chloride, about 0.2% by weight of Poloxamer, about 0.5% by weight of carbopol 980, about 2.5 % by weight of glycerin, about 2% by weight of besifloxacin hydrochloride, Sodium hydroxide (pH 6-6.5); and purified water (q.s.), wherein the formulation is administered into the infected ear of patient.
  • a method of treating an otic disease or condition associated with a microbial infection comprising administering into the middle ear of a patient in need thereof, a formulation comprising about 0.9% by weight of sodium chloride, about 15% by weight of Poloxamer, about 5 % by weight of glycerin, about 2.18% by weight of Besifloxacin Hydrochloride and Sodium hydroxide (quantity sufficient to pH 7.0), hydrochloric acid (quantity sufficient to pH 7.0); and water (q.s.), wherein the formulation is administered into the infected ear of patient.
  • otic disease or conditions is otitis media, otitis externa or otitis interna.
  • a method of treating otitis externa in a human patient in need thereof, wherein said otitis externa is caused by bacterial infection which comprises topically administering to the bacterial infection-affected external ear canal of said human patient a therapeutically effective amount of a liquid ear drop composition which comprises a compound of formula I optionally along with excipient(s).
  • the present disclosure provides a compound of formula I for use in treating infections, wherein the compound of formula I is as defined above.
  • the present disclosure provides a compound of formula I for use in treating ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna wherein the compound of formula I is as defined above.
  • the present disclosure provides a compound of formula I for use in treating ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna
  • the compound is: ; wherein ‘E’ is a salt; wherein ‘E’ is a salt; wherein ‘E’ is a salt; wherein ‘E’ is a salt; and combinations thereof.
  • the present disclosure also provides a process for the preparation of compound represented by Formula I as mentioned above, said process comprising step of reacting free base of compound of formula I with salt forming reagent to obtain compound of formula I.
  • the present disclosure also provides a process for the preparation of compound represented by ‘Formula I-A’ as mentioned above, said process comprising step of reacting ‘free base of compound of formula I-A’ with salt forming reagent to obtain compound of formula I-A.
  • a process for the preparation of compound represented by Formula 2 as mentioned above said process comprising step of reacting free base of compound of formula 2 with salt forming reagent to obtain compound of formula 2.
  • a process for the preparation of compound represented by Formula 3 as mentioned above comprising step of reacting free base of compound of formula 3 with salt forming reagent to obtain compound of formula 3.
  • a process for the preparation of compound represented by Formula 4 as mentioned above comprising step of reacting free base of compound of formula 4 with salt forming reagent to obtain compound of formula 4.
  • the salt forming reagent is selected from a group comprising hydrochloric acid, methane sulfonic acid, oxalic acid, tartaric acid, malic acid, hydrobromic acid, sulfuric acid, alpha hydroxy acid, beta hydroxy acid, acetic acid, phenyl acetic acid, trifluoro acetic acid, propionic acid, stearic acid, palmitic acid, lauric acid, oleic acid, benzoic acid, 2-acetoxybenzoic acid, naphthalic acid, fumaric acid, ethanedisulfonic acid, isethionic acid, p-toluenesulfonic acid, benezenesulfonic acid, laurylsulfonic acid, glucoheptonoic acid, sulfanilic acid, lactobionic acid, valeric acid, salicylic acid, mandelic acid, lactic acid, glycolic acid, glutamic acid, 2-hydroxygluta
  • a process for the preparation of compound represented by Formula 3-2 as mentioned above comprising step of reacting a suspension of 7-[(3R)-3-aminoazepan-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline- 3-carboxylic acid in anhydrous methanol with methanesulfonic acid to obtain Formula 3-2.
  • a process for the preparation of compound represented by Formula 3-3 as mentioned above comprising step of reacting a suspension of 7-[(3R)-3-aminoazepan-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline- 3-carboxylic acid in methanol:water mixture with oxalic acid to obtain Formula 3-3.
  • a process for the preparation of compound represented by Formula 3-4 as mentioned above comprising step of reacting a suspension of 7-[(3R)-3-aminoazepan-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline- 3-carboxylic acid in methanol:water mixture with malic acid to obtain Formula 3-4.
  • a process for the preparation of compound represented by Formula 2-1 as mentioned above comprising step of reacting a suspension of 1-cyclopropyl-6-fluoro-8-methoxy-7-(4-((5-nitrofuran-2-yl)methyl)piperazin-1- yl)-4-oxo-1,4 dihydroquinoline-3-carboxylic acid in methanol with hydrochloric acid to obtain Formula 2-1.
  • the process is carried out at a temperature ranging from about 0°C to about 100°C, and for a time period ranging from about 10 minutes to about 6 hours.
  • the processes of the present disclosure further comprise isolation and/or purification of the corresponding product; wherein said isolation and purification is carried out by acts selected from a group comprising addition of solvent, washing with solvent, cooling, quenching, filtration, extraction, chromatography and combination of acts thereof.
  • the present disclosure provides a method for preparing in situ gel formulation, wherein the said process comprising the steps of a. mixing the excipients to form a main phase; b. dispersing the Formula I in a solvent followed by adjusting the pH to form a drug phase; c. adding the drug phase to the main phase followed by adjusting the pH of the formulation using pH modifying agent; and d. homogenising the suspension to obtain the formulation comprising compound of Formula I.
  • the present disclosure provides a method for preparing in situ gel formulation, wherein the said process comprising the steps of a. mixing the excipients to form a main phase; b. dispersing the Formula I-A in a solvent followed by adjusting the pH to form a drug phase; c. adding the drug phase to the main phase followed by adjusting the pH of the formulation using pH modifying agent; and d. homogenising the suspension to obtain the formulation comprising compound of Formula I-A.
  • the present disclosure also provides a method for the preparation of aqueous suspension of compound of formula I suspension formulation comprising compound of Formula I as mentioned above, said process comprising step of: a. mixing the excipients to form a main phase; b.
