CN101959502A - Process for preparing concentrated aqueous micellar solutions - Google Patents
Process for preparing concentrated aqueous micellar solutions Download PDFInfo
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- CN101959502A CN101959502A CN200980107400XA CN200980107400A CN101959502A CN 101959502 A CN101959502 A CN 101959502A CN 200980107400X A CN200980107400X A CN 200980107400XA CN 200980107400 A CN200980107400 A CN 200980107400A CN 101959502 A CN101959502 A CN 101959502A
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
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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
- A61K9/14—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
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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Abstract
The present invention provides a method for preparing supersaturated aqueous solutions of micelles of compounds in which the solubility in water is less than the critical micelle concentration. The solutions can be process to prepare solid micelles which have advantageous properties for drug delivery.
Description
The present invention relates to prepare the method for supersaturation micellar solution, described supersaturation micellar solution can be used for preparing the new formulation with low water-insoluble bioactive molecule.
Often find to have the molecule of high biological activity and the not good enough physical property that causes low bioavailability in the medicament research and development project.The change of physicochemical properties (mainly being dissolubility and dissolution) may change the pharmacodynamics and the pharmacokinetic property of chemical compound.Usually, character for example the change of dissolubility, dissolution, hygroscopicity, stability and crystal habit be to realize by the salt that forms ionizable molecule and various pharmaceutically acceptable counter ion counterionsl gegenions.Recently, polymorph and pseudopolymorph are screened, so that differentiate the crystal form of physicochemical property with improvement.Usually, the crystal structure of different salt and polymorph is different, and its physical property difference thus.Cocrystallization also provides the technology of the new crystalline material of another kind of evaluation.
Though be to seek crystal salt traditionally, recently, the amorphous form of active pharmaceutical ingredient is studied.Be different from the crystalline solid of forming by regular geometric pattern or lattice, amorphous solid by at random towards molecular composition.The common example of amorphous solid is glass and plastics.Be different from crystalline solid, amorphous solid does not have definite fusing point and has than higher dissolution of crystal form and bigger dissolubility.In preparation, use a difficulty of amorphous solid to be that they trend towards being transformed into more stable crystal form.
Other technology that is used to improve dissolubility and dissolution comprises by crystalline micronization and nanorize (nanosizing) and changes crystalline nature.
The invention provides the method for preparing the over-saturation micellar aqueous solution from amphipathic compound, the solubility product (K of described amphipathic compound in water
Sp) less than the critical micelle concentration in water (CMC), described method comprises the following steps:
A) amphipathic compound is dissolved in water can miscible (miscible) organic solvent in;
B) add entry, and optional aqueous alkali (aqueous alkaline) or alkali metal hydroxide or the aqueous acid (aqueous acid) that adds stoichiometric amount, with formation salt, thereby provide mixed uniformly aqueous solvent system;
C) under reduced pressure, causing heated solution under the distillatory temperature of organic solvent, to obtain the supersaturation micellar aqueous solution and to be lower than 0.5% organic solvent.
Can by routine techniques for example lyophilization or freeze-drying further handle the supersaturation micellar solution that obtains, so that the solid that can be mixed in the regular dosage form to be provided.
Fig. 1 is that (Fig. 1 a) and the microphotograph of concentrated micellar solution according to the disodium salt of the I of preparation described in the embodiment 1 of lyophilization (Fig. 1 b), it has shown that two kinds of resulting solid different shapes of dry technology learn (morphologies) to spray drying.
Fig. 2 is that it shows that described chemical compound does not have regular crystal structure by the solid x-ray powder figure of spray drying according to the concentrated micellar solution acquisition of the disodium salt of the I of preparation described in the embodiment 1.
Fig. 3 is the microphotograph according to the concentrated micellar solution of the spray-dired Compound I I of preparation described in the embodiment 4.
Fig. 4 is by the concentrated micellar solution resulting solid x-ray powder figure of spray drying according to the Compound I I of preparation described in the embodiment 4.
As used herein, phrase " " or " a kind of " entity refer to one (kind) or a plurality of (kind) described entity; For example, a kind of compound refers to one or more compounds or at least a compound. So, in the text term " a kind of " (or " "), " one or more " and " at least a " can Alternate.
