WO2003032959A1 - Compositions nanoparticulaires comprenant des noyaux inorganiques - Google Patents

Compositions nanoparticulaires comprenant des noyaux inorganiques Download PDF

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WO2003032959A1
WO2003032959A1 PCT/US2002/032619 US0232619W WO03032959A1 WO 2003032959 A1 WO2003032959 A1 WO 2003032959A1 US 0232619 W US0232619 W US 0232619W WO 03032959 A1 WO03032959 A1 WO 03032959A1
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agents
composition
nanoparticulate
therapies
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PCT/US2002/032619
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WO2003032959A9 (fr
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William H. Bosch
Eugene R. Cooper
Egon Matijevic
Niels P. Ryde
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Bosch William H
Cooper Eugene R
Egon Matijevic
Ryde Niels P
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Application filed by Bosch William H, Cooper Eugene R, Egon Matijevic, Ryde Niels P filed Critical Bosch William H
Publication of WO2003032959A1 publication Critical patent/WO2003032959A1/fr
Publication of WO2003032959A9 publication Critical patent/WO2003032959A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug

Definitions

  • the invention is directed to nanoparticulate compositions comprising inorganic cores and methods of making and using such compositions.
  • compositions that exhibit poor solubility often can diminish the efficacy of a drug formulation. Improved solubility can be achieved by reducing a drug's particle size, which increases its surface area.
  • Amorphous small particle compositions are described in, for example, U.S. Patent Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent," 4,826,689 for “Method for Making Uniformly Sized Particles from Water- Insoluble Organic Compounds," 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds,” 5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods," and 5,776,496, for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.
  • the present invention is directed to the procedure by which nanoparticulate inorganic cores can be coated with pharmaceutically active agents to produce stable dispersions.
  • compositions have a smaller and more narrow particle size distribution than prior art nanoparticulate compositions, the compositions can have, for example, a more rapid dissolution rate, which may allow for better dose uniformity, higher bioavailability, and a faster onset of action. This is an improvement over prior art nanoparticulate technologies.
  • compositions comprising a nanoparticulate composition of the invention.
  • the pharmaceutical composition comprises at least one nanoparticulate inorganic core, at least one active agent adsorbed or bound to the surface of the core, and a pharmaceutically acceptable carrier, as well as any desired excipients.
  • This invention further discloses methods of making a nanoparticulate composition having at least one inorganic core and adsorbed or bound to the sur ace thereof at least one active agent.
  • Such a method comprises contacting at least one solubilized active agent with at least one suitable inorganic core for a time and under conditions until adsorption between the core and active agent occurs.
  • at least one solubilized active agent is contacted with at least one suitable inorganic core in the presence of a coupling agent for a time and under conditions until binding between the core-coupling agent-active agent occurs.
  • the present invention is further directed to methods of treatment comprising administering to a mammal in need a therapeutically effective amount of a nanoparticulate composition according to the invention.
  • Yet another aspect of the invention is directed to the application of the described nanoparticulate compositions to any biological surface of an animal.
  • Such application encompasses, for example, the application of nanoparticulate compositions useful as cosmetics, perfumes, shampoos, cleansers, moisturizers, deodorants, topical creams, ointments, nail polish, hair cosmetic compositions, etc.
  • compositions of the invention can also be applied to plant tissue.
  • Such methods include applying nanoparticulate compositions useful as fertilizers, pesticides, herbicides, etc. to a biological surface of a plant.
  • Figure 1 Shows ⁇ -potential as a function of the pH of: (a) Nalco alumina (O); and
  • Figure 7 Shows FTIR spectra of: (a) naproxen; (b) Ludox CL ® (2 wt%) + naproxen (0.01 mol. dm "3 in ethanol; and (c) Ludox CL ® silica;
  • Figure 8 Shows FTJR spectra of: (a) naproxen; (b) Nissan silica (2 wt%) + naproxen (0.01 mol. dm " in methanol; and (c) Nissan silica;
  • Figure 9 Shows FTIR spectra of: (a) naproxen; (b) Nalco alumina (0.1 wt%) + naproxen (0.0025 mol. dm "3 in water; and (c) alumina Nalco;
  • Figure 10 Shows shows FTJR spectra of: (a) naproxen; (b) Nalco alumina (2 wt%)
  • Figure 11 Shows the ⁇ -potentials of both alumina cores, Nalco alumina (O) and
  • Figure 14 Shows the FTJR spectra of Degussa C alumina (a), naproxen (b), and
  • Figure 17 Shows transmission electron micrographs of the Degussa C alumina core
  • Figure 19 Shows the adsorption data of ketoprofen on Degussa C alumina in water
  • Figure 20 Shows the FTIR spectra of Degussa C alumina (a), ketoprofen (b), and
  • Figure 21 Shows a TEM of Degussa C alumina coated with ketoprofen
  • Figure 22 Shows a SEM of silica MP4540
  • Figure 24 Shows FTIR spectra of silica (MP4540) (a), cyclosporin (b), and silica equilibrated with cyclosporin (1 xlO " mol dm " ) (c);
  • Figure 25 Shows a SEM of hematite particles
  • Figure 26 Shows a SEM of hematite particles after equilabration with cyclosporin (5 x 10 "3 mol dm "3 );
  • the present invention is directed to novel compositions comprising at least one type of inorganic core having adsorbed or bound to the surface thereof at least one type of active molecule.
