WO2004096180A1 - Formulation destinee a rendre un medicament antimicrobien efficace contre des organismes normalement consideres comme etant resistant a ce medicament - Google Patents

Formulation destinee a rendre un medicament antimicrobien efficace contre des organismes normalement consideres comme etant resistant a ce medicament Download PDF

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WO2004096180A1
WO2004096180A1 PCT/US2004/013268 US2004013268W WO2004096180A1 WO 2004096180 A1 WO2004096180 A1 WO 2004096180A1 US 2004013268 W US2004013268 W US 2004013268W WO 2004096180 A1 WO2004096180 A1 WO 2004096180A1
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composition
agent
surfactant
acid
group
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PCT/US2004/013268
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English (en)
Inventor
Barrett E. Rabinow
Randy White
Chong-Son Sun
Joseph Chung Tak Wong
James E. Kipp
Mark J. Doty
Christine L. Rebbeck
Pavlos Papadopoulos
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Baxter International Inc.
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Priority to EP04760446A priority Critical patent/EP1617818A1/fr
Priority to BRPI0409929-0A priority patent/BRPI0409929A/pt
Priority to CA002523151A priority patent/CA2523151A1/fr
Priority to MXPA05011607A priority patent/MXPA05011607A/es
Priority to JP2006513447A priority patent/JP2006525345A/ja
Priority to AU2004234003A priority patent/AU2004234003A1/en
Publication of WO2004096180A1 publication Critical patent/WO2004096180A1/fr
Priority to NO20055616A priority patent/NO20055616L/no

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to compositions of antimicrobial agents. More particularly the invention relates to formulations of an antimicrobial agent which render the drug potent against organisms normally considered to be resistant to the agent.
  • the level of an antimicrobial drug considered effective against a particular organism may be determined. This is referred to as the MIC (minimum inhibitory concentration) of the drug.
  • MIC minimum inhibitory concentration
  • safety studies will determine the amount of drug that can be safely given to a patient or test animal. This maximal amount of drug that can be dosed will determine the maximal biological exposure to the host animal, normally measured by the area under the curve (AUC) of the plot of drug concentration vs. time, the peak height of the plot of drug concentration vs. time, tissue levels vs. time, etc.
  • AUC area under the curve
  • the instantaneous tissue or plasma level of the in vivo experiment can be compared with the MIC value to determine relative efficacy of the attainable drug levels in the biological fluids.
  • the actual comparison must be corrected for plasma protein binding, inasmuch as only the free drug level is the important parameter because it is in this state that the drug is freely diffusible to cross biological membranes.
  • an antimicrobial agent which is conventionally formulated to increase the solubility of the drug is the triazole antifungal agent itraconazole (FIG. 2).
  • Itraconazole is effective against systemic mycoses, particularly aspergillosis and candidiasis.
  • New oral and intravenous preparations of itraconazole have been prepared in order to overcome bioavailability problems associated with a lack of solubility.
  • the bioavailability of itraconazole is increased when it is formulated in hydroxypropyl-beta-cyclodextrin, a carrier oligosaccharide that forms an inclusion complex with the drug, thereby increasing its aqueous solubility.
  • the commercial preparation is known by the tradename SPORANOX ® Injection and was originated by JANSSEN PHARMACEUTICAL PRODUCTS, L.P.
  • the drug is currently manufactured by Abbott Labs and distributed by Ortho Biotech, Inc.
  • Intravenous itraconazole may be useful in selected clinical situations. Examples are achlorhydria in ADDS patients, an inability to effectively absorb oral medications due to concurrent treatments with other drugs, or in critical-care patients who cannot take oral medications.
  • the current commercial product, SPORANOX ® Inj ection is made available in 25 mL glass vials that contain 250 mg of itraconazole, with 10 g of hydroxypropyl-beta-cyclodextrin (referenced as "HPBCD"). These vials are diluted prior to use in 50 mL of 0.9% saline. The resulting cyclodextrin concentration exceeds 10% (w/v) in the reconstituted product.
  • HPBCD has been traditionally regarded as safe for injection
  • high concentrations such as 10%
  • have been reported in animal models to induce significant changes to endothelial tissues (Duncker G.; Reichelt J., Effects of the pharmaceutical cosolvent hydroxypropyl-beta- cyclodextrin on porcine corneal endothelium. Graefe's Archive for Clinical and Experimental Ophthalmology (Germany) 1998, 236/5, 380-389).
  • paclitaxel (Taxol®, produced by Bristol-Myers Squibb) contains 52.7% (w/v) of Cremophor® EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP.
  • Cremophor® EL polyoxyethylated castor oil
  • Administration of Cremophor® EL can lead to undesired hypersensitivity reactions (Volcheck, G.W., Van Dellen, R.G. Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and review.
  • the present invention discloses a composition which renders antimicrobial drugs more effective on the basis of their physical and biological properties than in their unformulated state or in their existing formulations.
  • the approach used is to formulate the antimicrobial agents as nanosupensions. This permits using of the improved formulation to treat microbes conventionally thought to be resistant to the unformulated drug.
  • Conventional formulation approaches attempt to enliance solubility or bioavailability only. Such methods include pH change, modification of the salt form, use of organic modifiers, or cyclodextrin.
  • the approach disclosed in the present invention involves altering the pharmacokinetic characteristic of the drug, permitting far greater dosing, resulting in improved efficacy over and above what can be accomplished by improving solubility and bioavailability only. Acute toxicity tests have demonstrated that much more drug, when formulated as a nanosuspension, can be administered to animals. More of the drug is therefore available at the target organ to exert efficacy.
  • the present invention relates to a composition of an aqueous suspension of submicron- to micron-size particles of an antimicrobial agent that renders the agent potent against organisms normally considered to be resistant to the agent.
  • the composition includes 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- eighted mean particle size of less than 5 ⁇ m as measured by light scattering (HORJJB A) or by microscopic measurements. More preferably the particles should be less than about 1 micron and most preferably from about 150 nm to about 1 micron or any range or combination of ranges therein.
  • the present invention is suitable for pharmaceutical use.
  • the antimicrobial agent is an antifungal agent
  • the antifungal agent is a triazole antifungal agent.
  • the triazole antifungal agent is selected from itraconazole, ketoconazole, miconazole, fluconazole, ravuconazole, voriconazole, saperconazole, eberconazole, genaconazole, clotrimazole, econazole, oxiconazole, sulconazole, terconazole, tioconazole, and posaconazole.
  • the antifungal agent is itraconazole.
  • Suitable surfactants for coating the particles in the present invention can be selected from ionic surfactants, nonionic surfactants, biologically derived surfactants, or amino acids and their derivatives.
  • the composition of the present invention is prepared by a microprecipitation method which includes the steps of: (i) dissolving in the antifungal agent in a first 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 ⁇ m; more preferably less than about 1 micron, and most preferably from about 150 nm to about 1 micron or any range or combination of ranges therein, wherein the solubility of the antifungal agent is greater in the first solvent than in the second solvent, and the first solvent or 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.
  • the present invention also relates to a method of rendering an antimicrobial agent potent against organisms normally considered to be resistant to the agent by 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.
  • the present invention further relates to a method of treating infection of a subject by organisms normally considered to be resistant to an antimicrobial agent by administering the agent to the subject 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.
