WO2003086609A1 - Nanocapsules remplies d'huile provenant de microemulsions utilisant des tensioactifs reticulables - Google Patents
Nanocapsules remplies d'huile provenant de microemulsions utilisant des tensioactifs reticulables Download PDFInfo
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- WO2003086609A1 WO2003086609A1 PCT/US2003/010423 US0310423W WO03086609A1 WO 2003086609 A1 WO2003086609 A1 WO 2003086609A1 US 0310423 W US0310423 W US 0310423W WO 03086609 A1 WO03086609 A1 WO 03086609A1
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- oil
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- water
- layer
- microemulsion
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
Definitions
- microemulsions more particularly oil-in-water microemulsions having one or more coating layers on the oil droplets.
- Background The development of microemulsion technology has enabled formation of improved dispersions for some materials.
- Microemulsions are thermodynamically stable dispersions of one liquid phase into another, stabilized by an interfacial film of surfactant.
- the dispersion may be either an oil-in-water or water-in-oil dispersion.
- Microemulsions are typically clear solutions, as the droplet diameters are approximately 100 nanometers or less. The interfacial tension between the two phases is generally extremely low.
- Drug toxicity a major health problem having an estimated yearly cost in excess of $10 billion/year. Drug overdoses can potentially cause death or permanent injury, such as brain damage. There are no known antidotes for most of toxic drugs.
- Core-shell particle systems are promising candidates for the removal of drugs from the bloodstream.
- Certain core-shell particle systems prepared by self-assembly have been already proven as promising drug uptake candidates.
- Oil-in-water microemulsions can utilize self-assembly to form transparent, isotropic solutions which are thermodynamically stable.
- Oil droplets less than 250 nm in diameter can be compartmentalized in a continuous domain of water.
- the oil droplets can be stabilized by a layer of surfactant on the surface at the interface between the oil droplets and the water.
- this arrangement is highly susceptible to droplet destabilization from certain environmental changes, including pH and temperature. Accordingly, stability problems have limited the potential utility of oil-in-water emulsions.
- a method of forming an oil-in-water microemulsion includes the steps of mixing at least one oil and at least one surfactant to water or a water based solution, wherein the oil forms a plurality of oil droplets in the water or water based solution.
- the surfactant forms a surfactant layer which coats the oil droplets.
- a polymer shell layer is then formed on the oil droplets.
- the method can include the step of polymerizing the surfactant layer to form at least a portion of the polymer shell layer.
- a cross-linking agent can be added, wherein the cross-linking agent reacts with the surfactant layer or a product derived from surfactant to provide at least a portion of the shell layer.
- the cross-linking agent can be a surfactant.
- the surfactant can be lecithin, C 64 H 12 0 263 (TweenTM) or OTMS.
- the oil can vary from 0.5% to 20 % weight by weight (w/w) of the microemulsion. A weight ratio of the surfactant to the oil can be from 0.2 to 5 (w/w).
- the size of the coated oil droplets included the polymer shell can range from approximately 80 nm to 250 nm.
- the polymer shell layer can include silicon, such as from Si-O-Si layers.
- the method can include the step of forming a biocompatible layer, wherein the shell layer includes a biocompatible outer shell layer, such as PEO, polylactic acid or chitosane. DNA, RNA, antibodies, proteins, enzymes, cells or cell components, or biomimetics can be added to the mixing step for inclusion in any portion of the coated oil droplets.
- An oil in water microemulsion includes water or a water based solution, at least one oil, at least one surfactant coating layer, wherein the oil forms a plurality of oil droplets in the water or water based solution.
- the surfactant forms a surfactant layer which coats the oil droplets.
- a polymer shell layer is disposed on the oil droplets.
- the surfactant layer can be polymerizable, wherein polymerization of the surfactant layer provides at least a portion of the polymer shell layer.
- the polymer shell layer can include silicon.
- the polymer shell layer preferably includes a biocompatible surface layer, such as PEO, polylactic acid or chitosane.
- the invention can be used for a variety of applications.
- Exemplary applications include drug detoxification, environmental remediation and pesticide poisoning therapy.
