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US20060003012A9 - Preparation of submicron solid particle suspensions by sonication of multiphase systems - Google Patents

Preparation of submicron solid particle suspensions by sonication of multiphase systems Download PDF

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Publication number
US20060003012A9
US20060003012A9 US09964273 US96427301A US2006003012A9 US 20060003012 A9 US20060003012 A9 US 20060003012A9 US 09964273 US09964273 US 09964273 US 96427301 A US96427301 A US 96427301A US 2006003012 A9 US2006003012 A9 US 2006003012A9
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phase
particles
aqueous
organic
compound
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US20050037083A1 (en )
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Sean Brynjelsen
Shmuel Sternberg
Andy Dunham
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Baxter International Inc
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Baxter International Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/513Organic macromolecular compounds; Dendrimers
    • A61K9/5169Proteins, e.g. albumin, gelatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5192Processes

Abstract

The present invention provides a method for preparing submicron-sized particles. The method includes the steps of: (1) providing a multiphase system having an organic phase and an aqueous phase, the organic phase having a pharmaceutically effective compound therein; and (2) sonicating the system to evaporate a portion of the organic phase to cause precipitation of the compound in the aqueous phase and having an average effective particle size of less than about 2 m.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • [0001]
    Not Applicable.
  • FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
  • [0002]
    Not Applicable.
  • TECHNICAL FIELD
  • [0003]
    The present invention provides a multistep process for generating submicron-sized particles of water insoluble organic compounds and more particularly a process for preparing submicron-sized particles of a pharmaceutically effective compound by sonicating a multiphase liquid.
  • BACKGROUND OF THE INVENTION
  • [0004]
    Background Art
  • [0005]
    The ability to deliver pharmaceutical medications in a water-soluble formulation is a critical concern in therapeutic drug development. The fact that poorly soluble drugs can pose difficulties in this area has resulted in the need for new technologies that can address this obstacle. One solution to this problem is the production of extremely small particles of the insoluble drug candidate and the creation of a microparticulate suspension. In this way, drugs that were previously unable to be formulated in an aqueous based system can be made suitable for parenteral administration. Suitability for parental administration includes small particle size (<7 μm), low toxicity (as from toxic formulation components or residual solvents), and bioavailability of the drug particles after administration.
  • [0006]
    One approach utilized with the anesthetic, propofol (2,6 diisopropylphenol) as an example, involves incorporating the pharmacological agent in a vegetable oil emulsion to enable intravenous administration. See, e.g., U.S. Pat. Nos. 4,056,635; 4,452,817 and 4,798,846, all to Glen et al. Such emulsions, however, tend to be unstable given the predominance of the oil phase and the absence of antimicrobial agents. In other instances, even where the pharmacological agent is successfully incorporated into an oil-free formulation, particles containing the pharmacological agent may cause irritation at the site of delivery because of their size or form.
  • [0007]
    A variety of approaches have been explored for formulating a substantially water-insoluble pharmacologically active agent for in vivo delivery. One approach is directed to the production of suspended particles coated with protein. U.S. Pat. No. 5,916,596, issued to Desai et al., discloses the application of high shear to a mixture of an organic phase having a pharmacologically active agent dispersed therein and an aqueous medium containing a biocompatible polymer. The mixture is sheared in a high pressure homogenizer at a pressure in the range of from about 3,000 to 30,000 psi. The claims explicitly provide that the mixture must contain substantially no surfactants because the combined use of a surfactant with a protein results in the formation of large, needle-like crystalline particles that increase in size during storage. See columns 17-18, example 4. Example 2 discloses that crude emulsion may be sonicated to produce nanoparticles ranging from 350-420 nanometers.
  • [0008]
    U.S. Pat. No. 5,560,933, issued to Soon-Shiong et al., discloses the formation of a polymeric shell around the water-insoluble drug for in vivo delivery. The method discloses the application of sonication to a mixture comprising a polymer-containing aqueous medium and a dispersing agent having a substantially water-insoluble drug dispersed therein. In this reference, sonication is used to drive the formation of disulfide bonds in the polymer, causing it to crosslink so as to produce a polymeric shell around the drug. Sonication is conducted for a time sufficient for the disulfide bonds to form.
  • [0009]
    In U.S. Pat. No. 5,665,383, Grinstaff et al. discloses the application of ultrasound to a single-phase B i.e., an aqueous medium—to encapsulate an immunostimulating agent within a polymeric shell for in vivo delivery. The ultrasound promotes crosslinking of the encapsulating agent by disulfide bonds to form the shell.
  • [0010]
    Another approach to preparing a water-insoluble drug for in vivo delivery centers on reducing the size of the particles that deliver the drug. In one such series of patents, which include U.S. Pat. Nos. 6,228,399; 6,086,376; 5,922,355; and 5,660,858, Parikh et al. discloses that sonication may be used to prepare microparticles of the water-insoluble compound. Of these patents, U.S. Pat. No. 5,922,355 discloses an improvement to a method that uses sonication for making the smaller particles. The improvement comprises mixing an active pharmacological agent with a phospholipid and surfactants in a single-phase aqueous system and applying energy to the system to produce the smaller particles.
  • [0011]
    U.S. Pat. No. 5,091,188, issued to Haynes, also discloses reducing the size of particles of a pharmacologically active water-insoluble drug and employing a lipid coating on the particles to confer a solid form. The patent is directed to a pharmaceutical composition consisting essentially of an aqueous suspension of solid particles of the drug having a diameter of about 0.05 to about 10 microns. The lipid coating affixed to the surface of the particles contributes to their solid form. The composition is produced by adding the drug to water and then reducing the particle size within the aqueous suspension. Example 6 of this reference discloses the use of a pharmacologically acceptable oil which is selected for its inability to dissolve the crystalline drug. See column 16, lines 8-12.
  • [0012]
    Still another approach for preparing microparticles of a pharmacological agent focuses on the use of phase inversion principles. U.S. Pat. Nos. 6,235,224B1 and 6,143,211, both issued to Mathiowitz et al., disclose the use of phase inversion phenomena to precipitate microencapsulated microparticles. The method includes mixing a polymer and a drug with a solvent. This mixture is introduced into an effective amount of a miscible nonsolvent, thereby causing spontaneous formation of the microencapsulated product.
  • [0013]
    Microprecipitation is another technology used to prepare dispersions of a nanoparticulate pharmaceutical agent. See, e.g., U.S. Pat. Nos. 5,766,635; 5,665,331; and 5,662,883. This technology involves dissolving a pharmaceutical in an aqueous base which is then neutralized to form a dispersion.
  • [0014]
    In yet another approach, such as that disclosed in U.S. Pat. No. 5,766,635, issued to Spenlenhauer et al., nanoparticles have been prepared by dissolving a poly(ethylene) oxide and/or poly(propylene) oxide in an organic solvent, mixing the organic solution so formed with an aqueous solution to cause nanoparticles to precipitate out of solution, and microfluidizing the precipitated solution without the use of surfactants.
  • [0015]
    Because of the difficulties posed by poorly soluble drugs in drug therapy, the need for new technologies continues to expand for addressing these problems.
  • SUMMARY OF THE INVENTION
  • [0016]
    The present invention provides a method for preparing submicron sized particles. The method includes the steps of: (1) providing a multiphase system having an organic phase and an aqueous phase, the organic phase having a pharmaceutically effective compound therein; and (2) sonicating the system to evaporate a portion of the organic phase to cause precipitation of the compound in the aqueous phase and having an average effective particle size of less than about 400 m.
  • [0017]
    The present invention further provides a process for preparing an aqueous suspension of submicron sized particles. The process includes the steps of: (1) providing an organic phase of a pharmacologically active compound dissolved in a water immiscible solvent, (2) providing an aqueous phase, (3) combining the organic phase with the aqueous phase, and (3) sonicating the emulsion to cause precipitation of the compound as a suspension of particles in the aqueous phase wherein the aqueous phase is essentially free of the water immiscible solvent.
  • [0018]
    These and other aspects and attributes of the present invention will be discussed with reference to the following drawings and accompanying specification.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0019]
    FIG. 1 is a schematic representation of a process of the present invention;
  • [0020]
    FIG. 2 is a high magnification SEM photograph of itraconazole particles;
  • [0021]
    FIG. 3 is a low magnification SEM photograph of itraconazole particles; and
  • [0022]
    FIG. 4 is an x-ray powder diffraction spectrum of itraconazole nanoparticles and raw material.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0023]
    While this invention is susceptible of embodiment in many different forms, there is shown in the drawing, and will be described herein in detail, specific embodiments thereof with the understanding that the present disclosure is to be considered as an exemplification of the principles of the invention and is not intended to limit the invention to the specific embodiments illustrated.
  • [0024]
    The present invention provides a process for preparing submicron-sized particle suspensions. The process comprises the steps of: (1) providing a multiphase system having an organic phase and an aqueous phase, the organic phase having a pharmaceutically effective compound therein; and (2) sonicating the system to evaporate a portion of the organic phase to cause precipitation of the compound in the aqueous phase and having an average effective particle size of less than about 2 μm. The step of providing a multiphase system includes the steps of: (1) mixing a water immiscible solvent (oil phase) with the pharmaceutically effective compound to define an organic solution, (2) preparing an aqueous based solution with one or more surface active compounds, and (3) mixing the organic solution with the aqueous solution to form the multiphase system. The multiphase system can be agitated or mixed to form a crude emulsion. The crude emulsion will have oil droplets in the water of a size of approximately less than 1 μm in diameter. The crude emulsion is sonicated to define a microemulsion and eventually to define a submicron particle suspension. (See FIG. 1).
  • [0025]
    What is meant by the term “multiphase system” is an emulsion having at least one organic phase and at least one aqueous phase and in a preferred form of the invention is an oil in water (O/W) emulsion where the water phase forms the continuous phase and the oil phase forms the dispersed phase. The ratio by weights of the organic phase to the aqueous phase is from about 1:99 to about 40:60, more preferably from about 2:98 to about 30:70 or any range or combination of ranges therein. The present invention further contemplates utilizing reverse emulsions or water in oil emulsion (W/O) where the oil phase forms the continuous phase and water the dispersed phase. The present invention further contemplates utilizing emulsions having more than two phases such as an oil in water in oil emulsion or O/W/O.