  • FIG. 1 is the general molecular structure of a triazole antifungal agent
  • FIG. 2 is the molecular structure of itraconazole
  • FIG. 3 is a schematic diagram of Method A of the microprecipitation process used in the present invention to prepare the suspension
  • FIG. 4 is a schematic diagram of Method B of the microprecipitation process used in the present invention to prepare the suspension
  • FIG. 6 is a graph comparing the drug level for the rapidly dissolving formulation, Form A, and the slow dissolving (macrophage targeting) formulation, Form B, as determined in an in vitro dissolution experiment; the drug level for Form A is much higher than that attained by Form B;
  • FIG. 7 is a graph showing the comparison of results for body weight over time for immuno-suppressed rats treated with SPORANOX ® Injection and Formulations 14288-1 and 14288-B;
  • FIG. 8 is a graph of kidney drug level vs. dose showing that the greater dosing that could be administered permitted greater drug levels to be manifested in the target organs, in this case, the kidney;
  • FIG. 10 is a graph showing the mortality/moribundity profile after daily or every other day dosing with antifungal drugs for 10 days in rats systemically infected with itraconazole resistant C. albicans.
  • the present 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 composition disclosed in the present invention involves altering the pharmacokinetic characteristic of the drug, permitting far greater dosing, resulting in improved efficacy over and above what can be accomplished by improving solubility and bioavailability only.
  • Submicron sized drug crystals stabilized by a surfactant coating have been found, in some cases, not to dissolve immediately upon injection into the blood stream. Instead, they are captured by fixed macrophages of the spleen and liver. From this sanctuary, the drug can be slowly released over a prolonged period of days. Acute toxicity tests have demonstrated that much more drug, when formulated as a nanosuspension, can be administered to animals or human beings. More of the drug is therefore available at the target organ to exert efficacy.
  • the particles in the present invention have a volume- weighted mean particle size of less than 5 ⁇ m as measured by light scattering (HORD3A) or by microscopic measurements.
  • the particles should be less than about 1 micron and most preferably from about 150 nm to about 1 micron or any range or combination of ranges therein.
  • the composition can be administered to a subj ect to treat infection by organisms normally considered to be resistant to the agent.
  • the antimicrobial agent is preferably a poorly water soluble organic compound. What is meant by “poorly water soluble” is that the water solubility of the compound is less than 10 mg/ml, and preferably, less than 1 mg/ml.
  • a preferred class of antimicrobial agent is an antifungal agent.
  • a preferred antifungal agent is the triazole antifungal agents having a general molecular structure as shown in FIG. 1.
  • triazole antifungal agents include, but are not limited to : itraconazole, ketoconazole, miconazole, fluconazole, ravuconazole, voriconazole, saperconazole, eberconazole, genaconazole, clotrimazole, econazole, oxiconazole, sulconazole, terconazole, tioconazole, and posaconazole.
  • a preferred antifungal agent for the present invention is itraconazole. The molecular structure of itraconazole is shown in FIG. 2.
  • the present invention is suitable for pharmaceutical use.
  • the compositions can be administered by various routes, including but not limited to, intravenous, intracerebral, intrathecal, intralymphatic, pulmonary, intraarticular, and intraperitoneal.
  • the aqueous medium of the composition is removed to form dry particles.
  • the method to remove the aqueous medium can be any method known in the art. One example is evaporation. Another example is freeze drying or lyophilization.
  • the dry particles may then be formulated into any acceptable physical form including, but is not limited to, solutions, tablets, capsules, suspensions, creams, lotions, emulsions, aerosols, powders, incorporation into reservoir or matrix devices for sustained release (such as implants or transdermal patches), and the like.
  • the particles can be larger than 5 ⁇ m (e.g., less than 50 ⁇ m, or less than 7 ⁇ m) or less than 150 nm (e.g., less than 100 ⁇ m).
  • These particles can be administered by various routes, including but not limited to parenteral, oral, buccal, periodontal, rectal, nasal, pulmonary, transdermal, or topical.
  • modes of parenteral administration include intravenous, intra arterial, intrathecal, intraperitoneal, intraocular, intra articular, intrathecal, intracerebral, intramuscular, subcutaneous, and the like.
  • the aqueous suspension of the present invention may also be frozen to improve stability upon storage. Freezing of an aqueous suspension to improve stability is disclosed in the comrnonly assigned and co-pending U.S. Patent Application Serial No. 60/347,548, which is incorporated herein by reference and made a part hereof.
  • the antimicrobial agent is present in an amount preferably from about 0.01% to about 50% weight to volume (w/v), more preferably from about 0.05% to about 30% w/v, and most preferably from about 0.1% to about 20% w/v.
  • Suitable surfactants for coating the particles in the present invention can be selected from ionic surfactants, nonionic surfactants, biologically derived surfactants or amino acids and their derivatives.
  • Ionic surfactants can be anionic, cationic, or zwitterionic.
  • Suitable anionic surfactants include but are not limited to: alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidylglycerol, phosphatidylinosine, phosphatidylinositol, diphosphatidylglycerol, phosphatidylserine, phosphatidic acid and their salts, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.).
  • cholic acid and other bile acids e
  • phospholipids maybe used. Suitable phospholipids include, for example, phosphatidylserine, phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol, or phosphatidic acid and its salts.
  • Zwitterionic surfactants are electrically neutral but posses local positive and negative charges within the same molecule.
  • Suitable zwitterionic surfactants include but are not limited to zwitterionic phospholipids.
  • Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine (such as dimyristoyl-glycero- phosphoethanolamine (DMPE), dipalmitoyl-glycero-phosphoethanolamine (DPPE), distearoyl- glycero-phosphoethanolamine (DSPE), and dioleolyl-glycero-phosphoethanolamine (DOPE)).
  • DMPE dimyristoyl-glycero- phosphoethanolamine
  • DPPE dipalmitoyl-glycero-phosphoethanolamine
  • DSPE distearoyl- glycero-phosphoethanolamine
  • DOPE dioleolyl-glycero-phosphoethanolamine
  • phospholipids that include anionic and zwitterionic phospholipids may be employed in this invention. Such mixtures include but are not limited to lysophospholipids, egg or soybean phospholipid or any combination thereof.
  • the phospholipid, whether anionic, zwitterionic or a mixture of phospholipids, may be salted or desalted, hydrogenated or partially hydrogenated or natural semisynthetic or synthetic.
  • the phospholipid may also be conjugated with a water- soluble or hydrophilic polymer to specifically target the delivery to macrophages in the present invention. However, conjugated phospholipids may be used to target other cells or tissue in other applications.
  • a preferred polymer is polyethylene glycol (PEG), which is also known as the monomethoxy polyethyleneglycol (mPEG).
  • PEG polyethylene glycol
  • mPEG monomethoxy polyethyleneglycol
  • the molecule weights of the PEG can vary, for example, from 200 to 50,000.
  • PEG's that are commercially available include PEG 350, PEG 550, PEG 750, PEG 1000, PEG 2000, PEG 3000, and PEG 5000.
  • the phospholipid or the PEG-phospholipid conjugate may also incorporate a functional group which can covalently attach to a ligand including but not limited to proteins, peptides, carbohydrates, glycoproteins, antibodies, or pharmaceutically active agents.
  • ligand-binding functional groups include but are not limited to hexanoylamine, dodecanylamine, 1,12-dodecanedicarboxylate, thioethanol, 4-(p-maleimidophenyl)butyramide (MPB), 4-(p-maleimidomethyl)cyclohexane- carboxamide (MCC), 3-(2-pyridyldithio)propionate (PDP), succinate, glutarate, dodecanoate, and biotin.
  • MPB 4-(p-maleimidophenyl)butyramide
  • MCC 4-(p-maleimidomethyl)cyclohexane- carboxamide
  • PDP 3-(2-pyridyldithio)propionate
  • Suitable cationic surfactants include but are not limited to quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, acyl carnitine hydrochlorides,or alkyl pyridinium halides, or long-chain alkyl amines such as, for example, n-octylamine and oleylamine.
  • quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, acyl carnitine hydrochlorides,or alkyl pyridinium halides, or long-chain alkyl amines such as, for example, n-octylamine and oleylamine.
  • Suitable nonionic surfactants include: glyceryl esters, polyoxyethylene fatty alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters (Myrj), 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, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, polysaccharides including starch and starch derivatives such as hydroxyethylstarch (HES), polyvinyl alcohol, and polyvinylpyrrolidone.
  • HES hydroxyethylstarch
  • the nonionic surfactant is a polyoxyethylene and polyoxypropylene copolymer and preferably a block copolymer of propylene glycol and ethylene glycol.
  • Such polymers are sold under the tradename POLOXAMER also sometimes referred to as PLURONIC®, and sold by several suppliers including Spectrum Chemical and Ruger.
  • polyoxyethylene fatty acid esters is included those having short alkyl chains.
  • SOLUTOL® HS 15 polyethylene-660-hydroxystearate, manufactured by BASF Aktiengesellschaft.
  • Surface-active biological molecules include such molecules as albumin, casein, hirudin or other appropriate proteins.
  • Polysacchari.de biologies are also included, and consist of but are not limited to, starches, heparin and chitosans.
  • Other suitable surfactants include any amino acids such as leucine, alanine, valine, isoleucine, lysine, aspartic acid, glutamic acid, methionine, phenylalanine, or any derivatives of these amino acids such as, for example, amide or ester derivatives and polypeptides formed from these amino acids.
  • a preferred ionic surfactant is a bile salt, and a preferred bile salt is deoxycholate.
  • a preferred nonionic surfactant is a polyalkoxyether, and a preferred polyalkoxyether is Poloxamer 188.
  • Another preferred nonionic surfactant is Solutol HS 15 (polyetliylene-660-hydroxystearate).
  • Still yet another preferred nonionic surfactant is hydroxyethylstarch.
  • a preferred biologically derived surfactant is albumin.
  • the surfactants are present in an amount of preferably from about 0.001% to 5% w/v, more preferably from about 0.005% to about 5% w/v, and most preferably from about 0.01% to 5% w/v.
  • the particles are suspended in an aqueous medium further including a pH adjusting agent.
  • Suitable pH adjusting agents include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, monocarboxylic acids (such as, for example, acetic acid and lactic acid), dicarboxylic acids (such as, for example, succinic acid), tricarboxylic acids (such as, for example, citric acid), THAM (tris(hydroxymethyl)aminomethane), meglumine (N-methylglucosamine), sodium hydroxide, and amino acids such as glycine, arginine, lysine, alanine, histidine and leucine.
  • the aqueous medium may additionally include an osmotic pressure adjusting agent, such as but not limited to glycerin, a monosaccharide such as dextrose, a disaccharide such as sucrose, a trisaccharide such as raff ⁇ nose, and sugar alcohols such as mannitol, xylitol and sorbitol.
  • an osmotic pressure adjusting agent such as but not limited to glycerin, a monosaccharide such as dextrose, a disaccharide such as sucrose, a trisaccharide such as raff ⁇ nose, and sugar alcohols such as mannitol, xylitol and sorbitol.
  • the composition comprises an aqueous suspension of particles of itraconazole present at 0.01 to 50% w/v, the particles are coated with 0.001 to 5% w/v of a bile salt (e.g., deoxycholate) and 0.001 to 5% w/v polyalkoxyether (for example, Poloxamer 188), and glycerin added to adjust osmotic pressure of the formulation.
  • a bile salt e.g., deoxycholate
  • polyalkoxyether for example, Poloxamer 188
  • the composition comprises an aqueous suspension of particles of itraconazole present at about 0.01 to 50% w/v, the particles coated with about 0.001 to 5% w/v of a bile salt (for example, deoxycholate) and 0.001 to 5% polyethylene-660-hydroxystearate w/v, and glycerin added to adjust osmotic pressure of the formulation.
  • a bile salt for example, deoxycholate
  • the composition comprises an aqueous suspension of itraconazole present at about 0.01 to 50% w/v, the particles are coated with about 0.001 to 5% of polyethylene-660-hydroxystearate w/v, and glycerin added to adjust osmotic pressure of the formulation.
  • the composition comprises an aqueous suspension of itraconazole present at 0.01 to 50% w/v, the particles are coated with about 0.001 to 5% albumin w/v.
  • the processes can be separated into three general categories. Each of the categories of processes share the steps of: (1) dissolving an antifungal agent in a water miscible first organic solvent to create a first solution; (2) mixing the first solution with a second solvent of water to precipitate the antifungal agent to create a pre-suspension; and (3) adding energy to the presuspension in the form of high-shear mixing or heat to provide a stable form of the antifungal agent having the desired size ranges defined above.
  • the three categories of processes are distinguished based upon the physical properties of the antifungal agent as determined through x-ray diffraction studies, differential scanning calorimetry (DSC) studies or other suitable study conducted prior to the energy-addition step and after the energy-addition step.
  • the antifungal agent in the presuspension takes an amorphous form, a semi-crystalline form or a supercooled liquid form and has an average effective particle size.
  • the antifungal agent is in a crystalline form having an average effective particle size essentially the same as that of the presuspension (i.e., from less than about 50 ⁇ m).
  • the antifungal agent is in a crystalline form and has an average effective particle size.
  • the antifungal agent is in a crystalline form having essentially the same average effective particle size as prior to the energy-addition step but the crystals after the energy-addition step are less likely to aggregate.
  • the antifungal agent prior to the energy-addition step is in a crystalline form that is friable and has an average effective particle size. What is meant by the term “friable” is that the particles are fragile and are more easily broken down into smaller particles.
  • the organic compound is in a crystalline form having an average effective particle size smaller than the crystals of the pre-suspension.
  • the energy-addition step can be carried out in any fashion wherein the pre-suspension is exposed to cavitation, shearing or impact forces, hi one preferred form of the invention, the energy-addition step is an annealing step.
  • Annealing is defined in this invention as the process of converting matter that is thermodynamically unstable into a more stable form by single or repeated application of energy (direct heat or mechanical stress), followed by thermal relaxation. This lowering of energy may be achieved by conversion of the solid form from a less ordered to a more ordered lattice structure. Alternatively, this stabilization may occur by a reordering of the surfactant molecules at the solid-liquid interface.
  • the first process category as well as the second and third process categories, can be further divided into two subcategori.es, Method A, and B shown diagrammatically in FIG. 3 and FIG. 4, respectively.
  • the first solvent according to the present invention is a solvent or mixture of solvents in which the organic compound of interest is relatively soluble and which is miscible with the second solvent.
  • solvents include, but are not limited to water-miscible protic compounds, in which a hydrogen atom in the molecule is bound to an electronegative atom such as oxygen, nitrogen, or other Group VA, VIA and VII A in the Periodic Table of elements.
  • solvents include, but are not limited to, alcohols, amines (primary or secondary), oximes, hydroxamic acids, carboxylic acids, sulfonic acids, phosphonic acids, phosphoric acids, amides and ureas.
  • the first solvent also include aprotic organic solvents. Some of these aprotic solvents can form hydrogen bonds with water, but can only act as proton acceptors because they lack effective proton donating groups.
  • aprotic solvents is a dipolar aprotic solvent, as defined by the International Union of Pure and Applied Chemistry (IUPAC).
  • Dipolar aprotic solvents can be selected from the group consisting of: amides (fully substituted, with nitrogen lacking attached hydrogen atoms), ureas (fully substituted, with no hydrogen atoms attached to nitrogen), ethers, cyclic ethers, nitriles, ketones, sulfones, sulfoxides, fully substituted phosphates, phosphonate esters, phosphoramides, nitro compounds, and the like.