  • the present disclosure also provides a method for the preparation of aqueous suspension of compound of formula I-A suspension formulation comprising compound of Formula I as mentioned above, said process comprising step of: a. mixing the excipients to form a main phase; b. dispersing the Formula I-A in a solvent followed by adjusting the pH to form a drug phase; and c. adding the drug phase to the main phase followed by adjusting the pH of the formulation using pH modifying agent; and d.
  • the method is carried out at a temperature ranging from about 0°C to about 100°C, and for a time period ranging from about 30 minutes to about 48 hours.
  • the homogenisation is carried out using a homogenizer.
  • the homogenisation is carried out using IKA T25 homogenizer.
  • the homogenisation is carried out at a temperature ranging from about room temperature 0°C to about 100°C, and for a time period ranging from about 30 minutes to about 48 hours using homogenizer.
  • the homogenisation is carried out using homogenizer in presence of dispersing agent, thickener or their combination.
  • the dispersing agent comprises Tween 80, Povidone or their combination.
  • the homogenization is performed at 5000, 8000, 15000 rpm using homogenizer.
  • a formulation comprising compounds of formula I, 2, 3 or 4 for the manufacture of a medicament for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna by suitable mode of administration.
  • a method for treatment and/or prevention and/or management of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna comprising administering to an individual a formulation comprising compounds of formula I, 2, 3 or 4 optionally along with excipient(s).
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, carbomer 980, glycerine, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, glycerine, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, glycerine, tween 80, polyvinyl alcohol, povidone, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, poloxamer 407, propylene glycol, glycerine, and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, boric acid, tween 80, polyvinyl alcohol, poloxamer 407, glycerine, propylene glycol and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, poloxamer 407, propylene glycol, tween 80, povidone, polyvinyl alcohol, glycerine and purified water.
  • a formulation comprising besifloxacin or besifloxacin. HCl, sodium chloride, poloxamer 407, glycerine, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, sodium chloride, poloxamer 407, disodium EDTA, hydroxyethyl cellulose, polyvinyl alcohol, tween 80, tyloxapol, povidone, glycerin, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, boric acid, sodium chloride, hydroxyethyl cellulose, poloxamer 407, polyvinyl alcohol, tween 80, tyloxapol, glycerin, propylene glycol, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, boric acid, sodium chloride, hydroxyethyl cellulose, poloxamer 407, polyvinyl alcohol, tween 80, tyloxapol, glycerin, propylene glycol, Hydroxy Propyl Cellulose, sodium hydroxide and purified water.
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, boric acid, sodium chloride, hydroxyethyl cellulose, poloxamer 407, polyvinyl alcohol, tween 80, tyloxapol, glycerin, tocopherol polyethylene glycol succinate (TPGS), cetyl Alcohol, propylene glycol , sodium lauryl sulphate, polyoxyl stearate 40, PEG-21 stearyl ether, sodium hydroxide and purified water.
  • TPGS tocopherol polyethylene glycol succinate
  • a formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, dexamethasone, sodium hydroxide and purified water.
  • a formulation comprising 0.25% of hydroxyethyl cellulose, 0.9% of sodium chloride, 0.2% of poloxamer 407, 0.5% of carbopol 980, 2.5% of glycerine, 2 % of compound of formula I, sodium hydroxide (pH 6-6.5), and purified water (q.s.).
  • a formulation comprising 0.25% of hydroxyethyl cellulose, 0.9% of sodium chloride, 0.2% of poloxamer 407, 0.5% of carbopol 980, 2.5% of glycerine, 2 % of besifloxacin hydrochloride, sodium hydroxide (pH 6-6.5), and purified water (q.s.).
  • an otic/ear drops formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, sodium hydroxide (pH 6-7), and purified water (q.s.).
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, carbomer 980, glycerine, sodium hydroxide (pH 6-7), and purified water (q.s.).
  • an otic/ear gel (in-situ) formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, glycerine, hydroxyethyl cellulose, poloxamer 407, (pH 5-6), and purified water (q.s.).
  • an otic/ear gel (in-situ) formulation comprising besifloxacin or besifloxacin.HCl, propylene glycol, poloxamer 188, poloxamer 407, sodium hydroxide (pH 4.5-7), and purified water (q.s.).
  • an otic oil in water emulsion formulation comprising besifloxacin or besifloxacin.HCl, Peanut oil, Isopropyl myristate, Oleath 2, Cetyl alcohol, Tween 80, Poloxamer 407, sodium hydroxide (pH 6-7), and purified water (q.s.).
  • an otic/ear drops formulation comprising besifloxacin or besifloxacin.HCl, sodium chloride, hydroxyethyl cellulose, poloxamer 407, glycerin, besifloxacin hydrochloride, sodium hydroxide (q.s. to pH 6.0-7.0) and purified water (q.s.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, hydroxyethyl cellulose, poloxamer 407, glycerine, tween 80, polyvinyl alcohol, povidone, sodium hydroxide (q.s. to pH 6.0-7.0) and purified water (q.s. to 100).
  • an otic/ear suspension (Insitu) formulation comprising poloxamer 407, sodium chloride, disodium EDTA, glycerine, tween 80, besifloxacin hydrochloride-PVA EG 30 PW complex or besifloxacin hydrochloride- poloxamer 407 complex or besifloxacin hydrochloride-PVP 90 F complex, sodium hydroxide (q.s. to pH 6.5-6.7) and purified water (q.s. to 100).
  • an otic/ear formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, poloxamer 407, propylene glycol, glycerine, purified water (q.s. to 100) and maintained the pH of formulation ranging from 4.2-4.6.
