JP2006525345A - Formulations that give antibacterial drugs efficacy against organisms normally considered to be drug resistant - Google Patents

Abstract

The present invention relates to a composition of submicron sized to micron sized particles of an antimicrobial agent. More specifically, the present invention relates to antibacterial agent compositions that enable the agent to be effective against organisms that are normally considered resistant to the agent. The composition comprises an agent covered with at least one surfactant selected from the group consisting of ionic surfactants, nonionic surfactants, biologically derived surfactants, and amino acids and derivatives thereof. Including aqueous suspensions of submicron to micron sized particles. The particles have an average particle size weighted with a volume of less than 5 μm as measured by laser diffraction analysis.

Description

(Cross-reference for related applications)
This application claims priority from provisional patent application No. 60 / 466,354, filed Apr. 29, 2003.
(Background of the Invention)
(Technical field)
The present invention relates to an antibacterial agent composition. More particularly, the present invention relates to antimicrobial formulations that provide drug efficacy against organisms that are normally considered resistant to the drug.

(Background of the Invention)
Based on in vitro antimicrobial susceptibility testing, the level of antimicrobial drug that is considered effective against a particular organism can be determined. This is called the MIC (minimum growth inhibitory concentration) of the drug. On the other hand, safety studies determine the amount of drug that can be safely given to a patient or test animal. The maximum amount of this drug that can be administered determines the biological maximum exposure to the host animal, the area under the curve (AUC) plotting drug concentration versus time, and the peak plotting drug concentration versus time Usually measured by height, peak height plotting tissue level against time, etc. Instantaneous tissue or plasma levels in in vivo experiments can be compared to the MIC value to determine the relative potency of drug levels that can be reached in biological fluids. The actual comparison must be corrected for plasma protein binding since only free drug level is an important parameter. This is because in this state, the drug can freely diffuse through the biological membrane.

As a result of such an analysis, the clinical literature identifies which drugs can generally be used for a particular organism strain, more precisely to a particular organism strain with a MIC value lower than a particular level. Was established. By way of example, the antibacterial agent itraconazole is effective against Candida albicans strains with an MIC of greater than 8 for this drug (eg C. Albicans strain c43 (ATCC number 201794 for SPORANOX®) itraconazole, MIC ₈₀ = 16 μg / ml) Is not considered. These strains of Candida albicans are considered resistant to itraconazole. This presupposes a standard dosage level of this drug that can be administered.

  However, if a method capable of substantially increasing the amount of antimicrobial drug (eg, itraconazole) that can be administered is possible, it may be possible to treat infections that have previously been deemed impossible to treat with this agent. Such a method is possible by formulating the drug as a nanosuspension. It has been found that submicron sized drug crystals stabilized by a surfactant coating, in some cases, do not dissolve immediately when injected into the bloodstream. Instead, they are captured by established spleen and liver macrophages. From this protected area, the drug is slowly released over days. This is in contrast to traditional dissolved drugs, which reduce blood levels at a much faster rate when injected.

  An example of an antibacterial agent conventionally formulated to increase the solubility of the drug is the triazole antifungal agent itraconazole (FIG. 2). Itraconazole is effective against systemic mycosis, especially aspergillosis and candidiasis. New oral and intravenous preparations of itraconazole have been prepared to overcome the bioavailability problems associated with lack of solubility. For example, the bioavailability of itraconazole is increased when formulated with hydroxypropyl-β-cyclodextrin (a carrier oligosaccharide that forms an inclusion complex with the drug and thereby increases water solubility). Such commercial preparations are known under the trade name SPORANOX® injection solution and are described in JANSEN PHARMACEUTICAL PRODUCTS, L.A. P. Was created by. The drugs are currently manufactured by Abbott Labs and marketed by Ortho Biotech, Inc.

  Intravenous itraconazole may be useful in selected clinical situations. Examples are hydrochloric acid deficiency in AIDS patients, patients who do not have the ability to efficiently absorb oral medications due to concurrent treatment with other drugs, or in critically ill patients who cannot take oral medications. The current commercial product, SPORANOX® Injection, is available in 25 mL glass vials containing 10 g of hydroxypropyl-β-cyclodextrin (referred to as “HPBCD”) and 250 mg of itraconazole. These vials are diluted with 50 mL of 0.9% saline prior to use. The resulting cyclodextrin concentration exceeds 10% (w / v) of the reconstituted product. HPBCD has traditionally been considered safe for injection, but at concentrations as high as 10%, it has been reported in animal models to induce significant changes in endothelial tissue (Dunker G .; Reichelt J., Effects of the pharmaceutical cosolvent hydropropylpropyl-beta-cycloidrin on porcine conceal endotherm. Graefe's Arge.

  Other excipients are often used to formulate poorly water soluble drugs for intravenous injection. For example, paclitaxel (Taxol®, produced by Bristol-Myers Squibb) is 52.7% (w / v) Cremophor® EL (polyoxyethylene castor oil) and 49.7% (v / V) dehydrated alcohol USP. Administration of Cremophor® EL can cause undesirable hypersensitivity reactions (Volcheck, GW, Van Dellen, RG Anaphylaxis to intracranogenic and tolerance to oral cyclosporine. Allergy, Asthma, and Immunology, 1998, 80, 159-163; Singla AK; Garg A .; Agarwal D., Palitaxel and its formations, 2nd International Journal, 35/200. 2,179～192).

  The present invention discloses compositions that make antimicrobial drugs more effective based on their physical and biological properties than the unformulated state or their existing formulations. The approach used is to formulate the antimicrobial agent as a nanosuspension. This allows the use of improved formulations that treat microorganisms that were previously considered resistant to unprescription drugs. Traditional formulation approaches attempt to increase only solubility and bioavailability. Such approaches include pH changes, salt form modifications, the use of organic modifiers or the use of cyclodextrins. The approach disclosed in the present invention results in improved efficacy over that which can be achieved by altering the kinetic characteristics of the drug, allowing greater dosing, and improving only solubility and bioavailability. Can be mentioned. Acute toxicity studies have demonstrated that much more drug can be administered to animals than when formulated as nanosuspensions. Thus, more drugs are available in the target tissue so that they are effective.

(Summary of the Invention)
The present invention relates to a composition of an aqueous suspension of submicron to micron sized particles of an antimicrobial agent that makes the drug effective against organisms that are normally considered resistant to the drug. The composition is coated with at least one surfactant selected from the group consisting of ionic surfactants, nonionic surfactants, biologically derived surfactants, and amino acids and their derivatives. Examples include aqueous suspensions of submicron to micron sized particles containing the drug. The particles have an average particle size weighted with a volume of less than 5 μm as measured by light scattering (HORIBA) or microscopic measurements. More preferably, the particles should be smaller than about 1 micron, and most preferably within the range of about 150 nm to about 1 micron or a combination in between.

  The present invention is suitable for pharmaceutical use.

  In one embodiment of the invention, the antibacterial agent is an antifungal agent. In a preferred embodiment, the antifungal agent is a triazole antifungal agent. In yet another embodiment of the present invention, the triazole antifungal agent comprises itraconazole, ketoconazole, miconazole, fluconazole, ravconazole, voriconazole, saperconazole, eberconazole, olconazole, genoconazole, Selected from trimazole, econazole, oxyconazole, sulconazole, terconazole, thioconazole and posaconazole. In a preferred embodiment of the invention, the antifungal agent is itraconazole.

  In the present invention, suitable surfactants for covering the particles may be selected from ionic surfactants, nonionic surfactants, biologically derived surfactants or amino acids and their derivatives.

  In a further preferred embodiment, the composition of the present invention is prepared by a microprecipitation method comprising the following steps: (i) dissolving the antimicrobial agent in a water-miscible first solvent to form a solution (Ii) mixing the solution with a second solvent that is water soluble to define a pre-suspension; and (iii) applying energy to the pre-suspension to average effective less than 5 μm Forming particles having a particle size; more preferably less than about 1 micron, most preferably from about 150 nm to about 1 micron or any range or combination thereof, wherein the solubility of the antifungal agent is The first solvent or the second solvent is larger than that of the second solvent in one solvent, and includes a nonionic surfactant, an ionic surfactant, a biologically derived surfactant, and an amino acid and its solvent. Comprising one or more surfactants selected from the group consisting et derivatives.

  The present invention also provides a drug coated with at least one surfactant selected from the group consisting of nonionic surfactants, ionic surfactants, biologically derived surfactants and amino acids and derivatives thereof. The present invention relates to a method of conferring an antibacterial agent against an organism that is normally considered resistant to the drug by containing the drug as an aqueous suspension of submicron to micron sized particles.

  The present invention relates to the aqueous suspension of particles from submicron to micron size containing a drug coated with at least one surfactant, by infecting a subject with organisms normally considered resistant to antibacterial agents. Further relates to a method of treating a subject's infection by administering to a subject the above agent formulated as a suspension, the surfactant comprising: an ionic surfactant, a nonionic surfactant , Selected from the group consisting of biologically derived surfactants and amino acids and their derivatives.

  These and other aspects and features of the invention will be discussed with reference to the accompanying drawings and specification.

(Detailed description of preferred embodiments)
While the present invention is capable of many different forms of embodiment, the present disclosure should be construed as illustrative of the principles of the invention and to limit the invention to the specific embodiments illustrated. With the understanding that it is not intended, specific embodiments of the invention are shown in the drawings and are described in detail herein.

  The present invention relates to an antibacterial agent composition that allows the agent to be effective against organisms normally considered to be resistant to the agent. The composition comprises an ionic surfactant, a nonionic surfactant, a biologically derived surfactant, and at least one surfactant selected from the group consisting of amino acids and derivatives thereof. Containing an aqueous suspension of particles from submicron to micron size. The composition disclosed in the present invention results in a change in the pharmacokinetic characteristics of the drug, which change allows for much higher dosages, resulting in only improved solubility and bioavailability. Results in improved efficacy over what can be achieved. It has been found that submicron sized drug crystals stabilized by a surfactant coating do not readily dissolve upon infusion into the bloodstream in some cases. Instead, the drug is captured by spleen and liver fixed macrophages. From this sanctuary, the drug is released slowly over a long period of time. Acute toxicity studies have shown that more drugs can be administered to animals or humans when formulated as nanosuspensions. Thus, more of the above drugs can be used in the target organ to exert efficacy.