  • [0026]
    What is meant by the term “pharmaceutically effective compound” is any compound that has therapeutic effect and more particularly to such compounds that are insoluble or slightly soluble in water (those having a solubility of less than 10 mg/ml). Such compounds can be found in the Physicians' Desk Reference (PDR), which is incorporated herein by reference. Particularly suitable pharmaceutically active compounds include, but are not limited to, antihyperlipidemics; antimicrobials, e.g., antibacterials such as sulfadiazine, antifungals such as itraconazole; non-steroidal anti-inflammatory drugs, e.g., indomethacin; antihypercholesteremic agents, e.g., probucol; and steroidal compounds, e.g., dexamethasone; immunosuppresants, e.g., cyclosporin A, tacrolimus, and mycophenolate mofetil. Or the organic compound might be from the group used as adjuvants or excipients in pharmaceutical preparations and cosmetics, such as, but not limited to, preservatives, e.g., propylparaben.
  • [0027]
    The pharmaceutically effective compound can be present in a concentration to the extent it is soluble in the organic phase. In a preferred form of the invention the pharmaceutically effective compound can be present in an amount from less than 1% to about 40%, more preferably from about 1% to about 25%, and most preferably from about 1% to about 10% by weight of the organic phase or any range or combination of ranges therein.
  • [0028]
    What is meant by the term “water immiscible solvent” are those solvents which form an interfacial meniscus when combined with an aqueous solution in a 1:1 ratio (o/w). In a preferred form of the invention the water immiscible solvent (oil phase) will have a vapor pressure higher than that of water when both the solvent and water are measured at room temperature. Suitable water immiscible solvents include, but are not limited to, substituted or unsubstituted, linear, branched or cyclic alkanes with a carbon number of 5 or higher, substituted or unsubstituted, linear, branched or cyclic alkenes with a carbon number of 5 or higher, substituted or unsubstituted, linear, branched or cyclic alkynes with a carbon number of 5 or higher; aromatic hydrocarbons completely or partially halogenated hydrocarbons, ethers, esters, ketones, mono-, di- or tri-glycerides, native oils, alcohols, aldehydes, acids, amines, linear or cyclic silicones, hexamethyldisiloxane, or any combination of these solvents. Halogenated solvents include, but are not limited to carbon tetrachloride, methylene chloride, chloroform, tetrachloroethylene, trichloroethylene, trichloroethane, hydrofluorocarbons, chlorinated benzene (mono, di, tri), trichlorofluoromethane. Particularly suitable solvents are methylene chloride, chloroform, diethyl ether, toluene, xylene and ethyl acetate.
  • [0029]
    What is meant by the term “surface active compounds” are compounds such as an anionic surfactant, a cationic surfactant, a nonionic surfactant or a biological surface active molecule. The surface-active compound can be added to the organic phase, the aqueous phase or to both the organic phase and the aqueous phase. The surface active compound should be present in an amount by weight of the aqueous phase or the organic phase, whatever the case may be, from less than about 1% to about 30%, more preferably from about 1% to about 20% or any range or combination of ranges therein.
  • [0030]
    Suitable anionic surfactants include but are not limited to: potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid and their salts, glyceryl esters, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.).
  • [0031]
    Suitable cationic surfactants include but are not limited to quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, acyl camitine hydrochlorides, or alkyl pyridinium halides. As anionic surfactants, phospholipids may be used. Suitable phospholipids include, for example, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidyl inositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination thereof. The phospholipid may be salted or desalted, hydrogenated or partially hydrogenated or natural, semisynthetic or synthetic.
  • [0032]
    Suitable nonionic surfactants include: polyoxyethylene fatty alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters (Myrj), sorbitan esters (Span), glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxomers), polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polysaccharides including starch and starch derivatives such as hydroxyethylstarch (HES), polyvinyl alcohol, and polyvinylpyrrolidone. In a preferred form of the invention the nonionic surfactant is a polyoxyethylene and polyoxypropylene copolymer and preferably a block copolymer of propylene glycol and ethylene glycol. Such polymers are sold under the tradename POLOXAMER also sometimes referred to as PLLRONIC®, and sold by several suppliers including Spectrum Chemical and Ruger. Among polyoxyethylene fatty acid esters is included those having short alkyl chains. One example of such a surfactant is SOLUTOL® HS 15, polyethylene-660-hydroxystearate, manufactured by BASF Aktiengesellschaft.
  • [0033]
    Surface-active biological molecules include such molecules as albumin, casein, heparin, hirudin or other appropriate proteins.
  • [0000]
    Sonicating
  • [0034]
    The step of sonicating can be carried out with any suitable sonication device (Branson Model S-450A or Cole-Parmer 500/750 Watt Model). Such devices are well known in the industry. Typically the sonication device has a sonication horn or probe that is inserted into the multiphase system of interest to emit sonic energy into the solution. The sonicating device, in a preferred form of the invention, is operated at a frequency of from about 1 kHz to about 90 kHz and more preferably from about 20 kHz to about 40 kHz or any range or combination of ranges therein. The probe sizes can vary and preferably is in distinct sizes such as ½ inch or ¼ inch or the like. It may also be desirable to cool the solution during sonication to temperatures below room temperature. It may also be desirable to employ other mixing devices such as homogenizers, blenders or other stirring devices to assist in the process.
  • [0035]
    Exposing the emulsion droplets to shear energy can reduce the droplet sizes. Sonication provides a source of shear energy that effectively reduces the diameters of the emulsion droplets. Shear from sonication results from the compression and rarefaction of the propagation medium of the sound waves. In pure liquids this oscillation between compression and rarefaction is sufficiently energetic to cause cavitation, which is the tearing of the liquid to cause bubble formation. In an emulsion, the analogous process results in tearing the emulsified liquid particles into smaller particles. Cavitation and the warming of the emulsion during sonication also appear to effect removal of the water immiscible solvent. As the solvent is removed the solubility of the water-insoluble compound in the emulsion decreases, eventually allowing precipitation of the compound. Under appropriate conditions, the precipitation of the insoluble compound occurs in a manner which retains the original particle size of the sonicated emulsion.
  • [0036]
    The sonicating step is effective to remove nearly all solvent in the system to provide a particle suspension essentially free of the organic phase.
  • [0037]
    The present invention further contemplates additional processing of the resulting dispersion including removal of any residual solvent that may exist by means such as evaporation by the addition of heat or under reduced pressure, or through diafiltration. The solvent-free suspension can then be filtered through an appropriate 0.2 μm filter, resulting in a sterile suspension. This suspension is then amenable to further processing including freezing or lyophilization.
  • [0038]
    The particles of the pharmaceutically effective compound should be less than about 2 μm in diameter as determined by light scattering (HORIBA) or microscopic measurements. More preferably the particles should be less than about 1 μm, even more preferably less than about 400 nm and even more preferably less than about 200 nm and most preferably less than about 100 nm or any range or combination of ranges therein.
  • [0039]
    The particles have a generally spherical shape. Further, in a preferred form of the invention the particles will be amorphous. What is meant by amorphous is an X-ray crystal study of the particles shows virtual absence of x-ray peaks. See example 8 and FIG. 4.
  • [0040]
    In another preferred form of the invention the aqueous phase includes a combination of a non-phospholipid containing surface active compound (selected from the group of surface active compounds set forth above) and a phospholipid containing compound selected from the group set forth above. The ratio by weight of phospholipid to the non-phospholipid surface active compound should be within the range of from about 1:99 to about 99:1, and more preferably from about 75:25 to 50:50 or any range or combination ranges therein.
  • EXAMPLES Example 1 Preparation of a 0.5% Itraconazole Suspension Using a 1:10 Ratio of O/W
  • [0041]
    A 5% lecithin/glycocholate surfactant solution was prepared (100 mL) and combined with 10 mL of a chloroform solution containing itraconazole (0.5 grams). The resulting mixture was manually shaken to generate a crude emulsion and set in an ice bath to chill. After cooling for 5 minutes the emulsion was sonicated every other minute for 10 minutes (5 minutes total sonication time at 40% power using a ½″ probe at 20 kHz) and then rotovapped at ˜120 Torr (no heat) to remove the chloroform. The resulting solid particle dispersion was analyzed by light scattering detection (HORIBA) which revealed particles having a mean diameter of 97.78 nm.
  • Example 2 Preparation of a 1.0% Itraconazole Suspension Using a 1:5 Ratio of O/W
  • [0042]
    A 5% lecithin/glycocholate surfactant solution was prepared (50 mL) and combined with 5 mL of a chloroform solution containing itraconazole (0.5 grams). The resulting mixture was manually shaken to generate a crude emulsion and set in an ice bath to chill. After cooling for 5 minutes the emulsion was sonicated every other minute for 10 minutes (5 minutes total sonication time) and then rotovapped at ˜100 Torr (no heat) to remove the chloroform. The resulting solid particle dispersion was analyzed by light scattering detection (HORIBA) which revealed particles having a mean diameter of 135 nm.
  • Example 3
  • [0043]
    The process described in example 1 was repeated with the resulting particles having a mean diameter of 139 nm. This suspension was further analyzed by scanning electron microscopy to reveal solid spherical particles less than 200 nm in size. See FIG. 2.
  • [0044]
    FIG. 2 reveals the spherical nature of the particles produced. The sample was prepared by filtration of a small portion o the suspension through a 80 nm filter and using standard SEM sample preparation techniques. Analysis of particles produced by this process revealed the particles to be completely amorphous as determined by x-ray powder diffraction.
