New regulations for ophthalmic components

Abstract

The present invention relates to novel pharmaceutical compositions containing antibiotics, such as plazomycin or a pharmaceutically acceptable salt thereof, suitable for ophthalmic use for use in the treatment of eye infections, and methods for their preparation.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to novel pharmaceutical compositions containing antibiotics suitable for ophthalmic use and methods for preparing the same. More specifically, the present invention relates to pharmaceutical compositions containing an aminoglycoside antibiotic, such as plazomicin, or a pharmaceutically acceptable salt thereof, for treating ophthalmic infections.

[0002] Approximately 74% of eye infections worldwide are thought to be bacterial, followed by viral, fungal, and parasitic infections. Infections can be monomicrobial or polymicrobial and are associated with many factors, including contact lenses, trauma, surgery, aging, dry eyes, chronic nasolacrimal duct obstruction, and previous eye infections.

[0003] Bacteria are commonly associated with various types of ocular infections, such as conjunctivitis, keratitis, endophthalmitis, blepharitis, orbital cellulitis, and dacryocystitis. The most common bacteria involved in ocular infections are Staphylococcus aureus (S. aureus), coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Corynebacterium spp., Bacillus spp., Nocardia, Pseudomonas aeruginosa, Haemophilus influenzae, and Enterobacteriaceae. Among these bacteria, S. aureus and CoNS strains are of particular importance due to their high infection rates, and S. aureus is one of the most common causes of blepharitis, conjunctivitis, dacryocystitis, keratitis, and endophthalmitis.

[0004] Currently, there are many antibacterial agents approved for the treatment of ocular infections, such as penicillin, fluoroquinolones, tetracyclines, erythromycin, azithromycin, chloramphenicol, and aminoglycosides.

[0005] Aminoglycoside antibiotics have a broad antibacterial spectrum against both gram-positive and gram-negative bacteria, and their mechanism of action is believed to be based on the inhibition of bacterial protein synthesis. Aminoglycoside antibiotics exhibit a postantibiotic effect (PAE), which inhibits bacterial growth even after their blood concentrations fall below the MIC (minimum inhibitory concentration), resulting in a prolonged inhibitory effect on bacterial growth. This bacterial growth inhibitory effect is observed even after brief contact with gram-positive and gram-negative bacteria. For this reason, various aminoglycoside antibiotics, such as gentamicin, tobramycin, streptomycin, amikacin, and arbekacin, have been widely used to treat ocular infections.

[0006] However, like other drugs, aminoglycosides are prone to bacterial resistance. Resistance to aminoglycosides can occur based on several mechanisms. One is enzymatic modification and inactivation of aminoglycosides via aminoglycoside acetyltransferases, nucleotidyltransferases, or phosphotransferases. This is commonly observed in Gram-positive and Gram-negative bacteria. Bacterial resistance to aminoglycosides continues to increase and is widely recognized as a serious health threat. The emergence of ESBL, MBL, and pan-drug resistance in Pseudomonas aeruginosa from ocular infections is an alarming finding. Early detection of ESBL and MBL production, alone or in combination, in ocular isolates is necessary, potentially paving the way for appropriate treatment of sight-threatening diseases such as endophthalmitis.

[0007] Therefore, there remains a need for new antibiotics that have excellent activity against coagulase-negative Staphylococcus aureus, MRS A, and also maintain good activity against Gram-negative pathogens, including Pseudomonas aeruginosa.

[0008] Plazomicin is an aminoglycoside designed to overcome aminoglycoside-modifying enzymes (AMEs), the most common aminoglycoside resistance mechanism in Enterobacteriaceae. Accordingly, an object of the present invention is to provide an ophthalmic composition comprising plazomicin or a pharmaceutically acceptable salt thereof.

[0009] An object of the present invention is to provide an ophthalmic pharmaceutical composition comprising plazomycin or a pharmaceutically acceptable salt thereof.

[0010] Another object of the present invention is to develop an ophthalmic composition comprising plazomycin or a pharmaceutically acceptable salt thereof for use in treating external infections of the eye and its adnexa, which can be caused by susceptible bacteria such as Staphylococcus aureus (MSSA / MRSA), coagulase-negative Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, and Proteus.

[0011] It is a further object of the present invention to develop an ophthalmic composition comprising plazomycin or a pharmaceutically acceptable salt thereof for treating bacterial keratitis, which composition may optionally contain a second antibacterial agent, such as a cephalosporin. Summary of the Invention

[0012] The present invention relates to novel pharmaceutical compositions containing antibiotics suitable for ophthalmic use and methods for preparing the same. More specifically, the present invention relates to pharmaceutical compositions containing an aminoglycoside antibiotic, such as plazomicin, or a pharmaceutically acceptable salt thereof, for treating ophthalmic infections.

