IE72509B1 - Process for preparing nanoparticles - Google Patents
Process for preparing nanoparticlesInfo
- Publication number
- IE72509B1 IE72509B1 IE922109A IE922109A IE72509B1 IE 72509 B1 IE72509 B1 IE 72509B1 IE 922109 A IE922109 A IE 922109A IE 922109 A IE922109 A IE 922109A IE 72509 B1 IE72509 B1 IE 72509B1
- Authority
- IE
- Ireland
- Prior art keywords
- nanoparticles
- process according
- copolymer
- polymer
- methyl group
- Prior art date
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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
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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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
- A61K9/5192—Processes
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
- C08J3/14—Powdering or granulating by precipitation from solutions
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2371/02—Polyalkylene oxides
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Optics & Photonics (AREA)
- Nanotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Preparation (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Electroluminescent Light Sources (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
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Abstract
Process for the preparation of nanoparticles by solubilising a polylactic polyethylene oxide and/or polypropylene oxide copolymer in an organic solvent and then forming nanoparticles by mixing the solution containing the polymer with an aqueous solution by precipitation without employing any additional colloidal protective agent or by microfluidisation and solvent evaporation.
Description
- 1 PROCESS FOR PREPARING NANOPARTICLES The present invention relates to a new process for preparing small spherical particles, often smaller than 500 nm, capable of transporting or targeting an active principle. These particles, also referred to as nanoparticles, have the advantage of being able to circulate in the bloodstream without there being a problem of size in the capillaries. The invention also relates to the new particles obtained and to their use in human or animal pharmacy.
It is known from the prior art, described in Patent FR 2,608,988, to prepare particles smaller than 500 nm in size by at least three types of process.
The first type of process consists in performing a 15 polymerisation of a monomer in a solution so as to obtain a micellar dispersion of the polymer in the solution. This type of process is limited to monomers which can be polymerised in solution; it necessitates removal, after the polymerisation step, of the polymerisation catalyst, the low molecular weight oligomers, the monomers and the surfactants needed for the polymerisation. The polymer obtained has a random molecular weight distribution.
The second and third types of process consist in using preformed polymers, in dissolving them in a solvent, in forming a precipitate or a dispersion from a solution of these polymers and a non-solvent, and then in evaporating off the solvent so as to recover the nanoparticles in the - 2 form of a colloidal suspension. The solvent solution is generally an organic solution of the polymer, and the nonsolvent solution is often an aqueous solution.
According to the second type of process, the polymer 5 is dissolved in a water-miscible organic solvent. When the resulting solution is mixed with the aqueous phase, the polymer insoluble in the aqueous phase/organic solvent mixture precipitates in the form of nanoparticles.
According to the third type of process, a water10 immiscible organic solvent containing the polymer is emulsified in an aqueous phase, and the organic solvent is then evaporated off.
Formation of the precipitate or the emulsion requires the presence of a considerable amount of surfactant. It is very difficult to remove the surfactant remaining in the colloidal suspension during the subsequent evaporation to obtain the nanoparticles. Furthermore, the presence of a surfactant is often undesirable in the interest of good biocompatability. Hence the latter two techniques cannot be used for the preparation of biocompatible nanoparticles because a colloidal protective agent is present.
FR 2,608,988 relates to a process for preparing dispersible colloidal systems in the form of nanoparticles smaller than 500 nm. These nanoparticles, based on a substance which can equally well be a polymer and/or an active principle, are obtained by the second method mentioned above. The nanoparticles which are obtained, based, on a polylactic polymer, contain an amount of surfactant equal to the amount of polymer in the majority of the examples. In only one example (Example 4) does the inventor claim to obtain nanoparticles of polylactic polymer without a surfactant. The Applicant reproduced this experiment, and obtained nanoparticles of polylactic polymer from an acetone solution of polylactic acid and water with extremely low yields, always less than 10%.
Hence this technique cannot be used for the preparation of nanoparticles of polylactic acid in the absence of a surfactant.
