EP2555863A2 - Procédés et dispositifs pour la formation de vésicules, en particulier en utilisant des copolymères à blocs - Google Patents

Procédés et dispositifs pour la formation de vésicules, en particulier en utilisant des copolymères à blocs

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Publication number
EP2555863A2
EP2555863A2 EP11712554A EP11712554A EP2555863A2 EP 2555863 A2 EP2555863 A2 EP 2555863A2 EP 11712554 A EP11712554 A EP 11712554A EP 11712554 A EP11712554 A EP 11712554A EP 2555863 A2 EP2555863 A2 EP 2555863A2
Authority
EP
European Patent Office
Prior art keywords
fluid
porous material
vesicles
flow space
poly
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP11712554A
Other languages
German (de)
English (en)
Inventor
Arturo Bohm
Jochen Lisner
Jörg Braun
Helen Alicia Engel
Erich Josef Windhab
Wolfgang Meier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Buehler AG
Original Assignee
Buehler AG
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
Application filed by Buehler AG filed Critical Buehler AG
Priority to EP11712554A priority Critical patent/EP2555863A2/fr
Publication of EP2555863A2 publication Critical patent/EP2555863A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • 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
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • 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
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1277—Preparation processes; Proliposomes
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0097—Dye preparations of special physical nature; Tablets, films, extrusion, microcapsules, sheets, pads, bags with dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns

Definitions

  • the present invention relates to vesicles, in particular vesicles formed from block copolymers. Furthermore, processes for the preparation of in particular unilamellar vesicles are described. In particular, the present invention relates to Vesi ⁇ angle of amphiphilic block copolymers, wherein the block copolymer in particular an ester and / or an ether functionality comprises. Thus, vesicles are provided which, in turn, can be used to encapsulate and transport active ingredients, for example, nutritionally important components or drugs, cosmetics and food ingredients.
  • CTI Commission for Technology and in ⁇ novation
  • Vesicles consist of a closed arrangement of a bilayer of surfactant molecules to form, inter alia, self-organizing and self-aggregating beads or Cape ⁇ clauses, in particular hydrophilic agent ⁇ molecules may be incorporated in the interior and in particular ⁇ sondere in the edge region of hydrophobic molecules may be present. Vesicles are mostly spherically shaped lipid vesicles formed from a single or multiple lipid bilayers and internally encapsulate an aqueous phase.
  • MLV multilamellar vesicles
  • SUV small unilamellar vesicles
  • LUV large unilamellar vesicles
  • Phospholipids also called liposomes by.
  • the following advantages can be achieved by encapsulating active ingredients compared to conventional preparations:
  • nanocapsules or active substances encapsulated in vesicles are that they are often not visible since the dimensions are smaller than the visible wavelength range and that sedimentation and increased absorption are avoided, as for example in liposomes in skin creams is where assumed to be due to the penetration promoting effect of topically applied Lipo ⁇ somen to an interaction between vesicle and skin.
  • the ratio of surface area to volume is one order of magnitude greater than that of other capsules.
  • Each type of vesicle can be produced by different methods. By nature, only a few procedures suitable to produce drug-loaded vesicles, which can be used, for example, in medicines ⁇ example.
  • JM Gebicki and M. Hicks first reported the formation of a bilayer membrane structure in vesicles formed by the use of synthetic amphiphilic materials. Further processes for the preparation of vesicles consist of dispersing in aqueous phase concentrated solutions of suitable amphiphilic compounds in organic solvents (ether, chloroform, ethanol by injection). In this way, even large vesicles can be obtained with walls of one or more lamellae.
  • the vesicles are mainly used to entrap active ingredients and thus provide support for these substances.
  • the active compound ⁇ fe may be low molecular weight substances, such as drug ⁇ materials, or high molecular weight substances, for example Protei ⁇ ne. Due to this increasing importance, the vesicles for inclusion and transport of drugs by living tissue, eg. B. through the skin, in medicine and in cosmetics, are constantly new vesicle-forming substances and Ver- searched for the preparation of suitable vesicles and vesicle dispersions.