- FIG. 1 illustrates a schematic representation of a nanocapsule according to the invention, the nanocapsule cut open to reveal a plurality of absorbed lipophilic molecules absorbed within its oil core.
- FIGS. 2(A)-(D) illustrates a hydrophilic surfactant, a hydrophobic surfactant, an oil and a polymerizable surfactant, respectively.
- FIGs. 3(A) and (B) each show a step in a two step siloxane polycondensation chemistry reaction.
- FIG. 4 illustrates a reaction to form a Si-O-Si containing shell on nanocapsules.
- FIG. 5(A)-(D) illustrate the dependence of nanocapsule size on the concentration of the various nanocapsule components.
- FIG. 6(A) and (B) illustrate nanocapsule size as determined by quasi- elastic light scattering.
- FIG. 7(A)-(C) illustrate nanocapsule size as determined by transmission electron microscopy (TEM).
- FIG.8 illustrates the three dimensional shape of nanocapsules determined using atomic force microscopy.
- FIG. 9(A) and (B) illustrate nanocapsule size of PEO coated nanocapsules.
- FIG. 10(A) and (B) illustrate nanocapsule size distribution of PEO coated nanocapsules.
- FIG. 11(A)-(B) illustrate nanocapsule uptake rates of a lipohilic compound as a function of the concentration of the lipophilic compound.
- FIG. 12(A)-(C) illustrate uptake rates of test drugs for various nanocapsule formulations.
- Oil-in-water microemulsions can be prepared by mixing at least one oil and at least one surfactant to water or a water based solution, wherein the oil forms a plurality of oil droplets in the water or water based solution.
- Ethyl butyrate is an example of an oil that can be used.
- the surfactant forms a coating layer on the oil droplets.
- the surfactant layer can be cross linkable surfactant which can be polymerized.
- a shell layer can formed on the surface of the surfactant layer, such as through reaction of the surfactant with a suitable cross linking agent.
- Figure 1 shows a cut-open nanocapsule 100 including a Si-O-Si (silica) containing outer layer 105, the outer layer 105 disposed on a surfactant coating layer 1 1 0.
- the surfactant coating layer 1 10 is disposed on an oil core 1 1 5.
- the oil core 1 1 5 is depicted having a plurality of absorbed lipophilic molecules 1 20 trapped within.
- the surfactant layer 1 10 can be a hydrophilic, hydrophobic or a polymerizable surfactant layer.
- the surfactant layer 1 10 can be selected from TWEEN-80TM (hydrophilic), lecithin (hydrophobic), and octadecyltrimethoxysilane (OTMS) or alkoxysilane (polymerizable).
- TWEEN-80TM hydrophilic
- lecithin hydrophobic
- OTMS octadecyltrimethoxysilane
- an outer layer 105 may not be necessary.
- FIGS(A)-(D) illustrate examples of the structure of a selected hydrophilic surfactant (TweenTM), a hydrophobic surfactant (lecithin), an oil (ethyl butyrate) and a polymerizable surfactant (OTMS), respectively.
- TWEEN-80TM and the family of TRITON XTM compounds.
- TWEEN-80TM is manufactured by the ICI group of Companies, Newcastle, DE.
- TWEEN 80TM is polyoxyethylene sorbitan monooleate, and has the following synonyms: TWEEN 80-1TM, polyoxyethylene sorbitol ester; polysorbate 80 and PEG (20) sorbitan monooleate.
- This material has the molecular formula C 64 H 124 0 263 and a corresponding molecular weight of 131 03 amu.
- Preferred surfactants have reactive headgroups which are cross-linked to form a three (3) dimensional network at the surface of the oil droplet.
- the coating layer can be modified, for example, by reacting a small silicon containing molecule, such as an alkoxysilane, to build a thicker shell, the shell including polysiloxane.
- the polysiloxane layer can be chemically bound to surfactant layer species which include hydroxyl groups, such as OTMS.