The present invention has enabled nanoparticles of polymers containing a majority of degradable units to be obtained in the absence of a surfactant. It comprises preparing nanoparticles from poly(ethylene oxide) and/or poly(propylene oxide) polylactic copolymer in the absence of a surfactant or of an additional colloidal protective agent, using a copolymer containing a majority of polylactic units modified by incorporation of poly(ethylene oxide) and/or poly(propylene oxide) units.
According to the present invention there is provided a process for preparing nanoparticles which comprises dissolving poly(ethylene oxide) and/or poly(propylene oxide) polylactic copolymer containing a majority of units of formula: (I) R’« -och9-ch2 I R nL O-CO-CHI CHq OH in which R, independently in each of the alkylene oxide units, represents hydrogen or a methyl group; represents an alkyl unit containing 1 to 4 carbon atoms, preferably a methyl group; n is an integer between 20 and 1000; and m is an integer between 10 and 1500, in an organic solvent, and mixing the organic solution containing the polymer thus obtained with an aqueous solution, without using an additional colloidal protective agent.
The polylactic unit of this copolymer preferably has a molecular weight of between 700 and 100,000; the poly(ethylene oxide) and/or poly(propylene oxide) unit preferably has a molecular weight of between 1,000 and 40,000. Still more preferably, the polylactic polymeric unit has a molecular weight of between 1,000 and 60,000, and the poly(ethylene oxide) and/or poly(propylene oxide) unit has a molecular weight of between 1,000 and 6,000.
Preferably, the polylactic polymer is a polymer containing 50% of lactic units of D configuration (PLA50) and the poly(oxide) is a poly(ethylene oxide).
These polymers preferably take the form of a dibl-ock, i.e., according to a practical manner of implementation, the starting material is a monofunctional commercial polyethylene and/or polypropylene glycol in which Rr preferably represents a methyl group, of desired molecular weight, i.e. of molecular weight between 1,000 and 40,000, or alternatively containing approximately 20 to 1,000 ethylene oxide or propylene oxide units, and preferably containing 20 to 150 ethylene oxide units or 20 to 100 propylene oxide units (i.a. R = Me), onto which starting material lactide units are grafted until the desired molecular weight is obtained on the polylactic chain, in the presence of a catalyst such as, in particular, tin octoate.
To obtain polylactic blocks of molecular weight between 1,000 and 60,000, it is desirable to introduce between approximately 10 and 1,000 lactide units. It is most especially preferable to use polylactic poly(ethylene oxide) and/or poly(propylene oxide) copolymers in which the chain contains between 10 and 150 lactic units.
It is still more especially preferable to start with a commercial polyethylene glycol of molecular weight 2,100 containing 48 ethylene oxide units, which is reacted with 40 to 150 lactide units, i.e. to use a compound of formula (I) in which R is hydrogen, R is methyl, n is 48 and m is between 40 and 150.
After polymerisation in solution, the polymers obtained are purified so as to remove the catalyst and the remaining lactide completely. This purification is performed by precipitation of the polymer using a non6 solvent or by gel exclusion chromotography. The copolymer is then dried and stored in pulverulent form.
According to a first process for preparing the nanoparticles according to the invention, the desired poly(ethylene oxide) and/or poly(propylene oxide) polylactic polymer is dissolved in a solvent or in a mixture of solvents, and the organic solution is then poured into an aqueous solution so as to cause precipitation of the nanoparticles. No additional colloidal protective agent is used in this process. The term '"colloidal agent" is understood to mean an agent which promotes colloid formation, including surfactants.
The solvent or mixture of solvents in which the copolymer is soluble is typically a ketone such as acetone, a cyclic ether such as tetrahydrofuran, a dioxane, or a nitrile such as acetonitrile. It is preferable to use acetone. The solubility of the copolymer in these solvents should be at least 10 g/1.
The volume ratio between the aqueous solution and the solution of the copolymer is preferably between 0.5 and 10, and most especially between 1 and 10. The amount of copolymer introduced into the solvent naturally depends on its solubility but to obtain an optimum yield of nanoparticles, an amount of between 10 and 50 mg/ml is preferable.