  • the compositions exhibit superior properties as compared to conventional micronized and nanoparticulate active agent formulations.
  • the particle size of the compositions can be narrowly defined based on the particle size of the nanoparticulate inorganic core. This enables the preparation of nanoparticulate compositions having a very narrow particle size range, which is preferred as the particle size of a composition affects the dissolution rate, and thus bioavailability, of a composition.
  • compositions comprising different size inorganic cores can be made in which the smaller inorganic cores release drug at a faster rate than the larger inorganic cores.
  • Such formulations are useful in the pharmaceutical field, as well as, for example, in pesticides, insecticides, fertilizers, and personal care products.
  • nanoparticulate compositions are useful in a wide variety of applications.
  • the nanoparticulate compositions of the invention can be used in pharmaceuticals, including biologies such as proteins and peptides, organic compounds, such as therapeutic small molecules, agricultural agents, cosmetic agents, hair compositions, and others.
  • the inorganic cores of the invention comprise a suitable inorganic material having a nanoparticulate particle size.
  • the inorganic material can vary depending upon the intended use of the resulting composition. For example, compositions intended to be used as pharmaceutical formulations will have different requirements than those intended for agricultural, veterinary, or other uses.
  • Exemplary inorganic cores, suitable for pharmaceutical and other uses are nanoparticulate silica, alumina, and hematite.
  • the general class of inorganic compounds may be expressed as metal oxides, metal hydroxides, metal hydrous oxides, metal sulfides, metal sulfates, metal carbonates, metal phosphates, etc.
  • the core For the core to be useful in a pharmaceutical composition, it must be non-toxic, reactive to the coupling agent or the drug, and be available as colloid particles in the specified particle size range. For all applications, the core must be reactive to the coupling agent or active agent, and be available as colloid particles in the specified particle size range.
  • Other exemplary inorganic core materials include, but are not limited to, titanium dioxide, zinc oxide, chromium oxide, chromium hydroxide, and silver halides. Furthermore, cadmium oxide, cadmium sulfide, zinc sulfide, copper oxide, barium sulfate, cerium oxide, and cobalt oxide may also be used (several of the latter inorganic cores may exhibit toxicity which prevent their use in a pharmaceutical application).
  • the inorganic cores have a particle size of less than about 1 micron, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, less than about 50 nm, less than about 25 nm, less than about 15 nm, less than about 10 nm, or less than about 5 nm.
  • Particle size refers to an "average" particle size in which at least 50% of the particles are less than the recited size.
  • inventions encompass a particle size in which at least 60%, 70%, 80%, or 90% of the particles are less than the recited size.
  • an inorganic core particle size of 10 nm at least 50% of the inorganic cores of the composition are less than 10 nm.
  • at least 60%, 70%, 80%, or 90% of the inorganic cores are less than 10 nm.
  • a coupling agent can be used to form the nanoparticulate compositions of the invention.
  • Suitable coupling agents are, for example, N-phenylaminopropyltrimethoxysilane, 3- aminopropylmethyldiethoxysilane, and methacryloxypropyltrimethoxysilane.
  • the general class of useful coupling agents may be expressed as, but not limited to, amino silanes and caroxy silanes.
  • the active agent must be substantially soluble in at least one liquid medium.
  • the invention can be practiced with liquid media in which a drug substance is substantially soluble including, for example, water, aqueous salt solutions, safflower oil, and solvents such as ethanol, t-butanol, hexane and glycol.
  • the pH of the dispersion media can be adjusted by techniques known in the art.
  • the active agent can be a drug, which is preferably present in an essentially pure form.
  • a drug can be selected from a variety of known classes of drugs, as provided in U.S. Patent No. 5,145,684, including, for example, proteins, peptides, nutraceuticals, anti-obesity agents, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adreno
  • nutraceuticals and dietary supplements are disclosed, for example, in Roberts et al., Nutraceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001), which is specifically incorporated by reference.
  • a nutraceutical or dietary supplement also known as phytochemicals or functional foods, is generally any one of a class of dietary supplements, vitamins, minerals, herbs, or healing foods that have medical or pharmaceutical effects on the body.
  • nutraceuticals or dietary supplements include, but are not limited to, folic acid, fatty acids (e.g., DHA and ARA), fruit and vegetable extracts, vitamin and mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids (e.g., iso-leucine, leucine, lysine, methionine, phenylanine, threonine, tryptophan, and valine), green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish and marine animal oils, and probiotics.
  • folic acid fatty acids
  • fatty acids e.g., DHA and ARA
  • fruit and vegetable extracts e.g., fatty acids (e.g., DHA and ARA)
  • Nutraceuticals and dietary supplements also include bio-engineered foods genetically engineered to have a desired property, also known as "pharmafoods.”
  • Drugs to be administered in an aerosol formulation are preferably selected from the group consisting of proteins, peptides, bronchodilators, corticosteroids, elastase inhibitors, analgesics, anti-fungals, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, respiratory illness therapies associated with acquired immune deficiency syndrome, oncology drugs, anti-emetics, analgesics, and cardiovascular agents.
  • the active ingredient may be present in any amount which is sufficient to elicit a therapeutic effect and, where applicable, may be present either substantially in the form of one optically pure enantiomer or as a mixture, racemic or otherwise, of enantiomers.