  • DMSO Dimethylsulfoxide
  • NMP N-methyl-2-pyrrolidinone
  • 2-pyrrolidinone 1,3- dimethylimidazolidinone
  • DMA dimethylacetamide
  • DMF dimethylformamide
  • HMPA hexamethylphosphoramide
  • Solvents may also be chosen that are generally water-immiscible, but have sufficient water solubility at low volumes (less than 10%) to act as a water-miscible first solvent at these reduced volumes.
  • Examples include aromatic hydrocarbons, alkenes, alkanes, and halogenated aromatics, halogenated alkenes and halogenated alkanes.
  • Aromatics include, but are not limited to, benzene (substituted or unsubstituted), and monocyclic or polycyclic arenes. Examples of substituted benzenes include, but are not limited to, xylenes (ortho, meta, or para), and toluene.
  • alkanes include but are not limited to hexane, neopentane, heptane, isooctane, and cyclohexane.
  • halogenated aromatics include, but are not restricted to, chlorobenzene, bromobenzene, and chlorotoluene.
  • halogenated alkanes and alkenes include, but are not restricted to, trichloroethane, methylene chloride, ethylenedichloride (EDC), and the like.
  • solvent classes include but are not limited to: N-methyl- 2-pyrrolidinone (also called N-methyl-2-pyrrolidone), 2-pyrrolidinone (also called 2-pyrrolidone), l,3-dimethyl-2-imidazolidinone (DMI), dimethylsulfoxide, dimethylacetami.de, carboxylic acids (such as acetic acid and lactic acid), aliphatic alcohols (such as methanol, ethanol, isopropanol, 3- pentanol, andn-propanol), benzyl alcohol, glycerol, butylene glycol (butanediol), ethylene glycol, propylene glycol, mono- and diacylated monoglycerides (such as glyceryl caprylate), dimethyl isosorbide, acetone, dimethylsulfone, dimethylformamide, 1,4-dioxane, teframethylenesulfone (sulfolane
  • a preferred first solvent is N-methyl-2-pyrrolidinone.
  • Another preferred first solvent is lactic acid.
  • the second solvent is an aqueous solvent. This aqueous solvent may be water by itself. This solvent may also contain buffers, salts, surfactant(s), water-soluble polymers, and combinations of these excipients.
  • Method A h Method A the antimicrobial agent is first dissolved in the first solvent to create a first solution.
  • the antimicrobial agent can be added from about 0.01% (w/v) to about 50% (w/v) depending on the solubility of the antimicrobial agent in the first solvent. Heating of the concentrate from about 30°C to about 100°C maybe necessary to ensure total dissolution of the antimicrobial agent in the first solvent.
  • a second aqueous solution is provided with one or more surfactants added thereto.
  • the surfactants can be selected from an ionic surfactant, a nonionic surfactant or a biologically derived surfactant set forth above.
  • the method for preparing submicron sized particles of an antimicrobial agent includes the steps of adding the first solution to the second solution.
  • the addition rate is dependent on the batch size, and precipitation kinetics for the antimicrobial agent. Typically, for a small-scale laboratory process (preparation of 1 liter), the addition rate is from about 0.05 cc per minute to about 10 cc per minute. During the addition, the solutions should be under constant agitation.
  • the method further includes the step of subjecting the pre-suspension to an annealing step to convert the amorphous particles, supercooled liquid or semicrystalline solid to a crystalline more stable solid state.
  • the resulting particles will have an average effective particles size as measured by dynamic light scattering methods (e.g., photocorrelation spectroscopy, laser diffraction, low- angle laser light scattering (LALLS), medium-angle laser light scattering (MALLS), light obscuration methods (Coulter method, for example), rheology, or microscopy (light or electron) within the ranges set forth above).
  • dynamic light scattering methods e.g., photocorrelation spectroscopy, laser diffraction, low- angle laser light scattering (LALLS), medium-angle laser light scattering (MALLS), light obscuration methods (Coulter method, for example), rheology, or microscopy (light or electron) within the ranges set forth above).
  • the energy-addition step involves adding energy through sonication, homogenization, counter current flow homogenization (e.g., the Mini DeBEE 2000 homogemzer, available from BEE Incorporated, NC, in which a jet of fluid is directed along a first path, and a structure is interposed in the first path to cause the fluid to be redirected in a controlled flow path along a new path to cause emulsification or mixing of the fluid), microfluidization, or other methods of providing impact, shear or cavitation forces.
  • the sample may be cooled or heated during this stage.
  • the annealing step is effected by homogenization.
  • the annealing may be accomplished by ultrasonication.
  • the annealing may be accomplished by use of an emulsification apparatus as described in U.S. Patent No. 5,720,551 which is incorporated herein by reference and made a part hereof.
  • an emulsification apparatus as described in U.S. Patent No. 5,720,551 which is incorporated herein by reference and made a part hereof.
  • Method B differs from Method A in the following respects.
  • the first difference is a surfactant or combination of surfactants are added to the first solution.
  • the surfactants maybe selected from ionic surfactants, nonionic surfactants, or biologically derived as set forth above.
  • a drug suspension resulting from application of the processes described in this invention may be administered directly as an injectable solution, provided Water for Injection is used in formulation and an appropriate means for solution sterilization is applied.
  • Sterilization maybe accomplished, by separate sterilization of the drug concentrate (drug, solvent, and optional surfactant) and the diluent medium (water, and optional buffers and surfactants) prior to mixing to form the pre-suspension.
  • Sterilization methods include pre-filtration first through a 3.0 micron filter followed by filtration through a 0.45-micron particle filter, followed by steam or heat sterilization or sterile filtration through two redundant 0.2-micron membrane filters.
  • a solvent-free suspension may be produced by solvent removal after precipitation. This can be accomplished by centrifugation, dialysis, diafiltration, force-field fractionation, high-pressure filtration or other separation techniques well known in the art. Complete removal of N-methyl-2-pyrrolidinone was typically carried out by one to three successive centrifugation runs; after each centrifugation the supernatant was decanted and discarded. A fresh volume of the suspension vehicle without the organic solvent was added to the remaining solids and the mixture was dispersed by homogenization. It will be recognized by others skilled in the art that other high-shear mixing techniques could be applied in this reconstitution step.
  • any undesired excipients such as surfactants may be replaced by a more desirable excipient by use of the separation methods described in the above paragraph.
  • the solvent and first excipient may be discarded with the supernatant after centrifugation or filtration.
  • a fresh volume of the suspension vehicle without the solvent and without the first excipient may then be added.
  • a new surfactant may be added.
  • a suspension consisting of drug, N-methyl-2-pyrrolidinone (solvent), Poloxamer 188 (first excipient), sodium deoxycholate, glycerol and water may be replaced with phospholipids (new surfactant), glycerol and water after centrifugation and removal of the supernatant.
  • the methods of the first process category generally include the step of dissolving the antimicrobial agent in a water miscible first solvent followed by the step of mixing this solution with an aqueous solution to form a presuspension wherein the antimicrobial agent is in an amorphous form, a semicrystalline form or in a supercooled liquid form as determined by x-ray diffraction studies, DSC, light microscopy or other analytical techniques and has an average effective particle size within one of the effective particle size ranges set forth above.
  • the mixing step is followed by an energy-addition step and, in a preferred form of the invention is an annealing step.
  • the methods of the second processes category include essentially the same steps as in the steps of the first processes category but differ in the following respect.
  • An x-ray diffraction, DSC or other suitable analytical techniques of the presuspension shows the antimicrobial agent in a crystalline form and having an average effective particle size.
