WO1990015593A1 - A process for the preparation of drug particles - Google Patents

A process for the preparation of drug particles

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Publication number
WO1990015593A1
WO1990015593A1 PCT/SE1990/000426 SE9000426W WO1990015593A1 WO 1990015593 A1 WO1990015593 A1 WO 1990015593A1 SE 9000426 W SE9000426 W SE 9000426W WO 1990015593 A1 WO1990015593 A1 WO 1990015593A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
drug
surfactant
size
organic
example
Prior art date
Application number
PCT/SE1990/000426
Other languages
French (fr)
Inventor
Brita Sjöström
Bengt Kronberg
Johan Carlfors
Irena Blute
Original Assignee
Ytkemiska Institutet
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • 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
    • A61K9/5123Organic compounds, e.g. fats, sugars
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate 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
    • A61K9/145Intimate 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 organic compounds

Abstract

A process for the preparation of submicron size, monodisperse drug-particles of a drug of low water-solubility by emulsifying an organic solution of the drug in an aqueous phase and then removing the organic solvent resulting in drug precipitation, containing the steps: a) emulsifying the organic solution in the presence of an emulsifier comprising a surfactant capable of adsorption on the surface of a precipitated drug-particle; b) removing the organic solvent from the suspension; and c) recovering the precipitated drug-particles from the aqueous phase or storing the same in the original aqueous phase.

Description

A process for the preparation of drug particles.

The present invention relates to a process for the preparation of submicron size, relatively monodisperse drug-particles of a drug of low water-solubility.

The size of water-insoluble drug-particles or such particles of a drug of low water-solubility is of considerable importance for the bioavailability of the drug. The rate of dissolution of the particles is directly proportional to their specific area and, accordingly, the size is critical for the absorption and distribution of the drug in the tissue. Another argument for producing submicron particles is that the smaller particle size will allow alternative ways of administration of the drug substance. For pharmaceutical applications drug-particles of submicron size are therefore desirable. Such particles are, in accordance with conventional techniques, produced by milling, a process which reduces the mean particle size to a few microns. However, the process produces a rather broad size-distribution thus resulting in illdefined dissolution kinetics. Such milling process frequently also results in contamination and degradation of the drug.

An alternative to such milling is to precipitate particles by crystallization. This is a more complex process which involves nucleation and growth kinetics but which is an alternative that overcomes the particle size limitations of milling processing. However, also according to this alternative the difficult inherent in using crystallization is that of controlling the particle size and the size distribution to meet with the requirements. Crystallization is a subject to several phenomena that aggravate the problem of controlling particle size. First, a crystal growth can uncontrollably change particle size and broaden the size distribution. Second, crystals formed may aggragate or agglomerate also resulting in uncontrolled size growth and distribution. The present invention has for an object to provide a process for the preparation of small particles of water-in-soluble drugs or drugs of low water-solubility while controlling size distribution to avoid widely varying particle sizes.

Another object of the invention is to provide a process for such drug particle manufacture which is highly reproducible and easily controlled.

Yet another object of the invention is to device a process through which small drug particles can be produced which meet with the usual pharmaceutical requirements.

These and other objects of the invention will be clear from the following detail description. Accordingly, the invention resides m a process for the preparation of submicron size relatively monodisperse drug-particles of a drug of low water-solubility or a water-insoluble drug by emulsifying an organic solution of the drug in an aqueous phase and then removing the organic solvent resulting in drug precipitation. Such process comprises the following steps:

a) emulsifying the organic solution in the presence of an emulsifier and if needed a protective colloid comprising a surfactant capable of adsorption on the surface of a precipitated drug particle;

b) removing the organic solvent from the suspension; and c) recovering the precipitated drug particles from the aqueous phase or storing the same in the original aqueous phase.

Removal of the organic solvent from the suspension can take place in different ways. The following procedures are examples of such organic solvent removal:

the organic solvent can be removed by evaporation; the organic solvent can be removed by washing through continuous renewal of the aqueous phase;

the organic solvent can be removed by washing away same through dialysis by contact with a pure aqueous phase;

the organic solvent can be removed by contacting the emulsion with an excess of aqueous phase to dissolve the or- game solvent therein resulting m precipitation of the drug

When removing the organic solvent by evaporation it may occur that water of the aqueous phase evaporates at the same time resulting in reduced water content of the emulsion Such evaporation of water can be compensated for by adding further quantities of aqueous phase to the emulsion during evaporation of the organic solvent.