  • Example 4
  • [0045]
    Preparation of a 1.0% Itraconazole Suspension Using a 2:5 Ratio of O/W
  • [0046]
    A 5% lecithin/sodium glycocholate solution was prepared (50 mL) and combined with 20 mL of chloroform containing itraconazole (0.5 grams). The resulting mixture was manually shaken to generate a crude emulsion and set in ice bath to chill. After cooling for 5 minutes the emulsion was sonicated every other minute for 8 minutes and than sonicated for 30 seconds (giving 4 minutes and 30 seconds of total sonication time) using a ½″ probe at 40% amplitude. The sonicated dispersion was solvent evaporated at ˜100 Torr (no heat) to remove chloroform. 10 mL of the final solution was filtered through a 0.2 micron filter. Both filtered and unfiltered solid particle dispersions were analyzed by light scattering detection (HORIBA), which revealed particles having a mean diameter of 110 nm and 106 nm respectively.
  • Example 5
  • [0047]
    A 5% lecithin/sodium glycocholate solution was prepared (50 mL) and combined with 10 mL of methylene chloride containing itraconazole (0.5 grams). The resulting mixture was manually shaken to generate a crude emulsion and set in ice bath to chill. After cooling for 5 minutes the emulsion was sonicated every other minute for 6 minutes (giving 3 minutes of total sonication time) using a ½″ probe at 40% amplitude. The sonicated dispersion was solvent evaporated at ˜100 Torr (no heat) to remove methylene chloride. The resulting solid particle dispersion was analyzed by light scattering detection (HORIBA) which revealed particles having a mean diameter of 144 nm.
  • Example 6
  • [0048]
    A 5% lecithin/sodium glycocholate solution was prepared (50 mL) and combined with 5 mL of methylene chloride containing itraconazole (0.5 grams). The resulting mixture was manually shaken to generate a crude emulsion and set in ice bath to chill. After cooling for 5 minutes the emulsion was sonicated every other 30 seconds for 6 minutes (giving 3 minutes of total sonication time) using a ¼″ probe at 20% amplitude. The sonicated solution was evaporated using rotavapor at ˜100 Torr (no heat) to remove methylene chloride. Resulting solid particle dispersions was analyzed by light scattering detection (HORIBA) which revealed particles having a mean diameter of 109 nm.
  • Example 7 Determination of Solid Particle Size and Morphology Directly After Sonication
  • [0049]
    The process described in example 6 was repeated except that no solvent removal was performed after sonication. Instead the sample was submitted for particle size determination by HORIBA analysis and scanning electron microscopy. HORIBA results indicated a mean particle diameter of 156 nm. The SEM pictures revealed solid spherical particles under 200 nm in size.
  • Example 8 Determination of Amorphous Nature of Drug Particles
  • [0050]
    A crude itraconazole emulsion was prepared by combining 50 mL of a surfactant solution (2.2% lecithin, 0.5% sodium glycocholate, 1.0% polyvinylpyrrolidone) with 5 mL of a methylene chloride solution containing 0.5 grams of itraconazole. The mixture was then manually shaken to disperse the oil droplets into the surfactant matrix.
  • [0051]
    The crude emulsion was sonicated every other 30 seconds for 6 minutes using ¼″ probe at 20% amplitude and 20 kHz (temperature ˜5° C. using an ice bath). The sonicated solution was then rotovapped under house vacuum (100 torr) for 15-20 minutes followed by 10 minutes under a high vacuum (<20 Torr). Part of the solution was stored at −70 degrees celsius for about an hour, and subsequently lyophilized (>48 hours). Particle size of the remaining suspension was determined to be 168 nm by light scattering analysis (HORIBA). Inspection of the freeze-dried nanoparticles after lyophilization by visible light microscopy did not reveal any crystals present. Spherical particle halos were barely observable indicating that the itraconazole nanoparticles were intact.
  • [0052]
    The lyophilized itraconazole nanoparticles were assessed by X-ray powder diffraction and determined to be completely amorphous (virtual absence of x-ray peaks). In the raw material scan (the lower curve in FIG. 4) many peaks are observable revealing the crystalline nature of the compound in its original state.
  • [0053]
    While the specific embodiments have been illustrated and described, numerous modifications come to mind without significantly departing from the spirit of the invention and scope of protection is only limited by the scope of the accompanying Claims.

Claims (29)

  1. 1. A process for preparing submicron sized particles comprising the steps of:
    providing a multiphase system having an organic phase and an aqueous phase, the organic phase having a pharmaceutically effective compound therein; and
    sonicating the system to evaporate a portion of the organic phase to cause precipitation of the compound in the aqueous phase and having an average effective particle size of less than about 2 μm.
  2. 2. The process of claim 1, wherein the ratio by weights of the organic phase to the aqueous phase is from about 1:99 to about 99:1.
  3. 3. The process of claim 1, wherein the compound is present in an amount by weight of the organic phase from less than about 1% to about 40%.
  4. 4. The process of claim 1, wherein the step of sonicating the system comprises the steps of:
    providing a sonication device having a transducer for emitting sonic energy; and
    exposing the system to said sonic energy sufficient to allow for cavitation to occur.
  5. 5. The process of claim 4, wherein the step of sonicating comprises the steps of:
    operating the device at a frequency of from about 1 kHz to about 90 kHz.
  6. 6. The process of claim 1, further comprising the step of adding a surface active compound to either the organic phase, the aqueous phase or to both the organic phase and the aqueous phase.
  7. 7. The process of claim 6, wherein the surface active compound is selected from the group consisting of anionic surfactants, cationic surfactants, nonionic surfactants and biological surface active molecules.
  8. 8. The method of claim 7, wherein the nonionic surfactant is selected from the group consisting of: polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers, polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polysaccharides, starch, starch derivatives, hydroxyethylstarch, polyvinyl alcohol, and polyvinylpyrrolidone.
  9. 9. The method of claim 8, wherein the anionic surfactant is selected from the group consisting of: anionic surfactant is selected from the group consisting of: potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidyl inositol, phosphatidylserine, phosphatidic acid and their salts, glyceryl esters, sodium carboxymethylcellulose, bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, and calcium carboxymethylcellulose.
  10. 10. The method of claim 7, wherein the cationic surfactant is selected from the group consisting of quaternary ammonium compounds, benzalkonium chloride, cetyltrimethyl ammonium bromide, chitosans and lauryldimethylbenzylammonium chloride.
  11. 11. The method of claim 2, wherein the surface active biological modifiers are selected from the group consisting of: albumin, casein, heparin, hirudin, or other proteins.
  12. 12. The method of claim 1, further comprising the step of: adding a phospholipid to either the organic phase, the aqueous phase or to both the organic phase and the aqueous phase.
  13. 13. The method of claim 12, wherein the phospholipid is selected from natural phospholipids and/or synthetic phospholipids.
  14. 14. The method of claim 12, wherein the phospholipid is selected from the group consisting of: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg phospholipid and soybean phospholipid.
  15. 15. The method of claim 12, wherein further comprising the step of adding a surface-active compound to the system.
  16. 16. The method of claim 15, wherein the surfactant is selected from the group consisting of anionic surfactants, cationic surfactants, and biological surface-active molecules.
  17. 17. The method of claim 16, wherein the nonionic surfactant is selected from the group consisting of: polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, albumin, heparin, and hirudin.
  18. 18. The method of claim 16, wherein the anionic surfactant is selected from the group consisting of: potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidyl inositol, phosphatidylserine, phosphatidic acid and their salts, glyceryl esters, sodium carboxymethylcellulose, bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, and calcium carboxymethylcellulose.
  19. 19. The method of claim 16, wherein the cationic surfactant is selected from the group consisting of quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitosans and lauryldimethylbenzylammonium chloride.
  20. 20. The method of claim 1, wherein the organic phase comprises a water immiscible solvent.
  21. 21. The method of claim 20, wherein the water immiscible solvent is selected from the group consisting of: is selected from the group consisting of: linear, branched or cyclic alkanes with carbon number of 5 or higher, linear, branched or cyclic alkenes with carbon number of 5 or higher, linear, branched or cyclic alkynes with carbon number of 5 or higher; aromatic hydrocarbons completely or partially halogenated hydrocarbons, ethers, esters, ketones, mono-, di- or tri-glycerides, native oils, alcohols, aldehydes, acids, amines, linear or cyclic silicones, hexamethyldisiloxane, or any combination of these solvents
  22. 22. The method of claim 21, wherein the water immiscible solvent has a vapor pressure higher than water at room temperature.
  23. 23. The method of claim 1, wherein generation of the crude emulsion is accomplished by use of piston gap homogenizers, colloidal mills, high speed stirring, extrusion, manual agitation or shaking, microfluidization, or other high shear conditions.
  24. 24. The method of claim 1, wherein the compound is selected from the group consisting of: antihyperlipidemics, anesthetics, antiasthamatics, antimicrobials, antifungals, antineoplastics, non-steroidal anti-inflammatory drugs, antihypercholesteremic agents, analgesics, steroidal compounds, antipyretics, antidepressants, antiarrhtlimics, antianxiety drugs, antimanics, antiarthritics, antihistamines, anti-infectives, water insoluble vitamins, antipsychotics, sedatives, antihypertensive agents, diagnostic agents, anticonvulsants and immunosuppresants.
  25. 25. A process for preparing an aqueous suspension of submicron sized particles comprising the steps of:
    providing an organic phase of a pharmacologically active compound dissolved in a water immiscible solvent;
    providing an aqueous phase;
    combining the organic phase with the aqueous phase; and
    sonicating the emulsion to cause precipitation of the compound as a suspension of particles in the aqueous phase wherein the aqueous phase is essentially free of the water immiscible solvent.
  26. 26. The process of claim 25, wherein the particle is in an amorphous form.
  27. 27. The process of claim 26, wherein the particle has an average effective particle size of less than about 2 μm.
  28. 28. The process of claim 26, wherein the particle has an average effective particle size of less than about 400 nm.