According to a second process for preparing the nanoparticles, the poly(ethylene oxide) and/or poly(propylene oxide) polvlactic polymer is dissolved in an ester, preferably ethyl acetate, and the organic solution is then poured into the aqueous solution» The nanoparticles are formed by using a microfluidiser.
The solvent of the copolymer is then evaporated off by heating the colloidal solution of nanoparticles above the boiling point of the solvent in the case where the removal is performed at atmospheric pressure, or at a temperature below the boiling point of the solvent if the evaporation is performed under reduced pressure. After the solvent has been removed, the suspension of nanoparticles in water is filtered through a filter of pore diameter approximately 1 /xm so as to remove aggregates and large particles. The yield of nanoparticles obtained generally exceeds 50%.
The formation of nanoparticles may be performed in the presence of a pharmaceutical active principle, which may be introduced either in the solvent of the copolymer or in the precipitation solvent; the active principle should preferably be soluble in the solvent of the polymer and insoluble in water. Although it is still possible to form nanoparticles if the active principle is soluble in water, the yield thereof will nevertheless be reduced.
The nanoparticles obtained, which also form part of the present invention, contain only the polymer of formula (I) , and optionally an active principle if the precipitation is performed in the presence of an active principle. The nanoparticles generally have an average diameter of between 50 and 500 nm, and preferably an average diameter of between 50 and 250 nm.
The nanoparticles obtained may be used in many fields, such as agrochemistry, reprography paper and photographic paper but, as a result of their fully biocompatible nature, are intended more especially for the human or animal pharmaceutical industry. These products may be injected intramuscularly, subcutaneously, intra-arterially, intravenously, into organs or into cavities without risk of an anaphylactic reaction.
The following Examples illustrate the invention.
E3CAMPLE 1 Preparation of polyethylene glycol polylactic copolymers 1.1) polymer PLA ^°°-PEG2100 The following are introduced into a 250 ml threenecked round-bottomed flask equipped with a paddle stirrer and a reflux condenser and under a stream of dry nitrogen, the flask being heated on a temperature-regulated oil bath; DL-lactide ............... 144 g polyethylene glycol .....79.3 g stannous octoate ..„.„,.0.256 g toluene, distilled ... ..335 g The lactide is recrystallised on the previous day in ethyl acetate, and then washed on the day itself with ethyl ether. It is dried under vacuum. All the reactants are charged, and the mixture is then heated under gentle reflux (110-114°C) for 5 and a half hours. The solvent is then removed under vacuum using a rotary evaporator (40 mm Hg 100°C).
A concentrate (226.3 g) is obtained.
Purification of the copolymer is performed in the following manner: The following are charged: concentrate .............215 g dichloromethane .........280 g The mixture is stirred until a homogeneous solution is formed. This solution is poured slowly into hexane (900 ml) in the cold state. The polymer precipitates in the form of a paste, which is separated after settling has taken place. The polymerisation catalyst is removed in the hexane phase.
After separation of the polymer, it is dried in an oven under vacuum at 40°C. A copolymer (188.4 g) is obtained, the mass of which is analysed by nuclear magnetic resonance; the mass of polyethylene glycol is 2,100 and that of polylactic 2,900, representing 40 lactic units and 48 ethylene oxide units. 1.2) polymer PLA ^°°-PEG2100 Example l.l is repeated, introducing the following compounds: DL-lactide ..„....„„.„...48.6 g polyethylene glycol ..10 g stannous octoate .......0.085 g toluene, distilled ........90 g After reaction, a concentrate (63.6 g) is obtained, which is purified by the following method; concentrate (40 g) is dissolved in dichloromethane (200 g) until a homogeneous solution is obtained. This solution is poured slowly into water (800 ml) maintained at between 55 and 60°C. The polymer precipitates and the dichloromethane is evaporated off, the unreacted lactide remains in agueous solution and the polymer is centrifuged and then dried in an oven under vacuum at 40°C.