The different possibilities of controlling the drop diameter of the emulsion, and the drop size of the emulsion can be maintained within relatively broad range, such as between about 0.1 and about 20 mm. The size of the drops of the emulsion can be controlled by varying the supply of mechanic energy, by varying the concentration of surfactant and by varying the ratio between organic solvent and aqueous phase in the emulsion. The concentration of surfactant can for practical reasons be molarly related to the molar concentration of the drug.

The surfactant used is subject to several requirement as to its function. Thus, it shall operate satisfactorily as an emulsifying agent, i.e. it shall result in the formation of a stable emulsion. It is possible to use a protective colloid in combination with the surfactant to improve the stability of the emulsion. The basic requirement according to the invention is to use a surfactant which is capable of adsorption on the surface of a precipitated drug-particle. By using such surfactants a controlled and reproducible precipitation of small drug-particles takes place and the particle size distribution will be maintained within fairly narrow ranges.

Furthermore, the surfactant preferably inhibits aggregation and agglomeration of the particles and should advantageously be capable of inhibiting crystal growth. Such crystal growth is partly eliminated in view of reduced surface energy when the surfactant is adsorbed on the surface of the crystals.

It is preferred to use a protective colloid to stabilize the suspension. Said colloid can be synthetic, semisynthetic or can be constituted by a polysaccharide or a pro tern. Parts of the protective colloid must be water-soluble to give colloidal stability. Micell formation in solution should be avoided but this is not necessary if the solubilizing capacity thereof on the crystal-forming substance is low. Possible incorporation of the tenside and/or the protective colloid in the crystal structure of the particle is permissible.

It is important to note that the process of the present invention does not involve any reaction in the system and that the process is not based on so called micro-emulsions.

It is advantageous in the process of the invention that no or very little mass transportation takes place between the drops of the emulsion and this requires a certain minimum concentration of drug in said drops.

Below there are given non-limitmg examples of drugs, organic solvents and surfactants suitable for use in the process of the invention. DRUGS

As water-insoluble drugs or drugs of low water-solubility the following are of interest.

Examples of drugs whose bioavailability has been increased as a result of particle size reduction

A, vitamin Medroxyprogesterone acetate 4-Acetamidophenyl,2,2,2-triNitrofurantoin

-chlorethyl carbonate Phenobarbital

Aspirin Phenacetin

Bishydroxycoumarin Procaine penicillin

Chloramphenicol Reserpme

Cyheptamide Spironolactone

Digoxin Sulfadiazine

Fluocmolone acetonide Sulfasoxazole

Griseofulvin Sulfur

p-Hydroxypropiophenone To1butamide Drugs with potential bioequivalency problems

Acetazolamide Para-ammo sal icyl i c ac id

Acetyldigitoxin Para-methadione

Alseroxylon Perphenazine

Aminophyllin Phenacemide

Aminosalicylic acid Phensuximide

Bendroflumethiazide Phenylaminosalicylate

Benzthiazide Phenytoin

Betamethasone Phytonadione

Bishydroxycoumarin Polythiazide

Chlorambucil Prednisolone

Chlorodiazepoxide Primidone

Chlorothiazide Probenec id

Chloropromazme Procamamide

Cortisone acetate Prochlorperazme

Deserpidme Promazme

Dexamethasone Promethazme

Dichlorphenamide Propylthi ourac i l

Dienestrol Pyrimethamine

Diethylstilbestrol Qumethiaz ide

Dyphylline Qumidine

Ethinyl estradiol Rauwolfia serpentina

Ethosuxmide Rescinnamme

Ethotoin Reserpine

Ethoxzolamide Salicylazosulfapyridine

Fludrocort is one Sodium sulfoxone

Fluphenazine Spironolactone

Fluprednisolone Sulf adiazme

Hydralazine Sulfadimethoxine

Hydrochlorothiazide Sulfamerazine

Hydroflumethiazide Sulfaphenazole

Imipramine Sulfasomidine

Isoproterenol Sulfasoxazole

Liothyronme Theophylline

Menadione Thioridazine

Mepheny to rn Tolbutamide cont.