  29. 29. The process of claim 26, wherein the particle has an average effective particle size of less than about 300 nm.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013066735A1 (en) * 2011-10-31 2013-05-10 Merck Sharp & Dohme Corp. Nano-suspension process

Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001131087A (en) * 1999-11-05 2001-05-15 Chemo Sero Therapeut Res Inst Oil adjuvant vaccine
US20040022862A1 (en) * 2000-12-22 2004-02-05 Kipp James E. Method for preparing small particles
US20040256749A1 (en) * 2000-12-22 2004-12-23 Mahesh Chaubal Process for production of essentially solvent-free small particles
US6884436B2 (en) * 2000-12-22 2005-04-26 Baxter International Inc. Method for preparing submicron particle suspensions
US20030096013A1 (en) * 2000-12-22 2003-05-22 Jane Werling Preparation of submicron sized particles with polymorph control
US9700866B2 (en) * 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
US8067032B2 (en) * 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US20050048126A1 (en) * 2000-12-22 2005-03-03 Barrett Rabinow Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug
US20030072807A1 (en) * 2000-12-22 2003-04-17 Wong Joseph Chung-Tak Solid particulate antifungal compositions for pharmaceutical use
JP4731793B2 (en) * 2000-12-28 2011-07-27 アルセア テクノロジーズ インコーポレイテッド Crystals whole antibodies or fragments thereof, and methods for making and using this crystal
US6939564B2 (en) * 2001-06-08 2005-09-06 Labopharm, Inc. Water-soluble stabilized self-assembled polyelectrolytes
JP2005500304A (en) * 2001-06-21 2005-01-06 アルタス バイオロジックス インコーポレイテッド Globular protein particles and and using manufacturing thereof
ES2287293T3 (en) * 2001-08-06 2007-12-16 Astrazeneca Ab stable aqueous dispersion comprising nanoparticles of medium-chain triglycerides (MCT) active, water insoluble excipient type.
CA2461349C (en) * 2001-09-26 2011-11-29 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal
US20060003012A9 (en) * 2001-09-26 2006-01-05 Sean Brynjelsen Preparation of submicron solid particle suspensions by sonication of multiphase systems
US7112340B2 (en) * 2001-10-19 2006-09-26 Baxter International Inc. Compositions of and method for preparing stable particles in a frozen aqueous matrix
GB0216700D0 (en) * 2002-07-18 2002-08-28 Astrazeneca Ab Process
GB0230088D0 (en) * 2002-12-24 2003-01-29 Astrazeneca Ab Therapeutic agents
GB0230087D0 (en) * 2002-12-24 2003-01-29 Astrazeneca Ab Therapeutic agents
GB0302673D0 (en) * 2003-02-06 2003-03-12 Astrazeneca Ab Pharmaceutical formulations
GB0302672D0 (en) * 2003-02-06 2003-03-12 Astrazeneca Ab Pharmaceutical formulations
GB0302671D0 (en) * 2003-02-06 2003-03-12 Astrazeneca Ab Pharmaceutical formulations
US7177487B2 (en) * 2003-04-21 2007-02-13 Baxter International Inc. Determination of particle size by image analysis
US7009169B2 (en) * 2003-04-21 2006-03-07 Baxter International Inc. Method for measuring particle size distribution of a population of particles
US20050244503A1 (en) * 2003-05-19 2005-11-03 Rabinow Barrett E Small-particle pharmaceutical formulations of antiseizure and antidementia agents and immunosuppressive agents
GB0314057D0 (en) * 2003-06-18 2003-07-23 Astrazeneca Ab Therapeutic agents
JP2006527770A (en) * 2003-06-18 2006-12-07 アストラゼネカ アクチボラグ 2-substituted as Cb1 modulator 5,6-diaryl - pyrazine derivatives
GB0314261D0 (en) * 2003-06-19 2003-07-23 Astrazeneca Ab Therapeutic agents
EP1663158A2 (en) * 2003-06-24 2006-06-07 Baxter International Inc. Specific delivery of drugs to the brain
US8986736B2 (en) * 2003-06-24 2015-03-24 Baxter International Inc. Method for delivering particulate drugs to tissues
WO2005002546A1 (en) * 2003-06-27 2005-01-13 Smithkline Beecham Corporation Stabilized topotecan liposomal composition and methods
RU2392004C2 (en) 2003-09-22 2010-06-20 Бакстер Интернэшнл Инк. High pressure final sterilisation of pharmaceutic preparations and medical products
ES2349774T3 (en) * 2003-10-22 2011-01-11 Chiesi Farmaceutici S.P.A. Process for the preparation of pharmaceutical suspensions for inhalation.
DE10351644A1 (en) * 2003-11-05 2005-06-09 Bayer Technology Services Gmbh Process for preparing storage-stable multiple emulsions
RU2006130958A (en) * 2004-01-29 2008-03-10 Бакстер Интернэшнл Инк. (Us) Nanosuspension antiretroviral agents for enhanced delivery to the central nervous system
EP1711163A2 (en) * 2004-02-05 2006-10-18 Baxter International Inc. Dispersions prepared by use of self-stabilizing agents
US8535716B2 (en) * 2004-04-01 2013-09-17 Tsrl, Inc. Methods and composition of extended delivery of water insoluble drugs
US20070219131A1 (en) * 2004-04-15 2007-09-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier
US20110135734A1 (en) * 2004-04-20 2011-06-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method For the Preparation of Nanoparticles From Nanoemulsions
US20070259348A1 (en) * 2005-05-03 2007-11-08 Handylab, Inc. Lyophilized pellets
KR20070037444A (en) * 2004-06-15 2007-04-04 박스터 헬쓰케어 에스.에이. Ex-vivo application of solid microparticulate therapeutic agents
JP4998888B2 (en) 2004-11-15 2012-08-15 オーストラリアン ニュークリア サイエンス アンド テクノロジー オーガニゼーション Solid particles from a controlled destabilization of the microemulsion
US20090098044A1 (en) * 2004-11-15 2009-04-16 Australian Nuclear Science And Technology Organisation Solid particles from controlled destabilisation of microemulsions
US20060198891A1 (en) 2004-11-29 2006-09-07 Francois Ravenelle Solid formulations of liquid biologically active agents
EP1847602B1 (en) * 2005-01-12 2014-04-23 Kyowa Hakko Kirin Co., Ltd. STABILIZED HUMAN IgG2 ANTIBODIES
US20060280787A1 (en) * 2005-06-14 2006-12-14 Baxter International Inc. Pharmaceutical formulation of the tubulin inhibitor indibulin for oral administration with improved pharmacokinetic properties, and process for the manufacture thereof
JP2008543842A (en) * 2005-06-14 2008-12-04 バクスター インターナショナル インコーポレイテッド Drug - Pharmaceutical formulations for minimizing drug interaction
EP1906915B1 (en) * 2005-06-17 2017-09-27 Australian Nuclear Science And Technology Organisation Particles having hydrophobic material therein
CN101242814A (en) 2005-06-17 2008-08-13 澳大利亚核科学技术组织 Particles comprising a releasable dopant therein
EP1922150A1 (en) * 2005-07-07 2008-05-21 Nanotherapeutics, Inc. Process for milling and preparing powders and compositions produced thereby
EP1782797A1 (en) * 2005-11-02 2007-05-09 Pharmatex Italia Srl Process for the preparation of sterile powdered pharmaceutical compounds.