  • the antimicrobial agent after the energy-addition step has essentially the same average effective particle size as prior to the energy- addition step but has less of a tendency to aggregate into larger particles when compared to that of the particles of the presuspension. Without being bound to a theory, it is believed the differences in the particle stability may be due to a reordering of the surfactant molecules at the solid-liquid interface.
  • Friable particles can be formed by selecting suitable solvents, surfactants or combination of surfactants, the temperature of the individual solutions, the rate of mixing and rate of precipitation and the like. Friability may also be enhanced by the introduction of lattice defects (e.g., cleavage planes) during the steps of mixing the first solution with the aqueous solution. This would arise by rapid crystallization such as that afforded in the precipitation step.
  • lattice defects e.g., cleavage planes
  • these friable crystals are converted to crystals that are kinetically stabilized and having an average effective particle size smaller than those of the presuspension.
  • Kinetically stabilized means particles have a reduced tendency to aggregate when compared to particles that are not kinetically stabilized, hi such instance the energy-addition step results in a breaking up of the friable particles.
  • any other known precipitation methods for preparing submicron sized particles or nanoparticles in the art can be used in conjunction with the present invention.
  • the following is a description of examples of other precipitation methods. The examples are for illustration purposes, and are not intended to limit the scope of the present invention.
  • the step of providing a multiphase system includes the steps of: (1) mixing a water immiscible solvent with the pharmaceutically effective compound to define an organic solution, (2) preparing an aqueous based solution with one or more surface active compounds, and (3) mixing the organic solution with the aqueous solution to form the multiphase system.
  • the step of mixing the organic phase and the aqueous phase can include the use of piston gap homogenizers, colloidal mills, high speed stirring equipment, extrusion equipment, manual agitation or shaking equipment, microfiuidizer, or other equipment or techniques for providing high shear conditions.
  • the crude emulsion will have oil droplets in the water of a size of approximately less than 1 ⁇ m in diameter.
  • the crude emulsion is sonicated to define a microemulsion and eventually to define a submicron sized particle suspension.
  • the step of providing a multiphase system includes the steps of: (1) mixing a water immiscible solvent with the pharmaceutically effective compound to define an organic solution; (2) preparing an aqueous based solution with one or more surface active compounds; and (3) mixing the organic solution with the aqueous solution to fomi the multiphase system.
  • the step of mixing the organic phase and the aqueous phase includes the use of piston gap homogenizers, colloidal mills, high speed stirring equipment, extrusion equipment, manual agitation or shaking equipment, microfiuidizer, or other equipment or techniques for providing high shear conditions.
  • the process includes the steps of: (1) preparing a liquid phase of a biologically active substance in a solvent or a mixture of solvents to which may be added one or more surfactants; (2) preparing a second liquid phase of a non-solvent or a mixture of non-solvents, the non-solvent is miscible with the solvent or mixture of solvents for the substance; (3) adding together the solutions of (1) and (2) with stirring; and (4) removing of unwanted solvents to produce a colloidal suspension of nanoparticles.
  • the '528 Patent discloses that it produces particles of the substance smaller than 500 nm without the supply of energy.
  • phase inversion precipitation is disclosed in U.S. Pat. Nos. 6,235,224, 6,143,211 and U.S. patent application No. 2001/0042932 which are incorporated herein by reference and made a part hereof.
  • Phase inversion is a term used to describe the physical phenomena by which a polymer dissolved in a continuous phase solvent system inverts into a solid macromolecular network in which the polymer is the continuous phase.
  • One method to induce phase inversion is by the addition of a nonsolvent to the continuous phase. The polymer undergoes a transition from a single phase to an unstable two phase mixture: polymer rich and polymer poor fractions. Micellar droplets of nonsolvent in the polymer rich phase serve as nucleation sites and become coated with polymer.
  • the '224 patent discloses that phase inversion of polymer solutions under certain conditions can bring about spontaneous formation of discrete microparticles, including nanoparticles.
  • the '224 patent discloses dissolving or dispersing a polymer in a solvent.
  • a pharmaceutical agent is also dissolved or dispersed in the solvent.
  • the agent is dissolved in the solvent.
  • the polymer, the agent and the solvent together form a mixture having a continuous phase, wherein the solvent is the continuous phase.
  • the mixture is then introduced into at least tenfold excess of a miscible nonsolvent to cause the spontaneous formation of the microencapsulated microparticles of the agent having an average particle size of between 10 nm and 10 ⁇ m.
  • the particle size is influenced by the solven nonsolvent volume ratio, polymer concentration, the viscosity of the polymer-solvent solution, the molecular weight of the polymer, and the characteristics of the solvent-nonsolvent pair.
  • the process eliminates the step of creating microdroplets, such as by forming an emulsion, of the solvent. The process also avoids the agitation and/or shear forces.
  • pH Shift Precipitation pH shift precipitation techniques typically include a step of dissolving a drug in a solution having a pH where the drug is soluble, followed by the step of changing the pH to a point where the drug is no longer soluble.
  • the pH can be acidic or basic, depending on the particular pharmaceutical compound.
  • the solution is then neutralized to form a presuspension of submicron sized particles of the pharmaceutcially active compound.
  • One suitable pH shifting precipitation process is disclosed in U.S. Pat. No. 5,665,331, which is incorporated herein by reference and made a part hereof.
  • the process includes the step of dissolving of the pharmaceutical agent together with a crystal growth modifier (CGM) in an alkaline solution and then neutralizing the solution with an acid in the presence of suitable surface-modifying surface- active agent or agents to form a fine particle dispersion of the pharmaceutical agent.
  • CGM crystal growth modifier
  • the precipitation step can be followed by steps of diafiltration clean-up of the dispersion and then adjusting the concentration of the dispersion to a desired level.
  • This process of reportedly leads to microcrystalline particles of Z-average diameters smaller than 400 nm as measured by photon correlation spectroscopy.
  • Other examples of pH shifting precipitation methods are disclosed in U.S. Pat. Nos.
  • Suitable infusion precipitation techniques are disclosed in the U.S. Pat. Nos. 4,997,454 and 4,826,689, which are incorporated herein by reference and made a part hereof.
  • a suitable solid compound is dissolved in a suitable organic solvent to fon a solvent mixture.
  • a precipitating nonsolvent miscible with the organic solvent is infused into the solvent mixture at a temperature between about -10°C and about 100°C and at an infusion rate of from about 0.01 ml per minute to about 1000 ml per minute per volume of 50 ml to produce a suspension of precipitated non-aggregated solid particles of the compound with a substantially uniform mean diameter of less than 10 ⁇ m.
  • the nonsolvent may contain a surfactant to stabilize the particles against aggregation.
  • the particles are then separated from the solvent.
  • the parameters of temperature, ratio of nonsolvent to solvent, infusion rate, stir rate, and volume can be varied according to the invention.
  • the particle size is proportional to the ratio of nonsolvent: solvent volumes and the temperature of infusion and is inversely proportional to the infusion rate and the stirring rate.
  • the precipitating nonsolvent may be aqueous or non-aqueous, depending upon the relative solubility of the compound and the desired suspending vehicle.
  • lipospheres are prepared by the steps of: (1) melting or dissolving a substance such as a drug to be delivered in a molten vehicle to form a liquid of the substance to be delivered; (2) adding a phospholipid along with an aqueous medium to the melted substance or vehicle at a temperature higher than the melting temperature of the substance or vehicle; (3) mixing the suspension at a temperature above the melting temperature of the vehicle until a homogenous fine preparation is obtained; and then (4) rapidly cooling the preparation to room temperature or below.