A polymer (35 g) is obtained, analysis of which by nuclear magnetic resonance enables the molecular weight to be determined. The latter is 9,600 for the lactic chain and 2,100 for the poly(ethylene oxide) chain, representing 133 lactic units and 48 ethylene oxide units. 1.3) polymer PLA^000 Xylene (180 g) distilled before use, and tin octoate (0.180 g) are introduced into a one-litre reactor heated on an oil bath and equipped with an anchor-shaped stirrer and a reflux condenser and maintained under nitrogen, the mixture is heated, and DL-lactide S (120 g) of the company Boehringer, recrystallised beforehand in ethyl acetate and washed with sulphuric ether, is then introduced.
The mixture is allowed to react for 5 hours at 140°C and, at the end of the reaction, it is cooled rapidly and a portion of the xylene is then removed under vacuum. The polymer is dissolved in dichloromethane and precipitated with methanol. It is dried in a vacuum oven at 65°C.
EXAMPLE 2 Preparation of nanoparticles from these polymers The copolymer (50 mg) prepared in 1-1 is used, this being dissolved in acetone (0.5, 2.5, 5 and 10 ml). The 5 nanoparticles are prepared by precipitation, pouring this volume slowly into water (5 ml). The colloidal suspension obtained is evaporated for 30 minutes in a rotary evaporator at room temperature and at a pressure of 3 mm Hg. The suspension is then filtered through a 1.2 μκι filter in order to remove large particles and aggregates. The particle diameter and also the yield of production of the particles with respect to the polymer introduced are shown in the table below.
Water/acetone 10:1 2:1 1:1 0.5:1 Yield 75% 76% 92% 79% Diameter (nm) 67+36 63±30 50±21 38±10 COMPARATIVE EXAMPLE ACCORDING TO EXAMPLE 4 OF FR 2,608,988 The same protocol is used, but with the lactic polymer of Example 1.3, of molecular weight 40,000. The nanoparticles are prepared by precipitation, pouring the acetone solution into water (5 ml). The acetone is evaporated off in a rotary evaporator for 30 minutes.
During this phase, the polymer precipitates and sticks to the walls. The suspension is collected and filtered through a filter 1.2 μιη in diameter. The filtrate is completely clear. The polymer concentration is too low to be measurable.
EXAMPLE 3 Preparation of nanoparticles containing an active principle.
Spiramycin (40 mg) and the copolymer (200 mg) prepared according to point 1.2 above are dissolved in acetone (2 ml). The nanoparticles are prepared by precipitation, pouring the acetone solution into 0.1 M phosphate buffer, pH 7.4 (20 ml).
The acetone is evaporated off in a rotary evaporator for 30 minutes, and the solution is then filtered through a 1.2 Mm filter. Nanoparticles of spiramycin and copolymer 74 nm in diameter are obtained.
EXAMPLE 4 Preparation of nanoparticles by microfluidisation Without surfactant.
The polymer (100 mg) is solubilised in ethyl acetate (1 ml). This organic solution is poured into water (10 ml) with stirring using an ultraturrax. After 30 seconds of stirring, the emulsion is homogenised and fined for 2 minutes by recycling using a microfluidiser (MICROFLUIDICS 110 S). The ethyl acetate is removed by evaporation under partial vacuum for 45 minutes, and the nanoparticles are then filtered through a SARTORIUS or MILLIPORE filter of porosity 1.2 μτα.
Claims (16)
1. A process for preparing nanoparticles, which comprises dissolving a poly(ethylene oxide) and/or poly(propylene oxide) polylactic copolymer containing a majority of units of formula: R‘- “O-CH ? -CH” z I O-CO-CH- 1 OH 1 R n -δ _1 m (I) in which R, independently in each of the alkylene oxide units, represents hydrogen or a methyl group; R f ' represents an alkyl unit containing 1 to 4 carbon atoms; n is an integer between 20 and 1000; and m is an integer between 10 and 1500, in. an organic solvent, and mixing the organic solution containing the polymer thus obtained with an aqueous solution, without using an additional colloidal protective agent.