As in this manual used, no matter in transitional phrases or the main body at claims, term " comprises " and " comprising " is interpreted as having the implication of " open ". That is to say that this term can " contain " or the explanation of " comprising at least " synonym at least with phrase. When using in the situation in method, term " comprises " and refers to that the method comprises at least described step, but can comprise other step. When using in the situation of compound or composition, term " comprises " and refers to that this compound or composition contain at least described feature or component, but can also comprise further feature or component.
As used herein, term " optional " or " choosing wantonly " refer to that event or the situation described subsequently can take place, but are not to take place, and this description comprises situation that event or situation take place and wherein event or the nonevent situation of situation. For example, " the optional replacement " refer to that the optional part (moiety) that replaces can be in conjunction with hydrogen or substituting group.
That term " about " is used for meaning in the text is approximate, approximately, roughly or nearby. When term " about " and number range are united when using, it by extended boundary to give on the numerical value and under change described scope. Usually, term " about " be used for to change in the text numerical value make its with 20% deviation above and below described numerical value.
When crystallization and amorphous state represent the extreme of molecular order in the solid state, described extreme between, may have mesomorphic state (the people .J.Pharm Sci.200594 (9) such as C.L.Stevenson: 1861-80) of continuous partial order. These are the solids with molecular order intermediateness (being characterised in that the orientation order to a certain degree that partially or completely loses position order (order) and keep ingredient).
It is amphipathic having hydrophilic and chemical compound hydrophobic part at same intramolecularly.Soap and detergent are the common examples of amphiphile, amphiphilic molecule.When the concentration of amphiphile, amphiphilic molecule in solution surpassed its critical micelle concentration, then their self-assembly (self assemble) were to form micelle.Because the volumetric balance of hydrophilic and hydrophobic part, many amphiphile, amphiphilic molecules show lyotropic (lyotropic) liquid crystal phase sequence.If it has large-scale orientation order mutually, liquid crystal material is a lyotropic so.These structures are that the microphase-separated by two incompatible components on the Nano grade forms.Soap is the daily example of lyotropic liquid crystal.
The content of water or other solvent molecule changes the structure of self-assembly.Under low-down amphipathic compound concentration, molecule will be by without any order ground random dispersion.Under the concentration of higher a little (but still low), amphiphile, amphiphilic molecule is with spontaneous spherical micelle or the film bubble (vesicles) of being assembled into.The assembling of micelle aggregation exposes hydrophilic (water-soluble) surface to aqueous solution with the hydrophilic segment of the amphipathic compound in the oriented nucleus micelle.Yet these ball-type individualities do not make them self sort in solution.In higher concentration, more orderly assembly (assemblies) will be formed.Typically be six prismatic column phases mutually, wherein amphipathic compound forms the elongated cylinder (also having water-wetted surface) that will oneself be aligned in the six prismatic lattices roughly.Soap phase in the middle of being referred to as.Under the concentration of more increasing, lamellar phase (pure mild soap phase) can form, and wherein the lamella of the stretching, extension of amphipathic compound (sheets) is separated by the water thin layer.For some systems, cube phase (also be called thickness etc. to (viscous isotropic) phase) can be present in six prismatics mutually and between the lamellar phase, wherein forms spheroid, causes to produce intensive cubic lattice.Described spheroid can also be interconnection, forms co-continuous cube phase.
Remove the generation solid that desolvates from spissated micellar solution, according to used dry technology and drying condition, it forms liquid crystal micelle solid or amorphous solid.Amorphous and lyotropic liquid crystal all is very unordered, so that they do not produce sharp-pointed diffraction maximum in the X-ray powder diffraction pattern.These forms cause usually and produce the halo pattern.Opposite with amorphous solid, when using polarized light microscope observing, liquid crystalline phase shows birefringence.
The micelle solid provides some peculiar properties that can use in the research and development of new formulation.Particularly the molecular order that provides in the liquid crystal is different from amorphous solid, has increased to postpone the stability that it is transformed into more stable crystalline solid.Yet the stability that obtains from gathering significantly is lower than crystalline state, causes the dissolubility and the dissolution of the typical increase of pure amorphous materials.