  • Solvent Evaporation Precipitation Solvent evaporation precipitation techniques are disclosed in U.S. Pat. No. 4,973,465 which is incorporated herein by reference and made a part hereof.
  • the '465 Patent discloses methods for preparing microcrystals including the steps of: (1) providing a solution of a pharmaceutical composition and a phospholipid dissolved in a common organic solvent or combination of solvents, (2) evaporating the solvent or solvents and (3) suspending the film obtained by evaporation of the solvent or solvents in an aqueous solution by vigorous stirring.
  • the solvent can be removed by adding energy to the solution to evaporate a sufficient quantity of the solvent to cause precipitation of the compound.
  • the solvent can also be removed by other well known techniques such as applying a vacuum to the solution or blowing nitrogen over the solution.
  • Reaction precipitation includes the steps of dissolving the pharmaceutical compound into a suitable solvent to form a solution.
  • the compound should be added in an amount at or below the saturation point of the compound in the solvent.
  • the compound is modified by reacting with a chemical agent or by modification in response to adding energy such as heat or UV light or the like to such that the modified compound has a lower solubility in the solvent and precipitates from the solution.
  • a suitable technique for precipitating by compressed fluid is disclosed in WO 97/14407 to Johnston, which is incorporated herein by reference and made a part hereof.
  • the method includes the steps of dissolving a water-insoluble drug in a solvent to form a solution.
  • the solution is then sprayed into a compressed fluid, which can be a gas, liquid or supercritical fluid.
  • a compressed fluid which can be a gas, liquid or supercritical fluid.
  • the addition of the compressed fluid to a solution of a solute in a solvent causes the solute to attain or approach supersaturated state and to precipitate out as fine particles, hi this case, the compressed fluid acts as an anti-solvent which lowers the cohesive energy density of the solvent in which the drug is dissolved.
  • the drug can be dissolved in the compressed fluid which is then sprayed into an aqueous phase.
  • the rapid expansion of the compressed fluid reduces the solvent power of the fluid, which in turn causes the solute to precipitate out as fine particles in the aqueous phase.
  • the compressed fluid acts as a solvent.
  • the particles of the present invention can also be prepared by mechanical grinding of the active agent.
  • Mechanical grinding include such techniques as jet milling, pearl milling, ball milling, hammer milling, fluid energy milling or wet grinding techniques such as those disclosed in U.S. Pat. No. 5,145,684, which is incorporated herein by reference and made a part hereof.
  • Another method to prepare the particles of the present invention is by suspending an active agent, hi this method, particles of the active agent are dispersed in an aqueous medium by adding the particles directly into the aqueous medium to derive a pre-suspension.
  • the particles are normally coated with a surface modifier to inhibit the aggregation of the particles.
  • One or more other excipients can be added either to the active agent or to the aqueous medium.
  • Example 1 Preparation of 1% Itraconazole Suspension with deoxycholic acid coating.
  • Each 100 mL of suspension contains:
  • Preparation of Replacement Solution Preparation of 4 liters of replacement solution. Fill a properly cleaned tank with WFI and agitate. Add the weighed Poloxamer 188 (Spectrum Chemical) to the measured volume of water.
  • Poloxamer 188 to the 250 mL beaker with N-methyl-2-pyrrolidinone. Stir until dissolved, then add the itraconazole. Heat and stir until dissolved. Cool the drug concentrate to room temperature and filter through a 0.2-micron filter.
  • Microprecipitation Add sufficient WFI to the surfactant solution already in the vessel supplying the homogenizer so that the desired target concentration is reached.
  • the surfactant solution is cooled, start adding the drug concentrate into the surfactant solution with continuous mixing.
  • Homogenization Slowly increase the pressure of the homogenizer until the operating pressure 10,000 psi has been reached. Homogenize the suspension with recirculation while mixing. For 2,000 mL of suspension at 50Hz, one pass should require approximately 54 seconds. Following homogenization, collect a 20-mL sample for particle size analysis. Cool the suspension.
  • wash Replacement The suspension is then divided and filled into 500-mL centrifuge bottles. Centrifuge until clean separation of sediment is observed. Measure the volume of supernatant and replace with fresh replacement solution, prepared earlier. Quantitatively transfer the precipitate from each centrifuge bottle into a properly cleaned and labeled container for resuspension (pooled sample). Resuspension of the pooled sample is performed with a high shear mixer until no visible clumps are observed. Collect a 20-mL sample for particle size analysis.
  • the suspension is then divided and filled into 500-mL centrifuge bottles. Centrifuge until clean separation of sediment is observed. Measure the volume of supernatant and replace with fresh replacement solution, prepared earlier. Quantitatively transfer the precipitate from each centrifuge bottle into a properly cleaned and labeled container for resuspension (pooled sample). Resuspension of the pooled sample is performed with a high shear mixer until no visible clumps are observed. Collect a 20-mL sample for particle size analysis.
  • Example 2 Preparation of 1% Itraconazole Nanosuspension with phospholipid coating. Each 100 mL of suspension contains: Itraconazole 1.0 g (1.0% w/v)
  • Target pH (range) 8.0 (7.5 to 8.5)
  • the surfactant solution is prepared in two phases. Phase 1 is dispersed phospholipids, whereas Phase 2 includes filtered glycerin. The two fractions are combined prior to pH adjustment.
  • Phase 1 Fill a properly cleaned vessel with approximately 700 mL of Sterile Water for Injection, USP (WFI) with agitation at 50 - 500 rpm. Increase the temperature of the filtrate to 50°C - 70°C and add the required amount of phospholipids with mixing at 50 - 500 rpm until complete dispersion is achieved. Document the time and temperature at which the phospholipids were added and at which it was dispersed. Determine the total mixing time required to disperse the phospholipids. Cool the surfactant solution to 18°C - 30°C prior to the addition of glycerin.
  • Phase 2 Fill a properly cleaned vessel with approximately 700 mL of WFI with agitation at 50 - 500 rpm. Add the required amount of glycerin at 18°C - 30°C and agitate at 50 - 500 rpm until dissolution.
  • Combined Phases Filter the glycerin solution through a 0.2 ⁇ m filter set-up into Phase 1 (at 18°C - 30°C) while mixing at 50-500 rpm. Volume is approximately 1.4 liters. Record the pH of the surfactant solution. If necessary, adjust the pH of the surfactant solution with a minimum amount of sodium hydroxide and/or hydrochloric acid to a pH of 8.0 ⁇ 0.5. Measure the volume of the surfactant solution at 18°C - 30°C using a 2-L graduated cylinder.
  • the replacement solution is prepared in two phases.
  • Phase 1 includes dispersed phospholipids
  • Phase 2 includes filtered glycerin. The two fractions are combined prior to pH adjustment.
  • Phase 1 Fill a properly cleaned vessel with approximately 1.4 liters of WFI with agitation at 50 - 500 rpm. Increase the temperature of the water to 50°C - 70°C and add the required amount of phospholipids with mixing at 50 - 500 rpm until complete dispersion is achieved. Cool the surfactant solution to 18°C - 30°C prior to the addition of glycerin.
  • Phase 2 Fill a properly cleaned vessel with approximately 1.4 L of WFI with agitation at 50 - 500 rpm. Add the required amount of glycerin and agitate at 50 - 500 rpm until dissolution.
  • Combined Phases Filter the glycerin solution through a 0.2 ⁇ m filter set-up into Phase 1 (at 18°C - 30°C) while mixing at 50 - 500 rpm. Dilute to volume with Water for Injection to 4.0 L using a graduated cylinder. Record the pH of the wash solution. If necessary, adjust the pH of the wash solution with the minimum amount sodium hydroxide and/or hydrochloric acid to a pH of 8.0 + 0.5.