  • an otic/ear drops formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, sodium chloride, boric acid, tween 80, polyvinyl alcohol, poloxamer 407, glycerine, propylene glycol, sodium hydroxide (q.s.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, disodium edetate, boric acid, sodium chloride, propylene glycol, glycerin, poloxamer 407, sodium hydroxide (q.s. to pH 4.5-5) and purified water (q.s. to 100).
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, propylene glycol, purified water (q.s. to 100) and maintained the pH of formulation ranging from 4.76.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, poloxamer 407, sodium chloride, disodium EDTA, glycerine, tween 80, besifloxacin hydrochloride-PVA EG 30 PW complex or Besifloxacin hydrochloride-Poloxamer 407 complex or Besifloxacin hydrochloride-PVP 90 F complex, Sodium hydroxide (q.s. to pH 6.5-6.7) and purified water (q.s. to 100).
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, peanut oil, isopropyl myristate, oleath 2, light mineral oil, cetyl alcohol, besifloxacin hydrochloride-PVA EG 30 PW complex or besifloxacin hydrochloride-Poloxamer 407 complex or besifloxacin hydrochloride-PVP 90 F complex.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, glycerine optionally along with excipients, wherein the excipient is selected from a group poloxamer 407, tween 80, propylene glycol, polyvinyl alcohol and purified water.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, poloxamer 407, propylene glycol, tween 80, polyvinyl alcohol, glycerine optionally along with purified water.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, poloxamer 407, polyvinyl alcohol, glycerine optionally along with purified water.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, poloxamer 407, povidone, tween 80, polyvinyl alcohol, glycerine optionally along with purified water.
  • an otic/ear drop formulation comprising besifloxacin or besifloxacin.HCl, poloxamer 407, propylene Glycol, Polyvinyl alcohol, Glycerine, optionally along with excipients, wherein the excipient is selected from a group tween 80, povidone, and purified water.
  • an otic/ear drop formulation comprising besifloxacin or besifloxacin.HCl, Sodium chloride, Poloxamer 407, Sodium hydroxide (q.s. to pH 7-8), purified water and optionally along with glycerine.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, sodium chloride, poloxamer 407, disodium EDTA, hydroxyethyl cellulose, polyvinyl alcohol, tween 80, tyloxapol, povidone, glycerin, Sodium hydroxide and purified water.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, boric acid and sodium chloride.
  • an otic/ear suspension formulation comprising besifloxacin or besifloxacin.HCl, hydroxyethyl cellulose, poloxamer 407, polyvinyl alcohol, tween 80, tyloxapol, glycerin, and propylene glycol, sodium hydroxide (q.s. to pH 6.5- 7.0) and purified water (q.s. to 100).
  • an otic/ear micro-suspension formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, boric acid, sodium chloride, hydroxyethyl cellulose, poloxamer 407, polyvinyl alcohol, tween 80, tyloxapol, glycerin, propylene glycol, sodium hydroxide (q.s. to pH 6.5-7.0) and purified water (q.s. to 100).
  • an otic/ear nano suspension formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, boric acid, sodium chloride, hydroxyethyl cellulose, poloxamer 407, polyvinyl alcohol, tween 80, tyloxapol, glycerin, propylene glycol, Hydroxy Propyl Cellulose, sodium hydroxide (q.s. to pH 5-7.0) and purified water (q.s. to 100).
  • an otic/ear micro-emulsion or nano- emulsion formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, boric acid, sodium chloride, hydroxyethyl cellulose, poloxamer 407, polyvinyl alcohol, tween 80, tyloxapol, glycerin, tocopherol polyethylene glycol succinate, cetyl alcohol, propylene glycol, sodium lauryl sulphate, polyoxyl stearate 40, PEG-21 stearyl ether, sodium hydroxide (q.s. to pH 4.5-5.5) and purified water (q.s. to 100).
  • an otic/ear drop formulation comprising besifloxacin or besifloxacin.HCl, disodium EDTA, sodium chloride, hydroxyethyl cellulose, poloxamer 407, Dexamethasone, sodium hydroxide (q.s. to pH 6-7.0) and purified water (q.s. to 100).
  • an otic/ear in-situ suspension formulation comprising besifloxacin or besifloxacin.HCl, poloxamer 407, sodium chloride, disodium EDTA, glycerine,tween 80, besifloxacin hydrochloride-PVA EG 30 PW complex, besifloxacin hydrochloride-Poloxamer 407 complex, besifloxacin hydrochloride-PVP 90 F complex, sodium hydroxide (q.s. to pH 6.5 – 6.7) and purified water (q.s. to 100).
  • an otic/ear oil in water Emulsion formulation comprising besifloxacin or besifloxacin.HCl, peanut oil, IPM, oleath 2, poloxamer 407, tween 80 and RHLB (Emulsifier).
  • an otic/ear oil in water Emulsion formulation comprising besifloxacin or besifloxacin.HCl, peanut oil, isopropyl myristate, oleath 2, cetyl alcohol, tween 80, poloxamer 407, sodium hydroxide (q.s. to pH 6 – 7) and purified water (q.s. to 100).
  • an otic/ear oil in water Emulsion formulation comprising besifloxacin or besifloxacin.HCl, peanut oil, glyceryl monostearate, oleath 2, cetyl alcohol, tween 80, poloxamer 407, sodium hydroxide (q.s. to pH 6 – 7) and purified water (q.s. to 100).
  • an otic/ear oil in water Emulsion formulation comprising besifloxacin or besifloxacin.HCl, peanut oil, glyceryl monostearate, Hydrogenated lecithin, oleath 2, cetyl alcohol, tween 80, poloxamer 407, sodium hydroxide (q.s. to pH 6 – 7) and purified water (q.s. to 100).
  • an otic/ear oil in water Emulsion formulation comprising besifloxacin or besifloxacin.HCl, peanut oil, IPM, Oleath 2, Cetyl alcohol, Poloxamer 407, Tween 80, Tween 20, Sodium hydroxide (Q.s.) and RHLB (Emulsifier) and purified water (q.s. to 100).