Though the micelle solid has indicated advantage to the medicine scholar, the physical property of many pharmacological activity molecules makes and is difficult to produce the solid concentrated micellar solution of therefrom recyclable liquid crystal.The water solublity that a reason of described difficulty is many molecules is low-down, to such an extent as to can not reach CMC, so micelle can't form.The invention provides the method that makes things convenient for that concentrates micellar aqueous solution by the low water-soluble compound preparation.
As used herein, term " amphipathic compound " refers to have hydrophilic and chemical compound hydrophobic property.Described chemical compound also is called amphipathic or facultative chemical compound.The hydrophilic segment of amphiphile, amphiphilic molecule can be cationic, anionic or neutral.The neutral hydrophilic group is polyethers normally, similarly the group of energy hydrogen bonding.The hydrophobic part of amphiphile, amphiphilic molecule normally is made up of the alkyl or aryl group.
As used herein, term " micelle " refers to be scattered in the aggregation of the amphiphile, amphiphilic molecule in the liquid.The micelle formation aggregation of typical positive (oil-in-water) in aqueous solution, its have with on every side around the outer surface of water contact on hydrophilic " head " zone and to isolate from environment wherein be in the heart hydrophobic tail zone in the relative anhydrous micelle.Micelle in the dilute solution be in shape approach spheric.When micellar solution becomes more enriching, can form more complicated liquid crystalline phase, and described micellar shape and size are for example functions of surfactant concentration, temperature, pH and ionic strength of the molecular geometry of its surfactant molecule and solution condition.
As used herein, term " liquid crystal " refers to have the phase of the material of the character between amorphous solid character and the solid crystal character.Liquid crystal is normally by having certain order but lack the typical rule of crystal lattices and repeat the molecular of subunit.When liquid crystal being placed between the pair of cross Polarization filter and passing through observation by light microscope, liquid crystal manifests birefringence, and promptly with respect to dark (iso) background, sample manifests light.
In an embodiment of the present invention, provide the method for preparing the over-saturation micellar aqueous solution from amphipathic compound, the solubility product (K of described amphipathic compound in water
Sp) less than the critical micelle concentration in water (CMC), described method comprises the following steps: a) amphipathic compound to be dissolved in the water miscible organic solvent; B) add entry, and the optional aqueous alkali that adds stoichiometric amount or alkali metal hydroxide or aqueous acid to be forming salt, thereby mixed uniformly aqueous solvent system is provided; And c) under reduced pressure, causing heated solution under the distillatory temperature of organic solvent, to obtain the supersaturation micellar aqueous solution and to be lower than 0.5% organic solvent.It will be appreciated by those skilled in the art that the amount of water and the property quality and quantity of nonaqueous solvent can change the mixing aqueous solvent system of dissolving amphipathic compound to provide, and do not need undue experimentation just can determine this tittle.
At first active pharmaceutical ingredient (API) is dissolved in the organic solvent, and adds a certain amount of water to produce uniform aqueous organic solution.Can randomly handle with acidic conjugate base with the aqueous alkali of stoichiometric amount having acid substituent active pharmaceutical ingredient (API), the anion of formation can improve the hydrophilic of API.Similarly, the API with basic group can be handled the hydrophilic conjugate acid that can improve API to produce with the aqueous acid of stoichiometric amount.Transforming API, to become salt be optional composition of the present invention, if to such an extent as to and neutral API enough amphipathicly can form micelle, then do not need to transform the API salify.Can also use anhydrous acid or alkali to produce salt, and in step subsequently, add entry.Usually the amount of organic solvent and water of regulating is to produce uniform solution.Selection can be miscible with water organic solvent, and the boiling point of organic solvent should be the decomposition that the heating of using in enough low so that the still-process does not cause API.
The distillation organic solvent is to produce oversaturated API micellar solution under vacuum.Continuing distillation contains until solvent and is lower than 0.5% organic solvent.Can easily adjust the API concentration in the water.In another embodiment, continue distillation and contain the supersaturated solution that is lower than 1% organic solvent with generation.In another embodiment, continue distillation and contain the supersaturated solution that is lower than 2% organic solvent with generation.
In second embodiment of the present invention, provide to prepare the micellar method of stable amorphous solid, this method comprises the described supersaturation micellar aqueous solution of spray drying to produce stable solid amorphous micelle, it shows birefringence under micropolariscope.