  • V 2,000 mL - Volume of Drug Concentrate - Volume of Surfactant Solution
  • each syringe needle assembly using a syringe pump. Position the outlet of the needle on top of the vessel.
  • the surfactant solution is not more than 10°C
  • the concentrate should be added so that the drops hit the point of highest shear, at the bottom of the vortex.
  • the rate of addition should be approximately 2.5 mL/min.
  • An Avestin C160 homogenizer was used. Slowly increase the pressure of the homogenizer until the operating pressure 10,000 psi has been reached. Homogemze the suspension for 20 passes (18 minutes) with recirculation while mixing at 100 - 300 rpm and maintaining the suspension temperature below 70°C. For 2,000 mL of suspension at 50 Hz, one pass requires approximately 54 seconds. Following homogenization, collect a 20 mL sample in a 50 mL glass vial for particle size analysis. Cool the suspension to not more than 10°C.
  • the suspension is then divided and filled into 500-mL centrifuge bottles.
  • the total centrifuge time is 60 min at not more than 10°C. Measure the volume of supernatant and replace with fresh replacement solution.
  • spatula(s) quantitatively transfer the precipitant from each centrifuge bottle into a properly cleaned and labeled container for resuspension (pooled sample). Resuspension of the pooled sample is performed with a high shear mixing until no visible clumps are observed. Second Washing and Centrifuging Step
  • the suspension is then divided and filled into 500-mL centrifuge bottles. Set the speed for the centrifuge at 11 ,000 rpm using the rotor SLA-3000, Superlite equivalent to approximately 20,434 g. The total centrifuge time is 60 min at not more than 10°C. Measure the volume of 5 supernatant and replace with fresh replacement solution. Using spatula(s), quantitatively transfer the precipitant from each centrifuge bottle into a properly cleaned and labeled container for resuspension (pooled sample). Resuspension of the pooled sample is performed under high-shear mixing until no visible clumps are observed. Record the pH of the suspension. If necessary, adjust the pH of the suspension with the minimum amount sodium hydroxide and/or hydrochloric 0 acid to a pH of 8.0 + 0.5.
  • Example 3 Other formulations of Itraconazole Suspensions
  • compositions of itraconazole suspensions with different combinations of the 5 surfactants can also be prepared using the method described in Example 1 or Example 2.
  • Table 1 summarizes the compositions of the surfactants of the various itraconazole suspensions.
  • Example 4 Comparison of the acute toxicity between commercially available itraconazole formulation (SPORANOX®) and the suspension compositions of the present invention.
  • SPORANOX® The acute toxicity of the commercially available itraconazole formulation (SPORANOX®) is compared to that of the various 1% itraconazole formulations in the present invention as listed in Table 1.
  • SPORANOX® is available from Janssen Pharmaceutical Products, L.P. It is available as a 1% intravenous (IV.) solution solubilizedby hydroxypropyl- ⁇ - cyclodextrin. The results are shown in Table 2 with the maximum tolerated dose (MTD) indicated for each formulation.
  • Example 5 Pharaiacokinetic comparison of SPORANOX® vs. suspension formulation of itraconazole.
  • the time points were as follows: 0.03, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, 96, 144, 192, 288, and 360 hours (SPORANOX ® Injection only to 192 hours).
  • Blood was collected into tubes with EDTA and centrifuged at 3200 rpm for 15 minutes to separate plasma. The plasma was stored frozen at -70°C until analysis.
  • concentration of the parent itraconazole and the metabolite hydroxy-itraconazole were determined by high- performance liquid chromatography (HPLC).
  • PK Pharmacokinetic
  • Table 3 provides a comparison of the plasma pharmacokinetic parameters determined for each itraconazole formulation.
  • Plasma itraconazole was no longer detected at 24 hours for SPORANOX ® Injection at 5 mg/kg, at 48 hours for SPORANOX ® Injection at 20 mg/kg, and at 96 hours for Formulations 1 and B.
  • Plasma hydroxy-itraconazole was initially detected at 0.25 hours for SPORANOX ® Injection and Formulations 1 and B.
  • Plasma hydroxy-itraconazole was initially detected at 0.25 hours for SPORANOX® Injection at 5 and 20 mg/kg and Formulations 1 and ;B at 20 mg/kg, Hydroxy-itraconazole was no longer detected at 48 hours for SPORANOX ® Injection at 5mg/kg, at 96 hours for SPORANOX ® Injection at 20 mg/kg, and at 144 hours for Formulations 1 and B.
  • Table 3 Comparison of Plasma Pharmacokinetic Parameters for Sporanox and a Suspension Formulation After IV Administration in Rats
  • FIG. 5 compares the pharmacokinetics (PK) of SPORANOX® with Formulation 1 suspension of itraconazole particles. Because, as shown above, the present suspension formulation is less toxic than Sporanox®, it was administered at higher amounts in this equitoxic experiment. Sporanox was dosed at 20 mg/kg and Formulation 1 at 80 mg/kg. The SPORANOX® decreases in plasma concentration relatively quickly, over 20 hours. The nanosuspension plasma levels remain elevated for approximately 3-4 times longer. The nanosuspension exhibits an initial minimum at 30 minutes in the plasma level.
  • PK pharmacokinetics
  • the metabolite persists in circulation for a much longer time than is the case with the metabolite for the SPORANOX® formulation.
  • the AUC area under the blood concentration vs time curve
  • the nanosuspension is at least as bioavailable as SPORANOX®.
  • Example 6 Acute Toxicity Of Fast Dissolving Nanosuspensions Additional experiments were performed. Itraconazole nanosuspensions were formulated differently, so as to dissolve much more readily in blood. This was accomplished by making the particles either smaller or amorphous, or both. These acute toxicity of these formulations is described for formulation entries 14331-1 and 14443-1 in Table 1. In contrast to the slowly dissolving nanosuspensions, the fast dissolving nanosuspension caused death in the animals at much lower levels, similar to what was found with SPORANOX®. Since these fast dissolving nanosuspensions did not contain cyclodextrin, it is clear that this excipient was not responsible for the toxicity.
  • albicans/ml saline were intravenously treated with Formulation 1 or B each at 20, 40, or 80 mg/kg once every other day for ten days, beginning the day of inoculation.
  • the SPORANOX ® Injection, Formulation 1, and Formulation B treatment rats were terminated 11 days after the C. albicans inoculation and the kidneys were collected, weighed and cultured for determination of C. albicans colony counts and itraconazole and hydroxy-itraconazole concentration. Kidneys were collected from untreated control rats when a moribund condition was observed or when an animal had a 20% body weight, hi addition, body weights were measured periodically during the course of each study.
  • Formulation 1 40 mg/kg, (2.5 x 10 6 cfu/ml) 0 0/6 18.5 6.0
  • Formulation 1 80 mg/kg, (2.5 x 10 6 cfu/ml) 0 0/6 41.2 6.2
  • Formulation B 20 mg/kg, (2.5 x 10 6 cfu/ml) 8.9 4/6 2.5 2.5
  • Formulation B 40 mg/kg, (2.5 x 10 6 cfu ml) 0 0/6 7.8 4.0
  • Formulation B 80 mg/kg, (2.5 x 10 6 cfu/ml) 0 0/6 21.3 4.6
  • a nanosuspension formulation of an anti-fungal agent was shown to be less toxic than a conventional totally soluble formulation of the same drug. Thus, more of the drug could be administered without eliciting adverse effects. Because the nanoparticles of the drug did not immediately dissolve upon injection, they were trapped in a depot store in the liver and spleen. These acted as prolonged release sanctuaries, permitting less frequent dosing. The greater dosing that could be administered permitted greater drug levels to be manifested in the target organs, in this case, the kidney ( Figure 8). The greater drug levels in this organ led to a greater kill of infectious organisms. ( Figure 9).