KR20080080119A (en) * 2005-11-15 2008-09-02 박스터 헬쓰케어 에스.에이. Compositions of lipoxygenase inhibitors
WO2007064912A3 (en) * 2005-12-02 2007-10-25 Elan Pharma Int Ltd Mometasone compositions and methods of making and using the same
GB0613925D0 (en) * 2006-07-13 2006-08-23 Unilever Plc Improvements relating to nanodispersions
US20080075777A1 (en) * 2006-07-31 2008-03-27 Kennedy Michael T Apparatus and methods for preparing solid particles
ES2645851T3 (en) 2006-09-14 2017-12-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Nanoparticles of pesticides obtained from microemulsions and nanoemulsions
EP2061583A2 (en) * 2006-09-14 2009-05-27 Yissum Research Development Company, of The Hebrew University of Jerusalem Organic nanoparticles obtained from microemulsions by solvent evaporation
WO2008035229A3 (en) * 2006-09-22 2009-08-13 Labopharm Barbados Ltd Compositions and methods for ph targeted drug delivery
US20080121733A1 (en) * 2006-11-29 2008-05-29 Donald Ackley Droplet generating device and method
WO2008080047A3 (en) * 2006-12-23 2008-08-14 Baxter Int Magnetic separation of fine particles from compositions
EP2124898B1 (en) 2007-01-10 2013-08-14 Board of Regents, The University of Texas System Enhanced delivery of immunosuppressive drug compositions for pulmonary delivery
CN101270128B (en) * 2007-03-23 2012-05-23 清华大学 Method for preparing 8-hydroxyquinoline aluminum nanocrystalline
US8426467B2 (en) * 2007-05-22 2013-04-23 Baxter International Inc. Colored esmolol concentrate
US20080293814A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Concentrate esmolol
US8722736B2 (en) * 2007-05-22 2014-05-13 Baxter International Inc. Multi-dose concentrate esmolol with benzyl alcohol
RU2496482C2 (en) 2008-03-05 2013-10-27 Бакстер Интернэшнл Инк. Compositions and methods for drug delivery
US20100151037A1 (en) * 2008-08-07 2010-06-17 Yivan Jiang Method for the preparation of nanoparticles containing a poorly water-soluble pharmaceutically active compound
EP2156823A1 (en) * 2008-08-14 2010-02-24 Pharmatex Italia Srl Process for the preparation of sterile powdered pharmeceutical compounds in the form of micro and nanoparticles
RU2552324C2 (en) 2008-09-17 2015-06-10 Киазма Инк. Pharmaceutical compositions and respective delivery methods
US9399075B2 (en) 2008-12-29 2016-07-26 General Electric Company Nanoparticle contrast agents for diagnostic imaging
US20100290983A1 (en) * 2009-05-15 2010-11-18 Baxter International Inc. Compositions and Methods for Drug Delivery
CN102048702B (en) * 2010-12-03 2012-05-23 山东大学 Bifendate nano crystal preparation and preparation method thereof
EP2468258A1 (en) * 2010-12-22 2012-06-27 LEK Pharmaceuticals d.d. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient
US20130122058A1 (en) * 2011-11-11 2013-05-16 The Chinese University Of Hong Kong Engineering of polymer-stabilized nanoparticles for drugs with log p values below 6 by controlled antisolvent precipitation
US9370514B2 (en) 2013-08-14 2016-06-21 Board Of Regents, The University Of Texas System Methods for fine particle manufacture
CN106061470A (en) * 2013-10-22 2016-10-26 北卡罗来纳大学查珀尔希尔分校 Polymer nanoparticles containing multiple agents and methods thereof
WO2017112614A1 (en) * 2015-12-21 2017-06-29 Nuvox Pharma Llc Compositions of fluorocarbon nanoemulsion, and methods of preparation and use thereof

Citations (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2745785A (en) * 1952-10-29 1956-05-15 American Home Prod Therapeutic composition comprising tabular nu, nu'-dibenzylethylenediamine di-penicillin, and process for preparing same
US4056635A (en) * 1974-03-28 1977-11-01 Imperial Chemical Industries Limited 2,6-Diisopropylphenol as an anaesthetic agent
US4073943A (en) * 1974-09-11 1978-02-14 Apoteksvarucentralen Vitrum Ab Method of enhancing the administration of pharmalogically active agents
US4540602A (en) * 1979-04-13 1985-09-10 Freund Industry Company, Limited Process for the preparation of activated pharmaceutical compositions
US4606940A (en) * 1984-12-21 1986-08-19 The Ohio State University Research Foundation Small particle formation and encapsulation
US4606670A (en) * 1981-10-08 1986-08-19 Avon Industrial Polymers Limited Fixing rigid inserts in flexible material
US4608278A (en) * 1983-06-22 1986-08-26 The Ohio State University Research Foundation Small particule formation and encapsulation
US4622219A (en) * 1983-06-17 1986-11-11 Haynes Duncan H Method of inducing local anesthesia using microdroplets of a general anesthetic
US4725442A (en) * 1983-06-17 1988-02-16 Haynes Duncan H Microdroplets of water-insoluble drugs and injectable formulations containing same
US4798846A (en) * 1974-03-28 1989-01-17 Imperial Chemical Industries Plc Pharmaceutical compositions
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US4973465A (en) * 1986-12-05 1990-11-27 Ire-Celltarg S.A. Microcrystals comprising an active substance having an affinity for phospholipids, and at least one phospholipid, process of preparation
US5009819A (en) * 1987-11-12 1991-04-23 The Liposome Company, Inc. Taste moderating composition
US5023271A (en) * 1985-08-13 1991-06-11 California Biotechnology Inc. Pharmaceutical microemulsions
US5049322A (en) * 1986-12-31 1991-09-17 Centre National De La Recherche Scientifique (C.N.R.S.) Process for the preparaton of dispersible colloidal systems of a substance in the form of nanocapsules
US5078994A (en) * 1990-04-12 1992-01-07 Eastman Kodak Company Microgel drug delivery system
US5091187A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5091188A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5100591A (en) * 1989-09-14 1992-03-31 Medgenix Group S.A. Process for preparing lipid microparticles
US5118528A (en) * 1986-12-31 1992-06-02 Centre National De La Recherche Scientifique Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles
US5122543A (en) * 1987-05-04 1992-06-16 Ciba-Geigy Corporation Oral forms of administration with delayed release
US5133908A (en) * 1986-12-31 1992-07-28 Centre National De La Recherche Scientifique (Cnrs) Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5151264A (en) * 1988-05-27 1992-09-29 Centre National De La Recherche Scientifique Particulate vector useful in particular for the transport of molecules with biological activity and process for its preparation
US5152923A (en) * 1989-06-26 1992-10-06 Hans Georg Weder Process for the production of a nanoemulsion of oil particles in an aqueous phase
US5174930A (en) * 1986-12-31 1992-12-29 Centre National De La Recherche Scientifique (Cnrs) Process for the preparation of dispersible colloidal systems of amphiphilic lipids in the form of oligolamellar liposomes of submicron dimensions
US5188837A (en) * 1989-11-13 1993-02-23 Nova Pharmaceutical Corporation Lipsopheres for controlled delivery of substances
US5231112A (en) * 1984-04-12 1993-07-27 The Liposome Company, Inc. Compositions containing tris salt of cholesterol hemisuccinate and antifungal
US5246707A (en) * 1990-04-26 1993-09-21 Haynes Duncan H Sustained release delivery of water-soluble bio-molecules and drugs using phospholipid-coated microcrystals, microdroplets and high-concentration liposomes
US5250236A (en) * 1991-08-05 1993-10-05 Gasco Maria R Method for producing solid lipid microspheres having a narrow size distribution
US5269979A (en) * 1988-06-08 1993-12-14 Fountain Pharmaceuticals, Inc. Method for making solvent dilution microcarriers
US5298262A (en) * 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) * 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5314506A (en) * 1990-06-15 1994-05-24 Merck & Co., Inc. Crystallization method to improve crystal structure and size
US5318767A (en) * 1991-01-25 1994-06-07 Sterling Winthrop Inc. X-ray contrast compositions useful in medical imaging
US5326552A (en) * 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5336507A (en) * 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5340564A (en) * 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5346702A (en) * 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5352459A (en) * 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5354563A (en) * 1985-07-15 1994-10-11 Research Development Corp. Of Japan Water dispersion containing ultrafine particles of organic compounds
US5389377A (en) * 1989-12-22 1995-02-14 Molecular Bioquest, Inc. Solid care therapeutic compositions and methods for making same
US5389263A (en) * 1992-05-20 1995-02-14 Phasex Corporation Gas anti-solvent recrystallization and application for the separation and subsequent processing of RDX and HMX
US5399363A (en) * 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5417956A (en) * 1992-08-18 1995-05-23 Worcester Polytechnic Institute Preparation of nanophase solid state materials
US5429824A (en) * 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5466646A (en) * 1992-08-18 1995-11-14 Worcester Polytechnic Institute Process for the preparation of solid state materials and said materials
US5474989A (en) * 1988-11-11 1995-12-12 Kurita Water Industries, Ltd. Drug composition
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5518187A (en) * 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5518738A (en) * 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5543133A (en) * 1995-02-14 1996-08-06 Nanosystems L.L.C. Process of preparing x-ray contrast compositions containing nanoparticles
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5560933A (en) * 1993-02-22 1996-10-01 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US5565383A (en) * 1993-12-03 1996-10-15 Nec Corporation Method for selective formation of silicide films without formation on vertical gate sidewalls using collimated sputtering
US5569448A (en) * 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5573783A (en) * 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
US5578325A (en) * 1993-07-23 1996-11-26 Massachusetts Institute Of Technology Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
US5580579A (en) * 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5587143A (en) * 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5591456A (en) * 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5605785A (en) * 1995-03-28 1997-02-25 Eastman Kodak Company Annealing processes for nanocrystallization of amorphous dispersions
US5626864A (en) * 1993-02-18 1997-05-06 Knoll Aktiengesellscahft Preparation of colloidal aqueous solutions of active substances of low solubility
US5635609A (en) * 1993-04-13 1997-06-03 Coletica Particles prepared by transacylation reaction between an esterified polysaccharide and a polyamine, methods of preparation therefor and compositions containing same
US5637568A (en) * 1991-07-22 1997-06-10 Asta Medica Ag Composition for the sustained and controlled release of medicamentous substances and a process for preparing the same
US5641515A (en) * 1995-04-04 1997-06-24 Elan Corporation, Plc Controlled release biodegradable nanoparticles containing insulin
US5641745A (en) * 1995-04-03 1997-06-24 Elan Corporation, Plc Controlled release biodegradable micro- and nanospheres containing cyclosporin
US5660858A (en) * 1996-04-03 1997-08-26 Research Triangle Pharmaceuticals Cyclosporin emulsions
US5662883A (en) * 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5662932A (en) * 1993-05-18 1997-09-02 Pharmos Corporation Solid fat nanoemulsions
US5665383A (en) * 1993-02-22 1997-09-09 Vivorx Pharmaceuticals, Inc. Methods for the preparation of immunostimulating agents for in vivo delivery
US5665331A (en) * 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5707634A (en) * 1988-10-05 1998-01-13 Pharmacia & Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
US5716642A (en) * 1995-01-10 1998-02-10 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents using surface active material derived from similar pharmaceutical agents
US5720551A (en) * 1994-10-28 1998-02-24 Shechter; Tal Forming emulsions
US5874111A (en) * 1997-01-07 1999-02-23 Maitra; Amarnath Process for the preparation of highly monodispersed polymeric hydrophilic nanoparticles
US5916596A (en) * 1993-02-22 1999-06-29 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US5922355A (en) * 1996-08-22 1999-07-13 Research Triangle Pharmaceuticals Composition and method of preparing microparticles of water-insoluble substances
US6063138A (en) * 1994-06-30 2000-05-16 Bradford Particle Design Limited Method and apparatus for the formation of particles
US6090406A (en) * 1984-04-12 2000-07-18 The Liposome Company, Inc. Potentiation of immune responses with liposomal adjuvants
US6207178B1 (en) * 1993-03-05 2001-03-27 Kabi Pharmacia Ab Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof
US6462093B1 (en) * 1995-08-11 2002-10-08 Nissan Chemical Industries, Ltd. Method for converting sparingly water-soluble medical substance to amorphous state
US20030096013A1 (en) * 2000-12-22 2003-05-22 Jane Werling Preparation of submicron sized particles with polymorph control
US6616869B2 (en) * 1995-07-21 2003-09-09 Brown University Research Foundation Process for preparing microparticles through phase inversion phenomena
US20030211083A1 (en) * 2001-03-15 2003-11-13 Jean-Marie Vogel Injectable microspheres for tissue construction
US20040022861A1 (en) * 2001-01-30 2004-02-05 Williams Robert O. Process for production of nanoparticles and microparticles by spray freezing into liquid
US20040022862A1 (en) * 2000-12-22 2004-02-05 Kipp James E. Method for preparing small particles
US20040043077A1 (en) * 2000-10-27 2004-03-04 Brown Larry R. Production of microspheres
US20040256749A1 (en) * 2000-12-22 2004-12-23 Mahesh Chaubal Process for production of essentially solvent-free small particles
US20050013868A1 (en) * 2001-09-26 2005-01-20 Sean Brynjelsen Preparation of submicron sized nanoparticles via dispersion lyophilization
US20050037083A1 (en) * 2001-09-26 2005-02-17 Sean Brynjelsen Preparation of submicron solid particle suspensions by sonication of multiphase systems

Family Cites Families (131)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1282405C (en) 1984-05-21 1991-04-02 Michael R. Violante Method for making uniformly sized particles from water-insoluble organic compounds
ES2054052T3 (en) 1988-06-30 1994-08-01 Centre Nat Rech Scient Process for preparing dispersible colloidal systems of a protein in the form of nanoparticles.