  The particles in the present invention have an average particle size weighted with a volume of less than 5 μm as measured by light scattering (HORIBA) or microscopic measurements. More preferably, the particles are less than about 1 micron, and most preferably about 150 nm to about 1 micron, or any range or combination of ranges therein. The composition can be administered to a subject to treat an infection by an organism that would normally be resistant to the agent.

  The antibacterial agent is preferably a poorly water soluble organic compound. What is meant by “poorly water soluble” is that the compound has a water solubility of less than 10 mg / ml, and preferably less than 1 mg / ml. A preferred type of antibacterial agent is an antifungal agent. A preferred antifungal agent is a triazole antifungal agent having the general molecular formula shown in FIG. Examples of triazole antifungal agents include itraconazole, ketoconazole, miconazole, fluconazole, ravconazole, voriconazole, saperconazole, eberconazole, genaconazole, genaconazole, , Sulconazole, terconazole, thioconazole and posaconazole, but are not limited thereto. A preferred antifungal agent for the present invention is itraconazole. The molecular structure of itraconazole is shown in FIG.

  The present invention is suitable for pharmaceutical use. The compositions described above can be administered by a variety of routes including intravenous, intracerebral, intrathecal, intralymphatic, pulmonary, intraarticular, and intraperitoneal routes. For example, but not limited to. In an embodiment of the present invention, the aqueous medium of the composition is removed to form dry particles. The method for removing the aqueous medium can be any method known in the art. One example is evaporation. Another example is freeze drying or freeze drying. The dried particles can then be formulated into any acceptable physical form, including solutions, tablets, capsules, suspensions, creams, lotions, emulsions, aerosols, powders, sustained release For example, but not limited to incorporation into a reservoir or matrix device (eg, an implant or transdermal patch).

  If the particles do not need to be captured by the macrophages, the particles can be greater than 5 μm (eg, less than 50 μm, or less than 7 μm), or less than 150 nm (eg, less than 100 μm). These particles can be administered by a variety of routes including parenteral route, oral route, buccal route, periodontal route, rectal route, nasal route, pulmonary route, transdermal route, or topical route. But not limited to these routes. Parenteral administration forms include intravenous administration, intraarterial administration, intrathecal administration, intraperitoneal administration, intraocular administration, intraarticular administration, intrathecal administration, intracerebral administration, intramuscular administration, and subcutaneous administration. Etc.

  The aqueous suspensions of the present invention can also be frozen during storage to improve stability. Freezing an aqueous suspension to improve stability is assigned to the same person and is co-pending US patent application Ser. No. 60 / 347,548 (incorporated herein by reference) Part of).

  In an embodiment of the present invention, the antimicrobial agent is preferably present in an amount of from about 0.01% by volume to about 50% by weight to volume (w / v)%, more preferably from about 0.05% to It is present at about 30% (w / v), and most preferably at about 0.1% to about 20% (w / v).

  Suitable surfactants for coating the particles in the present invention may be selected from ionic surfactants, nonionic surfactants, biologically derived surfactants, or amino acids and derivatives thereof. The ionic surfactant can be anionic, cationic, zwitterionic.

  Suitable anionic surfactants include: alkyl sulfonate, alkyl phosphate, alkyl phosphonate, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecyl sulfate, polyoxyethylene sodium sulfate, sodium alginate, Dioctyl sodium sulfosuccinate, phosphatidylglycerol, phosphatidylinosin, phosphatidylinositol, diphosphatidylglycerol, phosphatidylserine, phosphatidic acid and its salts, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g. cholic acid, deoxycholic acid, glycochol) Acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (for example, sodium deoxycholate) It is, but is not limited thereto. Phospholipids can be used as an anionic surfactant. Suitable phospholipids include, for example, phosphatidylserine, phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol, or phosphatidic acid and salts thereof.

  Zwitterionic surfactants are electrically neutral but have 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 (eg, dimyristoyl-glycero-phosphoethanolamine (DMPE), dipalmitoyl-glycero-phosphoethanolamine (DPPE), distearoyl-glycero) -Phosphoethanolamine (DSPE), and dioleolyl-glycero-phosphoethanolamine (DOPE)). Mixtures of phospholipids including anionic and zwitterionic phospholipids can be utilized in the present invention. Such a mixture includes, but is not limited to, lysophospholipid, egg phospholipid or soybean phospholipid or any combination thereof. The above phospholipids (whether anionic, zwitterionic or a mixture of phospholipids) may or may not be salted, hydrogenated or partially hydrogenated. Or may be a natural semi-synthetic product or a synthetic product. The phospholipid can also be conjugated with a water-soluble or hydrophilic polymer to specifically target delivery to macrophages in the present invention. However, conjugated phospholipids can also be used to target other cells or tissues in other applications. A preferred polymer is polyethylene glycol (PEG), also known as monomethoxypolyethylene glycol (mPEG). The molecular weight of this PEG can vary, for example, from 200 to 50,000. Some commonly used PEGs that are commercially available include PEG350, PEG550, PEG750, PEG1000, PEG2000, PEG3000, and PEG5000. The phospholipid or the PEG-phospholipid conjugate can also incorporate a functional group that can be covalently bound to a ligand, including a protein, peptide, carbohydrate, glycoprotein, antibody, or pharmaceutically active agent. However, it is not limited to these. These functional groups can conjugate the above ligands through, for example, amide bond formation, disulfide formation or thioether formation, or biotin / streptavidin binding. Examples of the ligand-linked functional group include hexanoylamine, dodecanylamine, 1,12-dodecanedicarboxylate, thioethanol, 4- (p-maleimidophenyl) butylamine (MPB), 4- (p-maleimide) Methyl) cyclohexane-carboxamide (MCC), 3- (2-pyridyldithio) propionate (PDP), succinic acid, glutarate, dodecanoate, and biotin, but are not limited to these.

  Suitable cationic surfactants include quaternary ammonium compounds (eg benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, acylcarnitine hydrochloride, or alkylpyridinium halides) or long chain alkyls Examples include, but are not limited to, amines such as n-octylamine and oleylamine.

  Suitable nonionic surfactants include: glyceryl esters, polyoxyethylene fatty alcohol esters (Macrogor and Brij), polyoxyethylene sorbitan fatty acid esters (polysorbate), polyoxyethylene fatty acid esters (Myrj), sorbitan esters (Span) , Glycol monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, arylalkyl polyether alcohol, polyoxyethylene-polyoxypropylene copolymer (poloxamer), poloxamine, methylcellulose , Hydroxymethylcellulose, hydroxypropylcellulose, hydride Carboxymethyl cellulose, amorphous cellulose, starch and starch derivatives (e.g., hydroxyethyl starch (HES)) polysaccharides including, polyvinyl alcohol, and polyvinylpyrrolidone and the like. In a preferred form of the invention, the nonionic surfactant is a copolymer of polyoxyethylene and polyoxypropylene, and preferably a block copolymer of propylene glycol and ethylene glycol. Such polymers are sold under the trade name POLOXAMER (sometimes also referred to as PLURONIC®) and are sold by several vendors including Spectrum Chemical and Ruger. Polyoxyethylene fatty acid esters include those having short alkyl chains. One example of such a surfactant is SOLUTOL® HS 15, polyethylene-660-hydroxystearate manufactured by BASF Aktiengesellschaft.

  Surfactant biological molecules include molecules such as albumin, casein, hirudin, or other suitable proteins. Polysaccharide biologics are also included and are not limited to starch, heparin, and chitosan. Other suitable surfactants include any amino acid (eg, leucine, alanine, valine, isoleucine, lysine, aspartic acid, glutamic acid, methionine, phenylalanine), or any derivative of these amino acids (eg, an amide derivative or Ester derivatives and polypeptides formed by these amino acids).

  A preferred ionic surfactant is a bile salt, and a preferred bile salt is deoxycholate. A preferred nonionic surfactant is a polyalkoxy ether and a preferred polyalkoxy ether is Poloxamer 188. Another preferred nonionic surfactant is Solutol HS 15 (polyethylene-660-hydroxystearate). Yet another preferred nonionic surfactant is hydroxyethyl starch. A preferred biologically derived surfactant is albumin.

  In another embodiment of the invention, the surfactant is preferably present in an amount of about 0.001% to 5% w / v, more preferably about 0.005% to about 5% w / v. And most preferably present in an amount of about 0.01% to 5% w / v.

  In a preferred embodiment of the invention, the above particles are suspended in an aqueous medium further comprising a pH adjusting agent. Suitable pH adjusters include hydrochloric acid, sulfuric acid, phosphoric acid, monocarboxylic acids (such as acetic acid and lactic acid), dicarboxylic acids (such as succinic acid), tricarboxylic acids (such as citric acid). N), THAM (tris (hydroxymethyl) aminomethane), meglumine (N-methylglucosamine), sodium hydroxide, and amino acids such as glycine, arginine, lysine, alanine, histidine and leucine. However, it is not limited to these. The aqueous medium further includes osmotic pressure regulators (eg, glycerin, monosaccharides (eg, glucose), disaccharides (eg, sucrose), trisaccharides (eg, raffinose), and sugar alcohols (eg, mannitol, xylitol). And sorbitol), but not limited thereto.

  In a preferred embodiment of the invention, the above composition contains an aqueous suspension of itraconazole particles present at 0.01-50% (w / v), the particles comprising 0.001-5% ( coated with w / v) bile salt (eg deoxycholic acid) and 0.001-5% (w / v) polyalkoxy ether (eg Poloxamer 188) and glycerin penetrating the above formulation Applied to adjust the pressure.

  In another preferred embodiment of the invention, the composition comprises an aqueous suspension of itraconazole particles present at about 0.01-50% (w / v), the particles comprising about 0.001- Coated with 5% (w / v) bile salt (e.g. deoxycholic acid) and 0.001-5% (w / v) polyethylene-660-hydroxystearate, and glycerin is the above formulation It is added to adjust the osmotic pressure.