  • the active agents are commercially available and/or can be prepared by techniques known in the art.
  • the active agents according to the present invention include but are not limited to active agents which can be used in dermal applications, e.g., sunscreens, cosmetics, topical application of pharmaceuticals to the dermis (acne medication, anti-wrinkle drugs, such as alpha-hydroxy formulations), nail polish, moisturizers, deodorant, etc.
  • Cosmetic compositions are generally defined as compositions suitable for application to the human body. Cosmetic compositions such as creams and lotions are used to moisturize the skin and keep it in a smooth, supple condition. Pigmented cosmetic compositions, such as makeup, blush, lipstick, and eye shadow, are used to color the skin and lips. Since color is one of the most important reasons for wearing cosmetics, color-containing cosmetics must be carefully formulated to provide maximum wear and effect.
  • Coloring agents or pigments are used in cosmetic applications as well as in fabric applications. Suitable pigments can be inorganic and/or organic. Also included within the term pigment are materials having a low color or luster, such as matte finishing agents, and also light scattering agents. Examples of suitable pigments are iron oxides, acylglutamate iron oxides, ultramarine blue, D&C dyes, carmine, and mixtures thereof. Depending upon the type of cosmetic composition, e.g., foundation or blusher, a mixture of pigments will normally be used.
  • Fragrances and odiferous compounds are also suitable for use in the present inventive compositions.
  • Fragrances or perfumes are usually prepared from volatile oils distilled or extracted from the leaves, flowers, gums, or woods of plant life (occasionally from animal life). These include, for example, linalyl acetate from citral, jasmine, cedar, lavender, and attar of rose.
  • a typical fragrance may consist of many volatile components blended to create a pleasant sensory experience to the person wearing the fragrance and also impart a pleasant sensory experience to the people around that person. These blended oils, however, are typically too potent or too expensive to wear without being diluted in an appropriate solvent.
  • Nanoparticulate compositions comprising a fragrance or odiferous compound as an active agent could provide prolonged sensory stimulation following application; i.e., for up to 48 hours following application to the skin.
  • active agents to be applied to mucous include dental applications, such as oral nanoparticulate lidocain formulations, nanoparticulate fluoride treatments, application to the lungs, throat, gastrointestinal tract (GIT), application to wounds, etc. Also included is application to the throat using a liquid containing a nanoparticulate formulation containing, for example, menthol or other numbing compound for treatment of coughs or sore throats.
  • the stomach and GIT can also be treated using nanoparticulate formulations. This is particularly useful for treatment of diseases associated with the mucous of the gastrointestinal tract, such as Crohn's Disease.
  • compositions of the invention also encompass food products.
  • spice, oleoresin, flavor oil, color, or chemicals are often added during food processing to produce the desirable flavors, taste, and appearance.
  • These agents can be included in a nanoparticulate composition of the present invention for increased adhesion to biological surfaces. Nanoparticulate flavoring agents could be used in products such as gums to produce prolonged flavor.
  • Nanoparticulate compositions can be used in hair conditioner formulations, hair dyes, hair sprays, hair cosmetics, hair cleansers, depilatories, etc.
  • Yet another area of applicability of the present invention includes nanoparticulate compositions that can be applied to plant tissue.
  • Nanoparticulate compositions can be used for applications of pesticides, insecticides, fertilizers, etc. - any substance to be applied to the surface of a plant. All plants, such as grass, trees, commercial farm crops (such as corn, soybeans, cotton, vegetables, fruit, etc), weeds, etc., are encompassed by the scope of this invention.
  • the active agent of the nanoparticulate composition is an insecticidal ingredient applied to seeds, plants, trees, harvested crops, soil, and the like.
  • the insecticide ingredient can be selected from a wide variety of organic compounds or mixtures which are known and used in agriculture and horticulture applications, such as those listed in W. T. Thomson, Agricultural Chemicals, Book I, Insecticides (Thomson Publications, Fresno, Calif. 1989).
  • chlorinated hydrocarbon derivatives usually act as stomach and contact poisons affecting the nervous system. They are persistent in the environment and tend to accumulate in animal fatty tissue, as exemplified by DDT and chlordane.
  • insecticidal compounds are chlorfluazuron, chlorpyrifos, chlorpyrifos methyl, bromophos, diazinon, malathion, trichlorfon, dimethoate, phorate, lindane, toxaphene, diflubenuron, methomyl, propoxur, carbaryl, cyhexatin, cypermethrin, permethrin, fenvalerate, dicofol, tetradifon, propargite, and the like.