  • an otic/ear formulation comprising 0.25% of hydroxyethyl cellulose, 0.9% of sodium chloride, 0.2% of poloxamer 407, 0.5% of carbopol 980, 2.5% of glycerine, 2 % of compound of formula I , sodium hydroxide (pH 6-6.5), and purified water (q.s.).
  • an otic/ear formulation comprising 0.25% of hydroxyethyl cellulose, 0.9% of sodium chloride, 0.2% of poloxamer 407, 0.5% of carbopol 980, 2.5% of glycerine, 2 % of besifloxacin hydrochloride, sodium hydroxide (pH 6-6.5), and purified water (q.s.).
  • the formulation is formulated into a dosage form selected from the group consisting of ear drops, ear spray, solutions, suspensions, emulsions, or a combination thereof.
  • the formulation is administered to a subject through modes selected from a group comprising, topical administration, otic administration, intratympanic administration, and combinations thereof.
  • the present disclosure provides as a medicament in the treatment of a disease or a condition associated with ear infections, otitis, otitis externa, otitis interna, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa and combinations thereof, comprising administering to a subject in need thereof a compound or a composition as described herein.
  • in-situ gelling systems (i) It forms in-situ gel at application site and provide sustain drug release. (ii) Reduce frequency of multiple drug administration. (iii) It will provide more bioavailability as compared to other conventional dosage form like topical solution, suspension as it prevents drug drainage from Eustachian tube when administered. (iv) Penetration enhancers may increase permeation of Drug from hydrogel to middle ear by overcoming the Tympanic membrane barrier. (v) Local deliver maximizes otic exposure, minimize systematic exposure.
  • a formulation comprising a compound selected from: wherein ‘E’ is a salt; wherein ‘E’ is a salt; wherein ‘E’ is a salt; 5.
  • a formulation comprising compound of formula I as defined in paragraph 1 for the manufacture of a medicament for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna by suitable mode of administration. 9.
  • a formulation comprising compound of formula I-A as defined in paragraph 2 for the manufacture of a medicament for the treatment of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna by suitable administration of compound of formula I-A as defined in paragraph 2. 10.
  • a method for treatment and/or prevention and/or management of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna, comprising administering to an individual a formulation comprising a compound of formula I as defined in paragraph 1 optionally along with excipient(s).
  • a method for treatment and/or prevention and/or management of ear infections, otitis, otitis media including acute otitis media, recurrent otitis media, otitis media with effusion, chronic otitis media, chronic suppurative otitis media, otitis externa (including acute otitis externa, chronic otitis externa), otitis interna, comprising administering to an individual a formulation comprising a compound of formula I-A as defined in paragraph 2 optionally along with excipient(s).
  • Example 1 Preparation of Drug Loaded Suspension for Ear Infection Treatment (Optimisation of Poloxamer Content) Besifloxacin suspensions were prepared by varying the concentration of poloxamer 407 to understand the behaviour of suspension formulation. Suspension prepared at 0.2%, 5% 10% and 15% w/w concentration of poloxamer 407. Suspension with 15% w/w concentration is gel at room temperature, whereas, suspension with 10% w/w of poloxamer concentration observed more viscous than others. These formulations have off-white appearance with pH of 6-7. (Table 1).
  • disodium edetate sodium chloride dissolved in purified water followed by addition of hydroxyethyl cellulose, carbopol 980 and poloxamer 407 to form clear phase.
  • Besifloxacin hydrochloride dispersed in purified water/glycerine. Then pH was adjusted by sodium hydroxide. (Note: Homogenization was performed only in batch # VLN-F- 71/PGK/023 at 5000 rpm for 15 minutes).
  • Drug phase was added to main phase, then pH of formulation has been adjusted by using sodium hydroxide aqueous solution and finally weight make up was done by purified water.
  • Example 3 Besifloxacin Suspended In-situ formulation for Ear Infection Treatment
  • IT intra tympanic
  • a typical composition of such otic gel may include thermosensitive gelling polymer such as Poloxamer 407.
  • Besifloxacin in-situ gel formulation has been prepared by using poloxamer 407 as an in-situ agent. This formulation is white to off white suspension having pH 5-6 (table 3).
  • Manufacturing Procedure 1. In a main mixing vessel, disodium edetate, sodium chloride dissolved in purified water followed by addition of hydroxyethyl cellulose and poloxamer 407 to form clear phase. 2. Besifloxacin hydrochloride dispersed in glycerin and then pH was adjusted by aqueous sodium hydroxide. 3.
  • Step 2 was added to step 1, then pH of formulation was adjusted by using sodium hydroxide and final weight make up was done by purified water. At accelerated stability condition after 2 months assay and degradation product of batch no. VLN-F-71/PGK/068 was observed 96.84% and 0.439% respectively.
  • the formulations made with Poloxamer 407 are difficult to deliver into the ear as they under gel formation at room temperature, hence a combination of Poloxamer 407 and Poloxamer 188 was used to increase the gelling temperature for formulation. This system remains liquid at room temperature, however transforms into gel at body temperature.
  • Example 4 Preparation of Drug Loaded In-Situ Gel with higher gelling temperature using mixture of Poloxamer grades.
  • Besifloxacin in-situ gel formulation has been prepared by using mixture of poloxamer 407 and poloxamer 188 as an in-situ agent.
  • Propylene glycol and PEG 300 changes the viscosity of formulation which effect the dispersibility of final formulation. This formulation is white to off white suspension (table 4).
  • Example 5 Preparation of Drug Loaded Oil in Water Emulsion formulation for Ear Infection Treatment
  • Besifloxacin emulsion formulation has been prepared by using combination of emulsifiers at RHLB of 14.7 (table 5). Rheological evaluation was performed for the prepared formulation and the results are given below.