  In another preferred embodiment of the invention, the composition comprises an aqueous suspension of itraconazole particles present at about 0.01-50% (w / v), the particles comprising about 0.001- Coated with 5% (w / v) polyethylene-660-hydroxystearate and glycerin is added to adjust the osmotic pressure of the above formulation.

  In yet another preferred embodiment of the invention, the composition comprises an aqueous suspension of itraconazole present at 0.01-50% (w / v), and the particles comprise about 0.001- Coated with 5% (w / v) albumin.

  The method of preparing the suspension in the present invention is assigned to the same person and is co-pending, US Patent Application Nos. 60 / 258,160; 09 / 874,799; 09/874. No. 637; No. 09 / 874,499; No. 09 / 964,273; No. 0 / 035,821; No. 60 / 347,548; No. 0 / 021,692 1st 0 / 183,035; 1st 0 / 213,352; 1st 0 / 246,802; 1st 0 / 270,268; 1st 0 / 270,267 And No. 0 / 390,333 (incorporated herein by reference and made a part thereof). A general procedure for preparing suspensions useful in the practice of the present invention follows.

  The process can be divided into three general categories. Each of the process categories includes (1) dissolving an antifungal agent in a water-miscible first organic solvent to make a first solution; (2) making the first solution a second Admixing with the solvent water to precipitate the antifungal agent to make a pre-suspension; and (3) applying a high shear or mixed form energy to the pre-suspension. In addition, it shares the process of obtaining a stable form of an antifungal agent having the desired size range defined above.

  These three categories of processes are categorized based on the physical characteristics of the antifungal agent, which are characterized by X-ray diffraction studies, differential scanning performed before and after the energy application step. Determined through calorimetry (DSC) studies or other suitable studies. In the first process category, prior to the energy application step, the antifungal agent in the pre-suspension takes an amorphous form, a quasicrystalline form or a supercooled liquid form, and the antifungal agent Has an average effective particle size. After the above energy application step, the antifungal agent is in crystalline form and has an average effective particle size that is essentially the same as the particle size of the pre-suspension (ie, less than about 50 μm).

  In the second process category, prior to the energy application step, the antifungal agent is in crystalline form and has an average effective particle size. After the energy addition step, the antifungal agent is in the form of crystals having the same average effective particle size as that before the energy addition step, but the crystals after the energy addition step are less likely to aggregate.

  The low aggregation frequency of the organic compound is observed by laser dynamic light scattering and an optical microscope.

  In the third process category, before the energy application step, the antifungal agent is brittle and is in a crystalline form having an average effective particle size. What is meant by the term “friable” is that the above particles are fragile and prone to breaking into smaller particles. After the energy addition step, the organic compound is in a crystalline form having an average effective particle size smaller than the crystals of the previous suspension. By going through the steps necessary to bring the compound into a brittle crystalline form, the subsequent energy addition step can be performed more quickly and more efficiently compared to the less brittle crystalline form of the organic compound. .

  The energy application step can be performed in any manner, where the pre-suspension is exposed to cavitation, shear or impact forces. In one preferred form of the invention, this energy addition step is an annealing step. Annealing is defined in the present invention as a process of converting a thermodynamically unstable material to a more stable material by one or repeated energy additions (direct heating or mechanical stress) and subsequent thermal relaxation. Is done. This energy reduction can be achieved by conversion of the solid form described above from a less regular lattice structure to a more regular lattice structure. Alternatively, this stabilization can occur by reordering of surfactant molecules located at the solid-liquid interface.

  These three process categories are discussed separately below. However, the process conditions (eg, surfactant selection or surfactant combination, amount of surfactant used, reaction temperature, degree of solution mixing, rate of precipitation, etc.) It should be understood that it can be selected to allow processing in any one of the categories discussed.

  Similar to the first process category and the second and third process categories described above, it can be further divided into two subcategories (Method A and Method B illustrated in FIGS. 3 and 4, respectively).

  The first solvent according to the present invention is a solvent or mixture of such solvents in which the organic compound of interest is relatively soluble and miscible with the second solvent. Such solvents include water-miscible protic compounds in which the hydrogen atoms of the molecule are bonded to electronegative atoms (eg, oxygen, nitrogen or other group VA, VIA, and VIIA groups of the periodic table). Although it is mentioned, it is not limited to this. Examples of such solvents include, but are not limited to, alcohols, amines (primary and secondary), oximes, hydroxamic acids, carboxylic acids, sulfonic acids, phosphonic acids, phosphoric acids, amides and ureas. Not.

Other examples of the first solvent also include aprotic organic solvents. Some of these aprotic solvents can form hydrogen bonds with water because they lack an effective proton donating group, but can only act as proton acceptors. One class of aprotic solvents is a dipolar aprotic solvent as defined by International Union of Pure and Applied Chemistry (IUPAC Compendium of Chemical Terminology, 2nd edition, 1997):
Relatively high (greater than about 15) relative dielectric constant (or dielectric constant) and a fairly large permanent dipole moment, and suitable hydrogen atoms that are unstable enough to form strong hydrogen bonds (eg dimethyl sulfoxide) It is a solvent that cannot be donated.

  The dipolar aprotic solvent may be selected from the group consisting of: an amide (having a nitrogen not bonded to a hydrogen atom and fully substituted), urea (having a hydrogen atom bonded to the nitrogen, completely Substituted), ethers, cyclic ethers, nitriles, ketones, sulfones, sulfoxides, fully substituted phosphonates, phosphonate esters, phosphoramides, nitro compounds and the like. Dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidine (NMP), 2-pyrrolidinone, 1,3-dimethylimidazolidinone (DMI), dimethylacetamide (DMA), dimethylformamide (DMF), dioxane, acetone, tetrahydrofuran (THF), tetramethylene sulfone (sulfolene), acetonitrile, and hexamethylphosphoramide (HMPA), nitromethane, and the like are members of this class.

  Solvents that are generally water immiscible but have sufficient water solubility at low volumes (less than 10%) can also be selected to act as water miscible primary solvents at these low 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, xylene (ortho, meta, or para) and toluene. Examples of alkanes include, but are not limited to, hexane, neopentane, heptane, isooctane and cyclohexane. Examples of halogenated aromatics include, but are not limited to, chlorobenzene, bromobenzene, and chlorotoluene. Examples of halogenated alkanes and halogenated alkenes include, but are not limited to, trichloroethane, methylene chloride, ethylene dichloride (EDC), and the like.

  Examples of all of the above solvent classes include, but are not limited to: N-methyl-2-pyrrolidinone (also referred to as N-methyl-2-pyrrolidone), 2-pyrrolidinone (also referred to as 2-pyrrolidone). ), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide, dimethylacetamide, carboxylic acids (eg acetic acid and lactic acid), aliphatic alcohols (eg methanol, ethanol, isopropanol, 3-pentanol and n-propanol), benzyl alcohol, glycerol, butylene glycol (butanediol), ethylene glycol, propylene glycol, monoacylated monoglycerides and diacylated monoglycerides (eg glyceryl caprylate), dimethylisosorby , Acetone, dimethylsulfone, dimethylformamide, 1,4-dioxane, tetramethylenesulfone (sulfolene), acetonitrile, nitromethane, tetramethylurea, hexamethylphosphoramide (HMPA), tetrahydrofuran (THF), dioxane, diethyl ether, tert- Butyl methyl ether (TBME), aromatic hydrocarbon, alkene, alkane, halogenated aromatic, halogenated alkene, halogenated alkane, xylene, toluene, benzene, substituted benzene, ethyl acetate, methyl acetate, butyl acetate, chlorobenzene, bromo Benzene, chlorotoluene, trichloroethane, methylene chloride, ethylene dichloride (EDC), hexane, neopentane, heptane, isooctane, cyclohexane, polyethylene glycol (PEG, for example, PEG-4, PEG-8, PEG-9, PEG-12, PEG-14, PEG-16, PEG-120, PEG-75, PEG-150), polyethylene glycol esters (for example, For example, PEG-4 dilaurate, PEG-20 dilaurate, PEG-6 isostearate, PEG-8 palmitostearate, PEG-150 palmitostearate), sorbitan polyethylene glycol (eg sorbitan PEG-20 isostearate) Polyethylene glycol monoalkyl ether (for example, PEG-3 dimethyl ether, PEG-4 dimethyl ether), polypropylene glycol (PPG), polypropylene alginate, PPG-10 butanediol, PPG-10 methylglucose Sose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether, propylene glycol dicaprylate / propylene glycol dicaprate, propylene glycol laurate and glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether). 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 itself be water. The solvent can also include buffers, salts, surfactants, water soluble polymers and combinations of these excipients.

(Method A)
In Method A (see FIG. 3), an antimicrobial agent is first dissolved in a first solvent to make a first solution. Depending on the solubility of the antimicrobial agent in the first solvent, the antimicrobial agent can be added from about 0.01% (w / v) to about 50% (w / v). It may be necessary to heat the concentrate from about 30 ° C. to about 100 ° C. to ensure dissolution of the antimicrobial agent in the first solvent.

  A second aqueous solution is provided having one or more surfactants added thereto. This surfactant may be selected from ionic surfactants, nonionic surfactants, or the above-mentioned biologically derived surfactants.

  It may be desirable to add a pH adjuster (eg, sodium hydroxide, hydrochloric acid, tris buffer or citric acid, acetic acid, lactic acid, meglumine, etc.) to the second solution. The second solution should have a pH in the range of about 3 to about 11.