  • a disadvantage is the difficult accessibility of such vesicle-forming compounds. It is also known to produce vesicles with monomolecular layers from symmetrical, amphiphilic molecules having hydrophilic end groups on a lipophilic hydrocarbon skeleton by imparting a curvature to the lipid membrane by introduction of spacers which are incorporated in the lipid membranes in the manner of a molecular wedge (See Y. Okahata and T. Kunnitake, J. Am. Chem. Soc., 101, 5231 (1979)). Even the heretofore known ⁇ amphiphilic compounds are difficult to access.
  • US 3 957 971 further discloses the external, topical application of skin moisturizers in which liposomes derived from soybean lecithin, dicetyl phosphate and sterols contain the active agents.
  • US Pat. No. 4,217,344 describes the preparation of vesicles which encapsulate hygroscopic substances and increase the water retention capacity of the skin via their osmotic behavior.
  • starting materials that can form vesicles with greater stability to interfering constituents and to mechanical and thermal stress.
  • such starting materials should meet the high requirements in pharmacy, cosmetics and the food industry compared with ⁇ example, purity and tolerability, but also against the transportable drug.
  • a first fluid containing an amphiphilic substance is forced through a membrane. After flowing through the membrane to form droplets which are separated by a second fluid, so that vesicles bil ⁇ .
  • the first fluid and the second fluid with the exception of the amphiphilic substance contained in the first fluid, are identical in their chemical composition. This is described, for example, in "Extrusion Technique to Generate Liposomes of Defined Size" by B. Mui el al., Methods in Enzymology, Vol. 367, p. 3 et seq.
  • composition is always both an indication of the ingredients and their Kon ⁇ concentrations. Accordingly, thus differ, the chemical compositions of the first fluid and the second fluid, if only the first fluid contains a certain ingredient, the second fluid this ingredient but does not include. however, the chemical ⁇ rule compositions of the first fluid and the second fluid also differ already when the ingredients are identical in both fluids, but the concentrations of at least one of these ingredients in the two fluids from ⁇ different from each other are.
  • the active compound concentrations in ⁇ vesicle and in the second fluid are identical in these known methods.
  • the Vesicles includes both an amphiphilic layer contained ⁇ tene outer layer and an inner area that is covered by this layer.
  • a total composition is obtained which contains on the one hand the vesicles formed from the first fluid and on the other hand the second fluid, which serves as a carrier fluid for the vesicles.
  • the proportion of active ingredient in the carrier fluid is present in an unencapsulated form and is exposed to premature and uncontrolled degradation. Only the portion of the active ingredient enclosed in the vesicles can be released in a controlled manner. The proportion of the active ingredient in the carrier fluid can thus be redundant or (with ⁇ play, in medical applications) even harmful. Although it is possible to dilute the total composition and thus also the concentration of the active ingredient in the carrier fluid. However, this requires an additional dilution step, which makes the process expensive.
  • US Pat. No. 5,762,957 discloses a process for producing a total composition, in which an accumulation of an active substance in the interior of a vesicle is achieved with the aid of a pH gradient between the interior region and the carrier fluid.
  • an additional step after the actual preparation of the vesicles is required.
  • the membranes of the vesicles must be permeable to the drug, which significantly limits the selection of the amphiphilic substance and the active ingredient.
  • a suffi ⁇ chender pH gradient must exist, which likewise the possibilities if limited.
  • the present invention has the object to produce vesicles with a fast, simple, inexpensive and continuous process, in which the problems known from the prior art are overcome.
  • vesicles of a defined size distribution and in particular with as identi ⁇ rule dimensions are produced in a simple process.
  • the vesicles are to be prepared from an inexpensive Products Available ⁇ ren material, the resulting products are said to have improved containment capacity. With the inclusion of this capacity, the amount of the vesicles contained ⁇ requested drug is meant. Because of their possible use in other areas, such.
  • a lower sensitivity to surfactant-containing media and organic solvents is desirable.
  • the porous material may for example be a membrane, so be formed substantially flat. Under a drop of the first fluid and is always seen from a ⁇ stülpung the first fluid hereinafter, which is delimited from the second fluid by the fluid contained in the first amphiphilic substance.