CA1340241C (en) 1988-06-08 1998-12-15 Fountain Pharmaceuticals, Inc. Method for marking solvent dilution microcarriers
EP0437451B1 (en) 1988-10-05 1993-06-09 The Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
US5066436A (en) 1989-01-04 1991-11-19 Gist-Brocades N.V. Process for microencapsulation
GB8901254D0 (en) 1989-01-20 1989-03-15 Allied Colloids Ltd Particulate materials and their production
WO1990015593A1 (en) 1989-06-21 1990-12-27 Ytkemiska Institutet A process for the preparation of drug particles
DK546289D0 (en) 1989-11-02 1989-11-02 Danochemo As carotenoid
DE4005711C1 (en) 1990-02-23 1991-06-13 A. Nattermann & Cie Gmbh, 5000 Koeln, De
DE69105106D1 (en) 1990-07-11 1994-12-15 Eurand Int In the water quickly suspendable pharmaceutical composition.
CA2046830C (en) 1990-07-19 1999-12-14 Patrick P. Deluca Drug delivery system involving inter-action between protein or polypeptide and hydrophobic biodegradable polymer
DE69231507D1 (en) 1991-05-31 2000-11-23 Fidia Spa A process for the preparation of biologically active components-containing microspheres
US5766635A (en) * 1991-06-28 1998-06-16 Rhone-Poulenc Rorer S.A. Process for preparing nanoparticles
CA2078388A1 (en) 1991-10-02 1993-04-03 Mridula Nair Biocompatible emulsion particles
US6063910A (en) * 1991-11-14 2000-05-16 The Trustees Of Princeton University Preparation of protein microparticles by supercritical fluid precipitation
US5298483A (en) 1992-03-30 1994-03-29 Tropicana Products, Inc. New matter of composition and method for using the same as plant bioregulators
EP0644755B1 (en) * 1992-06-10 1997-03-19 NanoSystems L.L.C. Surface modified nsaid nanoparticles
DE69329576D1 (en) * 1992-07-09 2000-11-23 Univ Ohio State Res Found Precipitation one or more active compounds in situ
CA2371912C (en) 1999-05-21 2010-02-16 Neil P. Desai Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
WO1999000113A9 (en) 1997-06-27 1999-04-08 Vivorx Pharmaceuticals Inc Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
CA2091152C (en) 1993-03-05 2005-05-03 Kirsten Westesen Solid lipid particles, particles of bioactive agents and methods for the manfuacture and use thereof
US6090925A (en) 1993-03-09 2000-07-18 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US5981719A (en) * 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6007845A (en) * 1994-07-22 1999-12-28 Massachusetts Institute Of Technology Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
DE4327063A1 (en) 1993-08-12 1995-02-16 Kirsten Dr Westesen Ubidecarenone particles with modified physico-chemical properties
US5500161A (en) 1993-09-21 1996-03-19 Massachusetts Institute Of Technology And Virus Research Institute Method for making hydrophobic polymeric microparticles
DE69427832T2 (en) * 1993-11-01 2001-11-22 Pharmacia Ab Drug delivery preparation containing nicotine or a derivative thereof and starch microspheres, and process for its manufacture
DK0730406T3 (en) 1993-11-15 1999-06-28 Zeneca Ltd Microcapsules containing suspensions of biologically active compounds
ES2158101T3 (en) 1994-04-06 2001-09-01 Elan Corp Plc Effervescent pharmaceutical formulations containing biodegradable controlled release microcapsules.
ES2152401T3 (en) * 1994-05-25 2001-02-01 Elan Pharma Int Ltd Grinding method of pharmaceutical substances.
FR2721510B1 (en) 1994-06-22 1996-07-26 Rhone Poulenc Rorer Sa Nanoparticles filterable under sterile conditions.
JPH10506121A (en) 1994-09-27 1998-06-16 ニコムド イメージング エイ/エス Contrast agent
JP4098827B2 (en) 1994-11-09 2008-06-11 ジ・オハイオ・ステイト・ユニバーシテイ・リサーチ・フアウンデイシヨン Formation of fine particles
DE4440337A1 (en) * 1994-11-11 1996-05-15 Dds Drug Delivery Services Ges Pharmaceutical nanosuspensions for drug administration than systems with increased saturation solubility and dissolution rate
CA2207961A1 (en) 1995-01-05 1996-07-11 Robert J. Levy Surface-modified nanoparticles and method of making and using same
EP0808154B1 (en) 1995-02-06 2000-12-20 Elan Pharma International Limited Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
EP0810853B1 (en) 1995-02-24 2004-08-25 Elan Pharma International Limited Aerosols containing nanoparticle dispersions
EP0817620B1 (en) 1995-03-28 2002-01-30 Fidia Advanced Biopolymers, S.R.L. Nanospheres comprising a biocompatible polysaccharide
ES2188750T3 (en) 1995-04-13 2003-07-01 Astrazeneca Ab Process for the preparation of respirable particles.
GB9511220D0 (en) 1995-06-02 1995-07-26 Glaxo Group Ltd Solid dispersions
US5667809A (en) 1995-06-07 1997-09-16 Alliance Pharmaceutical Corp. Continuous fluorochemical microdispersions for the delivery of lipophilic pharmaceutical agents
DK0752245T3 (en) 1995-07-05 2002-09-09 Europ Economic Community Biocompatible and biodegradable nanoparticles designed for the absorption and release of proteinaceous drugs
ES2306452T3 (en) 1995-10-17 2008-11-01 Jagotec Ag Contribution of insoluble drugs.
DE19545257A1 (en) 1995-11-24 1997-06-19 Schering Ag A process for the production of morphologically uniform microcapsules and produced by this process microcapsules
FR2742357B1 (en) 1995-12-19 1998-01-09 Rhone Poulenc Rorer Sa Nanoparticles Stabilized and filtered under sterile condition
US6245349B1 (en) 1996-02-23 2001-06-12 éLAN CORPORATION PLC Drug delivery compositions suitable for intravenous injection
DE69733966D1 (en) * 1996-04-02 2005-09-15 Pharmos Corp Solid lipid compositions of lipophilic compounds for improved oral bioavailability
US6231890B1 (en) 1996-05-02 2001-05-15 Taisho Pharmaceutical Co., Ltd. Suspension of sparingly water-soluble acidic drug
US5792477A (en) 1996-05-07 1998-08-11 Alkermes Controlled Therapeutics, Inc. Ii Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent
EP1210942B1 (en) 1996-05-07 2007-03-21 Alkermes, Inc. Microparticles
EP1039971B1 (en) 1997-12-17 2003-05-21 Universidad de Sevilla Device and method for creating aerosols for drug delivery
JP3391801B2 (en) 1996-05-20 2003-03-31 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Antimicrobial composition having improved bioavailability
CA2263765C (en) 1996-08-19 2010-03-30 Vivorx Pharmaceuticals, Inc. Methods for the production of protein particles useful for delivery of pharmacological agents
DE19637517A1 (en) 1996-09-13 1998-03-19 Basf Ag Preparation of pulverulent, coldwater-dispersible carotenoid preparation and the use of the novel carotenoid preparations
DK0951280T3 (en) 1996-10-03 2004-05-17 Hermes Biosciences Inc Hydrophilic microparticles and methods for their preparation
US5833891A (en) * 1996-10-09 1998-11-10 The University Of Kansas Methods for a particle precipitation and coating using near-critical and supercritical antisolvents
US6045829A (en) 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
WO1998035666A1 (en) 1997-02-13 1998-08-20 Nanosystems Llc Formulations of nanoparticle naproxen tablets
WO1998056362A1 (en) 1997-06-12 1998-12-17 Maria Rosa Gasco Pharmaceutical composition in form of solid lipidic microparticles suitable to parenteral administration
JP2002504930A (en) 1997-06-16 2002-02-12 ドン−エー・ファーマスーティカル・カンパニー・リミテッド Itraconazole exhibiting improved solubility, a method of manufacturing the same, and oral pharmaceutical composition comprising the same
US6217886B1 (en) 1997-07-14 2001-04-17 The Board Of Trustees Of The University Of Illinois Materials and methods for making improved micelle compositions
DE69814826T2 (en) 1997-07-15 2004-02-05 Coletica Particles, particularly micro- or nanoparticles of crosslinked plant proteins, processes for their preparation and food compositions containing them medicinal or cosmetic or
WO1999007466A1 (en) 1997-08-05 1999-02-18 Microfluidics International Corporation Multiple stream high pressure mixer/reactor
DE19737481A1 (en) 1997-08-28 1999-03-04 Hoechst Ag Spherical linear polysaccharides containing microparticles
FI973804A (en) 1997-09-26 1999-03-27 Orion Yhtymae Oy Levosimendan in oral compositions
US6284268B1 (en) 1997-12-10 2001-09-04 Cyclosporine Therapeutics Limited Pharmaceutical compositions containing an omega-3 fatty acid oil