- the oil filled nanocapsules 100 have the potential for removing hydrophobic compounds from an aqueous environment by absorbing the hydrophobic compounds inside the oil core region 1 1 5. Studies performed have shown that the nanocapsules are able to remove drugs and drug mimics from a saline solution and reverse poisonings due to pesticides. According, the invention has potential applications in drug and pesticide detoxification therapy.
- the nanocapsules 100 preferably include oil cores 1 1 5 and a Si-O-Si
- the naocapsules 100 are dispersible in water and water- based systems such as saline and blood plasma.
- the oil core 1 1 5 can capture (e.g. absorb) hydrophobic compounds and sequester the hydrophobic compounds inside the oil droplet 1 20, thus removing or preventing entry of the hydrophobic compound from an aqueous phase, such as blood or saliva.
- the various layers comprising nanocapsule 1 00 can be doped with a variety of molecules, including biomolecules. For example, at least one of DNA, RNA, antibodies, proteins, enzymes, cells or cell components, and biomimetics can be added to one or more of the particle layers (105, 1 10) as well as to the oil core 1 1 5.
- Magnetic particles can also be included in the nanocapsules. Magnetic particles can permit the nanocapsules to be steered into desired locations or flow paths using a suitable applied magnetic field.
- the nanocapsules have potential applications beyond drug detoxification therapy. Nanocapsules 100 may find use in contaminated- water remediation, and as vessels to solubilize water-insoluble components such as heterogeneous catalysts. As a drug detoxification therapy, the nanocapsules offer a number of significant benefits. First, there is no current effective therapy for most drugs. Second, the nanocapsules can be provided suspended in saline solution which allow inexpensive manufacture and will facilitate stocking in emergency rooms. Third, the manufacture of nanocapsules according to the invention is cost effective because the components are generally readily available and inexpensive. Finally, the coated nanocapsules are quite stable.
- Nanocapsules can be formed in the following exemplary way.
- a microemulsion can be formed by first dissolving a hydrophilic (e.g. Tween 80TM) or hydrophobic (e.g. lecithin) surfactant in a saline solution. An oil is then added to swell the surfactant micelles and then the solution is heated. OTMS (a polymerizable surfactant) can then be added. OTMS gets intercalated in the surface of the microemulsion droplets.
- the microemulsion can then be further stabilized by forming a shell layer containing Si-O-Si layers around the oil droplets.
- the shell layer can be formed by performing siloxane chemistry through a two step polycondensation reaction, the respective steps shown in FIGs. 3(A) and (B), respectively.
- the condensed OTMS skin layer formed on the surface of the nanocapsules may not be robust enough for certain applications.
- a cross-linking agent such as TMOS (tetramethoxysilane)
- TMOS tetramethoxysilane
- FIG. 4 shows the applicable reaction between OTMS and TMOS.
- Nanoparticles formed using the invention were characterized.
- the characterization included the size and position of the core and overall assembly of the nanocapsules.
- quasi-elastic light scattering was used as shown in FIGs. 6(A)-(B) . It revealed that the size of the nanocapsules are broadly distributed, but most were in the range of from 80-1 20 nm.
- Transmission Electron Microscopy (TEM) was used for the confirmation of the size and position of the oil core within the nanocapsule as shown in FIG. 7(A)-(C). The TEM images also confirmed the size of the nanocapsules to generally be 100 nm or less.
- Atomic Force Microscopy was used to further investigate the 3D appearance of the nanocapsules.
- the AFM results are shown in FIG. 8. Since a siloxane surface is neither generally biologically compatible nor tolerated by most bloodstream proteins, the introduction of biologically compatible (biocompatible) moiety on the surface of the nanocapsule can be used for applications involving animals or people. For example, a polyethylene oxide (PEO) covered nanocapsule is expected to be "stealth"
- FIGs. 10(A) and (B) Some biologically compatible alternatives to PEO for coating the surface of the nanocapsules include polylactic acid, and
- the uptake capability of the nanocapsules was evaluated. The ability of the nanocapsules to absorb lipophilic compounds into their core and the kinetics of the uptake was determined. HPLC (high-performance-liquid
- the uptake can be improved in case of formulation with a PEO shell as shown in FIG. 1 2(A)-(C) .