  In a preferred form of the invention, a method for preparing submicron sized particles of an antimicrobial agent comprises adding a first solution to a second solution. The rate of addition depends on the size of the batch and the precipitation kinetics of the antimicrobial agent. Typically, for small laboratory processes (1 L preparation), the addition rate is about 0.05 cc / min to about 10 cc / min. During the addition, the solution should be constantly stirred. In order to make a pre-suspension, it was observed using an optical microscope that amorphous particles, semi-crystalline solids or supercooled liquids were formed. The method further includes subjecting the pre-suspension to an annealing step to convert the amorphous particles, supercooled liquid or semi-crystalline solid into a crystalline, more stable solid state. The resulting particles can be analyzed by dynamic light scattering methods (eg, photocorrelation spectroscopy, laser diffraction, low angle laser light scattering (LALLS), medium angle laser light scattering (MALLS), light obscuration methods (light having an average effective particle size within the above range as measured by obscuration methods (eg Coulter method), rheology or microscopy (optical microscope or electron microscope).

  The energy supply process consists of sonication, homogenization, countercurrent flow homogenization (eg, Mini DeBEE 2000 homogenizer available from BEE Incorporated, NC, in which the liquid eruption follows the first path. Oriented, the structure is inserted into the first path and re-orients the liquid into a controlled flow path along the new path, resulting in liquid emulsification or mixing), microfluidization, or impact force (impact) forcing energy through other methods of providing a force, shear force or cavitation force. During this phase, the sample can be cooled or heated. Within a preferred form of the invention, the annealing step is accomplished by homogenization. In another preferred embodiment of the invention, annealing can be achieved by sonication. In yet another preferred form of the invention, annealing may be achieved by use of an emulsifying device as described in US Pat. No. 5,720,551, which is hereby incorporated by reference, It forms a part of this specification.

  Depending on the rate of annealing, it may be desirable to adjust the temperature of the processed sample within the range of about -30 ° C to 100 ° C. Alternatively, it is necessary to adjust the temperature of the pre-suspension to a temperature within the range of about −30 ° C. to about 100 ° C. during the annealing step in order to achieve the desired phase transition of the processed solid. possible.

(Method B)
Method B differs from Method A in the following respects. The first difference is that a surfactant or combination of surfactants is added to the first solution. This surfactant may be selected from ionic surfactants, nonionic surfactants or the above-mentioned surfactants derived from the organism.

  The drug suspension resulting from application of the process described in the present invention can be administered directly as an injectable solution, and when distilled water for injection is used in the formulation, appropriate means for solution sterilization are applied. The Sterilization is performed by mixing the drug concentrate (drug, solvent and optional surfactant) and diluent medium (water, and optionally buffer and surfactant) before mixing to form a pre-suspension. Can be achieved by separate sterilization. The sterilization method is first pre-filtered through a 3.0 micron filter, then filtered through a 0.45 micron particle filter, then steam sterilized or heat sterilized or two additional 0.2 micron membrane filters. Including sterilizing filtration through the filter.

  If necessary, a solvent-free suspension can be made by solvent removal after precipitation. This may be achieved 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 performed by performing 1 to 3 successive centrifugations (after each centrifugation, the supernatant was decanted and discarded). A fresh volume of suspension vehicle without organic solvent was added to the remaining solid and the mixture was dispersed by homogenization. One skilled in the art can appreciate that other high shear mixing techniques can be applied to this reshaping process.

  Furthermore, any undesirable excipients (eg, surfactants) can be replaced by more desirable excipients by using the separation method described in the above paragraph. The solvent and first excipient can be discarded along with the supernatant after centrifugation and filtration. Then a fresh volume of suspension vehicle without solvent and without first excipient may be added. Alternatively, new surfactant can be added. For example, a suspension consisting of drug, N-methyl-2-pyrrolidinone (solvent), Poloxamer 188 (first excipient), sodium deoxycholate, glycerol and water was centrifuged and the supernatant removed Later it can be replaced with phospholipids (new surfactant), glycerol and water.

(I. First process category)
The method of the first process category generally includes the steps of dissolving the antimicrobial agent in a water miscible first solvent and then mixing the solution with an aqueous solution to form a pre-suspension, wherein The antimicrobial agent is in an amorphous form, semi-crystalline form or supercooled liquid form as determined by X-ray diffraction studies, DSC, light microscopy or other analytical techniques, and the effective particle size range described above Having an average effective particle size in one range. After the mixing step, an energy supplying step is performed, and in a preferred embodiment of the present invention, an annealing step is performed.

(II. Second process category)
The method of the second process category includes essentially the same steps as the steps of the first process category, but differs in the following points. X-ray diffraction, DSC or other suitable pre-suspension analysis techniques indicate the antimicrobial agent in crystalline form and have an average effective particle size. The antibacterial agent after the energy supply step has essentially the same average effective particle size as before the energy supply step, but is less prone to agglomeration into larger particles when compared to the pre-suspension particles. Without being bound by theory, it is believed that the difference in particle stability may be due to the reconstitution of surfactant molecules at the solid-liquid interface.

(III. Third process category)
A third category of methods is used to ensure that the antimicrobial agent in the pre-suspension is present in a fragile form having an average effective particle size (eg, thin needles and thin plates). Modify the first two steps of the second process category. Brittle particles can be formed by selecting appropriate solvents, surfactants or surfactant combinations, individual solution temperatures, mixing rates, precipitation rates, and the like. Crushability can also be enhanced by introducing lattice defects (eg, planar division) during the mixing process of the first solution with the aqueous solution. This can occur, for example, by rapid crystallization performed in the precipitation process. In the energy supply step, these brittle crystals are converted to crystals that are kinetically stable and have an average effective particle size that is smaller than the average effective particle size of the pre-suspension. Dynamically stable particles have a reduced tendency to agglomerate when compared to particles that are not dynamically stable. In such an example, the energy supply process results in the breakdown of brittle particles. Compared to processing the organic compound by ensuring that the particles of the pre-suspension are in a fragile state (this step is not the step taken to bring the organic compound into a fragile form) Thus, organic compounds can be prepared more easily and more quickly into particles within a desired size range.

  In addition to the microprecipitation methods described above, any other art-known precipitation method for preparing submicron sized particles or nanoparticles can be used in conjunction with the present invention. Examples of other precipitation methods are described below. This example is for illustrative purposes and is not intended to limit the scope of the invention.

(Emulsion precipitation method)
One suitable emulsion precipitation technique is disclosed in co-pending and co-owned US patent application Ser. No. 09 / 964,273, which is incorporated herein by reference and is incorporated herein by reference. Eggplant. In this approach, the process includes the following steps: (1) providing a multiphase system having an organic phase and an aqueous phase to an organic phase having a pharmaceutically effective compound therein; 2) Sonicating the system to evaporate a portion of the organic phase, resulting in precipitation of the compound in the aqueous phase, the compound having an average effective particle size of less than about 2 μm. The step of providing a multiphase system includes the following steps: (1) mixing a water-immiscible solvent with a pharmaceutically effective compound to define an organic solution, (2) one or more surfactants. Preparing an aqueous based solution with the compound, and (3) mixing the organic solution with the aqueous solution to form a multiphase system. The process of mixing the organic phase and the aqueous phase can be a piston gap homogenizer, a colloidal mill, a high speed stirrer, an extruder, a manual stirrer or a manual shaker, a microfluidizer, or a high shear The use of other devices or techniques to provide conditions may be included. This crude emulsion has oil droplets in water with a diameter less than about 1 μm in water. This crude emulsion is sonicated to define a microemulsion and ultimately a submicron sized particle suspension.

  Another approach for preparing sub-micron sized particles is disclosed in co-pending US patent application Ser. No. 10 / 183,035, which is incorporated herein by reference, Part of the description. This process includes the following steps: (1) providing a multiphase crude dispersion having an organic phase and an aqueous phase, the organic phase having a pharmaceutical compound therein; (2) supplying energy to the crude dispersion to form a fine dispersion; (3) freezing the fine dispersion; and (4) lyophilizing the fine dispersion to obtain a pharmaceutical compound. Obtaining submicron sized particles. The step of providing a multiphase system includes the following steps: (1) mixing a water-immiscible solvent with a pharmaceutically active compound to define an organic solution; (2) one or more surfactants Preparing an aqueous based solution with the compound; and (3) mixing the organic solution with the aqueous solution to form a multiphase system. The process of mixing the organic and aqueous phases can be a piston gap homogenizer, a colloidal mill, a high speed stirrer, an extruder, a manual stirrer or manual shaker, a microfluidizer, or other to provide high shear conditions. Use of other devices or techniques.

(Solvent anti-solvent precipitation)
Suitable solvent antisolvent precipitation techniques are disclosed in US Pat. Nos. 5,118,528 and 5,100,591, which are incorporated herein by reference and are part of this specification. Make. This process includes the following steps: (1) preparing a liquid phase of a biologically active substance in a solvent or mixture of solvents to which one or more surfactants can be added; (2) Preparing a second liquid phase of a non-solvent or non-solvent mixture, wherein the non-solvent is miscible with the solvent or mixture of solvents with respect to the material; (3) the solution of (1) and Adding the solution of (2) together with stirring; and (4) removing unwanted solvent to produce a colloidal suspension of nanoparticles. The '528 patent discloses generating particles of matter smaller than 500 nm without supplying energy.

(Phase inversion precipitation)
One suitable phase inversion precipitation is disclosed in US Pat. Nos. 6,235,224, 6,143,211 and US Patent Application No. 2001/0042932, which are incorporated herein by reference. And forms part of this specification. Phase inversion is a term used to describe the physical phenomenon in which a polymer dissolves in a continuous phase and the solvent system becomes a solid polymer network in which the polymer is a continuous phase. One way to induce phase inversion is by adding a non-solvent to the continuous phase. The polymer is transferred from a single phase to an unstable biphasic mixture (polymer-rich and polymer-poor fractions). Non-solvent micelle droplets in the polymer rich phase serve as nucleation sites and are coated with the polymer. The '224 patent discloses that phase transitions of polymer solutions under certain conditions can cause the formation of naturally occurring individual microparticles (including nanoparticles). The '224 patent discloses dissolution and dispersion of polymers in solvents. The pharmaceutical is also dissolved and dispersed in the solvent. In the process of producing crystals in this process, it is desirable for the drug to dissolve in the solvent. The polymer, drug and solvent together form a mixture having a continuous phase, which is the continuous phase. This mixture is then introduced into at least a 10-fold excess of miscible non-solvent, causing spontaneous formation of microencapsulated drug microparticles having an average particle size between 10 nm and 10 μm. The particle size is affected by the solvent: non-solvent volume ratio, polymer concentration, polymer-solvent solution viscosity, polymer molecular weight, and solvent-non-solvent pair properties. This process does not require the step of creating microdroplets of solvent, for example by forming an emulsion. This process also does not require stirring and / or shearing forces.