Methazolamide Triamcinolone

Methyclothiazide Trichlormethiazide

Methylprednisolone Triethyl melamine

Methyltestoεterone Trifluoperazine

Nitrofurantoin Triflupromazine

Oxtriphylline Trimeprazine

Trimethadione

Uracil mustand

Warfarin

ORGANIC SOLVENTS

Among suitable organic solvents for use in the emulsion the following can be mentioned.

Any organic solvent that is a liquid and is poorly soluble in water. A prerequisite is that the solvent must be removed to concentrations that are acceptable from a toxicological point of view.

Examples :

- linear, branched or cyclic alkanes with carbon number of 5 or higher; e.g. n-pentane, n-heptane and higher linear alkanes; 2,2-dιmethyl butane or 2,2,4-trimethyl pentane; cyclopentane, cyclohexane, methylcyclohexane etc.

- linear, branched or cyclic alkenes with carbon number of 5 or higher; e.g. 2-pentene, cyelohexene, 1,3 cyclopentadiene or 2,3 dimethyl-1-pentene.

- linear, branched or cyclic alkynes with carbon number of 5 or higher; e.g. 2-pentyne or 4-methyl-2-pentyne.

- aromatic hydrocarbons; e.g. toluene, ethylbenzene.

- completely or partially halogenated hydrocarbons; e.g. dichlormetan, chloroform, chlorobenzene, chlorobenzoic acid etc.

- ethers; e.g. diethylether etc.

- esters; e.g. ethylacetate, 9-Octadecenoic acid, ethyl ester, ethyl oleate, tetradecanoic acid 1-methylethyl ester, etc. - ketones; e.g. cyclohexanone, 2-pentanone etc.

- mono-, di- or tri-glycerides; e.g. synthetic glycerol triacetate, glycerolmonolinolein etc., and native oils: almond oil, cotton seed oil, corn oil, olive oil, peanut oil, sesame oil, soybean oil etc.

- alcohols; e.g. benzenemethanol pentanol, hexanol etc.

- aldehydes; e.g. hexanol,

- acids; e.g. hexanoic acid,

- amines; e.g. 1-aminoheptane,

- nitriles; e.g. amylcyanide,

- silicones, linear or cyclic; e.g. octamethyltetrasiloxane or hexamethyldisiloxane,

- or any combination of these derivatives; e.g. 1-chloro-3-ethylhexane,

- or any combination of these solvents

SURFACTANTS

Surfactants or groups of surfactants meeting with the requirements as indicated above are for example:

Glyceryl monoalkylate; diacetyl tartaric acid esters of mono- and diglycerides of edible fats or oils, or edible fat-forming fatty acids; mono- and diglycerides of edible fats or oils, or edible fatforming acids; monosodium phosphate derivatives of mono- and diglycerides of edible fats or oils, or edible fat-forming fatty acids; glycerol ester of wood rosin alcyl monoglyceridyl citrate;

succistearin (stearoyl propylene glycol hydrogen succinate); dioctyl sodium sulf osuccinate; lecithins (pure and technical qualities); hydroxylated lecithins; methyl glucoside-coconut oil ester; sodium alcyl sulfate; potassium alcyl sulfate;

sodium or potassium mono- and dimethyl naphthalene sulfonates; sodium or potassium alcyl fumarate; acetylated monogly cerides; succinylated monoglycerides; monoglyceride citrate; ethoxylated mono- and diglycerides; ethoxylated sorbitan esters; sorbitan monostearate; sorbitan esters of fatty acids; calcium alcyloyl-2-lactylate; sodium alcyloyl-2-lactylate; potassium alcyloyl-2-lactylate; lactylic esters of fatty acids; lactylated fatty acid esters of glycerol and propylene glycol; glyceryl-lacto esters of fatty acids; ethoxylated alcyl phenols and alcohols; polyglycerol esters of fatty acids; propylene glycol mono- and diesters of fats and fatty acids; sucrose fatty acid esters; fatty acids; salts of fatty acids; synthetic fatty alcohols; poloxamers; meroxapol; poloxamine; "pluradot", or any combination of these.

PROTECTIVE COLLOIDS

In the following there are also given examples of preferred protective colloids:

Gums : e.g. acacia, agar, carrageenan, guar, karaya, locust bean, pectin, propylene glycol alginate, sodium alginate, tragacanth, xanthan, gum arabicum.