[0013] In one embodiment, the compositions of the invention comprise about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof.

[0014] In another embodiment, the compositions of the present invention comprise plazomycin sulfate.

[0015] In a further embodiment, the composition of the present invention further comprises at least one excipient selected from a buffering agent, a tonicity adjusting agent, a viscosity adjusting agent, a preservative, a chelating agent, and a pH adjusting agent.

[0016] In one embodiment, the composition of the invention further comprises from about 0.01% w / v to about 1.5% w / v of a buffering agent, hi another embodiment, the composition of the invention further comprises from about 0.01% w / v to about 5% w / v of a buffering agent.

[0017] In another embodiment, the compositions of the present invention further comprise from about 0.01% w / v to about 1.5% w / v of a tonicity adjusting agent, hi another embodiment, the compositions of the present invention further comprise from about 0.1% w / v to about 6% w / v of a tonicity adjusting agent.

[0018] In another embodiment, the composition of the present invention further comprises from about 0.01% w / v to about 3% w / v of a preservative. In one embodiment, the composition of the present invention further comprises from about 0.00010% w / v to about 1% w / v of a preservative.

[0019] In one embodiment, the compositions of the present invention comprise from about 0.01% w / v to about 5% w / v of a viscosity modifier.

[0020] In another embodiment, the compositions of the invention comprise from about 0.001% w / v to about 1% w / v of a chelating agent.

[0021] In one embodiment, the composition of the present invention further comprises a pH adjuster.

[0022] In one embodiment, the composition of the present invention is an aqueous composition.

[0023] In yet another embodiment, the compositions of the present invention comprise plazomycin or a pharmaceutically acceptable salt thereof in solubilized form.

[0024] In one embodiment, the present invention relates to an ophthalmic composition for use in treating eye infections.

[0025] The present inventors have developed an ophthalmic pharmaceutical composition comprising plazomycin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0026] Plazomicin is chemically known as (2'R,3'R,4'R,5'R)-2'-[(1S,2S,3R,4S,6R)-4-amino-6-[(2''S)-4''-amino-2''-hydroxybutamido)amino]-3-[(2'S,3'R)-3'-amino-6'-((2-hydroxyethylamino)methyl)-3',4'-dihydro-2H-pyran-2'-yloxy]-2-hydroxycyclohexyloxy]-5'-methyl-4'-(methylamino)tetrahydro-2H-pyran-3'',5'-diol. Its molecular formula is CHNO and its molecular weight is 592.69 g / mol. The chemical structure of plazomicin is shown below. JPEG2026506767000001.jpg70127

[0027] Suitable salts of plazomicin include, but are not limited to, sulfate, hydrochloride, hydrobromide, hydroiodide, methylsulfonate, perchlorate, sulfate, nitrate, phosphate, acetate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, maleate, tartrate, citrate, benzoate, carbonate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, benzenesulfonate, hydroxyethanesulfonate, p-toluenesulfonate, cyclohexanesulfonate, salicylate, p-aminosalicylate, 2-phenoxybenzoate, and 2-acetoxybenzoate. In a preferred embodiment, the ophthalmic composition contains plazomicin sulfate.

[0028] Plazomicin exhibits activity equivalent to that of gentamicin (higher activity than amikacin) against MRS-A and MS-SA. Plazomicin exhibits potent activity against Staphylococcus genus. Against gram-negative enteric bacteria, plazomicin exhibits more potent in vitro activity than amikacin, gentamicin, and tobramycin. As a result of extensive research into the above-mentioned problems, the present inventors have found that an ophthalmic composition containing plazomicin or a pharmaceutically acceptable salt thereof can treat ocular infections, particularly those in which bacterial resistance has developed.

[0029] Accordingly, one aspect of the present invention is to formulate an ophthalmic pharmaceutical composition comprising plazomycin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0030] The ophthalmic compositions of the present invention are typically administered to the affected ocular tissue by topical application of 1 to 4 drops of a sterile solution or suspension, or an equivalent volume of an ointment, gel, or other solid or semi-solid composition, 1 to 4 times daily, however, the compositions can also be formulated as irrigation solutions to be applied to the affected ocular tissue during surgery.