(PH shift precipitation)
The pH shift precipitation technique typically involves dissolving the drug in a solution having a pH at which the drug is soluble, and then changing the pH to a pH at which the drug is not soluble. The pH can be acidic or basic depending on the particular pharmaceutical compound. This solution is then neutralized to form a pre-suspension of submicron sized particles of the pharmaceutically active compound. One suitable pH shift precipitation process is disclosed in US Pat. No. 5,665,331, which is hereby incorporated by reference and made a part hereof. This process involves dissolving a pharmaceutical together with a crystal growth modifier (CGM) in an alkaline solution, and then using this solution to form a surface modified surfactant or a fine particle dispersion of the pharmaceutical. In the presence of an acid. After the precipitation step, a dispersion diafiltration cleanup step is performed, and then the concentration of the dispersion is adjusted to the desired level. This process reportedly produces microcrystalline particles with a Z average diameter of less than 400 nm as measured by photon correlation spectroscopy.

  Other examples of pH shift precipitation methods are disclosed in US Pat. Nos. 5,716,642; 5,662,883; 5,560,932 and 4,608,278, These are incorporated herein by reference and form part of this specification.

(Injection precipitation method)
Suitable injection precipitation techniques are disclosed in US Pat. Nos. 4,997,454 and 4,826,689, the disclosures of which are incorporated herein by reference and are Part of it. First, a suitable solid compound is dissolved in a suitable organic solvent to form a solvent mixture. Then, the precipitated non-solvent miscible with the organic solvent is added at a temperature between about −10 ° C. and about 100 ° C. and at an injection rate of about 0.01 ml / min to about 1000 ml / min per 50 ml volume. Injection into the mixture produces a precipitated, non-aggregated solid particle suspension of the compound having a substantially uniform average diameter of less than 10 μm. Agitation of the precipitating non-solvent and the infusion solution (eg, by stirring) is preferred. The non-solvent may contain a surfactant for stabilizing the particles against stirring. The particles are then separated from the solvent. Depending on the solid compound and the desired particle size, the temperature parameters, the ratio of non-solvent to solvent, injection rate, stirring rate and volume can be varied according to the present invention. The particle size is proportional to the ratio of non-solvent volume: solvent volume and the injection temperature, and inversely proportional to the injection and agitation rates. The precipitating non-solvent may be aqueous or non-aqueous depending on the relative solubility of the compound and the desired suspending vehicle.

(Temperature shift precipitation)
The temperature shift precipitation technique is also known as a thermal melting technique and is disclosed in US Pat. No. 5,188,837 to Domb, the disclosure of which is incorporated herein by reference and is incorporated herein by reference. Part of it. In one embodiment of the present invention, lipospheres are prepared by the following steps: (1) melting or dissolving a substance (eg, drug) to be delivered in a melting vehicle and delivering it. (2) adding a phospholipid with an aqueous medium to the molten material or vehicle at a temperature above the melting temperature of the material or vehicle; (3) uniform Mixing the suspension at a temperature above the melting temperature of the vehicle until a fine precipitate is obtained; and (4) then rapidly cooling the precipitate to below room temperature.

(Solvent evaporation precipitation)
Solvent evaporation precipitation techniques are disclosed in US Pat. No. 4,973,465, the disclosures of which are hereby incorporated by reference and made a part hereof. The '465 patent discloses a method for preparing microcrystals, which method comprises the following steps: (1) a pharmaceutical composition dissolved in a common organic solvent or combination of solvents and Providing a solution of phospholipid, (2) evaporating the solvent, and (3) suspending the film obtained by evaporation of the solvent in an aqueous solution by vigorous stirring. The solvent can be removed by loading the solution with energy and evaporating a sufficient amount 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 into the solution.

(Reaction precipitation)
Reaction precipitation involves dissolving the pharmaceutical compound in a suitable solvent to form a solution. The compound should be added in an amount below or below the saturation point of the compound in the solvent. The compound has less solubility in the solvent, either by reaction with a chemical substance or by modification in response to loading with energy (eg, heat or UV light), It is then modified to precipitate from the solution.

(Compressed fluid precipitation)
Suitable techniques for precipitation with compressed fluid are disclosed in WO 97/14407 to Johnston, the disclosures of which are hereby incorporated by reference and made a part hereof. The method includes 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. Addition of the compressed fluid to the solution (solute in solvent) causes the solute to achieve or approach supersaturation and precipitate out as fine particles. In this case, the compressed fluid acts as an antisolvent that lowers the adhesive energy density of the solvent that dissolves the drug.

  Alternatively, the drug can be dissolved in a compressed fluid and then sprayed into the aqueous phase. The rapid spread of the compressed fluid decreases the solvent power of the fluid and then causes the solute to precipitate out as fine particles in the aqueous phase. In this case, the compressed fluid acts as a solvent.

(Other methods for preparing particles)
The particles of the present invention can also be prepared by mechanical grinding of the active agent. Mechanical grinding includes techniques such as jet grinding, pearl grinding, ball grinding, hammer grinding, fluid energy grinding or wet grinding techniques (eg, wet grinding techniques disclosed in US Pat. No. 5,145,684). The disclosures of which are hereby incorporated by reference and made a part hereof.

  Another method for preparing the particles of the present invention is by suspending the active agent. In this method, the active agent particles are dispersed in the aqueous medium by adding the particles directly into the aqueous medium to form a pre-suspension. The particles are usually coated with a surface modifying agent to inhibit the aggregation of the particles. One or more other excipients may be added to either the active agent or the aqueous medium.

Example 1: Preparation of 1% Itraconazole Suspension with Deoxycholic Acid Coating
Each 100 mL suspension contains:
Itraconazole 1.0 g (1.0% w / v)
Deoxycholic acid sodium salt monohydrate 0.1 g (0.1% w / v)
Poloxamer 188, NF 0.1 g (0.1% w / v)
Glycerin, USP 2.2g (2.2% w / v)
Sodium hydroxide, NF (0.1 N or 1.0 N) For pH adjustment Hydrochloric acid, NF (0.1 N or 1.0 N) For pH adjustment Sterile water for injection, USP appropriate amount Target pH (range) 8.0 (6) ~ 9)
(Preparation of surfactant solution (2 L) for microprecipitation)
Fill a properly cleaned tank with sterile water for injection and agitate. Add the required amount of glycerin and stir until dissolved. Add the required amount of deoxycholate sodium salt monohydrate and stir until dissolved. 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. The surfactant solution is filtered through a 0.2 μm filter. The surfactant solution is measured and transferred to a tube that provides a homogenizer. Cool in the hopper while mixing the surfactant solution.

(Preparation of replacement solution)
Preparation of 4 liter replacement solution. Fill a properly cleaned tank with WFI and stir. Weighed Poloxamer 188 (Spectrum Chemical) is added to the measured volume of water. Begin mixing the Poloxamer 188 / water mixture until the Poloxamer 188 is completely dissolved. Add the required amount of glycerin and stir until dissolved. Once the glycerin is completely dissolved, the required amount of deoxycholate sodium salt monohydrate is added and stirred until dissolved. If necessary, adjust the pH of the wash solution with a minimum amount of sodium hydroxide and / or hydrochloric acid to a pH of 8.0. The replacement solution is filtered through a 0.2 μm membrane filter.

(Preparation of drug concentrate)
For a 2 L batch, add 120.0 mL N-methyl-2-pyrrolidinone in a 250 mL beaker. Weigh 2.0 g Poloxamer 188. Weigh 20.0 g of itraconazole (Wyckoff). Transfer the weighed Poloxamer 188 to a 250 mL beaker containing the N-methyl-2-pyrrolidinone. Stir until dissolved, then add the itraconazole. Heat and stir until dissolved. The drug concentrate is cooled to room temperature and filtered through a 0.2 μm filter.

(Trace precipitation)
Sufficient WFI is added to the surfactant solution already in the tube providing the homogenizer to reach the desired target concentration. When the surfactant solution cools, the addition of the drug concentrate to the surfactant solution is begun while mixing continues.

(Homogenization)
The homogenizer pressure is slowly increased until the operating pressure reaches 10,000 psi. During mixing, the suspension is homogenized with recirculation. For a 2000 mL suspension at 50 Hz, one pass should require about 54 seconds. Following homogenization, a 20 mL sample is collected for particle size analysis. Cool the suspension.

(Washing replacement)
The suspension is then divided and filled into 500 mL centrifuge tubes. Centrifuge until a clean separation of the precipitate is observed. Measure the volume of the supernatant and replace with the fresh replacement solution prepared previously. For resuspension (pooled sample), the precipitate is measured and transferred from each centrifuge tube to an appropriately washed and labeled container. The pooled sample is resuspended with a high shear mixer until no visible aggregates are observed. Collect a 20 mL sample for particle size analysis.

  The suspension is then divided and filled into 500 mL centrifuge tubes. Centrifuge until a clean separation of the precipitate is observed. Measure the volume of the supernatant and replace with the fresh replacement solution prepared previously. For resuspension (pooled sample), the precipitate is measured and transferred from each centrifuge tube to a well-washed and labeled container. The pooled sample is resuspended with a high shear mixer until no visible aggregation is observed. Collect a 20 mL sample for particle size analysis.

(Second homogenization)
The suspension is transferred to a homogenizer hopper and the suspension is cooled with mixing. The homogenizer pressure is slowly increased until the operating pressure reaches 10,000 psi. Homogenize while monitoring the temperature of the solution. Following homogenization, the suspension is cooled and three 30 mL samples are collected for particle analysis. Collect the remaining suspension in a 2 liter bottle.

