EP1617818A1 - Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug - Google Patents

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

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Publication number
EP1617818A1
EP1617818A1 EP04760446A EP04760446A EP1617818A1 EP 1617818 A1 EP1617818 A1 EP 1617818A1 EP 04760446 A EP04760446 A EP 04760446A EP 04760446 A EP04760446 A EP 04760446A EP 1617818 A1 EP1617818 A1 EP 1617818A1
Authority
EP
European Patent Office
Prior art keywords
composition
agent
surfactant
acid
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04760446A
Other languages
German (de)
English (en)
French (fr)
Inventor
Barrett E. Rabinow
Randy White
Chong-Son Sun
Joseph Chung Tak Wong
James E. Kipp
Mark J. Doty
Christine L. Rebbeck
Pavlos Papadopoulos
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Baxter International Inc
Original Assignee
Baxter International Inc
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Filing date
Publication date
Application filed by Baxter International Inc filed Critical Baxter International Inc
Publication of EP1617818A1 publication Critical patent/EP1617818A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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 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
  • 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.
  • the present invention is suitable for pharmaceutical use.
  • 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 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. 3 is a schematic diagram of Method A of the microprecipitation process used in the present invention to prepare the suspension
  • 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;
  • 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.
  • 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 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.
  • 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 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 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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).
  • 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.
  • 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®.
  • 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 B 20 mg/kg, (2.5 x 10 6 cfu/ml) 8.9 4/6 2.5 2.5
  • 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).

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SG170047A1 (en) * 2006-05-30 2011-04-29 Elan Pharma Int Ltd Nanoparticulate posaconazole formulations
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