  • insecticides include the pyrethroid insecticides, such a FenvalerateTM [ -cyano-3-phenoxybenzyl-2-(4-chlorophenyl)-3methylvalerate] and PyrethroidTM [cyano(4-fluoro-3-phenoxyphenylmethyl-3-(2,2-dichloroethenyl)-2,2-dimethyl cyclopropanecarboxylate]; organophosphorus insecticides, such as DDVPTM (2,2- dichlorovinyldimethyl phosphate), SumithionTM (dimethyl-4-nitro-m- tolylphosphorothionate), MalathoneTM ⁇ S-[l,2-bis(ethoxycarbonyl)ethyl]dimethyl- phosphorothiol thionate ⁇ , Dimethoate [dimethyl-S-(N-methylcarbamoylrnethyl)- phosphorothios thionate), ElsanTM
  • Examples of other agricultural agents include acaricides such as, but not limited to, SmiteTM ⁇ 2-[2-(p-tert-butylphenoxy)isopropoxy]isopropyl-2-chloroethyl sulfide ⁇ , AcricidTM (2,4-dinitro-6-sec-butylphenyl dimethylacrylate), ChlormitTM (isopropyl 4,4- dichlorobenzylate), AcarTM (ethyl 4,4-dichlorobenzylate), KelthaneTM [l,l-bis(p- chloro ⁇ henyl)-2,2,2-trichloroethanol], CitrazonTM (ethyl O-benzoyl-3-chloro-2,6- dimethoxybenzohydroxymate), PlictranTM (tricyclohexyltin hydroxide), and OmiteTM [2- (p-tert-butylphenoxy)cyclohexyl-2-propinyl sulfite] .
  • germicides include organosulfur germicides, such as Di thaneTM (zinc ethylenebisdithiocarbamate), ManeoTM (manganese ethylenebis-dithiocarbamate), ThiuramTM [bis(dimethylthiocarbamoyl) disulfide ], BenlateTM [methyl 1- (butylcarbamoyl)-2-benzimidazole carbamate], DifolatanTM (N-tetrachloroethylthio-4- cyclohexane-l,2-dicarboxyimide), DaconolTM (tetrachloroisophthalonitrile), PansoilTM (5-ethoxy-3-trichloromethyl-l,2,4-thiadiazole), Thiophanate-methyl[l,2-bis(3- methoxycarbonyl-2-thioureido)benzene] , RabcideTM (4,5,6,7-tetrachlorophthaloid), Mit
  • Example of plant growth regulating agents include, but are not limited to, MHTM (maleic acid hydrazide) and EthrelTM (2-chloroethylphosphonic acid).
  • herbicides include, but are not limited to StamTM (3,4- dichloropropionanilide), SaturnTM [S-(4-chlorobenzyl) N,N-diethylthiolcarbamate), Lasso (2-chloro-2',6'-diethyl-N-(methoxymethyl)acetanilide), GlyphosateTM [N- (phosphonomethyl)glycine isopropylamine salt], DCMU [3-(3,4-dichlorophenyl)-lJ- dimethylurea), and GramoxoneTM (l,r-dimethyl-4,4'-dipyridium dichloride].
  • auxin transport inhibitors e.g., naptalam
  • growth regulators including benzoic acids, e.g., dicamba
  • phenoxy acids such as (i) acetic acid type, e.g., 2,4-D, MCPA, (ii) propionic acid type, e.g., 2,4-DP, MCPP, and (iii) butyric acid type, e.g., 2,4-DB, MCPB
  • picolinic acids and related compounds e.g., picloram, triclopyr, fluroxypyr, and clopyralid.
  • Photosynthesis inhibitors are also herbicides useful in the compositions of the invention.
  • Such compounds include but are not limited to (a) s-triazines, such as (i) chloro substituted, e.g., atrazine, simazine, and cyanazine, (ii) methoxy substituted, e.g., prometon, (iii) methylthio substituted, e.g., ametryn and prometryn; (b) other triazines, such as hexazinone, and metribuzin; (c) substituted ureas, such as diuron, fluometuron, linuron, tebuthiuron, thidiazuron, and forchlorfenuron; (d) uracils, such as bromacil and terbacil; and (e) others, such as bentazon, desmedipham, pheninedipham, propanil, pyrazon, and pyridate.
  • s-triazines such as (i) chloro substituted, e.g., at
  • Pigment inhibitors are also herbicides useful in the compositions of the invention.
  • Such compounds include but are not limited to pyridazinones, such as norflurazon; isoxazolones, such as clomazone; and others, such as amitrole and fluridone.
  • growth inhibitors are herbicides useful in the compositions of the invention.
  • Such compounds include but are not limited to (a) mitotic disruptors, such as (i) dinitroanilines, e.g., trifluralin, prodiamine, benefin, ethalfluralin, isopropalin, oryzalin, and pendimethalin; and (ii) others, such as DCPA, dithiopyr, thiazopyr, and pronamide; (b) inhibitors of shoots of emerging seedlings, such as (i) thiocarbamates, e.g., EPTC, butylate, cycloate, molinate, pebulate, thiobencarb, triallate, and vernolate; (c) inhibitors of roots only of seedlings, such as bensulide, napropamide, and siduron; and (d) inhibitors of roots and shoots of seedlings, including chloroacetamides, such as alachlor,
  • Amino acid synthesis inhibitors are herbicides useful in the compositions of the invention.
  • Such compounds include, but are not limited to, (a) glyphosate, glufosinate; (b) sulfonylureas, such as rimsulfuron, metsulfuron, nicosulfuron, triasulfuron, primisulfuron, bensulfuron, chlorimuron, chlorsulfuron, sulfometuron, thifensulfuron, tribenuron, ethametsulfuron, triflusulfuron, clopyrasulfuron, pyrazasulfuron, prosulfuron (CGA-152005), halosulfuron, metsulfuron-methyl, and chlorimuron-ethyl; (c) sulfonamides, such as flumetsulam (a.k.a. DE498); (d) imidazolinones, such as imazaquin
  • Lipid biosynthesis inhibitors are herbicides useful in the compositions of the invention.