2. A process according to claim 1, wherein n is between 20 and 150 and m is between 10 and 1000.
3. A process according to claim 1 or 2, wherein R represents a methyl group, R‘‘ represents a methyl group and n is between 20 and 100.
4. A process according to claim 1, 2 or 3, wherein R represents hydrogen, R' represents a methyl group, n is 48, and m is between 40 and 150.
5. A process according to any one of the preceding claims, wherein the organic solvent is a ketone, ether, dioxane or nitrile.
6. A process according to claim 5, wherein the solvent is acetone.
7. A process according to any one of the preceding claims, wherein the volume ratio between the aqueous solution and the organic solution containing the copolymer is between 0.5 and 10.
8. A process according to any one of the preceding claims, wherein the concentration of the copolymer in the organic solution is not less than 10 g/1.
9. A process according to any one of the preceding claims, wherein one of the aqueous and organic solutions comprises a pharmaceutically active principle.
10. A process according to claim 1 substantially as hereinbefore described in any one of Examples 2 to 4.
11. Nanoparticles, which consist: predominantly of a copolymer of formula: R' O-CH 2 -CH O-CO-CHI OH ch 3 (I) in which R, independently in each of the alkylene oxide units, represents hydrogen or a methyl group; R* represents an alkyl unit containing 1 to 4 16 carbon atoms, n is an integer between 20 and 1000, and m is an integer between 10 and 1500, 5 and which contain no colloidal agent.
12. Nanoparticles according to claim II, having an average diameter of between 50 and 500 nm.
13. Nanoparticles according to claim 12, having an average diameter of between 50 and 250 nm. 10
14. Nanoparticles according to claim 11 substantially as hereinbefore described in any one of Examples 2 to 4.
15. Nanoparticles according to any one of claims 11 to 14 when prepared by a process according to any one of 15 claims 1 to 10.
16. » Nanoparticles according to any one of claims 11 to 15 for use in human or animal pharmacy» Dated this the 26th day of June, 1S92
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9108042A FR2678178A1 (en) | 1991-06-28 | 1991-06-28 | PROCESS FOR THE PREPARATION OF NANOPARTICLES. |
Publications (2)
Publication Number | Publication Date |
---|---|
IE922109A1 IE922109A1 (en) | 1992-12-30 |
IE72509B1 true IE72509B1 (en) | 1997-04-23 |
Family
ID=9414445
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE922109A IE72509B1 (en) | 1991-06-28 | 1992-07-01 | Process for preparing nanoparticles |
Country Status (14)
Country | Link |
---|---|
EP (2) | EP0591331B1 (en) |
JP (1) | JP3228742B2 (en) |
AT (1) | ATE135385T1 (en) |
CA (1) | CA2102185C (en) |
DE (1) | DE69209074T2 (en) |
DK (1) | DK0591331T3 (en) |
ES (1) | ES2084363T3 (en) |
FI (1) | FI106723B (en) |
FR (1) | FR2678178A1 (en) |
GR (1) | GR3019308T3 (en) |
IE (1) | IE72509B1 (en) |
MX (1) | MX9203354A (en) |
NO (1) | NO308313B1 (en) |
WO (1) | WO1993000388A1 (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5565215A (en) * | 1993-07-23 | 1996-10-15 | Massachusettes Institute Of Technology | Biodegradable injectable particles for imaging |
US5543158A (en) * | 1993-07-23 | 1996-08-06 | Massachusetts Institute Of Technology | Biodegradable injectable nanoparticles |