(filling)
Based on an acceptable particle size determination test (average volume weighing diameter of 50 nm to 5 μm), 30 mL of sample was collected in a 50 mL glass vial with a rubber stopper.

Example 2: Preparation of 1% itraconazole nanosuspension with phospholipid coating
Each 100 mL suspension contains:
Itraconazole 1.0 g (1.0% w / v)
Phospholipid (Lipoid E 80) 1.2 g (1.2% w / v)
Glycerin, USP 2.2g (2.2% w / v)
Sodium hydroxide, NF (0.1 N or 1.0 N) For pH adjustment Hydrochloric acid, NF (0.1 N or 1.0 N) For pH adjustment Sterile water for injection, USP appropriate amount Target pH (range) 8.0 (7 .5-8.5)
(Preparation of surfactant solution (2 L) for microprecipitation)
The surfactant solution was prepared in two phases. The first phase is a dispersed phospholipid, while the second phase contains filtered glycerin. The two fractions are combined before pH adjustment.

(Phase 1)
Fill an appropriately cleaned tube with about 700 mL of sterile water for injection, USP (WFI) with stirring at 50-500 rpm. Increase the temperature of the filtrate to 50-70 ° C. and add the required amount of phospholipid with mixing at 50-500 rpm until complete dispersion is reached. Record the time and temperature at which the phospholipid was added, and the time and temperature at which the phospholipid was dispersed. Determine the total mixing time required to disperse the phospholipid. The surfactant solution is cooled to 18-30 ° C. prior to the addition of glycerin.

(Phase 2)
Fill a properly cleaned tube with about 700 mL of WFI while stirring at 50-500 rpm. Add the required amount of glycerin at 18-30 ° C. and stir at 50-500 rpm until dissolved.

(Combined phases)
The glycerin solution is filtered through the 0.2 μm filter setup into the first phase (at 18 ° C.-30 ° C.) while mixing at 50-500 rpm. The capacity is about 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. The volume of the surfactant solution is measured at 18 ° C. to 30 ° C. using a 2 L graduated cylinder.

  The surfactant solution is measured and transferred to a tube (Avestin C-160) that provides the homogenizer. The surfactant solution is cooled in a hopper while mixing until the temperature is 10 ° C. or less at a speed at which solution vortex can be observed.

(Preparation of replacement solution (4 L))
A displacement solution is prepared in two phases. The first phase contains dispersed phospholipids, while the second phase contains filtered glycerin. The two fractions are combined before pH adjustment.

(Phase 1)
A properly cleaned tube is filled with about 1.4 liters of WFI with stirring at 50-500 rpm. The water temperature is raised to 50 ° C. to 70 ° C. and the required amount of phospholipid is added with mixing at 50-500 rpm until complete dispersion is reached. The surfactant solution is cooled to 18-30 ° C. prior to the addition of glycerin.

(Phase 2)
A properly cleaned tube is filled with about 1.4 liters of WFI with stirring at 50-500 rpm. Add the required amount of glycerin and stir at 50-500 rpm until dissolved.

(Combined phases)
Filter the glycerin solution through the 0.2 μm filter setup into the first phase (at 18 ° C.-30 ° C.) while mixing at 50-500 rpm. Dilute to 4.0 L volume with water for injection using a graduated cylinder. Record the pH of the wash 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.

(Preparation of drug concentrate)
To a 2 L batch, add 120.0 mL N-methyl-2-pyrrolidinone (Pharmacosolv®, ISP) in a 250 mL beaker. Weigh 20.0 g of itraconazole (Wyckoff). The weighed itraconazole is transferred to a 250 mL beaker containing NMP at NMT 70 ° C. Maintain below 70 ° C. and stir at 100-1000 rpm until dissolved. The drug concentrate is cooled to 18-30 ° C. The drug concentrate is filtered through a prefilter and filter setup. One polypropylene prefilter SBPP and two 0.2 μm filters are used at 15 psi and ambient temperature. The drug concentrate is transferred to three 60 mL syringes, and a syringe needle is attached to the syringe luer connection. Using the syringe, determine the volume of the drug concentrate.

(Trace precipitation)
Water for injection is added to the surfactant solution already in the tube that provides the homogenizer. The amount of water added at 18-30 ° C. should be calculated as follows:
V = 2,000 mL-volume of drug concentrate-volume of surfactant solution Install each needle assembly using a syringe pump. The needle outlet is located at the top of the tube. When the surfactant solution is below 10 ° C., the addition of the drug concentrate to the surfactant solution is started with continuous mixing at a rate necessary to produce significant solution vortexing. The concentrate should be added so that the drops hit the point of greatest shear at the bottom of the vortex. The addition rate should be about 2.5 mL / min.

(Homogenization)
Avestin C160 homogenizer was used. The homogenizer pressure is slowly increased until the operating pressure reaches 10,000 psi. Mix at 100-300 rpm and homogenize the suspension with recirculation for 20 passes (18 minutes) while maintaining the suspension temperature below 70 ° C. For a 2,000 mL suspension at 50 Hz, one pass requires about 54 seconds. Following homogenization, collect a 20 mL sample in a 50 mL glass vial for particle size analysis. The suspension is cooled to below 10 ° C.

(Washing replacement)
The suspension is then divided and filled into 500 mL centrifuge tubes. The speed for centrifugation is set to 11,000 rpm corresponding to about 20,434 g using a rotor SLA-3000, Superlite. The total centrifugation time is 60 minutes at 10 ° C. or lower. Measure the volume of the supernatant and replace with fresh replacement solution. Using a spatula, measure and transfer the precipitate from each centrifuge tube to an appropriately washed and labeled container (pooled sample) for resuspension. The pooled sample is resuspended with a high shear mixer until no visible aggregation is observed.

(Second washing and centrifugation step)
The suspension is then divided and filled into 500 mL centrifuge tubes. The speed for centrifugation is set to 11,000 rpm corresponding to about 20,434 g using a rotor SLA-3000, Superlite. The total centrifugation time is 60 minutes at 10 ° C. or lower. Measure the volume of the supernatant and replace with fresh replacement solution. Using a spatula, measure and transfer the precipitate from each centrifuge tube to an appropriately washed and labeled container (pooled sample) for resuspension. The pooled sample is resuspended with a high shear mixer until no visible aggregation is observed. Record the pH of the suspension. If necessary, adjust the pH of the suspension with a minimum amount of sodium hydroxide and / or hydrochloric acid to a pH of 8.0 ± 0.5.

(Second homogenization)
Transfer the suspension to the homogenizer hopper. The suspension is cooled with mixing until the temperature is below 10 ° C. The pressure is slowly increased until the operating pressure reaches 10,000 psi. Homogenize for 20 passes (18 minutes) while maintaining the solution temperature below 70 ° C. Following homogenization, the suspension is cooled to below 10 ° C. and three 30 mL samples are collected for particle size analysis. Collect the remaining suspension in a 2 liter bottle. The suspension is sprayed with nitrogen gas for 10 minutes. The nitrogen gas is surely filtered through a 0.2 μm filter.

(filling)
Based on an acceptable particle size determination test (average volume weighing diameter of 50 nm to 100 nm), 30 mL of sample was collected in a 50 mL glass vial with a PTFE® coated stopper. The top empty of each vial was purged with nitrogen before sealing.

Example 3: Other formulations of itraconazole suspension
Other formulations of itraconazole suspensions with different combinations of surfactants may also be prepared using the methods described in Example 1 or Example 2. Table 1 summarizes the surfactant compositions of various itraconazole suspensions.

  (Table 1: Summary of compositions of various 1% itraconazole suspensions)

Example 4: Comparison of acute toxicity between a commercial itraconazole formulation (SPORANOX®) and the suspension composition of the present invention.
The acute toxicity of a commercial itraconazole formulation (SPORANOX®) is compared to the various 1% itraconazole formulations of the present invention listed in Table 1. SPORANOX® is a registered trademark of Janssen Pharmaceutical Products, L.A. P. Is available from It is available as a 1% intravenous (IV) solution solubilized with hydroxypropyl-β-cyclodextrin. The results are shown in Table 2, along with the maximum tolerated dose (MTD) indicated for each formulation.

  Table 2: Comparison of acute toxicity of various formulations of itraconazole

LD ₁₀ = lethal dose resulting in 10% mortality LD ₄₀ = lethal dose resulting in 40% mortality LD ₅₀ = lethal dose resulting in 50% mortality NOEL = MTD not at effect level = maximum tolerated dose When formulated in a nanosuspension, the animals showed a much higher level of antifungal itraconazole than when formulated as a solution using cyclodextrin. The reason for this increased tolerance may be related to the absence of cyclodextrin. However, at the levels used in Sporanox, cyclodextrin itself does not provide the observed toxicity. Rather, the reason seems to be the change in pharmacokinetic profile caused by the nanosuspension.

Example 5: Pharmacokinetic comparison of SPORANOX® vs. itraconazole suspension formulation
Adult male Sprague Dawley rats were injected with SPORANOX®, or formulations 1 and B at 20 mg / kg, 40 mg / kg and 80 mg / kg, or formulations 3, 14, A6 at 80 mg / kg. And C were treated intravenously (IV) via the tail tail vein with a single injection at a rate of 1 ml / min.

  Following dosing, these animals were anesthetized and retro-orbital blood was collected at different time points (n = 3). The time points were as follows: 0.03 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours, 96 hours, 144 Hours, 192 hours, 288 hours, and 360 hours (SPORANOX® injections up to 192 hours only). Blood was collected in a tube with EDTA and centrifuged at 3200 rpm for 15 minutes to separate the plasma. The plasma was stored frozen at -70 ° C until analysis. The concentration of parent itraconazole and its metabolite hydroxy-itraconazole was determined by high performance liquid chromatography (HPLC). Unfractionated pharmacokinetic (PK) parameters for itraconazole (ITC) and hydroxy-itraconazole (OH-ITC) using WinNonlin® Professional Version 3.1 (Pharsight Corp., Mountain View, CA). Was derived using a manual method.