[0031] The ophthalmic pharmaceutical compositions according to the present invention may contain one or more pharmaceutically acceptable excipients suitable for their formulation, including, but not limited to, suspending agents, pH adjusting agents, tonicity adjusting agents, emulsifying or dispersing agents, surfactants, solubilizing agents, buffering agents, preservatives, chelating agents, humectants, viscosity adjusting agents, antioxidants, gelling agents, stabilizers, and mixtures thereof.

[0032] Ophthalmic pharmaceuticals are typically packaged in multi-dose forms. Therefore, preservatives are necessary to prevent microbial contamination during use. Suitable preservatives include, but are not limited to, quaternary ammonium derivatives, benzalkonium chloride, benzyl ammonium chloride, cetylmethylammonium bromide, stabilized oxychloride complexes, quaternary ammonium chloride, sodium perborate, benzododecinium bromide, zinc chloride, cetylpyridinium chloride, benzethonium chloride, chlorbutanol, chlorhexidine gluconate, chlorhexidine acetate, organic mercury compounds (thimerosal, phenylmercuric acetate, phenylmercuric nitrate), methyl and propyl p-hydroxybenzoates, beta-phenylethyl alcohol, benzyl alcohol, phenylethyl alcohol, phenoxyethanol, stabilized oxychloride complexes (SOC), Sofdia, and sodium perborate, as well as other agents and mixtures thereof known to those skilled in the art. Typically, such preservatives are used at concentrations of 0.001% to 1.0% by weight. In one embodiment, the compositions of the present invention comprise from about 0.01% w / v to about 3.00% w / v of a preservative. In another embodiment, the compositions of the present invention comprise from about 0.00010% w / v to about 1.00% w / v of a preservative. In a preferred embodiment, the compositions of the present invention comprise about 0.02% w / v of benzalkonium chloride.

[0033] The ophthalmic pharmaceutical compositions of the present invention may optionally contain one or more suspending agents. Suitable suspending agents may be selected from, but are not limited to, water-soluble / water-swellable polymers, such as cellulosic polymers (methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidine, polyvinyl alcohol, carbopol, carbophil), and one or more water-insoluble polymers (crosslinked carboxyl-containing polymers, ethylcellulose), and mixtures thereof. Other suspending agents that may be used include, but are not limited to, acacia, agar, alginic acid, sodium alginate, bentonite, carrageenan, gelatin, tragacanth, xanthan gum, and derivatives thereof. Such suspending agents may be used in a range of 0.005% w / v to 1.5% w / v, or in any amount deemed appropriate for the composition.

[0034] Suitable surfactants or wetting agents that can be incorporated into the ophthalmic pharmaceutical composition of the present invention include, but are not limited to, polyoxyethylene fatty acid esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 65, polysorbate 85), sorbitan fatty acid esters (e.g., Span 20, Span 40, Span 60, Span 80, Span 120), sodium lauryl sulfate, polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, sodium dodecyl sulfate, lauryl dimethylamine oxide, docusate sodium, cetyltrimethylammonium bromide, polyethoxylated alcohol, octoxynol, N,N-dimethyldodecylamine oxide, polyoxyl 10 lauryl ether, hexadecyltrimethylammonium bromide, polyoxyethylene surfactant (Brij), bile salts (e.g., but not limited to, sodium deoxycholate, sodium cholate), polyoxyl castor oil, nonylphenol ethoxylate, cyclodextrin, lecithin, methylbenzene chloride nitrite, carboxylate, sulfonate, petroleum sulfonate, alkylbenzene sulfonate, naphthalene sulfonate, olefin sulfonate, alkyl sulfate, sulfate, sulfated natural fats and oils, sulfate ester, sulfated alkanolamide, alkylphenol, ethoxylated fatty alcohol, carboxylic acid ester, polyethylene glycol ester, sorbitol anhydride ester and its ethoxylated derivative, glycol ester of fatty acid, carboxylic acid amide, monoalkanolamine condensate, polyoxyethylene fatty acid amide, quaternary ammonium salt, amine with amide bond, polyoxyethylene alkylamine and alicyclic amine, N,N,N,The surfactants may include one or more of N-tetrakis-substituted ethylenediamine 2-alkyl 1-hydroxyethyl 2-imidazoline, N-coco-3-aminopropionic acid / sodium salt, N-tallow-3-iminodipropionic acid disodium salt, N-carboxymethyl-n-dimethyl-n-9 octadecenyl ammonium hydroxide, n-cocoamidoethyl-n-hydroxyethyl glycine sodium salt, polyoxyethylene / polyoxypropylene surfactants (e.g., Pluronic F-68, F-84, P-103), poloxamines (e.g., Tetronic® 1508, Tetronic® 908), octoxynol 40, tyloxapol, cremophor, and other surfactants known in the art, as well as mixtures thereof. Surfactants may be used in the range of 0.001% w / v to 3.0% w / v.