  • Such compounds include, but are not limited to, (a) cyclohexanediones, such as sethoxydim and clethodim; (b) aryloxyphenoxys, such as fluazifop-(P-butyl), diclofop-methyl, haloxyfop-methyl, and quizalofop; and (c) others, such as fenoxaprop- ethyl.
  • Cell wall biosynthesis inhibitors are herbicides useful in the compositions of the invention. Such compounds include, but are not limited to, dichlobenil and isoxaben.
  • Rapid cell membrane disruptors are herbicides useful in the compositions of the invention.
  • Such compounds include, but are not limited to, (a) bipyridiliums, such as paraquat, and diquat; (b) diphenyl ethers, such as acifluorfen, fomesafen, lactofen, and oxyfluorfen; (c) glutamine synthetase inhibitors, such as glufosinate; and (d) others, such as oxadiazon.
  • Miscellaneous herbicides useful in the compositions of the invention include, but are not limited to, (a) carbamates, such as asulam; (b) nitriles, such as bromoxynil and ioxynil; (c) hydantocidin and derivatives; and (d) various other compounds, such as paclobutrazol, ethofumesate, quinclorac (a.k.a. BAS514), difenzoquat. endothall, fosamine, DSMA, and MSMA.
  • herbicides useful in the compositions of the invention include, but are not limited to, triketones and diones of the type described in U.S. Patent Nos. 5,336,662 and 5,608,101, the contents of each of which are incorporated herein by reference, and in EP-A-338-992; EP-A-394-889; EP-A-506,967; EP-A-137,963; EP-A-186-118; EP-A- 186-119; EP-A-186-120; EP-A-249-150; and EP-A-336-898.
  • MIKADOTM sulcotrione
  • 2-(2- chloro-4-methanesulfonylbenzoyl)-l,3-cyclohexanedione 2-(4-methylsulfonyloxy-2- nitrobenzoyl)-4,4,6,6-tetramethyl- 1 ,3-cyclohexane dione
  • teeth can be treated with teeth whiteners or fluoride nanoparticulate compositions
  • bones can be treated with calcium nanoparticulate compositions
  • nails can be treated with color or strengthening nanoparticulate formulations
  • insects or pests can be treated with insecticides or other toxic compositions to the pest.
  • compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients.
  • excipients are known in the art.
  • filling agents are lactose monohydrate, lactose anhydrous, and various starches
  • binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel ® PH101 and Avicel ® PH102, microcrystalline cellulose, and silicifized microcrystalline cellulose (SMCC).
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil " 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • flavoring agents are Magnasweet ® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
  • preservatives examples include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
  • Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • examples of diluents include microcrystalline cellulose, such as Avicel ® PH101 and Avicel ® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ® DCL21; dibasic calcium phosphate such as Emcompress ® ; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross- povidone, sodium starch glycolate, and mixtures thereof.
  • effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate.
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • sodium bicarbonate component of the effervescent couple may be present.
  • the relative amount of at least one inorganic core and one or more active agents can vary widely.
  • the optimal amount of the active agent can depend, for example, upon the particular active agent selected and the intended use of the nanoparticulate composition.
  • the concentration of the one or more inorganic cores can vary from about 0.1% to about 99.9% by weight based on the total combined dry weight of the inorganic core and active agent.
  • the concentration of the at least one active agent can vary from about 0.001% to about 99.9% by weight based on the total combined dry weight of the inorganic core and active agent.
  • the nanoparticulate compositions of the invention can be made by contacting at least one solubilized active agent with at least one suitable inorganic core for a time and under conditions until adsorption between the core and active agent occurs.
  • at least one solubilized active agent is contacted with at least one suitable inorganic core in the presence of a coupling agent for a time and under conditions until binding between the core-coupling agent-active agent occurs.
  • nanoparticulate compositions of the present invention can be administered to humans and animals in any pharmaceutically acceptable manner, such as orally, via pulmonary route, rectally, parenterally (intravenous, intramuscular, or subcutaneous), intracisternally, intravaginally, intraperitoneally, locally/topically (powders, ointments or drops), or as a buccal or nasal spray.
  • pharmaceutically acceptable manner such as orally, via pulmonary route, rectally, parenterally (intravenous, intramuscular, or subcutaneous), intracisternally, intravaginally, intraperitoneally, locally/topically (powders, ointments or drops), or as a buccal or nasal spray.
  • Such a method comprises administering to an animal or human in need a therapeutically effective amount of a nanoparticulate composition according to the invention.
  • compositions can be applied to the surface of hair by spraying or soaking, as well as by other techniques known to those skilled in the art.
  • the compositions can be applied to plant tissue by spraying, soaking, soil drench, pre-emergence and post- emergence, as well as by other techniques known to those skilled in the art.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Solid dosage forms for oral administration of a pharmaceutical active agent include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one of the following: (a) one or more inert excipients (or carrier), such as dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrohdone, sucrose and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as
  • the dosage forms may also comprise buffering agents.
  • Liquid application forms include emulsions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
  • Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • oils such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil
  • glycerol tetrahydrofurfuryl alcohol
  • polyethyleneglycols fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • compositions of the invention may be varied to obtain an amount of active ingredient that is effective to obtain a desired response for a particular composition and method of application.
  • the selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment, and other factors.