  • oil phase Peanutt oil, Isopropyl myristate, Oleath 2, Cetyl alcohol followed by Besifloxacin hydrochloride addition
  • water phase water, Tween 80, Poloxamer 407, followed by sodium hydroxide solution addition. Both phases were prepared by heating at same temperature (55° C-65°C).
  • Oil phase was added into the water phase under homogenization at 5000-9000 rpm. Homogenization was continued for 30 minutes. In these steps, 55° C-65°C temperature was maintained. 3. Slow Cooling of step 2 performed to 25° C under stirring. 4. pH of formulation was adjusted by using sodium hydroxide solution.
  • Example 6 Optimisation of Glycerin Content and Preparation of Drug Loaded Suspension and Infection Treatment Besifloxacin suspensions were prepared by varying the concentration of glycerin to understand the behaviour of suspension formulation. Suspension prepared by varying the concentration of glycerin do not impart any significant change in suspending ability of suspensions.
  • Example 8 Preparation of in-situ Drug Loaded Suspension using Drug and Polymer Complex (1:10 Drug: Polymer ratio) for Ear Infection Treatment
  • suspension formulation has been prepared by using aqueous approach. Manufacturing Procedure: 1. In a main mixing vessel, disodium edetate, sodium chloride dissolved in purified water followed by addition of poloxamer 407 to form clear phase. 2. Tween 80 phase (tween 80+ water) prepared 3.
  • Glycerin phase (glycerin + water) prepared. Both phases mixed under stirring. 4. Step 2 added to step 1 followed by step 3 and mixed. 5. Then pH was adjusted by sodium hydroxide solution. 6. Besifloxacin hydrochloride and Polymer (Polvinyl alcohol EG 30 PW / Besi-Poloxamer 407/ PVP 90F) complex added and mixed followed by pH adjustment by sodium hydroxide solution. 7. Finally weight make up was done by purified water.
  • Example 9 Besifloxacin Ear formulation with Propylene Glycol Besifloxacin HCl formulation has been manufactured using following composition (Table 9). The obtained formulations were white homogeneous dispersion. Manufacturing Procedure: 1.
  • Example 10 Preparation of Drug Loaded Suspension and Selection of Excipients for Improving the Dispersibility of Suspension Besifloxacin suspension formulation has been prepared by selecting different excipients which helps in improving dispersibility of formulations. To understand the better dispersibility and stability of suspension many combinations of suspension formulation have been prepared by varying the pH range and by addition and deletion of these excipients (table 10). Formulations (VLN-F-71/PGK/104, VLN-F-71/PGK/107, VLN-F-71/PGK/110 and VLN-F-78/PGK/010) were observed stable at accelerated condition.
  • Example 11 Preparation of Drug Suspension for Ear Infection Treatment using Particle Size Reduction technology
  • Besifloxacin suspension formulation has been prepared by using lab scale in-line homogenizer for particle size reduction of final suspension formulation (table 11). Particle size reduction improved dispersibility.
  • Manufacturing Procedure 1. In a main mixing vessel, disodium edetate, sodium chloride, boric acid dissolved in purified water followed by addition of poloxamer 407 to form clear phase. 2. Besifloxacin hydrochloride dispersed in glycerine and propylene glycol. Then pH was adjusted by sodium hydroxide. (Note: Homogenization was performed using a lab scale homogenizer at 2000-10000 rpm for 15 minutes). 3.
  • Step 2 was added to step 1, then pH of formulation has been adjusted by using sodium hydroxide and finally weight make up was done by purified water. Particle size reduction of final prepared suspension was performed by using an in-line homogenizer.
  • Examples 12 Preparation of Drug Loaded suspension for Ear Infection Treatment Besifloxacin suspension formulation has been prepared by using non-aqueous approach. Non- aqueous suspension formulation indicates better stability (table 5) as compared to aqueous suspension.
  • Example 13 Preparation of Drug Loaded Suspension using Drug and Polymer Complex for Ear Infection Treatment Besifloxacin hydrochloride and Polymer (Polvinyl alcohol EG 30 PW / Besi-Poloxamer 407/ PVP 90F) complex (10:1 Drug: Polymer ratio) prepared by solvent evaporation method.
  • suspension formulation has been prepared by using aqueous and non- aqueous approach.
  • Manufacturing Procedure 1. In a main mixing vessel, disodium edetate, sodium chloride dissolved in purified water followed by addition of poloxamer 407 to form clear phase. 2. Tween 80 phase (tween 80+ water) prepared 3. Glycerin phase (glycerin + water) prepared. Both phases mixed under stirring. 4. Step 2 added to step 1 followed by step 3 and mixed. 5. Then pH was adjusted by sodium hydroxide solution. 6. Besifloxacin hydrochloride and Polymer (Polvinyl alcohol EG 30 PW / Besi-Poloxamer 407/ PVP 90F) complex added and mixed followed by pH adjustment by sodium hydroxide solution.
  • Example 15 Besifloxacin Soluble Formulation for Ear Infection Treatment Besifloxacin soluble ear drop has been manufactured using composition given in Table 15. Manufacturing Procedure: (For batches VLN-F-71/PGK/059, VLN-F-71/PGK/061, VLN- F-71/PGK/088) 1. Polyvinyl alcohol was dispersed in glycerine. 2. Besifloxacin hydrochloride dispersed in glycerine. 3. Step 1 was added to propylene glycol, followed by addition of drug phase. 4.
  • Example 17 Besifloxacin Suspended Formulation for Ear Infection Treatment Besifloxacin suspended ear drop has been manufactured using following composition (Table 17). Procedure: 1. Sodium chloride dissolved in purified water and followed by addition of Poloxamer 407 to form clear solution. 2.