[0035] The composition may further include stabilizers such as, but not limited to, phosphonates (e.g., those sold under the name "DEQUEST" (a trademark of Montanto)), edetate disodium, sodium thiosulfate, and sodium stannate.

[0036] The compositions of the present invention may further contain one or more buffers, or acids, bases, or buffers for adjusting the pH, to maintain a pH of 4.5 to 8, preferably 6.5 to 7.5. Examples of such acids include acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid. Examples of such bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, THAM (trishydroxymethylaminomethane), and tromethamine. Examples of such salts and buffers include citric acid / glucose, sodium dihydrogen phosphate dihydrate, sodium bicarbonate, ammonium chloride, or mixtures of the aforementioned acids and bases. In one embodiment, the compositions of the present invention contain about 0.01% w / v to about 1.5% w / v of a buffer. In another embodiment, the compositions of the present invention contain about 0.01% w / v to about 5% w / v of a buffer. In a preferred embodiment, the compositions of the present invention contain about 0.3% w / v of boric acid.

[0037] In one embodiment, the pH of the composition of the present invention may be about 6 to about 7. In a preferred embodiment, the pH of the composition of the present invention may be about 6.5 to about 7.

[0038] Osmolality / tonicity adjusters that can be used include sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. Other tonicity adjusters include, but are not limited to, mannitol, anhydrous glucose, glycerol, sorbitol, trehalose, boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosphate, sodium chloride, glycerin, propylene glycol, or other inorganic or organic solutes, dextrose, or mixtures thereof. In one embodiment, the composition of the present invention comprises a tonicity adjuster in an amount of about 0.01% w / v to about 1.5% w / v. In another embodiment, the composition of the present invention comprises about 0.1% w / v to about 6% w / v of a tonicity adjuster. In a preferred embodiment, the composition of the present invention comprises about 0.73% w / v sodium chloride.

[0039] The compositions may also contain edetic acid (EDTA) or one of its known salts (e.g., sodium EDTA or disodium EDTA dihydrate (sodium edetate), trisodium edetate), malic acid, sodium citrate, and a complexing / chelating agent such as condensed sodium phosphate, at a concentration of 0.001% to 1% w / v. In one embodiment, the compositions of the present invention contain about 0.1% w / v EDTA.

[0040] The compositions may contain viscosity modifiers to increase the viscosity of the compositions above that of a simple aqueous solution, thereby enhancing ocular absorption of the active compound into target tissues or extending its residence time in the eye. Examples of viscosity modifiers include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, or other agents known to those skilled in the art. These agents may be used at concentrations ranging from 0.01% w / v to 2% w / v. In one embodiment, the compositions of the present invention contain from about 0.01% w / v to about 5% viscosity modifier.

[0041] The composition may further comprise sterile water for injection as a vehicle. Other aqueous and non-aqueous vehicles may also be used as vehicles in the present ophthalmic compositions.

[0042] However, it will be understood that the specific dosage and frequency of administration in accordance with the present invention for a particular patient may vary and will depend upon a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of that compound, the age, body weight, general health, sex, diet, method and time of administration, rate of excretion, the severity of the particular condition, and the host being treated.

[0043] In one embodiment, the compositions of the invention comprise about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof.

[0044] In another preferred embodiment, the ophthalmic pharmaceutical composition comprises plazomycin or a pharmaceutically acceptable salt thereof in an amount of about 0.1% w / v to about 5% w / v of the composition. In a more preferred embodiment, the composition comprises plazomycin or a pharmaceutically acceptable salt thereof in an amount of about 0.1% w / v to about 2% w / v of the composition. In another preferred embodiment, the composition comprises plazomycin or a pharmaceutically acceptable salt thereof in an amount of about 0.1% w / v to about 0.5% w / v of the composition. In one embodiment, the composition comprises plazomycin or a pharmaceutically acceptable salt thereof in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% w / v.

[0045] According to another embodiment of the present invention, the pharmaceutical composition of the present invention may contain the active substance in a micronized form. The micronized active substance may be obtained by any of the following methods, including but not limited to ball milling, jet milling, ultrasonic treatment, homogenization, and solvent precipitation. According to yet another embodiment of the present invention, the pharmaceutical composition of the present invention may contain the active substance in a nanosized form. The nanoparticles of the present invention may be obtained by any of the following methods, including but not limited to milling, precipitation, homogenization, spray freeze drying, supercritical fluid technology, double emulsion / solvent evaporation, PRINT, thermal condensation, ultrasonic treatment, and spray drying.