  • Example 9 Prophetic examples of other triazole antifungal agents
  • the present invention contemplates preparing a 1%> suspension of submicron- or micron size of a triazole antifungal agent using the method described in Example lor Example 2 and the fomiulations described in Example 3 with the exception that the antifungal agent is a triazole antifungal agent other than itraconazole.
  • triazole antifungal agents examples include, but are not limited to, ketoconazole, miconazole, fluconazole, ravuconazole, voriconazole, saperconazole, eberconazole, genaconazole, clotrimazole, econazole, oxiconazole, sulconazole, terconazole, tioconazole, and posaconazole.
  • Example 10 Prophetic example of a non-triazole antifungal agent
  • the present invention contemplates preparing a 1 % suspension of submicron- or micron size non-triazole antifungal agent using the method described in Example 1 or Example 2 and the formulations described in Example 3 with the exception that the antifungal agent is amphotericin B, nystatin, terbinafine, anidulafungin, or flucytosine instead of itraconazole.

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Abstract

L'invention concerne des compositions à base de particules de dimension micronique à sous-micronique d'agents antimicrobiens. Plus particulièrement, cette invention concerne une composition à base d'agents antimicrobiens qui rend l'agent efficace contre des organismes normalement considérés comme étant résistant à cet agent. La composition contient une suspension aqueuse à base de particules de dimension micronique et sous-micronique contenant l'agent revêtu d'au moins un tensioactif choisi dans le groupe constitué de: tensioactifs ioniques, tensioactifs non ioniques, tensioactifs biologiquement dérivés, acides aminés et leurs dérivés. Ces particules possèdent une dimension particulaire moyenne pondérée en fonction du volume de moins de 5 νm, mesurée par diffractométrie laser.
PCT/US2004/013268 2003-04-29 2004-04-29 Formulation destinee a rendre un medicament antimicrobien efficace contre des organismes normalement consideres comme etant resistant a ce medicament WO2004096180A1 (fr)

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EP04760446A EP1617818A1 (fr) 2003-04-29 2004-04-29 Formulation destinee a rendre un medicament antimicrobien efficace contre des organismes normalement consideres comme etant resistant a ce medicament
BRPI0409929-0A BRPI0409929A (pt) 2003-04-29 2004-04-29 formulação para tornar uma droga antimicrobiana potente contra organismos normalmente considerados serem resistentes à droga
CA002523151A CA2523151A1 (fr) 2003-04-29 2004-04-29 Formulation destinee a rendre un medicament antimicrobien efficace contre des organismes normalement consideres comme etant resistant a ce medicament
MXPA05011607A MXPA05011607A (es) 2003-04-29 2004-04-29 Formulacion para producir un medicamento antimicrobinao potente contra organismos normalmente considerados resistentes al medicamento.
JP2006513447A JP2006525345A (ja) 2003-04-29 2004-04-29 薬物耐性であると通常みなされている生物に対して抗菌薬物に効力を与える処方物
AU2004234003A AU2004234003A1 (en) 2003-04-29 2004-04-29 Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug
NO20055616A NO20055616L (no) 2003-04-29 2005-11-28 Formulering som gir et antimikrobielt medikament som er virksomt mot organismer som normalt er resistente mot medikamentet

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Cited By (3)

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WO2007143390A1 (fr) * 2006-05-30 2007-12-13 Elan Pharma International Ltd. Formulations de posaconazole nanoparticulaire
KR100858508B1 (ko) 2005-12-23 2008-09-12 주식회사 삼양사 아졸계 항진균제를 포함하는 조성물 및 그의 제조방법
EP2230906A1 (fr) * 2007-12-13 2010-09-29 Elan Pharma International Limited Compositions d'anidulafungine nanoparticulaires et leurs procédés de fabrication

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FR2922107B1 (fr) * 2007-10-10 2010-02-26 Aventis Pharma Sa Nouvelles compositions a base de taxoides
RS56687B1 (sr) * 2010-12-30 2018-03-30 Aktsionernoye Obshchestvo Nauchnyi Tsentr Protivoinfektsionnyh Preparatov Antibakterijsko sredstvo za tretman infektivnih bolesti bakterijskog porekla
CN102085176A (zh) * 2010-12-31 2011-06-08 江苏中丹制药有限公司 一种纳米级伊曲康唑外用制剂、其制备方法及其用途
CN102106832A (zh) * 2011-02-12 2011-06-29 华中师范大学 酮康唑纳米混悬剂冻干粉及其制备方法
JP6962655B2 (ja) * 2015-07-07 2021-11-05 ライフラフト バイオサイエンシーズ，インコーポレイテッド 低ナトリウムポロキサマー１８８製剤および使用方法

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WO2001021154A2 (fr) * 1999-09-21 2001-03-29 Rtp Pharma Inc. Compositions particulaires, a surface modifiee, de substances biologiquement actives
WO2002055059A2 (fr) * 2000-12-22 2002-07-18 Baxter Int Preparation de suspensions de particules submicroniques
US20030072807A1 (en) * 2000-12-22 2003-04-17 Wong Joseph Chung-Tak Solid particulate antifungal compositions for pharmaceutical use
US20030077329A1 (en) * 2001-10-19 2003-04-24 Kipp James E Composition of and method for preparing stable particles in a frozen aqueous matrix

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WO1999061001A1 (fr) * 1998-05-29 1999-12-02 Rtp Pharma Inc. Compositions de microparticules a protection thermique et procede de sterilisation a la vapeur apres conditionnement
WO2001021154A2 (fr) * 1999-09-21 2001-03-29 Rtp Pharma Inc. Compositions particulaires, a surface modifiee, de substances biologiquement actives
WO2002055059A2 (fr) * 2000-12-22 2002-07-18 Baxter Int Preparation de suspensions de particules submicroniques
US20030072807A1 (en) * 2000-12-22 2003-04-17 Wong Joseph Chung-Tak Solid particulate antifungal compositions for pharmaceutical use
US20030077329A1 (en) * 2001-10-19 2003-04-24 Kipp James E Composition of and method for preparing stable particles in a frozen aqueous matrix

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100858508B1 (ko) 2005-12-23 2008-09-12 주식회사 삼양사 아졸계 항진균제를 포함하는 조성물 및 그의 제조방법
WO2007143390A1 (fr) * 2006-05-30 2007-12-13 Elan Pharma International Ltd. Formulations de posaconazole nanoparticulaire
JP2009538927A (ja) * 2006-05-30 2009-11-12 エラン ファーマ インターナショナル，リミティド ナノ粒子状のポサコナゾール製剤
EP2343053A1 (fr) * 2006-05-30 2011-07-13 Elan Pharma International Limited Compositions de posaconazole nanoparticulaire
EP2230906A1 (fr) * 2007-12-13 2010-09-29 Elan Pharma International Limited Compositions d'anidulafungine nanoparticulaires et leurs procédés de fabrication
EP2230906A4 (fr) * 2007-12-13 2012-03-07 Elan Pharma Int Ltd Compositions d'anidulafungine nanoparticulaires et leurs procédés de fabrication

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NO20055616D0 (no) 2005-11-28
MXPA05011607A (es) 2005-12-15
ZA200508467B (en) 2006-09-27
CA2523151A1 (fr) 2004-11-11
JP2006525345A (ja) 2006-11-09
BRPI0409929A (pt) 2006-04-25

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