  • the formulations of the present invention can be administered in combination with other pharmaceutical agents in the form of a solution, suspension, syrup or elixir or as formulated for solid dose administration.
  • the total daily amount of the active agent included in the inventive composition can be applied to a host in single or divided doses. Individuated units may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, for example, when the host is a patient, such factors include the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
  • the purpose of this example was to prepare nanoparticulate alumina particles coated with naproxen or ketoprofen.
  • Nanoparticulate alumina particles having modal diameters of 8 and 13 nm were successfully coated by adsorption of naproxen [(+)-6-methoxy- ⁇ -methyl-2-naphthalene- acetic acid] or ketoprofen [ ⁇ -methyl-3-(4-methylbenzoi ⁇ ) benzene acetic acid] in aqueous and ethanol solutions.
  • the presence of the drugs at the alumina surface was confirmed by attenuated total reflection infrared spectroscopy and electrokinetic measurements, while the bound amounts were assessed by thermogravimetric analysis.
  • Naproxen (MW: 230 g mol "1 ) was purchased from Aldrich Chemicals Two commercially available alumina nanoparticles were used in the experiment.
  • Degussa C (DGC) alumina ⁇ -Al 2 0 3 , (particle size about 13 nm, specific surface area (SSA) of 100 ⁇ 10 m 2 g _1 ) was obtained in powder form, dispersions of which were prepared in aqueous and ethanol solutions under stirring or in an ultrasonic bath.
  • Nalco alumina (particle size 8 nm, SSA of 550 ⁇ 20 m 2 g "1 ) was supplied as a 22 wt% dispersion in water.
  • Ketoprofen (MW: 270 g mol "1 ) was obtained from Elan Pharmaceutical Technologies.
  • ketoprofen particles were prepared as described above for the naproxen particles.
  • the presence of the drugs at the alumina surfaces was checked by attenuated total reflection infrared (FTIR-ATR) spectroscopy over the 4000-500 cm “1 range at a resolution of 4 cm “1 .
  • the quantities of the adsorbed organics were assayed by the thermogravimetric analysis (TGA), carried out at temperatures ranging from 100 to 1000 °C, at the scan rate of 20 °C/min in air.
  • TGA thermogravimetric analysis
  • the alumina nanoparticles coated with drugs were also examined by transmission electron microscopy (TEM). Electrokinetic measurements of samples in water and ethanol were performed with a Zumblels instrument at a pH of 7.2 ⁇ 0.2 in 1J0 "3 mol dm "3 NaCl at 25°C. Each measurement was repeated ten times.
  • Electrophoresis was used as a convenient technique to preliminary assess if there was any drug attachment to the alumina cores. Since both naproxen and ketoprofen have carboxyl groups, it was expected that the carboxyl groups would condense with the basic surface sites of the adsorbent.
  • the ⁇ -potentials of both alumina samples were evaluated as a function of the pH in a 10 "3 mol dm "3 NaCl aqueous solutions, which yielded isoelectric points (IEP) between 9 and 9.5 ( Figure 1), characteristic of colloidal alumina. G.A. Parks, Chem. Revs., 65:111 (1965). Most experiments were carried out at pH ⁇ 7 to have cores positively charged.
  • Figure 2 displays the electrokinetic data of alumina particles in the presence of different concentrations of naproxen and ketoprofen.
  • ⁇ - potential first becomes less positive and with further addition of the drugs, the sign is reversed to negative.
  • the concentration of naproxen at which the reversal of charge takes place is ⁇ 5-10 " mol dm " for DGC and ⁇ 1.6-10 " mol dm “ for the Nalco sample, while the charge of the DGC is reversed with ketoprofen at 1-10 "3 mol dm "3 .
  • no charge reversal is observed in ethanol-containing dispersions.
  • the electron micrograph in Fig. 5 illustrates the Nalco alumina cores and the same material coated with naproxen.
  • the primary particle size is of the order of 10 nm, while the alumina coated particles consist of small aggregates estimated to be 30 nm in size.
  • Analogous electron micrographs were obtained with the DGC alumina systems.
  • ketoprofen at saturation is more than twice that of naproxen, both in aqueous and alcohol media.
  • Two properties of these molecules may account for the observed differences.
  • the other pa- rameter to consider is the shape of the molecules. Since the carboxyl groups are oriented towards the surface of the inorganic cores, a larger number of ketoprofen molecules can be accommodated at saturation than of naproxen molecules, due to the steric interference of their naphthalene rings.
  • the purpose of this example was to prepare nanoparticulate compositions of inorganic cores having naproxen coated thereon.
  • ATR-FTIR attenuated total reflection infra-red
  • Figure 7 shows FTJR spectra of: (a) naproxen; (b) Ludox CL ® (2 wt%) + naproxen (0.01 mol. dm "3 in ethanol; and (c) Ludox CL ® silica;
  • Figure 8 shows FTJR spectra of: (a) naproxen; (b) Nissan silica (2 wt%) + naproxen (0.01 mol.
  • Figure 9 shows FTJR spectra of: (a) naproxen; (b) Nalco alumina (0.1 wt%) + naproxen (0.0025 mol. dm "3 in water; and (c) alumina Nalco; and Figure 10 shows FTIR spectra of: (a) naproxen; (b) Nalco alumina (2 wt%) + naproxen (0.05 mol. dm "3 in methanol; and (c) alumina Nalco.