[0046] According to another embodiment of the present invention, the milling process involves dispersing drug particles in a liquid dispersion medium in which the drug is poorly soluble, followed by application of mechanical means in the presence of a milling medium to reduce the particle size of the drug to the desired effective average particle size.

[0047] In one embodiment, the compositions of the invention comprise about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment, the compositions of the present invention comprise plazomycin sulfate.

[0049] In a further embodiment, the composition of the present invention further comprises at least one excipient selected from a buffering agent, a tonicity adjusting agent, a viscosity adjusting agent, a preservative, a chelating agent, and a pH adjusting agent.

[0050] In one embodiment, the composition of the invention further comprises from about 0.01% w / v to about 1.5% w / v of a buffering agent, hi another embodiment, the composition of the invention further comprises from about 0.01% w / v to about 5% w / v of a buffering agent.

[0051] In another embodiment, the compositions of the present invention further comprise from about 0.01% w / v to about 1.5% w / v of a tonicity adjusting agent, hi another embodiment, the compositions of the present invention further comprise from about 0.1% w / v to about 6% w / v of a tonicity adjusting agent.

[0052] In another embodiment, the composition of the present invention further comprises from about 0.01% w / v to about 3% w / v of a preservative, hi another embodiment, the composition of the present invention further comprises from about 0.00010% w / v to about 1% w / v of a preservative.

[0053] In one embodiment, the compositions of the present invention comprise from about 0.01% w / v to about 5% w / v of a viscosity modifier.

[0054] In another embodiment, the compositions of the invention comprise from about 0.001% w / v to about 1% w / v of a chelating agent.

[0055] In one embodiment, the composition of the present invention further comprises a pH adjuster.

[0056] In one embodiment, the composition of the present invention is an aqueous composition.

[0057] In another embodiment, the compositions of the present invention comprise plazomycin or a pharmaceutically acceptable salt thereof in solubilized form.

[0058] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.50% w / v of a buffering agent, about 0.01% w / v to about 1.50% w / v of a tonicity adjusting agent, and water.

[0059] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.50% w / v of boric acid, about 0.01% w / v to about 1.50% w / v of sodium chloride, and water.

[0060] In a further embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3.00% w / v of a preservative, about 0.01% w / v to about 1% w / v of a buffering agent, about 0.01% w / v to about 1.50% w / v of a tonicity adjusting agent, about 0.01% w / v to about 5% w / v of a viscosity adjusting agent, and water.

[0061] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3.00% w / v of benzalkonium chloride, about 0.01% w / v to about 1% w / v of citric acid and disodium citrate, about 0.01% w / v to about 1.50% w / v of sodium chloride, about 0.01% w / v to about 5% w / v of polyvinyl alcohol, and water.

[0062] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3% w / v of a preservative, about 0.01% w / v to about 1.50% w / v of a tonicity adjusting agent, about 0.01% w / v to about 1.50% w / v of a buffering agent, about 0.01% w / v to about 1% w / v of a viscosity adjusting agent, and water.

[0063] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3% w / v benzalkonium chloride, about 0.01% w / v to about 1.50% w / v sodium chloride, about 0.01% w / v to about 1.50% w / v boric acid, about 0.01% w / v to about 1% w / v hydroxypropyl guar gum, and water.

[0064] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.00010% w / v to about 1% w / v of a preservative, about 0.01% w / v to about 1.50% w / v of a tonicity adjusting agent, about 0.01% w / v to about 1% w / v of a buffering agent, about 0.01% w / v to about 5% w / v of a viscosity adjusting agent, and water.

[0065] In a further embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.00010% w / v to about 1% w / v of the stabilized oxychloride complex, about 0.01% w / v to about 1.50% w / v of sodium chloride, about 0.01% w / v to about 1% w / v of citric acid and disodium citrate, about 0.01% w / v to about 5% w / v of polyvinyl alcohol, and water.

[0066] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3% w / v of a preservative, about 0.01% w / v to about 1.50% w / v of a tonicity adjusting agent, about 0.01% w / v to about 1% w / v of a buffering agent, about 0.01% w / v to about 5% w / v of a viscosity adjusting agent, and water.

[0067] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3% w / v of a quaternary ammonium chloride, about 0.01% w / v to about 1.50% w / v of sodium chloride, about 0.01% w / v to about 1% w / v of citric acid and disodium citrate, about 0.01% w / v to about 5% w / v of polyvinyl alcohol, and water.