- Quinoline was chosen as a model compound as it emulates the properties of certain target drugs. Quinoline absorption was monitored at 295 nm. Once it is inside the particle, absorption is quenched,
- Oil filled nanocapsules were formed by mixing 0.23g lecithin, 0.38g oil (e.g. ethyl-butyrate), 0.23g OTMS, 2.13g Tween-80TM and 25.3g saline. The above chemicals were heated (70 C) and stirred for 80 hours. Then, 1 g of HEPES (4-(2-hydroxyethyl)-piperazine-1 -ethane-sulfonic acid) buffer and 0.4g of (0.5 M) HCI were added. The mixture was then stirred at room temperature for 25 min.
- HEPES 4-(2-hydroxyethyl)-piperazine-1 -ethane-sulfonic acid
- TMOS tetramethoxysilane
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Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU2003220670A AU2003220670A1 (en) | 2002-04-05 | 2003-04-04 | Oil-filled nanocapsules from microemulsions utilizing cross-linkable surfactants |
Applications Claiming Priority (2)
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US37063002P | 2002-04-05 | 2002-04-05 | |
US60/370,630 | 2002-04-05 |
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WO2003086609A1 true WO2003086609A1 (fr) | 2003-10-23 |
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PCT/US2003/010423 WO2003086609A1 (fr) | 2002-04-05 | 2003-04-04 | Nanocapsules remplies d'huile provenant de microemulsions utilisant des tensioactifs reticulables |
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WO (1) | WO2003086609A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100431686C (zh) * | 2005-08-31 | 2008-11-12 | 上海杰事杰新材料股份有限公司 | 一种制备纳米中空无机微球的方法 |
CN100431685C (zh) * | 2005-08-31 | 2008-11-12 | 上海杰事杰新材料股份有限公司 | 一种制备纳米中空无机微球的方法 |
WO2009037310A2 (fr) * | 2007-09-18 | 2009-03-26 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nanocapsules lipidiques à noyau aqueux propres à encapsuler des molécules hydrophiles et/ou lipophiles |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5993846A (en) * | 1993-08-13 | 1999-11-30 | Pharmos Corporation | Bioadhesive emulsion preparations for enhanced drug delivery |
US6391288B1 (en) * | 1999-07-27 | 2002-05-21 | Shiseido Co., Ltd. | Microcapsule and method of making the same |
-
2003
- 2003-04-04 WO PCT/US2003/010423 patent/WO2003086609A1/fr not_active Application Discontinuation
- 2003-04-04 AU AU2003220670A patent/AU2003220670A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5993846A (en) * | 1993-08-13 | 1999-11-30 | Pharmos Corporation | Bioadhesive emulsion preparations for enhanced drug delivery |
US6391288B1 (en) * | 1999-07-27 | 2002-05-21 | Shiseido Co., Ltd. | Microcapsule and method of making the same |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100431686C (zh) * | 2005-08-31 | 2008-11-12 | 上海杰事杰新材料股份有限公司 | 一种制备纳米中空无机微球的方法 |
CN100431685C (zh) * | 2005-08-31 | 2008-11-12 | 上海杰事杰新材料股份有限公司 | 一种制备纳米中空无机微球的方法 |
WO2009037310A2 (fr) * | 2007-09-18 | 2009-03-26 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nanocapsules lipidiques à noyau aqueux propres à encapsuler des molécules hydrophiles et/ou lipophiles |
WO2009037310A3 (fr) * | 2007-09-18 | 2010-02-18 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nanocapsules lipidiques à noyau aqueux propres à encapsuler des molécules hydrophiles et/ou lipophiles |
CN101842088B (zh) * | 2007-09-18 | 2014-03-12 | 法国国家健康医学研究院 | 用于包封亲水性和/或亲油性分子的水性-核脂质纳米胶囊 |
US9522121B2 (en) | 2007-09-18 | 2016-12-20 | Universite D'angers | Aqueous-core lipid nanocapsules for encapsulating hydrophilic and/or lipophilic molecules |
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AU2003220670A1 (en) | 2003-10-27 |
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