  • the purpose of this example was to successfully prepare nanoparticulate compositions of inorganic cores having naproxen coated thereon.
  • Naproxen was obtained from Aldrich Chemicals.
  • Commercially available alumina nanoparticles Degussa C, ⁇ -Al 2 O 3 (particle size 13 nm, specific surface area (SSA) of 100 ⁇ 10 mY 1 ) and Nalco (particle size - 8 nm, SSA of 550 ⁇ 20 m 2 g "1 ) were supplied by the Degussa and Nalco Chemical Companies, respectively. These particles were used as inorganic cores.
  • Preparation of Naproxen Coated Alumina Particles Stocks solutions of naproxen in water and ethanol were prepared in concentrations of 0.05, 0J, and 0.2 mol dm "3 .
  • a known volume of the colloidal dispersion of Nalco or Degussa C alumina powders was mixed under stirring with a given volume of solvents (water or ethanol). Then the volumes of the stock solutions containing different concentrations of naproxen were added under stirring to reach a final volume of 100 cm 3 . To avoid aggregation of alumina nanoparticles, the concentration was kept at 0.05 wt% in all experiments, while the concentration of naproxen was varied from 5 x 10 " to 0J mol dm " . The mixtures were equilibrated for 15 hours at room temperature.
  • the obtained particles were separated from water or ethanol by centrifugation at 55,000 rpm for 3 hours.
  • the resulting solids were dried in a vacuum oven at 100°C overnight and stored in a desiccator before further analyses. This process produces cakes, which were ground before some of the analyses. To prevent the aggregation of particles by the described procedure, some of the dispersions were freeze-dried.
  • the size of obtained naproxen coated alumina nanoparticles was examined by transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • the presence of the naproxen at the alumina surfaces was checked by attenuated total reflection infrared (ATR-FTIR) spectroscopy over 4000-500 cm “1 range at a resolution of 4 cm “1 .
  • the TGA was carried out at temperatures ranging from 100 to 1000°C at the scan rate of 20 °C/min in air, to determine the quantities of the adsorbed naproxen on alumina.
  • Figure 11 shows the ⁇ -potentials of both alumina cores, Nalco alumina (O) and Degussa C alumina (D), in 1 x 10 "3 mol dm "3 aqueous NaCl solution, as a function of the pH.
  • the isoelectric point (IEP) of both samples is between 9 and 9.5, which is characteristic of colloidal alumina.
  • pH - 7 was chosen to have cores positively charged.
  • Figure 12 shows the ⁇ -potentials of both alumina cores, Nalco alumina (O) and Degussa C alumina ( ⁇ ), in 1 x 10 "3 mol dm "3 aqueous NaCl solution at a pH of 7.2 ⁇ 0J, and of Degussa C alumina in ethanol ( ⁇ ) as a function of the concentration of added naproxen.
  • Figure 12 thus gives the electrokinetic data of alumina particles in the presence of different concentrations of naproxen. The figure shows that with the addition of naproxen, the ⁇ -potential first becomes less positive but with an increasing concentration of the drug in aqueous dispersions the sign of the charge is reversed to negative.
  • Figure 13 shows the adsorption isotherms of naproxen on Degussa C alumina in water (D) at a pH of 7.2 ⁇ OJ and in ethanol ( ⁇ ).
  • the concentration of alumina in all samples was 0.05 wt.%. While at the lower drug concentration the adsorption is more efficient in alcohol, on saturation the same amount of adsorbed naproxen is found, which corresponds to 2.3 ⁇ mol m 2 (i.e. 5.2 wt%).
  • Figure 14 shows the FTJR spectra of Degussa C alumina (a), naproxen (b), and
  • Fig. 15 shows the FTJR spectra of Nalco alumina (a); naproxen (b); and Nalco alumina coated with naproxen in water (c).
  • Figure 16 shows transmission electron micrographs of the Nalco alumina core (a) and of Nalco alumina core coated with naproxen (b).
  • the primary particle size is about 10 nm ( Figure 16a).
  • the alumina coated with naproxen composition comprises particles consisting of small aggregates estimated to be about 30 nm in size.
  • the purpose of this example was to successfully prepare uniform nanoparticulate drug particles by coating nanoparticulate alumina cores with ketoprofen.
  • Ketoprofen was provided by Elan Pharmaceutical Technologies.
  • Commercially available alumina nanoparticles, Degussa C, ⁇ -Al 2 O 3 , (particle size 13 nm, specific surface area (SSA) of 100 ⁇ 10 m 2 g _1 ) were supplied by the Degussa Company.
  • Colloidal silica, MP4540 (particle size 0.45 ⁇ m), was purchased from Nissan Company.
  • Ketoprofen dissolves directly in ethanol.
  • the pH was first raised to 12 and then slowly decreased to 7.2 by adding a few drops of hydrochloric acid. All solutions were freshly prepared and filtered through 0.22 ⁇ m Millipore membranes before use.
  • a known volume of Degussa C alumina powder was mixed under stirring with a given volume of solvents (water or ethanol). Afterwards desired volumes of stock solutions, containing different concentrations of ketoprofen, were added under stirring to reach a final volume of 100 cm 3 . To avoid aggregation of alumina nanoparticles, the concentration was kept at 0.05 wt% in all experiments, while the concentration of ketoprofen was varied from 5 x 10 "5 to 0J5 mol dm " . The mixtures were equilibrated for 15 hours at room temperature. The obtained particles were separated from water or ethanol by centrifugation at 55,000 rpm for 3 5 hours.
