Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug

Abstract

The present invention relates to compositions of submicron- to micron-size particles of antimicrobial agents. More particularly the invention relates to a composition of an antimicrobial agent that renders the agent potent against organisms normally considered to be resistant to the agent. The composition comprises an aqueous suspension of submicron- to micron-size particles containing the agent coated with at least one surfactant selected from the group consisting of: ionic surfactants, non-ionic surfactants, biologically derived surfactants, and amino acids and their derivatives. The particles have a volume-weighted mean particle size of less than 5 μm as measured by laser diffractometry.

1 . A composition of an antimicrobial agent that renders the agent potent against organisms normally considered to be resistant to the agent, the composition comprising an aqueous suspension of submicron- to micron-size particles containing the agent coated with at least one surfactant selected from the group consisting of: ionic surfactants, non-ionic surfactants, biologically derived surfactants, and amino acids and their derivatives, wherein the particles have a volume-weighted mean particle size of less than 5 μm as measured by laser diffractometry.  
     
     
         2 . The composition of  claim 1 , wherein the particles have a volume-weighted mean particle size of less than 2 μm as measured by laser diffractometry.  
     
     
         3 . The composition of  claim 1 , wherein the particles have a volume-weighted mean particle size of less than about 1 μm as measured by laser diffractometry.  
     
     
         4 . The composition of  claim 1 , wherein the particles have a volume-weighted mean particle size of from about 150 nm to about 1 μm as measured by laser diffractometry.  
     
     
         5 . The composition of  claim 1 , wherein the antimicrocidal agent is an antifungal agent.  
     
     
         6 . The composition of  claim 5 , wherein the antimicrocidal agent is a triazole antifungal agent.  
     
     
         7 . The composition of  claim 6 , wherein the triazole antifungal agent is selected from the group consisting of: itraconazole, ketoconazole, miconazole, fluconazole, ravuconazole, voriconazole, saperconazole, eberconazole, genaconazole, clotrimazole, econazole, oxiconazole, sulconazole, terconazole, tioconazole, and posaconazole.  
     
     
         8 . The composition of  claim 1 , wherein the antimicrocidal agent is itraconazole.  
     
     
         9 . The composition of  claim 1 , wherein the ionic surfactant is selected from the group consisting of: anionic surfactants, cationic surfactants, zwitterionic surfactants, and combinations thereof.  
     
     
         10 . The composition of  claim 9 , wherein the anionic surfactant is selected from the group consisting of: alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidylserine, phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinosine, phosphatidic acid and its salts, sodium carboxymethylcellulose, cholic acid and other bile acids and salts thereof.  
     
     
         11 . The composition of  claim 10 , wherein the bile acid is selected from the group consisting of cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, and glycodeoxycholic acid.  
     
     
         12 . The composition of  claim 9 , wherein the anionic surfactant is a phospholipid.  
     
     
         13 . The composition of  claim 12 , wherein the phospholipid is natural or synthetic.  
     
     
         14 . The composition of  claim 12 , wherein the phospholipid is pegylated.  
     
     
         15 . The composition of  claim 8 , wherein the cationic surfactant is selected from the group consisting of: quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides, or aliphatic amines.  
     
     
         16 . The composition of  claim 9 , wherein the zwitterionic surfactant is a phospholipid.  
     
     
         17 . The composition of  claim 16 , wherein the phospholipid is natural or synthetic.  
     
     
         18 . The composition of  claim 16 , wherein the phospholipid is pegylated.  
     
     
         19 . The composition of  claim 1 , wherein the nonionic surfactant is selected from the group consisting of: glyceryl esters, polyoxyethylene fatty alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters (Myij), sorbitan esters (Span), glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxamers), poloxamines, methylcellulose, hydroxymethylcellulose, hydyoxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, polysaccharides including starch and starch derivatives such as hydroxyethylstarch (HES), polyvinyl alcohol, and polyvinylpyrrolidone.  
     
     
         20 . The composition of  claim 1 , wherein the biologically derived surfactant is selected from the group consisting of: albumin, casein, other proteins and polysaccharides.  
     
     
         21 . The composition of  claim 20 , wherein the polysaccharide is selected from the group consisting of starches, heparin and chitosans.  
     
     
         22 . The composition of  claim 1 , wherein the amino acid is selected from the group consisting of: leucine, alanine, valine, isoleucine, lysine, aspartic acid, glutamic acid, methionine, tyrosine and phenylalanine.  
     
     
         23 . The composition of  claim 1 , wherein the amino acid derivative is an amide, an ester, or a polypeptide.  
     
     
         24 . The composition of  claim 1 , wherein the surfactant is a bile salt.  
     
     
         25 . The composition of  claim 24 , wherein the bile salt is deoxycholate.  
     
     
         26 . The composition of  claim 1 , wherein the surfactant is a polyalkoxyether.  
     
     
         27 . The composition of  claim 26 , wherein the polyalkoxyether is Poloxamer 188.  
     
     
         28 . The composition of  claim 1 , wherein the surfactant is hydroxyethylstarch.  
     
     
         29 . The composition of  claim 1 , wherein the surfactant is polyethylene-660-hydroxystearate.  
     
     
         30 . The composition of  claim 1 , wherein the surfactant is albumin.  
     
     
         31 . The composition of  claim 1 , wherein the surfactant is a phospholipid.  
     
     
         32 . The composition of  claim 1 , wherein the aqueous medium further comprises a pH adjusting agent.  
     