FR2721510B1 (en) * | 1994-06-22 | 1996-07-26 | Rhone Poulenc Rorer Sa | Nanoparticles filterable under sterile conditions. |
US6007845A (en) * | 1994-07-22 | 1999-12-28 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
US5611344A (en) * | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
JPH11322948A (en) * | 1998-05-08 | 1999-11-26 | Nof Corp | Fine polymer particle and its production |
DE19839212C2 (en) | 1998-08-28 | 2002-05-23 | Celanese Ventures Gmbh | Process for the production of spherical nanoparticles which consist wholly or partly of at least one water-insoluble linear polysaccharide |
CA2309575A1 (en) | 2000-05-26 | 2001-11-26 | James E. Guillet | Internally cross-linked macromolecules |
US8012457B2 (en) | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
JP5398112B2 (en) * | 2005-10-27 | 2014-01-29 | 東レ株式会社 | Biodegradable particles and method for producing the same |
FR2936722B1 (en) * | 2008-10-07 | 2013-11-22 | Nanolege Inc | NANOCOMPOSITE MATERIALS AND PROCESS FOR MANUFACTURING BY NANOPRECIPITATION. |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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GB8416234D0 (en) * | 1984-06-26 | 1984-08-01 | Ici Plc | Biodegradable amphipathic copolymers |
FR2608988B1 (en) * | 1986-12-31 | 1991-01-11 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF COLLOIDAL DISPERSIBLE SYSTEMS OF A SUBSTANCE, IN THE FORM OF NANOPARTICLES |
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1991
- 1991-06-28 FR FR9108042A patent/FR2678178A1/en active Granted
-
1992
- 1992-06-25 ES ES92913337T patent/ES2084363T3/en not_active Expired - Lifetime
- 1992-06-25 EP EP92913337A patent/EP0591331B1/en not_active Expired - Lifetime
- 1992-06-25 EP EP92401789A patent/EP0520889A1/en active Pending
- 1992-06-25 DE DE69209074T patent/DE69209074T2/en not_active Expired - Lifetime
- 1992-06-25 JP JP50136793A patent/JP3228742B2/en not_active Expired - Lifetime
- 1992-06-25 WO PCT/FR1992/000582 patent/WO1993000388A1/en active IP Right Grant
- 1992-06-25 MX MX9203354A patent/MX9203354A/en unknown
- 1992-06-25 CA CA002102185A patent/CA2102185C/en not_active Expired - Lifetime
- 1992-06-25 AT AT92913337T patent/ATE135385T1/en active
- 1992-06-25 DK DK92913337.9T patent/DK0591331T3/en active
- 1992-07-01 IE IE922109A patent/IE72509B1/en not_active IP Right Cessation
-
1993
- 1993-12-01 NO NO934359A patent/NO308313B1/en not_active IP Right Cessation
- 1993-12-27 FI FI935869A patent/FI106723B/en not_active IP Right Cessation
-
1996
- 1996-03-14 GR GR950403440T patent/GR3019308T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
MX9203354A (en) | 1992-12-01 |
FR2678178B1 (en) | 1995-01-13 |
WO1993000388A1 (en) | 1993-01-07 |
ATE135385T1 (en) | 1996-03-15 |
CA2102185A1 (en) | 1992-12-29 |
DK0591331T3 (en) | 1996-04-01 |
ES2084363T3 (en) | 1996-05-01 |
JP3228742B2 (en) | 2001-11-12 |
FI106723B (en) | 2001-03-30 |
JPH06508867A (en) | 1994-10-06 |
FR2678178A1 (en) | 1992-12-31 |
EP0591331B1 (en) | 1996-03-13 |
IE922109A1 (en) | 1992-12-30 |
NO934359L (en) | 1993-12-01 |
FI935869A0 (en) | 1993-12-27 |
EP0520889A1 (en) | 1992-12-30 |
FI935869A (en) | 1993-12-27 |
DE69209074T2 (en) | 1996-09-05 |
CA2102185C (en) | 2003-07-22 |
NO308313B1 (en) | 2000-08-28 |
EP0591331A1 (en) | 1994-04-13 |
DE69209074D1 (en) | 1996-04-18 |
GR3019308T3 (en) | 1996-06-30 |
NO934359D0 (en) | 1993-12-01 |
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