  • the resulting solids were dried in a vacuum oven at 100°C overnight and stored in a desiccator before further analyses.
  • the produced cakes were ground before some of the analyses.
  • some dispersions were freeze-dried.
  • distilled water a nonsolvent for cyclosporin
  • Alumina nanoparticles coated with ketoprofen were examined by TEM.
  • the presence of the ketoprofen on alumina surfaces was evaluated by attenuated total reflection infrared (ATR-FTJR) spectroscopy over the 4000-500 cm “1 range at a resolution of 4 cm “1 .
  • ATR-FTJR attenuated total reflection infrared
  • the concentration of alumina was kept at 0.05 wt.% and the pH of the aqueous solutions was 7.2 ⁇ O.L
  • Electrokinetic data Figure 18 shows the ⁇ -potentials of Degussa C alumina (D) in 1 xlO "3 mol dm "3
  • Fig. 18 shows the electrokinetic data of alumina particles, in aqueous dispersions, in the presence of different concentrations of ketoprofen. The figure demonstrates that with the addition of ketoprofen, the ⁇ -potential first becomes less positive, and with an increasing concentration of ketoprofen the sign of the charge is reversed to negative. The concentration at which the reversal of charge takes place is less than 1J0 " mol dm " of ketoprofen for Degussa C.
  • Figure 19 shows the adsorption data of ketoprofen on Degussa C alumina in water and in ethanol.
  • the adsorption is more efficient in alcohol, yielding somewhat larger amounts of deposited drug.
  • the amounts on saturation are - 4.7 ⁇ mol m 2 (i.e., 12 wt%) for adsorption in ethanol and 4.3 ⁇ mol m (i.e., 10.8 wt%) for adsorption in water.
  • These data are based on the SSA supplied by the inorganic core manufacturer, and corresponds to an average molecular area per ketoprofen molecule of 37 A 2 . It is interesting to note that ketoprofen adsorbs twice as much as naproxen on the same cores ( ⁇ 5.2 wt%).
  • the ATR-FTJR spectra confirm the presence of ketoprofen at the Degussa C alumina surfaces.
  • the C-H stretching vibration between 2900 and 3000 cm "1 are characteristic of ketoprofen.
  • the purpose of this example was to prepare uniform nanoparticulate drug particles by coating nanoparticulate silica or hematite cores with cyclosporine.
  • Cyclosporine was provided by Elan Pharmaceutical Technologies. Colloidal silica,
  • MP4540 particle size 0.45 ⁇ m
  • Hematite ⁇ -
  • Figure 22 shows the SEM picture of the original monodispersed silica particles of 0.45 ⁇ m in diameter. In these experiments, relatively large silica cores were used for practical reasons to explore possible deposition of the drug. These particles are much more easily manipulated than nanoparticulate sized particles.
  • Figure 23 shows the SEM picture of the same silica after equilibration with cyclosporin
  • Figure 24 shows the infrared spectra of this system, which indicate no presence of the drug. Similarly, no uptake could be detected by TGA.
  • Figure 25 displays the SEM of the original hematite ( ⁇ -Fe 2 O 3 ) which are ellipsoidal ( ⁇ 0.7 ⁇ m long and 0J ⁇ m wide), while Figure 26 is the SEM of the same hematite after the equilibration with cyclosporin. No change in particles could be seen, although they appear to adhere to each other, possibly enmeshed by cyclosporin molecules.
  • Example 6 The purpose of this example was to determine the effect on the adsorption of naproxen and ketoprofen to a modified surface of nanoparticulate silica particles.
  • Ketoprofen was provided by Elan Pharmaceutical Technologies. Naproxen was obtained from Aldrich Chemicals. JPA-ST-S (particle size 12 nm) in isopropanol was purchased from Nissan Company. Ludox CL ® (particle size 22 nm, SSA of 130 ⁇ 10 m 2 g ⁇ ) and Ludox AM ® (particle size 12 nm specific surface area, SSA of 220 ⁇ 10 m 2 g _1 ) were obtained from Dupont Company. The coupling agents N- phenylaminopropyltrimethoxysilane, 3-aminopropylmethyldiethoxysilane, and methacryloxypropyltrimethoxysilane were obtained from United Chemical Technologies. 5 Experimental
  • Table 9 lists the different kinds of silica particles and coupling agents used in the experiment.
  • Modified silica was then centrifuged for three hours at 55,000 rpm and the resulting gel was redispersed in the original solvent. 15

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Abstract

La présente invention concerne des compositions nanoparticulaires comprenant des noyaux inorganiques et des procédés de fabrication et d'utilisation de telles compositions. Lesdites compositions nanoparticulaires comprennent au moins un type de noyau inorganique, ayant adsorbé ou fixé à sa surface, au moins un type de molécule active. Lesdites compositions présentent des propriétés supérieures comparées à des formulations d'agents actifs micronisés et nanoparticulaires classiques.
PCT/US2002/032619 2001-10-15 2002-10-15 Compositions nanoparticulaires comprenant des noyaux inorganiques WO2003032959A1 (fr)

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