In the 3rd embodiment of the present invention, the method for preparing stable amorphous solid is provided, this method comprises the described supersaturation micellar aqueous solution of lyophilization, to produce stable amorphous solid.
As used herein, term " stable " refer to physical form (physical form) stable at least about around.
In the 4th embodiment of the present invention, preparation I compound (people such as S.Hirono is provided, WO on May 22nd, 2003042150,2003 is open) the micellar method of stable amorphous solid, described method comprise the following steps: (a) with formula I compound dissolution in THF; (b) add 2 normal 1M NaOH; (c) under the reduced pressure, causing heated solution under the distillatory temperature of organic solvent, to obtain the supersaturation micellar aqueous solution and to be lower than 0.5% organic solvent.
In the 5th embodiment of the present invention, provide preparation to contain the micellar method of stable amorphous solid of formula I chemical compound, this method comprises the supersaturation micellar aqueous solution (above-mentioned) that produces in the 4th embodiment of spray drying.
In the 6th embodiment of the present invention, the solid method of stable amorphous of preparation formula II chemical compound is provided, this method comprise the following steps: (a) with formula II compound dissolution in isopropyl alcohol; (c) under the reduced pressure, causing heated solution under the distillatory temperature of organic solvent, to obtain the supersaturation micellar aqueous solution and to be lower than 0.5% organic solvent.
In the 7th embodiment of the present invention, provide preparation to contain the solid method of stable amorphous of formula II chemical compound, this method comprises the supersaturation micellar aqueous solution (above-mentioned) that produces in the 6th embodiment of spray drying.
The following examples illustrate the preparation and the biological assessment of the chemical compound in the scope of the invention.Those skilled in the art provide the following examples and preparation so that can more be expressly understood and implement the present invention.It should be interpreted as to limit the scope of the invention, but it should be interpreted as only explaining and representing as this invention.
Embodiment 1
The preparation of the 35-45% micellar aqueous solution of the disodium salt of Compound I
To be equipped with mechanical agitator and remain in N
212L round-bottomed flask under the atmosphere fill I (601.5g, 1.163mol) and THF (about 4.8L).Suspension stirred under the medium speed and is heated to about 60 ℃ to produce uniform solution.Cool off this solution to room temperature (RT) and also under agitation add 1MNaOH solution (2320mL, the aseptic wash water of the usefulness of 120g NaOH is diluted to the solution of 3L, is determined as 0.985M through titrimetry).The temperature of solution is risen to 30.8 ℃ from 22 ℃.This solution for vacuum is moved to Buchi Rotovap (12L flask).Vacuum (25-27 holder) is removed THF.Bath temperature is maintained at 50-55 ℃, and steam temperature is about 21 ℃, and changes rotary flask with per minute 67-72.Along with volume reduces, steam temperature rises to 35-36 ℃.Bath temperature is risen to 60 ℃ to keep distillation speed.When steam temperature reached about 35 ℃, solution became muddy, and with solution at about 60 ℃ of aging 1h so that solution is clarified again, make N simultaneously
2Slowly flow in the Rotary Evaporators, to prevent to send out foam (foaming) and bumping.When steam temperature when keeping constant for 36 ℃, shift out sample, test pH is 8.5.Solution is diluted with sterilized water (about 500mL), and continuation concentrated solution to final volume is about 1.5L.In engler distillation, residual THF concentration determination is 0.015%, the concentration determination of the disodium salt of I is for being 44% (weight/volume), and pH is about 8.5.The micellar solution (1.726kg) that obtains is stored in the aseptic bottle.
Embodiment 2
The spray drying of embodiment 1 micellar solution
To transfer to pH 9 from the pH of the solution of embodiment 1 with 1N NaOH, and it will be transferred in the Buchi B-290 spray dryer, and according to following adjusting operating parameter:
Inlet temperature-175 ℃ (causing about 106 ℃ of outlet temperature);
The air pressure of spray nozzle-Yue 30psi;
Spraying pump speed-18-20%;
Aspirator-Yue 80%.