  • Example 18 Besifloxacin Suspended Formulation for Ear Infection Treatment Besifloxacin suspended ear drop has been manufactured using following composition (Table 18).
  • Example 20 Besifloxacin Micro-suspension for Ear Infection Besifloxacin suspended ear drop has been manufactured using following composition (Table 20). Briefly, Besifloxacin hydrochloride aqueous dispersion in poloxamer was micronized at 15000 rpm for 20 min using IKA homogenisor. The obtained besifloxacin dispersion was used for the micro-suspension preparation as per procure given in example 11. Obtained micro suspension of besifloxacin for otic application has particle size of about 2 – 10 micron.
  • Example 21 Nanosuspension of Besifloxacin for Ear Infection Treatment Besifloxacin nanosuspension has been formulated using compositions given in table 13.
  • Besifloxacin hydrochloride has been nanonized using a bead mill (drug slurry containing dispersion agent and surface stabilizer (hydroxy Propyl Cellulose) and suspension was nanonized using single or multiple cycles). Briefly, In a main mixing vessel, disodium EDTA, boric acid, sodium chloride were dissolved in purified water and followed by addition of hydroxyethyl cellulose, poloxamer 407 to form clear phase. Then, aqueous phases of polyvinyl alcohol, tween 80 and tyloxapol added to main mixing vessel and mixed. Besifloxacin hydrochloride nano-dispersion along with propylene glycol, glycerin & sodium hydroxide was added to above mixture and mixed.
  • Example 22 Nanoemulsion / Microemulsion of Besifloxacin for Ear Infection Treatment Besifloxacin nanosuspension has been formulated using compositions given in Table 22. Drug was dissolved in lipid and surfactant mixture (i.e. TPGS, SLS, Tween) of desired ratio. The drug solution was transferred to cosolvent mixture.
  • lipid and surfactant mixture i.e. TPGS, SLS, Tween
  • Example 23 Preparation of Besifloxacin and Corticosteroid Loaded Ear Drop Besifloxacin and drug from class corticosteroid such as Dexamethasone has been loaded ear formulation and manufactured product has off-white appearance with pH of 6-7 (Table 23).
  • Example 24 Preparation of in-situ Drug Loaded Suspension using Drug and Polymer Complex (1:10 Drug: Polymer ratio) for Ear Infection Treatment
  • Besifloxacin hydrochloride and Polymer (Polvinyl alcohol EG 30 PW / Besi-Poloxamer 407/ PVP 90F) complex (1:10 Drug: Polymer ratio) prepared by solvent evaporation method.
  • suspension formulation has been prepared by using aqueous approach.
  • Example 25 Preparation of Drug Loaded Oil in Water Emulsion (without Cetyl alcohol- Poloxamer 407 combination) formulation for Ear Infection Treatment
  • Besifloxacin emulsion formulation has been prepared by using only Poloxamer 407 (i.e.without Cetyl alcohol-Poloxamer 407 combination) at different RHLB (table 25).
  • Example 26 Preparation of Drug Loaded Oil in Water Emulsion (with low peanut oil content) formulation for Ear Infection Treatment
  • Besifloxacin emulsion formulation has been prepared by using combination of emulsifiers and using less Peanut oil at RHLB of 14.74 (table 26).
  • Manufacturing Procedure 1. In mixing vessel, oil phase (Peanut oil, Isopropyl myristate, Oleath 2, Cetyl alcohol followed by Besifloxacin hydrochloride addition) prepared. In another mixing vessel, water phase (water, Tween 80, Poloxamer 407, followed by sodium hydroxide solution addition). Both phases were prepared by heating at same temperature (55° C-65°C). 2.
  • Oil phase was added into the water phase under homogenization at 5000-9000 rpm. Homogenization was continued for 30 minutes. In these steps, 55° C-65°C temperature was maintained. 3. Slow Cooling of step 2 performed to 25° C under stirring. 4. pH of formulation was adjusted by using sodium hydroxide solution and final weight make up was done by purified water. Glyceryl monostearate shows gelling behaviour in unsaturated oils (e.g. Peanut oil). Moreover, it also acts as co-emulsifier. Thus a stable formulation can be prepared with help of Glyceryl monostearate.
  • unsaturated oils e.g. Peanut oil
  • Example 27 Preparation of Drug Loaded Oil in Water Emulsion (without Isopropyl myristate and with Glyceryl monostearate) formulation for Ear Infection Treatment
  • Besifloxacin emulsion formulation has been prepared without Isopropyl myristate and with Glyceryl monostearate having both 5% & 2% Peanut oil content by using combination of emulsifiers and at RHLB of 14.34 (table 27) Procedure: 1. In mixing vessel, oil phase (Peanut oil, Glyceryl monostearate, Oleath 2, Cetyl alcohol followed by Besifloxacin hydrochloride addition) prepared.
  • water phase water, Tween 80, Poloxamer 407, followed by sodium hydroxide solution addition. Both phases were prepared by heating at same temperature (55° C-65°C). 2. Oil phase was added into the water phase under homogenization at 5000-9000 rpm. Homogenization was continued for 30 minutes. In these steps, 55° C-65°C temperature was maintained. 3. Slow Cooling of step 2 performed to 25° C under stirring. 4. pH of formulation was adjusted by using sodium hydroxide solution and final weight make up was done by purified water.
  • Example 28 Preparation of Drug Loaded Oil in Water Emulsion (without Isopropyl myristate and with Glyceryl monostearate, hydrogenated lecithin) formulation for Ear Infection Treatment
  • Besifloxacin emulsion formulation has been prepared without Isopropyl myristate and with Glyceryl monostearate, hydrogenated lecithin having 5% Peanut oil content by using combination of emulsifiers and at RHLB of 14.31 (table 28) Manufacturing Procedure: 1. In mixing vessel, oil phase (Peanut oil, Glyceryl monostearate, hydrogenated lecithin, Oleath 2, Cetyl alcohol followed by Besifloxacin hydrochloride addition) prepared.