Cellulosics: e.g. carboxymethylcellulose, sodium, microcrystalline cellulose and carboxymethylcellulose, sodium, hydroxyethylcellulose, hydroxypropylcelluloεe, hydroxypropyl methylcellulose, cellulose acetate phtalate, methylcellulose, ethyl hydroxyethyl cellulose, methocel.

Clays: e.g. Bentonite (colloidal aluminum silicate), colloidal magnesium aluminum silicate (hectorite), colloidal magnesium aluminum silicate (attapulgite), magnesium silicate (sepiolite).

Miscellaneous: e.g. Carbomer NF, gelatin, polyethylene glycols, polypropyleleglycols and copolymers thereof, lecithins, Carbopol 934, Veegum, polyacrylic acid, polymethacrylic acid, polyacrylic acid-CO-acrylamide, polyvinylpyrrolidon, polyvinylalcohol with varying degree of hydrolysis.

Proteins: e.g. albumine, gelatine, casein or any combination of these The invention will be further described in the following by non-limiting examples. In these examples the drug model used is cholesteryl acetate, which substance is useful for illustrating the problem solved by the present invention

In these examples reference is made to the appended drawings, wherein:

Fig. 1 illustrates the effect of the method of emulsification on the particle size;

Fig. 2 illustrates a diagram on the size of emulsion droplets and the cholesterol acetate particles as a function of the concentration of cholesterol acetate in toluene; and

Fig. 3 illustrates the size of the emulsion droplets and the cholesterol acetate particles as a function of the concentration of surfactant.

EXAMPLE 1

An emulsion of cholesteryl acetate dissolved in toluene and an aqueous phase containing ethoxylated nonylphenol ether as a surfactant is prepared in the following manner. The drug model substance, cholesteryl acetate, is dissolved in toluene. The solution is emulsified with an aqueous phase containing ethoxylated nonylphenol ether as a surfactant to form an oil-in-water-type emulsion.

The organic solvent, toluene, is then evaporated from the emulsion, whereby the drug model substance precipitates and the crystals are stabilized by the surfactant, said surfactant being adsorbed on the surface of the precipitated particles.

Using the emulsion ingredients indicated above a series of tests are made to establish the effect of the method of emulsification on the particle size, the influence of the concentration of the drug substance in toluene on the size of the particles and the influence of concentration of surfactant in the emulsion on the size of the emulsion droplets and thus also on the size of the model drug-particles. This illustration of different effects is made in relation to the appended drawings numbered 1 to 3 and related to the respective effects outlined above. In Fig. 1 the particles were obtained from emulsions which were prepared by vibration, and the particle sizes were measured by an electrozone sensing method. In Fig. 2 the emulsions were prepared by homogenization with a microfluidizer, and the particle sizes were measured by quasi-elastic light scattering. With regard to Fig. 3 the emulsions were prepared by homogenization with a microfluidizer.

Yet another alternative to control the emulsion droplet size is to vary the oil/water phase ratio.

EXAMPLE 2

This example illustrates the use of a surfactant capable of stabilizing the emulsion and suspension of cholesterol acetate and cyclohexane, respectively. The emulsion is homogenized in a microfluidizer. The oil/water phase ratio is 10/90, and the amount of surfactant is 5% by weight based on the weight of the oil phase. The surfactant used is a mixture of Tween 80 and Span 80 at a weight ratio of 1:9. Span 80 is a tradename for sorbitan monooleate and Tween 80 a tradename of POE-(20)-sorbitan monooleate.

The particle size in the suspension lies within the range of between about 80 nm and about 400 nm. The particle size is measured after 10 days and is found to be about constant.

EXAMPLE 3

Example 2 is repeated but using a mixture of Tween 20 and Span 80 (weight ratio 16:1) as a surfactant. Similar results are obtained.

EXAMPLE 4

Example 2 is repeated but using Tween 80 as a surfactant. EXAMPLE 5

Example 2 is repeated but using DK ESTER F-160 (a sucrose ester) as a surfactant.

EXAMPLE 6

Example 2 is repeated but using Ovothin 170 (egg phospholipid) as a surfactant. EXAMPLE 7

Example 2 is repeated but using Epikuran 145 (soybean lecithin) as a surfactant.

EXAMPLE 8

Example 2 is repeated but using Epikuran 200 SH

(soybean lecithin) and the sodium salt of glycocholic acid (4:1) as a surfactant.