When inlet temperature reaches 175 ℃ of beginning spray dryinges.Exhaust pressure is about 15psi under 80% aspirator speed normally.After flow of solution is crossed spray dryer, close import heat pump and air intlet, and aspirator is reduced to about 50%).When delivery temperature is reduced to 60-70 ℃, close aspirator, and from indoor collection powder.Can be in the baking oven dry powder that obtains is to reach required water content.
Embodiment 3
The lyophilization of embodiment 1 micellar solution
Round-bottomed flask is filled solution from embodiment 1, it is dipped in the dry ice/isopropanol slurry, and vortex therein, with frozen solution.The flask that will contain frozen solution is connected to freeze dryer and anhydrates to remove.Bone dry needs 8-20h.The vacuum of breaking also shifts out flask, collects the powder that obtains.Light pressure with spatula or mortar and pestle can fragmentation be fallen any agglomerate.
Embodiment 4
The preparation of the micellar aqueous solution of Compound I I
Compound I I (2g) slowly is scattered among the 70%IPA (20mL), and adds entry (14mL).(II is at 70%IPA/H
2Dissolubility among the O is about 47mg/mL, being 4mg/mL and being 0.08mg/mL in IPA in water).With suspension ultrasonic with the solid that dissolves all distributions to produce pale yellow solution.Utilize Rotary Evaporators with IPA distillation to obtain containing the aqueous solution of 400mg/mL II of having an appointment.Utilize the spissated aqueous solution of Buchi B-290 spray dryer spray drying, according to following adjusting operating parameter:
Inlet temperature-180 ℃ (causing about 100 ℃ of outlet temperature);
Spray nozzle air pressure-Yue 30psi;
Spraying pump speed-12%;
Aspirator-Yue 90%.
Embodiment 5
The solid stability study of the micelle that spray drying I obtains
(about 10mg is from embodiment 1) is weighed in the weighing botle with small amount of solid, and places and have the indoor of controlled relative humidity, places for 4 weeks, calculated the percentage composition of the water of absorption by the weight increase.Be marked in 276nm outside also on Waters 2690HPLC, contrasting and come specimen by HPLC.Utilize the 3.2nd edition software data processing of Waters Millennium.Also at 60 ℃ and 40 ℃/75% relative humidity mensuration heat stability.Utilize the external standard aliquot of the weighing purity of coming working sample after tested by HPLC.Test shows non-hygroscopic and be heat-staple at 40 and 60 ℃ at the test period micelle.
Explanation and embodiment have described above-mentioned invention in greater detail by way of example, so that illustrate and understand.It will be appreciated by those skilled in the art that and in the scope of subsequently claims, to change and to revise.Therefore, should be appreciated that top description is illustrative and not restrictive.Therefore, scope of the present invention should not determine with reference to top description, but the four corner of the equivalents that should give with reference to following appended claim and these claim is determined.
With all patents of quoting among the application, patent application with openly introduce in literary composition as a reference, be used for all purposes, just as each individual patent, patent application or disclose and pointed out individually with its full content.
Claims (7)
1. the method for preparing the over-saturation micellar aqueous solution from amphipathic compound, the described amphipathic compound solubility product (K in water
Sp) less than the critical micelle concentration in water (CMC), described method comprises the following steps:
(a) amphipathic compound is dissolved in the water miscible organic solvent;
(b) add entry, and the optional aqueous alkali that adds stoichiometric amount or alkali metal hydroxide or aqueous acid to be forming salt, thereby mixed uniformly aqueous solvent system is provided; With
(c) under reduced pressure, causing heated solution under the distillatory temperature of organic solvent, to obtain the supersaturation micellar aqueous solution and to be lower than 0.5% organic solvent.
2. according to the method for claim 1, it comprises that also solution that spray drying obtains is to obtain the micellar step of stable amorphous solid.
3. according to the method for claim 1, it comprises that also solution that lyophilization obtains is to obtain the step of stable amorphous solid.
4. according to the process of claim 1 wherein:
Described chemical compound is a formula I chemical compound:
Described organic solvent is oxolane (THF);
Add two normal 1M NaOH.
5. according to the method for claim 4, it comprises that also the spray drying micellar aqueous solution is to obtain the stable solid step of amorphous micelle.
6. according to the process of claim 1 wherein:
Described chemical compound is a formula II chemical compound; And
Described solvent is isopropyl alcohol (IPA).