  • water phase water, Tween 80, Poloxamer 407, followed by sodium hydroxide solution addition. Both phases were prepared by heating at same temperature (55° C-65°C). 2. Oil phase was added into the water phase under homogenization at 5000-9000 rpm. Homogenization was continued for 30 minutes. In these steps, 55° C-65°C temperature was maintained. 3. Slow Cooling of step 2 performed to 25° C under stirring. 4. pH of formulation was adjusted by using sodium hydroxide solution and final weight make up was done by purified water.
  • Example 29 Preparation of Drug Loaded Oil in Water Emulsion (Only Cetyl alcohol as thickner) formulation for Ear Infection Treatment Besifloxacin emulsion formulation has been prepared by using only Cetyl alcohol as thickner at RHLB of 12.22 (table 29).
  • Bacterial strains were cultured in Brain Heart Infusion Agar (BHIA) (Himedia) at 37oC for 18 - 24 hours for bacterial strains.
  • BHIA Brain Heart Infusion Agar
  • 100 Pl of sterile Brain Heart Infusion (BHI) broth was added into each well of 96 well plate.
  • 100 ⁇ l of broth containing drug was added to first well and serial (double) dilution was carried out till 10th well (column 1 to column 10 of 96- well plate).
  • bacterial culture turbidity was adjusted to was adjusted to 0.5 McFarland standard (approx. 1.5 ⁇ 10 8 cfu/ml) by adjusting absorbance to 0.1 at 600 nm and further 100 times diluted with sterile BHI broth. 100 ⁇ l of bacterial suspension was added to each well except sterility control wells. The plates were thereafter incubated at 37oC for 18 - 24 h. The assays were performed in triplicates. The MIC of the test compounds were determined by observing the lowest concentration of test compound that prevented the visual bacterial growth. Table 30 Minimum inhibitory concentration of compounds against drug susceptible and drug resistant bacterial strains *TBD: To be done Table 31 Minimum inhibitory concentration of compounds against clinical isolates of S.
  • MSSA methicillin susceptible S. aureus
  • MRSA methicillin resistant S. aureus
  • QRSA quinolone resistant S. aureus
  • MIC minimum inhibitory concentrations
  • Compounds displayed MIC values less than 0.13 ⁇ g/ml in S. aureus ATCC 25923 and MRSA ATCC 43300 strains. In a quinolone resistant S.
  • aureus strain CCARM 3505 with mutations at GyrA (Ser84Leu) and ParC (Ser80Phe) subunits of DNA gyrase and topoisomerase IV respectively, all these three molecules showed very low MIC values (1 ⁇ g/ml) suggesting their potency whereas the MICs of moxifloxacin, ciprofloxacin and finafloxacin were extremely high.
  • Formula 2, 3 and 4 were also potent against drug resistant Pseudomonas sp. strains. The molecules when tested against clinical isolates of S.
  • aureus showed MIC values less than or equal to 2 ⁇ g/ml compared to ciprofloxacin and moxifloxacin which showed high MIC ⁇ 8 ⁇ g/ml and ⁇ 4 ⁇ g/ml respectively.
  • the loop full of bacterial culture was suspended in sterile water and the turbidity adjusted to absorbance of 0.1 at 600 nm (approximately 1.5 x 10 8 cells) and further diluted 100 times with sterile BHI broth. 1ml of diluted culture suspension was added into 12-well plate and plates were further incubated at 37°C for 48 h for biofilm formation. The biofilm was carefully washed twice with sterile water to get rid of planktonic cells. Thereafter biofilm was treated with 1mL of BHI broth suspended with various concentrations of test molecules Formula 2, and Formula 3 along with the comparators, moxifloxacin and ciprofloxacin. The plates were further incubated at 37°C for another 24 h followed by washing with sterile water twice.
  • the biofilm was resuspended with 1 ml of 1X trypsin EDTA solution (0.25% Trypsin and 0.02% EDTA in Dulbecco’s Phosphate Buffered Saline), then serially diluted and plated on BHA agar followed by incubation for 18- 24 h. Plates were observed for colony forming units at 72 h.
  • Table 34 Antibiofilm activity of compounds by determination of bacterial reduction in S. aureus ATCC 6538P biofilms The bacterial CFU count were enumerated after treating pre-formed S. aureus biofilms with antibiotics at different concentrations. Viable cells in S.
  • aureus biofilms increased from the starting inoculum of approximately 1.5 x 10 6 CFU/ml to approximately 10 9 CFU/ml by 48 h.
  • growth control showed a bacterial count of (9.9 ⁇ 1.4) log CFU/ml.
  • Treatment with compound, Formula 2 showed a dose dependent reduction of the cell count compared to untreated control.
  • 16 Pg/ml of Formula 2 showed more than 4 log reduction of the cell count from the control cells.
  • Formula 3 was extremely potent against biofilm at both the concentrations showing almost 5 log reduction from the growth control at 72 hours. Both ciprofloxacin and moxifloxacin at the same concentrations did not show any significant antibiofilm activity.
  • Biofilm inhibition property of VCD-077 was further checked using scanning electron microscopy (SEM).
  • SEM scanning electron microscopy
  • Culture suspension of S. aureus ATCC 6538P was seeded on cover slip placed in 12 well plates and incubated at 37°C for 48 h for biofilm formation.
  • the biofilm was carefully washed twice with sterile water to get rid of planktonic cells.
  • biofilm was treated with test compounds dissolved in BHI broth and further incubated at 37°C for 24 h.
  • the coverslips were washed with PBS and fixed in 2.5% glutaraldehyde solution.
  • the coverslips were then washed twice with 0.1 M PBS buffer for 15 min and dehydrated by replacing the buffer with increasing concentrations of ethanol.