  Table 3 provides a comparison of plasma pharmacokinetic parameters determined for each itraconazole formulation. Plasma itraconazole in Formula 1 and Formula B at 24 hours for SPORANOX® injection at 5 mg / kg and 48 hours for SPORANOX® injection at 20 mg / kg. In contrast, it was no longer detected at 96 hours. Plasma hydroxy-itraconazole was detected at 0.25 hours for the first SPORANOX® injection and for Formula 1 and Formula B. Plasma hydroxy-itraconazole was initially detected at 0.25 hours for SPORANOX® injection at 5 mg / kg and 20 mg / kg and for Formula 1 and Formula B at 20 mg / kg. Hydroxy-Itraconazole is 48 hours for SPORANOX® injection at 5 mg / kg, 96 hours for SPRORANOX® injection at 20 mg / kg, for formulations 1 and B No longer detected in 144 hours.

  FIG. 5 compares the pharmacokinetics (PK) of SPORANOX® with a formulation 1 suspension of itraconazole particles. As indicated above, the suspension formulation of the present invention was less toxic than Sporanox®, so it was administered in higher doses in this equitoxic experiment. Sporanox was administered at 20 mg / kg and Formulation 1 was administered at 80 mg / kg. SPORANOX® decreased plasma concentrations relatively quickly over 20 hours. Nanosuspension plasma levels remain elevated for a period of about 3-4 times longer. The nanosuspension shows an initial minimum of plasma levels at 30 minutes. This corresponds to the lowest point in plasma concentration due to sequestration of drug nanocrystals by spleen and liver macrophages, thus temporarily removing the drug from the circulation. However, since macrophages apparently release the drug into the circulation, drug levels recover quickly. Furthermore, the nanosuspension drug is metabolized effectively as shown in the PK curve for hydroxy itraconazole metabolism. The rate of appearance of the metabolite for the nanosuspension is delayed compared to the PK curve for the metabolite for the SPORANOX® formulation. However, as in the case of the parent molecule for nanosuspensions, the metabolite persists in the circulation for a much longer time than in the case of metabolism for the SPORANOX® formulation. When AUC (area under blood concentration versus time curve) is normalized by dose, nanosuspensions are at least as bioavailable as SPORANOX®.

(Example 6: Acute toxicity of rapidly dissolving nanosuspension)
Further experiments were performed. Itraconazole nanosuspension was formulated differently to dissolve more easily in blood. This was achieved by making the particles smaller or amorphous, or both. These acute toxicities of these formulations are listed for formulation entries 14331-1 and 14443-1 in Table 1. In contrast to slowly dissolving nanosuspensions, rapidly dissolving nanosuspensions cause death at much lower levels in the animals, similar to those found in SPORANOX®. Brought. It is clear that these excipients do not cause toxicity because these rapidly dissolving nanosuspensions did not contain cyclodextrins. Rather, rapid dissolution resulted in immediate bioavailability of the drug in the blood and this was the causative factor. The drug level for the rapidly dissolving formulation (Form A) is much higher than that achieved by the slow dissolving (macrophage targeted) formulation (Form B) as determined in in vitro dissolution experiments. This included a plasma mock medium consisting of 5% albumin / Selensen buffer. The results are shown in FIG.

(Example 7: Antifungal efficacy study)
9.5 × 10 ⁶ cfu or 3 × 10 ⁶ cfu C.I. per ml saline. Normal and immunosuppressed rats (administered prednisolone twice daily on the day before and on the day of inoculation) once intravenously with albicans were injected with SPORANOX® injection for 10 consecutive days, 1 day Times, intravenously, and the first dose was given 4-5 hours after inoculation. SPORANOX® injected rats were dosed at 5 mg / kg or 20 mg / kg for the first 2 days, then at 5 mg / kg or 10 mg / kg due to toxicity at 20 mg / kg after 2 days of administration The remaining 8 days were administered. Similarly, 1 × 10 ^6.5 cfu C.I. per ml saline. Immunosuppressed rats incubated with albicans are treated intravenously once every other day for 10 days with Formula 1 or Formula B (20 mg / kg, 40 mg / kg, or 80 mg / kg, respectively). This started on the day of inoculation. SPORANOX® injection-treated rats, Formula 1 treated rats, and Formula B treated rats were treated with C.I. C. albicans inoculation 11 days after inoculation, kidneys harvested, weighed, and C.I. Cultivated for determination of total number of albicans colonies and itraconazole and hydroxy-itraconazole concentrations. Kidneys were collected from untreated control rats when moribund status was observed or when the animals had 20% body weight. In addition, body weight was measured periodically during the course of each study.

  A comparison of results for SPORANOX® injection and immunosuppressed rats treated with Formula 1 and Formula B is shown in Table 4 and FIG. The daily SPORANOX® injection treatment at 10-20 mg / kg appeared to be slightly more effective than the daily SPORANOX® injection treatment at 5 mg / kg. Based on the total number of kidney colonies, administration of Formula 1 or Formula B every other day at 20 mg / kg appears to be as effective as daily SPORANOX® injection at 20 mg / kg; Although likely to be more effective than daily SPORANOX® injection treatment at 5 mg / kg (ie, recommended clinical dose), higher doses for both Formula 1 and Formula B were Based on the total number of kidney colonies (ie, no C. albicans was detected) and increasing kidney itraconazole concentrations appeared to be most effective.

  The above experiments showed that the antifungal nanosuspension formulation was less toxic than the conventional totally soluble formulation of the same drug. Thus, more drugs can be administered without eliciting adverse effects. Because the drug nanoparticles did not dissolve immediately after injection, they were retained in storage in the liver and spleen. They act as long-term release shelters and allow less frequent dosing. The higher doses that can be administered allow higher drug levels to appear in the target organ, in this case the kidney (FIG. 8). More drug in this organ led to more killing of the infected organism (Figure 9).

(Example 8: Resistance strain antifungal efficacy test)
A lethal dose of C.I. albicans strain c43 (ATCC No. 201794) (MIC ₈₀ = 16 μg / ml for SPORANOX® Itraconazole; 8-16 for Vfend and 0.1 for Cancidas), an immunocompromised rat model ( Daily prednisolone). After 24 hours, test groups (n = 6) were tested every 2 hours with 20 mg / kg, 40 mg / kg or 80 mg / kg NANOEDGE ^™ itraconazole nanosuspension. The control group does not include treatment arms (Sporanox® (10 mg / kg / day), Vfend® (10 mg / kg / day), and Cancidas® (1 mg / kg / day)) It was. Treatment continued for 10 days. Survival numbers and kidney cfu / g were assessed.

  The number of animals that survived after 6 and 10 days were Sporanox (3, 0), 20 mg / kg and 40 mg / kg nanosuspension (5, 3), 80 mg / kg nanosuspension (6, 4 ), Vfend (0, 0), and Cancidas (0, 0). FIG.

  The higher doses possible with itraconazole nanosuspension were previously considered to be resistant to itraconazole. It can be concluded that infection with an albicans strain can be effectively treated, resulting in increased survival in an immunocompromised rat model.

  The current definition of susceptible and resistant fungal strains envisions a specific dose of itraconazole administered using conventional dosage forms. The higher drug burden associated with nanosuspension injections is currently itraconazole resistant C.I. It may allow treatment of what is considered an albicans infection.

(Example 9: Prophetic example of other triazole antifungal agents)
The present invention relates to submicron size or the use of the method described in Example 1 or Example 2 and the formulation described in Example 3 except that the antifungal agent is a triazole antifungal agent other than itraconazole. The preparation of a 1% suspension of micron sized triazole antifungal agent is contemplated. Examples of triazole antifungal agents that may be used are ketoconazole, miconazole, fluconazole, ravconazole, voriconazole, saperconazole, eberconazole, genaconazole, genaconazole, genaconazole, , Sulconazole, terconazole, thioconazole, and posaconazole.

(Example 10: Prophetic example of non-triazole antifungal agent)
The present invention relates to the method and practice described in Example 1 or Example 2, except that the antifungal agent is amphotericin B, nystatin, terbinafine, anidulafungin, or flucytosine instead of itraconazole. The preparation of a 1% suspension of submicron or micron sized non-triazole antifungal using the formulation described in Example 3 is contemplated.

  From the foregoing, it will be observed that numerous variations and modifications may be practiced without departing from the spirit and scope of the invention. It is understood that no limitation is intended and should be implied with respect to the particular apparatus illustrated herein. It is, of course, intended to encompass all such modifications that fall within the scope of the appended claims.

FIG. 1 is the general molecular structure of a triazole antifungal agent. FIG. 2 is the molecular structure of itraconazole. FIG. 3 is an illustration of Method A of the microprecipitation process used in the present invention to prepare the suspension. FIG. 4 is an illustration of Method B of the microprecipitation process used in the present invention to prepare the suspension. FIG. 5 is a graph comparing the SPORANOX® drug kinetics with the Itraconazole Formulation 1 suspension of the present invention, where ITC is the bolus of Formula 1 (80 mg / kg). Itraconazole plasma concentration measured after infusion, ITC-OH is the primary metabolite, hydroxyitraconazole plasma concentration measured after bolus infusion of formulation 1 (80 mg / kg), total Is the combined concentration of itraconazole and hydroxyitraconazole (ITC + ITC-OH) measured after a bolus infusion of Formula 1 (80 mg / kg), and Sporanox-ITC is measured after a bolus infusion of 20 mg / kg Sporanox IV Itraconazole concentration in the blood plasma, Sporanox-I C-OH is the concentration in plasma of hydroxyitraconazole, the primary metabolite in plasma, measured after a bolus infusion of 20 mg / kg Sporanox IV, and Sporanox-total is a bolus infusion of 20 mg / kg Sporanox IV It is the combined concentration (ITC + ITC-OH) of itraconazole and hydroxyitraconazole measured later. FIG. 6 is a graph comparing drug levels that dissolved Formulation Form A early and drug levels that dissolved Formulation Form B slowly (macrophage targeting) and were determined in an in vitro dissolution experiment; The drug level of is higher than that obtained with Form B. FIG. 7 is a graph showing comparison of body weight results over time of immunosuppressed rats treated with SPORANOX® injection solutions and formulations 14288-1 and 14228-B. FIG. 8 is a graph of renal drug levels versus dose, indicating that higher drug levels appear in the target organ (in this case the kidney) as the dose that can be administered is increased. FIG. 9 shows fungal counts against kidney drug levels (N = nanosuspension; S = Sporanox IV solution), indicating that higher drug levels in the target organ (kidney) lead to more death in the infectious organism. It is a graph of. FIG. 10 shows the mortality, morbidity profile after administration of antifungal drugs once or twice daily for 10 days in rats systemically infected with itraconazole-resistant Candida albicans It is a graph.