EXAMPLE 9

Example 2 is repeated but using Epikuran 200 SH and the sodium salt of taurocholic acid (4:1) as a surfactant.

EXAMPLE 10

Example 2 is repeated but using Ovothin 170 and the sodium salt of glycocholic acid (4:1) as a surfactant.

EXAMPLE 11

Example 2 is repeated but using Ovothin 170 and the sodium salt of taurocholic acid (4:1) as a surfactant.

EXAMPLE 12

Example 2 is repeated but using Triodan 55, polyglycerol esters of fatty acids as a surfactant. EXAMPLE 13

Example 2 is repeated but using Acidan N-12, citric acid esters of monoglycer ides as a surfactant. EXAMPLE 14

Example 2 is repeated but using Epikuran 200 SH as a surfactant and polyvinyIpyrrolidone as a protective colloid.

In the above Examples 4-14 results corresponding to those of Example 2 are obtained.

Claims

CLAI MS
1. A process for the preparation of submicron size, relatively monodisperse drug-particles of a drug of low water-solubility by emulsifying an organic solution of the drug m an aqueous phase and then removing the organic solvent resulting in drug precipitation, characterized by the steps:
a) emulsifying the organic solution in the presence of an emulsifier, and if needed a protective colloid, comprising a surfactant capable of adsorption on the surface of a
precipitated drug-particle;
b) removing the organic solvent from the suspension; and c) recovering the precipitated drug-particles from the aqueous phase or storing the same in the original aqueous phase.
2. A process according to claim 1, characterized in that the organic solvent is removed by evaporation.
3. A process according to claim 1, characterized in that the organic solvent is removed by washing through continuous renewal of the aqueous phase.
4. A process according to claim 1, characterized in that the organic solvent is removed by washing away same through dialysis by contact with a pure aqueous phase.
5. A process according to claim 1, characterized in that the organic solvent is removed by contacting the emulsion with an excess of aqueous phase to dissolve the organic solvent therein resulting in precipitation of the drug.
6. A process according to claim 2, wherein aqueous phase is added during evaporation to compensate for co-evaporation of water from the aqueous phase.
7. A process according to any preceding claim, wherein the drop diameter of the emulsion is controlled by the concentration of surfactant.
8. A process according to claim 7 , wherein said concentration is related to the molar concentration of the drug.
9. A process according to any preceding claim, wherein the surfactant is pharmaceutically acceptable.
10. Drug particles whenever prepared by the process of any preceding claim.
PCT/SE1990/000426 1989-06-21 1990-06-15 A process for the preparation of drug particles WO1990015593A1 (en)

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Cited By (21)

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EP0498482A2 (en) * 1991-01-25 1992-08-12 NanoSystems L.L.C. X-ray contrast compositions useful in medical imaging
EP0499299A2 (en) * 1991-01-25 1992-08-19 NanoSystems L.L.C. Surface modified drug nanoparticles
WO1993025190A1 (en) * 1992-06-10 1993-12-23 Eastman Kodak Company Surface modified nsaid nanoparticles
EP0577215A1 (en) * 1992-07-01 1994-01-05 NanoSystems L.L.C. Surface modified anticancer nanoparticles
EP0601619A2 (en) * 1992-12-04 1994-06-15 NanoSystems L.L.C. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
EP0605024A2 (en) * 1992-12-16 1994-07-06 NanoSystems L.L.C. Use of purified surface modifiers to prevent particle aggregation during sterilization
EP0615746A1 (en) * 1993-03-15 1994-09-21 Rhone-Poulenc Rorer Gmbh Aqueous liposomal system and process for preparing such a liposomal system
WO1995035101A1 (en) * 1994-06-22 1995-12-28 Rhone-Poulenc Rorer S.A. Nanoparticles stabilized and filterable in sterile conditions
EP0755222A1 (en) * 1994-04-11 1997-01-29 Mallinckrodt Medical, Inc. Microfluidization of calcium/oxyanion-containing particles
US5780062A (en) * 1994-11-09 1998-07-14 The Ohio State University Research Foundation Small particle formation
WO2001074332A1 (en) * 2000-04-05 2001-10-11 Vectura Limited Pharmaceutical preparations and their manufacture
WO2003059319A1 (en) * 2002-01-14 2003-07-24 Dow Global Technologies Inc. Drug nanoparticles from template emulsions
WO2003080027A1 (en) * 2002-03-20 2003-10-02 Elan Pharma International, Ltd. Nanoparticulate compositions of angiogenesis inhibitors
WO2003103632A1 (en) * 2002-06-10 2003-12-18 Elan Pharma International, Ltd. Nanoparticulate polycosanol formulations and novel polycosanol combinations
EP1423175A1 (en) * 2001-08-08 2004-06-02 Brown University Research Foundation Methods for micronization of hydrophobic drugs
US6835396B2 (en) 2001-09-26 2004-12-28 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
EP1800666A1 (en) * 2002-03-20 2007-06-27 Elan Pharma International Limited Nanoparticulate compositions of angiogenesis inhibitors
WO2009114695A1 (en) * 2008-03-14 2009-09-17 Elan Pharma International Ltd. Nanoparticulate compositions of angiogenesis inhibitors
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US8722091B2 (en) 2001-09-26 2014-05-13 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds

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Cited By (34)

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Publication number Priority date Publication date Assignee Title
US5494683A (en) * 1991-01-25 1996-02-27 Eastman Kodak Company Surface modified anticancer nanoparticles
EP0499299A2 (en) * 1991-01-25 1992-08-19 NanoSystems L.L.C. Surface modified drug nanoparticles
EP0498482A3 (en) * 1991-01-25 1993-03-03 Sterling Winthrop Inc. X-ray contrast compositions useful in medical imaging
EP0499299A3 (en) * 1991-01-25 1993-03-03 Sterling Winthrop Inc. Surface modified drug nanoparticles
US5451393A (en) * 1991-01-25 1995-09-19 Eastman Kodak Company X-ray contrast compositions useful in medical imaging
US5399363A (en) * 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
EP0498482A2 (en) * 1991-01-25 1992-08-12 NanoSystems L.L.C. X-ray contrast compositions useful in medical imaging
WO1993025190A1 (en) * 1992-06-10 1993-12-23 Eastman Kodak Company Surface modified nsaid nanoparticles
EP0577215A1 (en) * 1992-07-01 1994-01-05 NanoSystems L.L.C. Surface modified anticancer nanoparticles
EP0601619A2 (en) * 1992-12-04 1994-06-15 NanoSystems L.L.C. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
EP0601619A3 (en) * 1992-12-04 1995-11-02 Sterling Winthrop Inc Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization.
EP0605024A3 (en) * 1992-12-16 1995-04-12 Sterling Winthrop Inc Use of purified surface modifiers to prevent particle aggregation during sterilization.
EP0605024A2 (en) * 1992-12-16 1994-07-06 NanoSystems L.L.C. Use of purified surface modifiers to prevent particle aggregation during sterilization
EP0615746A1 (en) * 1993-03-15 1994-09-21 Rhone-Poulenc Rorer Gmbh Aqueous liposomal system and process for preparing such a liposomal system
EP0755222A4 (en) * 1994-04-11 2000-03-08 Mallinckrodt Medical Inc Microfluidization of calcium/oxyanion-containing particles
EP0755222A1 (en) * 1994-04-11 1997-01-29 Mallinckrodt Medical, Inc. Microfluidization of calcium/oxyanion-containing particles
FR2721510A1 (en) * 1994-06-22 1995-12-29 Rhone Poulenc Rorer Sa Nanoparticles filterable under sterile conditions.
WO1995035101A1 (en) * 1994-06-22 1995-12-28 Rhone-Poulenc Rorer S.A. Nanoparticles stabilized and filterable in sterile conditions
US6146663A (en) * 1994-06-22 2000-11-14 Rhone-Poulenc Rorer S.A. Stabilized nanoparticles which may be filtered under sterile conditions
US5780062A (en) * 1994-11-09 1998-07-14 The Ohio State University Research Foundation Small particle formation
WO2001074332A1 (en) * 2000-04-05 2001-10-11 Vectura Limited Pharmaceutical preparations and their manufacture
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
EP1423175A1 (en) * 2001-08-08 2004-06-02 Brown University Research Foundation Methods for micronization of hydrophobic drugs
US8524829B2 (en) 2001-08-08 2013-09-03 Brown University Research Foundation Methods for micronization of hydrophobic drugs
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US6835396B2 (en) 2001-09-26 2004-12-28 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
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