  • aureus LTA and PGN-induced monocytic cells The in vitro anti-inflammatory property of compound (Formula 3) was tested using human monocyte cell line (THP-1), a cell line well established for the study of immune modulation. The cells were induced with a combination of purified lipoteichoic acid (LTA) and peptidoglycan (PGN) from S. aureus to trigger cytokine response in the absence and presence of the compound. The anti-inflammatory effects of compound (Formula 3) were assessed by measuring the expression of cytokines IL-1 ⁇ , IL-1 ⁇ , IL-6 and IL-8 at the RNA level using quantitative polymerase chain reactions (qPCR). Table 35.
  • In vitro anti-inflammatory action of Compound in Toll-like receptor-2 -induced monocytic cells The in vitro anti-inflammatory property of Formula 3 was also tested using a Toll-like receptor- 2 specific inducer (Pam3CSK4). THP-1 cells were induced with Pam3CSK4 (10 ng/ml) in the absence or presence of Formula 3. The anti-inflammatory effects of Formula 3 were assessed by measuring the levels of secreted cytokines IL-1 ⁇ , IL-6 and IL-8 using Enzyme Linked Immunosorbent Assays (ELISA).
  • ELISA Enzyme Linked Immunosorbent Assays
  • the overnight culture was subjected for identification by microscopy and centrifuged at 3000 rpm for 15 min to harvest the cells.
  • the harvested cells were washed with normal saline and further re-suspended in sterile buffer solution and the absorbance of suspension was adjusted to 1.0 at 570 nm .
  • the inoculum was serially diluted using normal saline to bring inoculum size to ⁇ 1 x 10 7 CFU/ml.
  • the adjusted inoculum was serially diluted in sterile Casein Soyabean Digest broth (CSDB) broth and 0.05 ml of each dilution was plated on sterile pre-incubated CSDA agar plates and incubated at 37oC.
  • CSDB Casein Soyabean Digest broth
  • Guinea pigs were anaesthetized with isoflurane and 100 ⁇ l suspension of Pseudomonas aeruginosa ( ⁇ 1 x 10 6 live cells in PBS) were instilled into lumen of both the ears. Animals were left on lateral supine position for 3 minutes under anaesthesia after the infection to prevent the backflow of inoculum. Starting at 16 hours post infection, animals were anaesthetized and 100 ⁇ l of test (0.3% and 0.6% of formula 3) and Placebo solutions were instilled into lumen of the ear using pipette. Treatment was given at 12 hours interval on 16 h, 28 h, 40 h, 52 h, and 64 h post infection.
  • Example 31 Topical otic formulation with Formula 2 (mesylate or malate form) Formula 2 (mesylate or malate) was used for manufacturing aqueous, clear to off-white ear drop formulation with active concentration ranges from 0.3% to 6% w/w at pH 4.0 to 7.0.
  • Topical otic formulation with Formula 2 (mesylate or malate form) Procedure: 1) In a main mixing vessel, disodium edetate and sodium chloride were dissolved in purified water followed by addition of hydroxyethyl cellulose and poloxamer 407 to form clear phase. 2) Formula 2 (malate or mesylate) with definite concentration was dispersed / or solubilised in purified water and pH was adjusted by aqueous sodium hydroxide. 3) Drug phase was added into main phase followed by stirring at room temperature to form homogenous mixture. 4) Optionally diethylene glycol monoethyl ether was added into the resulting solution and stirred at RT to form homogenous mixture.
  • Method of preparation Formula 3 The present disclosure provides method of preparation of compound of Formula 3 wherein E is selected from the group consisting of methane sulfonic acid (mono acid), oxalic acid (di-acid) and malic acid (hydroxydiacid).
  • E is selected from the group consisting of methane sulfonic acid (mono acid), oxalic acid (di-acid) and malic acid (hydroxydiacid).
  • Formula 3 represents as 7-[(3R)-3-aminoazepan-1-yl]-8- chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid salt.
  • Method of preparation of Formula 2 The present disclosure provides method of preparation of compound of Formula 2 wherein E is selected from the group consisting of hydrochloric acid (inorganic acid), methane sulfonic acid (mono acid) and p-toluene sulfonic acid (mono acid).
  • E is selected from the group consisting of hydrochloric acid (inorganic acid), methane sulfonic acid (mono acid) and p-toluene sulfonic acid (mono acid).
  • Formula 2 represents as 1-cyclopropyl- 6-fluoro-8-methoxy-7-(4-((5-nitrofuran-2-yl)methyl)piperazin-1-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid salt.

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Abstract

La présente divulgation relève du domaine des sciences pharmaceutiques et chimiques. La présente divulgation concerne d'une manière générale la synthèse d'agents thérapeutiques, des procédés de préparation desdits agents, des compositions comprenant lesdits agents thérapeutiques et leurs utilisations. En particulier, la divulgation concerne des sels d'acide médicalement importants de molécules chimiques à base d'acide fluoroquinolone carboxylique [composés de formule (I)], un procédé de préparation desdites molécules, des compositions de celles-ci, et l'utilisation de telles molécules en tant qu'agents thérapeutiques. Lesdits sels d'acides de molécules chimiques à base d'acide fluoroquinolone carboxylique sont utiles dans le traitement d'infections telles que des infections de l'oreille, l'otite, l'otite moyenne notamment l'otite moyenne aiguë, l'otite moyenne récurrente, l'otite moyenne avec épanchement, l'otite moyenne chronique, l'otite moyenne suppurative, l'otite externe (y compris l'otite externe aiguë, l'otite externe chronique), l'otite interne et des combinaisons de celles-ci.
PCT/IB2021/055177 2020-06-11 2021-06-11 Sels d'acide de compositions à base d'acide fluoroquinolone carboxylique et procédés de fabrication et d'utilisation associés WO2021250635A1 (fr)

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