7. according to the method for claim 6, it comprises that also the spray drying micellar aqueous solution is to obtain the stable solid step of amorphous micelle.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3352908P | 2008-03-04 | 2008-03-04 | |
| US61/033,529 | 2008-03-04 | ||
| PCT/EP2009/052097 WO2009109476A1 (en) | 2008-03-04 | 2009-02-23 | Process for preparing concentrated aqueous micellar solutions |
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| Publication Number | Publication Date |
|---|---|
| CN101959502A true CN101959502A (en) | 2011-01-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200980107400XA Pending CN101959502A (en) | 2008-03-04 | 2009-02-23 | Process for preparing concentrated aqueous micellar solutions |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2262477A1 (en) |
| JP (1) | JP2011514897A (en) |
| CN (1) | CN101959502A (en) |
| CA (1) | CA2716082A1 (en) |
| WO (1) | WO2009109476A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| BR122021020474B1 (en) * | 2008-09-09 | 2022-06-07 | F. Hoffmann-La Roche Ag | Acyl sulfonamide polymorphs, their use, their preparation process and pharmaceutical composition that comprises them |
| KR101499867B1 (en) * | 2014-04-22 | 2015-03-06 | 에스케이케미칼주식회사 | Composition comprising active agent (I) and manufacturing method thereof |
| CN115209879A (en) * | 2019-12-31 | 2022-10-18 | 三养控股公司 | Method for preparing nanoparticles comprising amphiphilic block copolymers of low molecular weight |
| KR102688394B1 (en) * | 2020-12-10 | 2024-07-25 | 주식회사 삼양홀딩스 | Method for preparing polymeric micelle nanoparticle capable of reducing reconstitution time |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2087125A1 (en) * | 1992-01-23 | 1993-07-24 | Mridula Nair | Chemically fixed micelles |
| FR2715846A1 (en) * | 1994-02-07 | 1995-08-11 | Rhone Poulenc Rorer Sa | Injectable taxoid compsns. for treatment of tumours |
| NZ328751A (en) * | 1997-09-16 | 1999-01-28 | Bernard Charles Sherman | Solid medicament containing an anionic surfactant and cyclosporin |
| JP4939936B2 (en) * | 2003-06-27 | 2012-05-30 | 株式會社アモーレパシフィック | Method for producing self-assembling polymer nanoparticles containing physiologically active ingredients, and external preparation composition containing the obtained self-assembling polymer nanoparticles |
| US7617842B2 (en) * | 2003-07-29 | 2009-11-17 | SOCIéTé BIC | Valves for fuel cartridges |
| ATE531391T1 (en) * | 2004-05-06 | 2011-11-15 | Samyang Corp | DELIVERY SYSTEM FOR BIOLOGICALLY ACTIVE AGENTS BASED ON A POLYMERIC DRUG CARRIER WITH AN AMPIPHILIC BLOCK POLYMER AND A POLYLACTIC ACID DERIVATIVE |
| KR20070052747A (en) * | 2004-09-10 | 2007-05-22 | 도레이 가부시끼가이샤 | Medicinal preparation |
| EP2022497B1 (en) * | 2006-05-26 | 2014-04-30 | Toyama Chemical Co., Ltd. | Oral composition comprising 3-[5-[4-(cyclopentyloxy) -2-hydroxybenzoyl]-2-](3-hydroxy-1,2-benzisoxazol-6- yl)methoxy¨phenyl¨propionic acid or salt thereof |
-
2009
- 2009-02-23 CA CA2716082A patent/CA2716082A1/en not_active Abandoned
- 2009-02-23 JP JP2010549085A patent/JP2011514897A/en active Pending
- 2009-02-23 CN CN200980107400XA patent/CN101959502A/en active Pending
- 2009-02-23 WO PCT/EP2009/052097 patent/WO2009109476A1/en active Application Filing
- 2009-02-23 EP EP09717735A patent/EP2262477A1/en not_active Withdrawn
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| Publication number | Publication date |
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| CA2716082A1 (en) | 2009-02-23 |
| EP2262477A1 (en) | 2010-12-22 |
| JP2011514897A (en) | 2011-05-12 |
| WO2009109476A1 (en) | 2009-09-11 |
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