[0068] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1% w / v of a preservative, about 0.01% w / v to about 1.50% w / v of a tonicity adjusting agent, about 0.01% w / v to about 1% w / v of a buffering agent, about 0.01% w / v to about 5% w / v of a viscosity adjusting agent, and water.

[0069] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1% w / v sodium perborate, about 0.01% w / v to about 1.50% w / v sodium chloride, about 0.01% w / v to about 1% w / v citric acid and disodium citrate, about 0.01% w / v to about 5% w / v polyvinyl alcohol, and water.

[0070] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3% w / v of a preservative, about 0.01% w / v to about 1.50% w / v of a tonicity adjusting agent, about 0.01% w / v to about 1% w / v of a buffering agent, about 0.01% w / v to about 5% w / v of a viscosity adjusting agent, and water.

[0071] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 3% w / v of benzododecinium bromide, about 0.01% w / v to about 1.50% w / v of sodium chloride, about 0.01% w / v to about 1% w / v of citric acid and disodium citrate, about 0.01% w / v to about 5% w / v of polyvinyl alcohol, and water.

[0072] In a further embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.0010% w / v to about 0.1% w / v of a preservative, about 0.01% w / v to about 4% w / v of a tonicity adjusting agent, about 0.01% w / v to about 1.5% w / v of a buffering agent, and water.

[0073] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v plazomicin or a pharmaceutically acceptable salt thereof, about 0.0010% w / v to about 0.1% w / v zinc chloride, about 0.01% w / v to about 2% w / v propylene glycol, about 0.01% w / v to about 1.5% w / v sodium chloride, about 0.01% w / v to about 1.5% w / v boric acid, and water.

[0074] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.0010% w / v to about 0.1% w / v of a preservative, about 0.01% w / v to about 10% w / v of a tonicity adjusting agent, about 0.01% w / v to about 1.5% w / v of a buffering agent, and water.

[0075] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v plazomicin or a pharmaceutically acceptable salt thereof, about 0.0010% w / v to about 0.1% w / v zinc chloride, about 0.01% w / v to about 2% w / v propylene glycol, about 0.1% w / v to about 6% w / v mannitol, about 0.01% w / v to about 1.5% w / v boric acid, and water.

[0076] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.1% w / v to about 6% w / v of a tonicity adjusting agent, about 0.01% w / v to about 2.5% w / v of a buffering agent, and water.

[0077] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.1% w / v to about 6% w / v of mannitol, about 0.01% w / v to about 2.5% w / v of dibasic sodium phosphate, and water.

[0078] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.5% w / v of a tonicity adjusting agent, about 0.01% w / v to about 2.5% w / v of a buffering agent, and water.

[0079] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.5% w / v of sodium chloride, about 0.01% w / v to about 2.5% w / v of dibasic sodium phosphate, and water.

[0080] In a further embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.1% w / v to about 6% w / v of a tonicity adjusting agent, about 0.01% w / v to about 5% w / v of a buffering agent, and water.

[0081] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.1% w / v to about 6% w / v of mannitol, about 0.01% w / v to about 2.5% w / v of dibasic sodium phosphate, about 0.01% w / v to about 2.5% w / v of monobasic sodium phosphate, and water.

[0082] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.5% w / v of a tonicity adjusting agent, about 0.01% w / v to about 5% w / v of a buffering agent, and water.

[0083] In a further embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomycin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.5% w / v of sodium chloride, about 0.01% w / v to about 2.5% w / v of dibasic sodium phosphate, about 0.01% w / v to about 2.5% w / v of monobasic sodium phosphate, and water.

[0084] In one embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.5% w / v of a tonicity adjusting agent, about 0.01% w / v to about 5% w / v of a buffering agent, about 0.01% w / v to about 3% w / v of a preservative, about 0.001% w / v to about 1% w / v of a chelating agent, and water.

[0085] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v plazomycin or a pharmaceutically acceptable salt thereof, about 0.73% w / v tonicity adjusting agent, about 0.3% w / v buffering agent, about 0.02% w / v preservative, about 0.1% w / v chelating agent, and water.

[0086] In a further embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v plazomicin or a pharmaceutically acceptable salt thereof, about 0.01% w / v to about 1.5% w / v sodium chloride, about 0.01% w / v to about 5% w / v boric acid, about 0.01% w / v to about 3% w / v benzalkonium chloride, about 0.001% w / v to about 1% w / v EDTA, and water.