US6066292A (en) 1997-12-19 2000-05-23 Bayer Corporation Sterilization process for pharmaceutical suspensions
EP1039909B1 (en) 1997-12-31 2002-10-09 Choongwae Pharma Corporation Method of production and composition of an oral preparation of itraconazole
US6086376A (en) 1998-01-30 2000-07-11 Rtp Pharma Inc. Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant
CA2319565A1 (en) * 1998-02-06 1999-08-12 Eurand International S.P.A. Pharmaceutical compositions in form of nanoparticles comprising lipidic substances and amphiphilic substances and related preparation process
EP1067914B1 (en) 1998-03-30 2006-02-22 Jagotec Ag Composition and method of preparing microparticles of water-insoluble substances
US6337092B1 (en) 1998-03-30 2002-01-08 Rtp Pharma Inc. Composition and method of preparing microparticles of water-insoluble substances
JP4695260B2 (en) 1998-04-01 2011-06-08 オバン・エナジー・リミテッド Anti-cancer composition
CA2326349A1 (en) 1998-04-09 1999-10-21 F. Hoffmann-La Roche Ag Process for the manufacture of (sub)micron sized particles by dissolving in compressed gas and surfactants
FR2777193B1 (en) 1998-04-14 2001-06-08 Coletica Particle hydroxamic chelating group of metal ions and their use in cosmetics or pharmacy
WO1999061001A1 (en) 1998-05-29 1999-12-02 Rtp Pharma Inc. Thermoprotected microparticle compositions and process for terminal steam sterilization thereof
CN1160059C (en) 1998-06-19 2004-08-04 斯凯伊药品加拿大公司 Process of generating submicron particles of water-insuluble compounds
FR2780901B1 (en) 1998-07-09 2000-09-29 Coletica Particles, in particular microparticles or nanoparticles of monosaccharides and oligosaccharides reticules, their methods of preparation and cosmetic compositions, pharmaceutical or food containing
US6153225A (en) 1998-08-13 2000-11-28 Elan Pharma International Limited Injectable formulations of nanoparticulate naproxen
US6238677B1 (en) 1998-08-18 2001-05-29 The United States Of America As Represented By The Secretary Of Agriculture Starch microcapsules for delivery of active agents
WO2000012125A1 (en) 1998-09-01 2000-03-09 Elan Corporation, Plc Method for inducing a cell-mediated immune response and parenteral vaccine formulations therefor
WO2000012124A1 (en) 1998-09-01 2000-03-09 Elan Corporation, Plc Oral vaccine compositions
US6165506A (en) 1998-09-04 2000-12-26 Elan Pharma International Ltd. Solid dose form of nanoparticulate naproxen
US6350786B1 (en) 1998-09-22 2002-02-26 Hoffmann-La Roche Inc. Stable complexes of poorly soluble compounds in ionic polymers
JP2002525311A (en) 1998-10-01 2002-08-13 エラン ファーマ インターナショナル,リミティド Controlled release nanoparticle composition
US8293277B2 (en) 1998-10-01 2012-10-23 Alkermes Pharma Ireland Limited Controlled-release nanoparticulate compositions
US6344271B1 (en) 1998-11-06 2002-02-05 Nanoenergy Corporation Materials and products using nanostructured non-stoichiometric substances
US7521068B2 (en) 1998-11-12 2009-04-21 Elan Pharma International Ltd. Dry powder aerosols of nanoparticulate drugs
EP1133281A1 (en) 1998-11-20 2001-09-19 RTP Pharma Inc. Dispersible phospholipid stabilized microparticles
WO2000030615A1 (en) 1998-11-20 2000-06-02 Rtp Pharma Inc. Method of preparing stable suspensions of insoluble microparticles
DE69924004T2 (en) 1998-12-22 2006-02-09 United States Of America Represented By The Secretary, Department Of Health & Human Services Delivery system for water-insoluble drug substances
WO2000040220A1 (en) 1999-01-06 2000-07-13 Korea Research Institute Of Chemical Technology Method of preparing pharmaceutical active ingredient comprising water-insoluble drug and pharmaceutical composition for oral administration comprising the same
US6365191B1 (en) 1999-02-17 2002-04-02 Dabur Research Foundation Formulations of paclitaxel, its derivatives or its analogs entrapped into nanoparticles of polymeric micelles, process for preparing same and the use thereof
US6270806B1 (en) 1999-03-03 2001-08-07 Elan Pharma International Limited Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions
US6267989B1 (en) 1999-03-08 2001-07-31 Klan Pharma International Ltd. Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions
US6045826A (en) * 1999-04-02 2000-04-04 National Research Council Of Canada Water-soluble compositions of bioactive lipophilic compounds
US6632443B2 (en) 2000-02-23 2003-10-14 National Research Council Of Canada Water-soluble compositions of bioactive lipophilic compounds
US6610317B2 (en) 1999-05-27 2003-08-26 Acusphere, Inc. Porous paclitaxel matrices and methods of manufacture thereof
US6395300B1 (en) 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
KR100331529B1 (en) * 1999-06-16 2002-04-06 민경윤 Composition for Oral Administration of Hardly Soluble Antifungal Agent and Process for the Preparation Thereof
US6309663B1 (en) 1999-08-17 2001-10-30 Lipocine Inc. Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents
US6656504B1 (en) 1999-09-09 2003-12-02 Elan Pharma International Ltd. Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions
US6428814B1 (en) 1999-10-08 2002-08-06 Elan Pharma International Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
DE10007816A1 (en) 2000-02-21 2001-09-06 Bayer Ag A process for the preparation of nanosuspensions
CA2400172C (en) 2000-02-28 2010-04-20 Genesegues, Inc. Nanocapsule encapsulation system and method
DK2283818T3 (en) 2000-11-30 2017-10-16 Vectura Ltd A process for the preparation of particles for use in a pharmaceutical composition
WO2001080828A3 (en) 2000-04-20 2002-05-23 Rtp Pharma Inc Improved water-insoluble drug particle process
US6604698B2 (en) 2000-05-10 2003-08-12 Skyepharma Canada, Inc. Media milling
US6316029B1 (en) 2000-05-18 2001-11-13 Flak Pharma International, Ltd. Rapidly disintegrating solid oral dosage form
EP1355630B1 (en) 2000-08-15 2009-11-25 The Board Of Trustees Of The University Of Illinois Method of forming microparticles
DE60137943D1 (en) 2000-08-31 2009-04-23 Jagotec Ag milled particles
US6696084B2 (en) 2000-09-20 2004-02-24 Rtp Pharma Inc. Spray drying process and compositions of fenofibrate
US6375986B1 (en) 2000-09-21 2002-04-23 Elan Pharma International Ltd. Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate
US7105176B2 (en) 2000-11-29 2006-09-12 Basf Aktiengesellschaft Production of solid preparations of water-soluble, sparingly water-soluble or water-insoluble active compounds
US7193084B2 (en) 2000-12-22 2007-03-20 Baxter International Inc. Polymorphic form of itraconazole
EP1347747B1 (en) 2000-12-22 2006-03-08 Baxter International Inc. Method for preparing submicron particle suspensions of pharmaceutical agents
US20030031719A1 (en) 2000-12-22 2003-02-13 Kipp James E. Method for preparing submicron particle suspensions
US6951656B2 (en) 2000-12-22 2005-10-04 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US6607784B2 (en) * 2000-12-22 2003-08-19 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US6977085B2 (en) 2000-12-22 2005-12-20 Baxter International Inc. Method for preparing submicron suspensions with polymorph control
US20030072807A1 (en) 2000-12-22 2003-04-17 Wong Joseph Chung-Tak Solid particulate antifungal compositions for pharmaceutical use
US6884436B2 (en) 2000-12-22 2005-04-26 Baxter International Inc. Method for preparing submicron particle suspensions
US7704525B2 (en) 2000-12-27 2010-04-27 Ares Trading S.A. Lipid microparticles by cryogenic micronization
US6862890B2 (en) 2001-01-30 2005-03-08 Board Of Regents, University Of Texas System Process for production of nanoparticles and microparticles by spray freezing into liquid
JP2004527505A (en) 2001-03-09 2004-09-09 アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag H +, a method of manufacturing fine particles containing a k + -ATP-ase inhibitor
CN1507343A (en) 2001-03-09 2004-06-23 阿斯特拉曾尼卡有限公司 Method to obtain microparticle containing a H*, K*-ATP-enzyme inhibitor
EP1370239A1 (en) 2001-03-15 2003-12-17 AstraZeneca AB New composition
ES2332584T3 (en) 2001-03-27 2010-02-09 Phares Pharmaceutical Research N.V. Method and composition for solubilising a biologically active compound with low water solubility.