     
         33 . The composition of  claim 32 , wherein the pH adjusting agent is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, succinic acid, citric acid, tris(hydroxymethyl)aminomethane, meglumine, sodium hydroxide, and amino acids.  
     
     
         34 . The composition of  claim 33 , wherein the amino acid is selected from the group consisting of: glycine, arginine, lysine, alanine, methionine, valine, asparagine, tyrosine, proline, serine, isoleucine, tryptophan, phenylalanine, threonine, cysteine, glutamine, aspartic acid, glutamic acid, histidine, taurine and leucine.  
     
     
         35 . The composition of  claim 1 , further comprising an osmotic pressure adjusting agent.  
     
     
         36 . The composition of  claim 35 , wherein the osmotic pressure adjusting agent is selected from the group consisting of: glycerin, monosaccharides, disaccharides, trisaccharides, and sugar alcohols.  
     
     
         37 . The composition of  claim 36 , wherein the monosaccharide is dextrose.  
     
     
         38 . The composition of  claim 36 , wherein the disaccharide is selected from the group consisting of sucrose, maltose and trehalose.  
     
     
         39 . The composition of  claim 36 , wherein the trisaccharide is raffinose.  
     
     
         40 . The composition of  claim 36 , wherein the sugar alcohol is mannitol or sorbitol.  
     
     
         41 . The composition of  claim 1 , wherein the antimicrobial agent is present is an amount of from about 0.01% to about 50% w/v.  
     
     
         42 . The composition of  claim 1 , wherein the antimicrobial agent is present in an amount of from about 0.05% to about 30% w/v.  
     
     
         43 . The composition of  claim 1 , wherein the antimicrobial agent is present in an amount of about 0.1% to about 20% w/v.  
     
     
         44 . The composition of  claim 1 , wherein the surfactant is present in an amount of from about 0.001% to about 5% w/v.  
     
     
         45 . The composition of  claim 1 , wherein the surfactant is present in an amount of from about 0.005% to about 5% w/v.  
     
     
         46 . The composition of  claim 1 , wherein the surfactant is present in an amount of from about 0.01% to about 5% w/v.  
     
     
         47 . The composition of  claim 1  is administered by a route selected from the group consisting of: parenteral, oral, buccal, periodontal, rectal, nasal, pulmonary, and topical.  
     
     
         48 . The composition of  claim 1  is administered by a route selected from the group consisting of intravenous, intramuscular, intracerebral, subcutaneous, intradermal, intralymphatic, pulmonary, intraacticular, intrathecal, and intraperitoneal.  
     
     
         49 . The composition of  claim 1 , wherein the aqueous medium is removed to form dry particles.  
     
     
         50 . The composition of  claim 49 , wherein the method of removing the aqueous medium is selected from the group consisting of: evaporation and lyophilization.  
     
     
         51 . The composition of  claim 49 , wherein the method of removing the aqueous medium is by lyophilization.  
     
     
         52 . The composition of  claim 49 , wherein the dry particles are formulated into an acceptable pharmaceutical dosage form.  
     
     
         53 . The composition of  claim 52 , wherein the pharmaceutical dosage form is selected from the group consisting of: parenteral solutions, tablets, capsules, suspensions, creams, lotions, emulsions, pulmonary formulations, topical formulations, controlled or sustained release formulations, and tissue specific targeted delivery formulations.  
     
     
         54 . The composition of  claim 1 , wherein the composition is frozen.  
     
     
         55 . A composition of an antimicrobial agent that renders the agent potent against organisms normally considered to be resistant to the agent, the composition comprising an aqueous suspension of submicron- to micron-size particles of itraconazole coated with at least one surfactant, and an osmotic pressure adjusting agent, wherein the nanoparticles having a volume-weighted mean particle size of less than 5 μm as measured by laser diffractometry, and wherein the itraconazole is present in an amount of from about 0.01% to about 50% w/v, and the surfactant is present in an amount of from about 0.001% to about 5%.  
     
     
         56 . A composition of particles of an antimicrobial agent that renders the agent potent against organisms normally considered to be resistant to the agent, the composition prepared by a method comprising the steps of: 
 (i) dissolving the antimicrobial agent in a water-miscible first solvent to form a solution;    (ii) mixing the solution with a second solvent which is aqueous to define a pre-suspension; and    (iii) adding energy to the pre-suspension to form particles having an average effective particle size of less than 5 μm;    wherein the solubility of the antimicrobial agent is greater in the first solvent than in the second solvent, and the second solvent comprising one or more surfactants selected from the group consisting of: nonionic surfactants, ionic surfactants, biologically derived surfactants, and amino acids and their derivatives.    
     
     
         57 . A method for rendering an antimicrobial agent potent against organisms normally considered to be resistant to the agent, the method comprising formulating the agent as an aqueous suspension of submicron- to micron-size particles containing the agent coated with at least one surfactant selected from the group consisting of: ionic surfactants, non-ionic surfactants, biologically derived surfactants, and amino acids and their derivatives, wherein the particles have a volume-weighted mean particle size of less than 5 μm as measured by laser diffractometry.  
     
     
         58 . A method for treating a subject infected with an organism normally considered to be resistant to an antimicrobidcidal agent, the method comprising the step of administering the agent to the subject, wherein the agent is formulated as an aqueous suspension of submicron- to micron-size particles containing the agent coated with at least one surfactant selected from the group consisting of: ionic surfactants, non-ionic surfactants, biologically derived surfactants, and amino acids and their derivatives, wherein the particles have a volume-weighted mean particle size of less than 5 μm as measured by laser diffractometry.