[0087] In another embodiment, the ophthalmic composition comprises about 0.01% w / v to about 1.00% w / v plazomicin or a pharmaceutically acceptable salt thereof, about 0.73% w / v sodium chloride, about 0.3% w / v boric acid, about 0.02% w / v benzalkonium chloride, about 0.1% w / v EDTA, and water.

[0088] In one embodiment, the present invention relates to an ophthalmic composition for use in treating an eye infection.

[0089] According to one embodiment of the present invention, the present invention also relates to a method for preparing the ophthalmic pharmaceutical composition, comprising the steps of (i) autoclaving a slurry containing the active ingredient and optionally other excipients, (ii) preparing and autoclaving a solution containing other pharmaceutically acceptable excipients, (iii) aseptically adding the drug slurry to the excipient solution, and (iv) finally making up to volume with a vehicle.

[0090] According to a preferred embodiment, the present invention also relates to a method for preparing the ophthalmic pharmaceutical composition, comprising the steps of (i) milling and autoclaving a slurry containing the active ingredient, surfactant, and suspending agent, (ii) preparing and autoclaving a solution containing other pharmaceutically acceptable excipients, (iii) aseptically adding a preservative to the excipient solution, (iv) aseptically adding a drug slurry to the excipient solution, and (v) finally making up to volume with a vehicle.

[0091] According to another embodiment, the present invention also relates to a method for preparing the ophthalmic pharmaceutical composition, comprising the steps of (i) milling and autoclaving a slurry containing the active ingredient, surfactant, and suspending agent, (ii) preparing and autoclaving a solution containing other pharmaceutically acceptable excipients and preservatives, (iii) aseptically adding the drug slurry to the excipient and preservative solution, and (iv) finally making up to volume with vehicle.

[0092] The present invention also provides a method for treating and / or preventing an eye infection, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention.

[0093] The compositions of the present invention may be used topically to treat inflammatory eye infections such as conjunctivitis, dacryocystitis, hordeolum, keratitis, blepharitis, and corneal ulcers. The compositions of the present invention may also be used prophylactically in connection with various ophthalmic surgeries that carry a risk of infection.

[0094] The following examples are intended to illustrate the present invention but are not intended to limit the scope of the invention.

[0095] Example 1: JPEG2026506767000002.jpg187122JPEG2026506767000003.jpg18743JPEG2026506767000004.jpg187122JPEG2026506767000005.jpg18753

[0096] Example 2: JPEG2026506767000006.jpg54122

[0097] Manufacturing method: 1. Dissolve benzalkonium chloride in water for injection that has been previously sparged with nitrogen. 2. Dissolve boric acid in the solution from step 1 while stirring. 3. Dissolve sodium chloride and EDTA in the solution from step 2 while stirring. 4. Add plazomicin to the solution from step 3 while stirring and dissolve. 5. Adjust the pH of the solution from step 4 to 6.5-7 with sodium hydroxide / hydrochloric acid. 6. Adjust the volume of the solution from step 5 with water for injection.

[0098] Example 3: In vitro "proof-of-concept" study of the efficacy of plazomicin against isolates from bacterial keratitis and / or conjunctivitis Isolates from patients with clinically diagnosed bacterial keratitis were tested for antimicrobial susceptibility to plazomicins using the reference broth microdilution method.

[0099] a. Preparation of Mueller-Hinton broth 21 g of Mueller-Hinton broth powder was suspended in 1000 ml of distilled water.

[0100] b. Bacterial isolates Pure cultures of bacterial isolates were prepared on blood agar / Mueller-Hinton agar from cryovials.

[0101] c. Preparation of inoculum A standard inoculum of 0.5 McFarland was prepared by the direct colony suspension method. Isolated colonies from 3 to 5 wells were picked from plates cultured for 18 to 24 hours and suspended in 2 ml of sterile saline / Mueller-Hinton broth. Prepare a uniform suspension and measure the turbidity using a densitometer to a 0.5 McFarland turbidity standard (approximately 1*10 6 ' 8 CFU / ml). 0.1 ml of the standardized inoculum was added to 9.9 ml of sterile saline (ie, a 1:100 dilution).

[0102] d. Microculture dilution method For the microculture dilution method, 96-well round-bottom plates were used. 100 pl of Mueller-Hinton broth containing drug concentrations ranging from 0.125 mcg / ml to 64 mcg / ml (0.125 mcg / ml, 0.25 mcg / ml, 0.5 mcg / ml, 1 mcg / ml, 2 mcg / ml, 4 mcg / ml, 8 mcg / ml, 16 mcg / ml, 32 mcg / ml, and 64 mcg / ml) was added to the 96-well plates. To this, 100 pl of diluted bacterial inoculum (1 TOO) containing varying drug concentrations was added to each well. 5 CFU / ml of bacteria were present. Growth controls (each organism plus Mueller-Hinton broth) and sterility controls (sterile Mueller-Hinton broth) were added to the 96-well plates. The plates were incubated for 18 to 24 hours and the minimum inhibitory concentration (MIC) was read.