Claims (58)

A composition of an antibacterial agent that makes the drug effective against organisms normally considered to be resistant to the drug, the composition comprising an ionic surfactant, a nonionic surfactant Aqueous, submicron to micron sized particles comprising an agent, a biologically derived surfactant, and the agent covered with at least one surfactant selected from the group consisting of amino acids and derivatives thereof A composition comprising a suspension, wherein the particles have an average particle size weighted by a volume of less than 5 μm as measured by laser diffraction analysis. The composition of claim 1, wherein the particles have an average particle size weighted by a volume of less than 2 μm when measured by laser diffraction analysis. The composition of claim 1, wherein the particles have an average particle size weighted with a volume of less than 1 μm as measured by laser diffraction analysis. The composition of claim 1, wherein the particles have a volume-weighted average particle size of about 150 nm to about 1 μm as measured by laser diffraction analysis. The composition according to claim 1, wherein the antibacterial agent is an antifungal agent. The composition according to claim 5, wherein the antibacterial agent is a triazole antifungal agent. 7. The composition of claim 6, wherein the triazole antifungal agent is itraconazole, ketoconazole, miconazole, fluconazole, ravconazole, voriconazole, saperconazole, eberconazole, econconazole, genoconazole A composition selected from the group consisting of: clotrimazole, econazole, oxyconazole, sulconazole, terconazole, thioconazole and posaconazole. 2. The compound of claim 1, wherein the antimicrobial agent is itraconazole. The composition of claim 1, wherein the ionic surfactant is selected from the group consisting of a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, and combinations thereof. The composition. 10. The composition of claim 9, wherein the anionic surfactant is an alkyl sulfonate, an alkyl phosphate, an alkyl phosphonate, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecyl sulfate. , Polyoxyethylene alkyl sulfate, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidylserine, phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinosine, phosphatidic acid and its salts, sodium carboxymethylcellulose, cholic acid and other bile acids and their A composition selected from the group consisting of salts. 11. The composition of claim 10, wherein the bile acid is selected from the group consisting of cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, and glycodeoxycholic acid. The composition of claim 9, wherein the anionic surfactant is a phospholipid. 13. The composition of claim 12, wherein the phospholipid is natural or synthetic. The composition of claim 12, wherein the phospholipid is PEGylated. 9. The composition of claim 8, wherein the cationic interfacial agent is benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, acylcarnitine hydrochloride, alkylpyridinium chloride or an aliphatic amine. A composition selected from the group consisting of such quaternary ammonium compounds. The composition of claim 9, wherein the zwitterionic surfactant is a phospholipid. 17. The composition of claim 16, wherein the phospholipid is natural or synthetic. The composition of claim 16, wherein the phospholipid is PEGylated. The composition according to claim 1, wherein the nonionic surfactant includes glyceryl ester, polyoxyethylene fatty acid alcohol ester (Macrogol and Brij), polyoxyethylene sorbitan aliphatic ester (polysorbate), polyoxyethylene. Aliphatic ester (Myri), sorbitan ester (Span), glycerol monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, arylalkyl polyether alcohol, polyoxyethylene-polyoxypropylene copolymer (poloxamer) , Poloxamine, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl Cellulose, noncrystalline cellulose, starch and starch derivatives (e.g., hydroxyethyl starch (HES)) polysaccharides including, are selected from the group consisting of polyvinyl alcohol and polyvinyl pyrrolidone, composition. The composition according to claim 1, wherein the biologically derived surfactant is selected from the group consisting of albumin, casein, other proteins and polysaccharides. 21. The composition of claim 20, wherein the polysaccharide is selected from the group consisting of starch, heparin and chitosan. The composition according to claim 1, wherein the amino acid is selected from the group consisting of leucine, alanine, valine, isoleucine, lysine, aspartic acid, glutamic acid, methionine, tyrosine and phenylalanine. The composition of claim 1, wherein the amino acid derivative is an amide, ester or polypeptide. The composition of claim 1, wherein the surfactant is a bile salt. 25. The composition of claim 24, wherein the bile salt is deoxycholate. The composition according to claim 1, wherein the surfactant is a polyalkoxy ether. 27. The composition of claim 26, wherein the polyalkoxy ether is Poloxamer 188. The composition of claim 1, wherein the surfactant is hydroxyethyl starch. The composition of claim 1, wherein the surfactant is polyethylene-660-hydroxystearic acid. The composition of claim 1, wherein the surfactant is albumin. The composition of claim 1, wherein the surfactant is a phospholipid. The composition according to claim 1, wherein the aqueous suspension further comprises a pH adjusting agent. The pH adjuster is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, succinic acid, citric acid, tris (hydroxymethyl) aminomethane, magnesium, sodium hydroxide and amino acids. The composition as described. The amino acid is glycine, arginine, lysine, alanine, methionine, valine, asparagine, tyrosine, proline, serine, isoleucine, tryptophan, phenylalanine, threonine, cysteine, glutamine, aspartic acid, glutamic acid, histidine, taurine and leucine. 34. The composition of claim 33, which is selected. The composition of claim 1, further comprising an osmotic pressure regulator. 36. The composition of claim 35, wherein the osmotic pressure adjusting agent is selected from the group consisting of glycerin, monosaccharides, disaccharides, trisaccharides and sugar alcohols. 40. The composition of claim 36, wherein the monosaccharide is glucose. 37. The composition of claim 36, wherein the disaccharide is selected from the group consisting of sucrose, maltose and trehalose. 38. The composition of claim 36, wherein the trisaccharide is raffinose. 37. The composition of claim 36, wherein the sugar alcohol is mannitol or sorbitol. 2. The composition of claim 1, wherein the antimicrobial agent is present in an amount from about 0.01% w / v to about 50% w / v. 2. The composition of claim 1, wherein the antimicrobial agent is present in an amount from about 0.05% w / v to about 30% w / v. 2. The composition of claim 1, wherein the antimicrobial agent is present in an amount from about 0.1% w / v to about 20% w / v. The composition of claim 1, wherein the surfactant is present in an amount from about 0.001% w / v to about 5% w / v. The composition of claim 1, wherein the surfactant is present in an amount from about 0.005% w / v to about 5% w / v. 2. The composition of claim 1, wherein the surfactant is present in an amount from about 0.01% w / v to about 5% w / v. Administered by a route selected from the group consisting of parenteral route, oral route, buccal route, periodontal route, rectal route, nasal route, pulmonary route, transdermal route and topical route. The composition as described. Administered by a route selected from the group consisting of intravenous, intramuscular, intracerebral, subcutaneous, intradermal, intralymphatic, intrapulmonary, intraarticular, intrathecal and intraperitoneal. The composition according to claim 1. The composition of claim 1, wherein the aqueous medium is removed to form dry particles. 50. The composition of claim 49, wherein the method of removing the aqueous medium is selected from the group consisting of evaporation and lyophilization. 50. The composition of claim 49, wherein the method of removing the aqueous medium is lyophilization. 50. The composition of claim 49, wherein the dry particles are formulated into an acceptable pharmaceutical dosage form. The pharmaceutical dosage forms include parenteral solutions, tablets, capsules, suspensions, creams, lotions, emulsions, pulmonary formulations, topical formulations, controlled release or sustained release formulations, and tissues. 53. The composition of claim 52, selected from the group consisting of specific targeted delivery formulations. The composition of claim 1, wherein the composition is frozen. A composition of an antibacterial agent that makes the drug effective against organisms normally considered resistant to the drug, the composition being covered with at least one surfactant An aqueous suspension of itraconazole particles from submicron to micron size and an osmotic modifier, wherein the nanoparticles are weighted in a volume of less than 5 μm as measured by laser diffraction analysis And the itraconazole is present in an amount of about 0.01% w / v to about 50% w / v and the surfactant is about 0.001% to about 5% Present in an amount of. A composition of antibacterial agent particles that renders the drug effective against organisms normally considered resistant to the drug, the composition comprising the following steps:
(I) dissolving the antibacterial agent in a water-miscible first solvent to form a solution;
(Ii) mixing the solution with a second solvent that is water soluble to define a pre-suspension; and (iii) applying energy to the pre-suspension and having an average effective particle size of less than 5 μm Forming particles;
Prepared by a method comprising
Here, the solubility of the antimicrobial agent is greater in the first solvent than in the second solvent, and the second solvent is a nonionic surfactant, an ionic surfactant, a biologically derived interface A composition comprising an active agent and one or more surfactants selected from the group consisting of amino acids and derivatives thereof. A method for making a drug effective against an organism that is normally considered to be resistant to the drug, the method comprising: an ionic surfactant, a nonionic surfactant, a biological source Formulating the drug as an aqueous suspension of particles from sub-micron to micron size, comprising a drug coated with at least one surfactant selected from the group consisting of amino acids and derivatives thereof Wherein the particles have an average particle size weighted by a volume of less than 5 μm as measured by laser diffraction analysis. A method of treating a subject infected with an organism normally considered to be resistant to an antibacterial agent, the method comprising administering the agent to the subject, wherein the agent comprises: Submicron sized, comprising an ionic surfactant, a nonionic surfactant, a biologically derived surfactant, and a drug covered with at least one surfactant selected from the group consisting of amino acids and derivatives thereof A method formulated as an aqueous suspension of particles up to micron size, said particles having an average particle size weighted by a volume of less than 5 μm as measured by laser diffraction analysis.

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