WO2002089773A3 (en) 2001-05-09 2003-02-06 Novartis Ag Pharmaceutical compositions comprising cyclosporin
US7112340B2 (en) 2001-10-19 2006-09-26 Baxter International Inc. Compositions of and method for preparing stable particles in a frozen aqueous matrix

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2745785A (en) * 1952-10-29 1956-05-15 American Home Prod Therapeutic composition comprising tabular nu, nu'-dibenzylethylenediamine di-penicillin, and process for preparing same
US4056635A (en) * 1974-03-28 1977-11-01 Imperial Chemical Industries Limited 2,6-Diisopropylphenol as an anaesthetic agent
US4452817A (en) * 1974-03-28 1984-06-05 Imperial Chemical Industries Plc Anaesthetic compositions containing 2,6-diisopropylphenol
US4798846A (en) * 1974-03-28 1989-01-17 Imperial Chemical Industries Plc Pharmaceutical compositions
US4073943A (en) * 1974-09-11 1978-02-14 Apoteksvarucentralen Vitrum Ab Method of enhancing the administration of pharmalogically active agents
US4540602A (en) * 1979-04-13 1985-09-10 Freund Industry Company, Limited Process for the preparation of activated pharmaceutical compositions
US4606670A (en) * 1981-10-08 1986-08-19 Avon Industrial Polymers Limited Fixing rigid inserts in flexible material
US4622219A (en) * 1983-06-17 1986-11-11 Haynes Duncan H Method of inducing local anesthesia using microdroplets of a general anesthetic
US4725442A (en) * 1983-06-17 1988-02-16 Haynes Duncan H Microdroplets of water-insoluble drugs and injectable formulations containing same
US4608278A (en) * 1983-06-22 1986-08-26 The Ohio State University Research Foundation Small particule formation and encapsulation
US6090406A (en) * 1984-04-12 2000-07-18 The Liposome Company, Inc. Potentiation of immune responses with liposomal adjuvants
US5231112A (en) * 1984-04-12 1993-07-27 The Liposome Company, Inc. Compositions containing tris salt of cholesterol hemisuccinate and antifungal
US4997454A (en) * 1984-05-21 1991-03-05 The University Of Rochester Method for making uniformly-sized particles from insoluble compounds
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US4606940A (en) * 1984-12-21 1986-08-19 The Ohio State University Research Foundation Small particle formation and encapsulation
US5354563A (en) * 1985-07-15 1994-10-11 Research Development Corp. Of Japan Water dispersion containing ultrafine particles of organic compounds
US5023271A (en) * 1985-08-13 1991-06-11 California Biotechnology Inc. Pharmaceutical microemulsions
US4973465A (en) * 1986-12-05 1990-11-27 Ire-Celltarg S.A. Microcrystals comprising an active substance having an affinity for phospholipids, and at least one phospholipid, process of preparation
US5049322A (en) * 1986-12-31 1991-09-17 Centre National De La Recherche Scientifique (C.N.R.S.) Process for the preparaton of dispersible colloidal systems of a substance in the form of nanocapsules
US5174930A (en) * 1986-12-31 1992-12-29 Centre National De La Recherche Scientifique (Cnrs) Process for the preparation of dispersible colloidal systems of amphiphilic lipids in the form of oligolamellar liposomes of submicron dimensions
US5118528A (en) * 1986-12-31 1992-06-02 Centre National De La Recherche Scientifique Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles
US5133908A (en) * 1986-12-31 1992-07-28 Centre National De La Recherche Scientifique (Cnrs) Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles
US5122543A (en) * 1987-05-04 1992-06-16 Ciba-Geigy Corporation Oral forms of administration with delayed release
US5009819A (en) * 1987-11-12 1991-04-23 The Liposome Company, Inc. Taste moderating composition
US5151264A (en) * 1988-05-27 1992-09-29 Centre National De La Recherche Scientifique Particulate vector useful in particular for the transport of molecules with biological activity and process for its preparation
US5269979A (en) * 1988-06-08 1993-12-14 Fountain Pharmaceuticals, Inc. Method for making solvent dilution microcarriers
US5707634A (en) * 1988-10-05 1998-01-13 Pharmacia & Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
US5474989A (en) * 1988-11-11 1995-12-12 Kurita Water Industries, Ltd. Drug composition
US5152923A (en) * 1989-06-26 1992-10-06 Hans Georg Weder Process for the production of a nanoemulsion of oil particles in an aqueous phase
US5100591A (en) * 1989-09-14 1992-03-31 Medgenix Group S.A. Process for preparing lipid microparticles
US5188837A (en) * 1989-11-13 1993-02-23 Nova Pharmaceutical Corporation Lipsopheres for controlled delivery of substances
US5389377A (en) * 1989-12-22 1995-02-14 Molecular Bioquest, Inc. Solid care therapeutic compositions and methods for making same
US5078994A (en) * 1990-04-12 1992-01-07 Eastman Kodak Company Microgel drug delivery system
US5246707A (en) * 1990-04-26 1993-09-21 Haynes Duncan H Sustained release delivery of water-soluble bio-molecules and drugs using phospholipid-coated microcrystals, microdroplets and high-concentration liposomes
US5091187A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5091188A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
USRE35338E (en) * 1990-04-26 1996-09-24 Pharma-Logic, Inc. Sustained release delivery of water soluble bio-molecules and drugs using phosphokipid-coated microcrystals, microdroplets and high-concentration lipsomes
US5314506A (en) * 1990-06-15 1994-05-24 Merck & Co., Inc. Crystallization method to improve crystal structure and size
US5318767A (en) * 1991-01-25 1994-06-07 Sterling Winthrop Inc. X-ray contrast compositions useful in medical imaging
US5494683A (en) * 1991-01-25 1996-02-27 Eastman Kodak Company Surface modified anticancer nanoparticles
US5399363A (en) * 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5637568A (en) * 1991-07-22 1997-06-10 Asta Medica Ag Composition for the sustained and controlled release of medicamentous substances and a process for preparing the same
US5250236A (en) * 1991-08-05 1993-10-05 Gasco Maria R Method for producing solid lipid microspheres having a narrow size distribution
US5389263A (en) * 1992-05-20 1995-02-14 Phasex Corporation Gas anti-solvent recrystallization and application for the separation and subsequent processing of RDX and HMX
US5466646A (en) * 1992-08-18 1995-11-14 Worcester Polytechnic Institute Process for the preparation of solid state materials and said materials
US5417956A (en) * 1992-08-18 1995-05-23 Worcester Polytechnic Institute Preparation of nanophase solid state materials
US5518187A (en) * 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5298262A (en) * 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5346702A (en) * 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5302401A (en) * 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5340564A (en) * 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5470583A (en) * 1992-12-11 1995-11-28 Eastman Kodak Company Method of preparing nanoparticle compositions containing charged phospholipids to reduce aggregation
US5336507A (en) * 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5429824A (en) * 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5352459A (en) * 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5447710A (en) * 1992-12-17 1995-09-05 Eastman Kodak Company Method of making nanoparticulate X-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5326552A (en) * 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5626864A (en) * 1993-02-18 1997-05-06 Knoll Aktiengesellscahft Preparation of colloidal aqueous solutions of active substances of low solubility
US5665383A (en) * 1993-02-22 1997-09-09 Vivorx Pharmaceuticals, Inc. Methods for the preparation of immunostimulating agents for in vivo delivery
US5560933A (en) * 1993-02-22 1996-10-01 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US5916596A (en) * 1993-02-22 1999-06-29 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US6207178B1 (en) * 1993-03-05 2001-03-27 Kabi Pharmacia Ab Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof
US5635609A (en) * 1993-04-13 1997-06-03 Coletica Particles prepared by transacylation reaction between an esterified polysaccharide and a polyamine, methods of preparation therefor and compositions containing same
US5662932A (en) * 1993-05-18 1997-09-02 Pharmos Corporation Solid fat nanoemulsions
US5578325A (en) * 1993-07-23 1996-11-26 Massachusetts Institute Of Technology Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
US5565383A (en) * 1993-12-03 1996-10-15 Nec Corporation Method for selective formation of silicide films without formation on vertical gate sidewalls using collimated sputtering
US5587143A (en) * 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US6063138A (en) * 1994-06-30 2000-05-16 Bradford Particle Design Limited Method and apparatus for the formation of particles
US5720551A (en) * 1994-10-28 1998-02-24 Shechter; Tal Forming emulsions
US5665331A (en) * 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5662883A (en) * 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5716642A (en) * 1995-01-10 1998-02-10 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents using surface active material derived from similar pharmaceutical agents
US5569448A (en) * 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5518738A (en) * 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5591456A (en) * 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5573783A (en) * 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5543133A (en) * 1995-02-14 1996-08-06 Nanosystems L.L.C. Process of preparing x-ray contrast compositions containing nanoparticles
US5580579A (en) * 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5605785A (en) * 1995-03-28 1997-02-25 Eastman Kodak Company Annealing processes for nanocrystallization of amorphous dispersions
US5641745A (en) * 1995-04-03 1997-06-24 Elan Corporation, Plc Controlled release biodegradable micro- and nanospheres containing cyclosporin
US5641515A (en) * 1995-04-04 1997-06-24 Elan Corporation, Plc Controlled release biodegradable nanoparticles containing insulin
US6616869B2 (en) * 1995-07-21 2003-09-09 Brown University Research Foundation Process for preparing microparticles through phase inversion phenomena
US6462093B1 (en) * 1995-08-11 2002-10-08 Nissan Chemical Industries, Ltd. Method for converting sparingly water-soluble medical substance to amorphous state
US5660858A (en) * 1996-04-03 1997-08-26 Research Triangle Pharmaceuticals Cyclosporin emulsions
US5922355A (en) * 1996-08-22 1999-07-13 Research Triangle Pharmaceuticals Composition and method of preparing microparticles of water-insoluble substances
US5874111A (en) * 1997-01-07 1999-02-23 Maitra; Amarnath Process for the preparation of highly monodispersed polymeric hydrophilic nanoparticles
US20040043077A1 (en) * 2000-10-27 2004-03-04 Brown Larry R. Production of microspheres
US20040256749A1 (en) * 2000-12-22 2004-12-23 Mahesh Chaubal Process for production of essentially solvent-free small particles
US20030096013A1 (en) * 2000-12-22 2003-05-22 Jane Werling Preparation of submicron sized particles with polymorph control
US20040022862A1 (en) * 2000-12-22 2004-02-05 Kipp James E. Method for preparing small particles
US20040022861A1 (en) * 2001-01-30 2004-02-05 Williams Robert O. Process for production of nanoparticles and microparticles by spray freezing into liquid
US20030211083A1 (en) * 2001-03-15 2003-11-13 Jean-Marie Vogel Injectable microspheres for tissue construction
US20050037083A1 (en) * 2001-09-26 2005-02-17 Sean Brynjelsen Preparation of submicron solid particle suspensions by sonication of multiphase systems
US20050013868A1 (en) * 2001-09-26 2005-01-20 Sean Brynjelsen Preparation of submicron sized nanoparticles via dispersion lyophilization

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013066735A1 (en) * 2011-10-31 2013-05-10 Merck Sharp & Dohme Corp. Nano-suspension process
US9381518B2 (en) 2011-10-31 2016-07-05 Merck Sharp & Dohme Corp. Nano-suspension process

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US20030059472A1 (en) 2003-03-27 application
US6835396B2 (en) 2004-12-28 grant
US20050037083A1 (en) 2005-02-17 application

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