[0103] Gram-positive isolates evaluated: 1. Methicillin-susceptible Staphylococcus aureus (MSSA) 2. Methicillin-resistant Staphylococcus aureus (MRSA) 3. Staphylococcus epidermidis 4. Staphylococcus aureus 5. Staphylococcus aureus 6. Streptococcus pneumoniae 7. Corynebacterium

[0104] Gram-negative isolates evaluated: 1. Pseudomonas aeruginosa 2. Klebsiella pneumoniae 3. Klebsiella pneumoniae (ESBL) 4. Moraxella lacunata 5. Haemophilus influenzae 6. Proteus 7. Serratia 8. Intestinal bacteria

[0105] e. Results Plazomicin was active against MSSA isolates, 67.3% of which were susceptible (MIC50 / 90, 2 / 8 mcg / mL). Additionally, 60% of MRSA isolates were susceptible (MIC50 / 90, 2 / 8 mcg / mL). Plazomicin was active against 50% of Pseudomonas aeruginosa strains (MIC50 / 90, 4 / 16 mcg / mL). Plazomicin inhibited the majority (90.1%) of Staphylococcus species at <8 mcg / mL, 73.5% at <4 mcg / mL, and 46% at <2 mcg / mL. Plazomicin was 100% active against Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus pyogenes, Moraxella lacunae, Enterobacteriaceae, and Corynebacterium at <2 mcg / mL. Plazomicin inhibited 61.5% and 11.5% of Enterobacteriaceae isolates at <2 mcg / mL and <4 mcg / mL, respectively.

[0106] In conclusion, plazomicin demonstrated excellent antibacterial activity: 100% of conjunctival isolates were susceptible to plazomicin (<4 mcg / mL).

[0107] It will be apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the spirit of the invention. Thus, while the invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and such modifications and variations are deemed to be within the scope of the invention.

[0108] It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. As used herein, the words "comprises," "includes," or "having" and variations thereof are intended to encompass the items listed thereafter and equivalents thereof, as well as additional items.

[0109] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to a "buffer" encompasses not only one buffer but two or more different buffers. Also, reference to a "solvent" refers to a co-solvent or a combination of two or more solvents.

Claims

1. An ophthalmic composition comprising plazomycin or a pharmaceutically acceptable salt thereof.

2. 10. The composition of claim 1, wherein the composition comprises about 0.01% w / v to about 1.00% w / v of plazomicin or a pharmaceutically acceptable salt thereof.

3. The composition of claim 1 , wherein the composition comprises plazomicin sulfate.

4. 10. The composition of claim 1, wherein the composition further comprises at least one excipient selected from a buffering agent, a tonicity adjusting agent, a viscosity adjusting agent, a preservative, a chelating agent, and a pH adjusting agent.

5. 10. The composition of claim 1, wherein the composition further comprises about 0.01% w / v to about 1.5% w / v of a buffering agent.

6. 10. The composition of claim 1, wherein the composition further comprises about 0.01% w / v to about 5% w / v of a buffering agent.

7. The composition of claim 1, wherein the composition further comprises about 0.01% w / v to about 1.5% w / v of a tonicity adjusting agent.

8. The composition of claim 1, wherein the composition further comprises about 0.1% w / v to about 6% w / v of a tonicity adjusting agent.

9. 10. The composition of claim 1, wherein the composition further comprises about 0.01% w / v to about 3% w / v of a preservative.

10. 10. The composition of claim 1, wherein the composition further comprises about 0.00010% w / v to about 1% w / v of a preservative.

11. The composition of claim 1, wherein the composition further comprises about 0.01% w / v to about 5% w / v of a viscosity modifier.

12. 10. The composition of claim 1, wherein the composition further comprises about 0.001% w / v to about 1% w / v of a chelating agent.

13. The composition of claim 1 , wherein the composition further comprises a pH adjuster.

14. The composition of claim 1 , wherein the composition is an aqueous composition.

15. 10. The composition of claim 1, wherein the plazomycin or a pharmaceutically acceptable salt thereof is in a solubilized form.

16. 10. The composition of claim 1, wherein the pH of the composition is from about 6 to about 7.

17. 10. The composition of claim 1 for use in treating an eye infection.

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