  • the second fluid allows both detachment and removal of the formed vesicle so that a new vesicle can be formed on the second side of the porous material.
  • This inventive method is both quick, easy, inexpensive and can also continuously ⁇ to. Furthermore, high yields and long-term stable vesicles can be obtained.
  • the inventive method BacZusammenset ⁇ tongues are obtained from a second fluid formed by the carrier fluid and vesicles contained therein from the first fluid. Since the chemical composition of the second fluid differs from that of the first fluid, the properties of the overall composition can be adjusted selectively and independently of each other. The chemical composition of the first fluid and thus also the composition of the vesicle produced is thus virtually independent of the environment in which the first fluid is extruded, that is, the chemical composition of the second fluid. Further preferably, the first fluid comprises at least one active ingredient to be encapsulated in particular. This may ⁇ example as suspended in the first fluid or dissolved.
  • compositions of the first fluid and the second fluid may differ in that only contains the first fluid, a certain ingredient, but the second this in ⁇ retaining material does not contain. Conversely, even the two ⁇ te fluid containing a certain ingredient, the first fluid but not.
  • the ingredients in the first fluid and the second fluid are the same, but deviates, the concentration of at least one ingredient in the first Flu ⁇ id of the concentration of this ingredient in the second fluid.
  • this ingredient may be an active ingredient.
  • the first fluid contains at least one ingredient in a first concentration
  • the second fluid contains the ingredient in a second concentration that is different than the first concentration.
  • the second concentration may be less than the first concentration.
  • the second fluid is substantially free of the In ⁇ content; in this case the concentration of the content Fabric in the second fluid zero.
  • the ingredient may be an active ingredient.
  • the second concentration of drug Weni ⁇ ger than 80%, more preferably less than 50%, particularly ⁇ vorzugt be less than 30% of the first concentration of the active ingredient. So is for example the first concentration of the active ingredient is 30% and the second concentration of the active substance ⁇ less than 80% of the first concentration to the second concentration of the drug is less than 24%.
  • the first fluid contains the starting materials for vesicle formation.
  • the first fluid comprises a solvent insbesonde re ⁇ water.
  • the fluid can be introduced in a first flow space to the first side of the porous material.
  • the first fluid according to the method of the invention contains one or more amphiphilic substances.
  • amphiphilic describes the chemical property of a substance to be both hydrophilic and lipophilic, that is, it is soluble in both polar solvents and nonpolar solvents due to the fact that the molecules have both hydrophilic and hydrophobic regions ,
  • hydrophobicity may be that the substance readily soluble in fats or oils;. The substance is then called lipophilic.
  • Important amphiphilic substances are
  • Lipids with polar head groups in particular
  • Phospholipids a major component of cell membranes
  • amphiphilic substances are their tendency to self-organization, e.g. B. the formation of micelles and
  • All surfactants are composed of a non-polar and a polar part (functional groups) (polarity).
  • the nonpolar part is always an alkyl group.
  • the polar part can be constructed differently and is summarized in the following table.
  • Phospholipids are phosphorus-containing, amphiphilic lipids. They are involved in the organism as membrane lipids in the construction of the double lipid layer of a biomembrane. They are made up of one
  • hydrophilic head and two hydrophobic hydrocarbon tails together are thus amphiphilic.
  • Phospholipids form a double lipid layer in water
  • phosphatidylcholines also lecithins, PC for short
  • PE phosphatidylethanolamines
  • PS phosphatidylserines
  • phospholipids Due to their chemical structure, phospholipids are divided into the following two groups:
  • - Phosphoglycerides with glycerol as a backbone also called glycerophospholipids or phosphatides
  • Sphingolipids derived from sphingosine including sphingomyelin.
  • lipids are the following:
  • the first fluid may comprise at least one buffer and / or at least one surfactant and / or at least one salt and / or Minim ⁇ least one acid and / or at least one liquor.
  • ⁇ by the stability of the vesicle can be adjusted, and in particular the time period be set within which a contained in vesicles active ingredient is released.
  • the first fluid is in an ordered phase at least prior to passing through the pore.
  • ordered phases is understood to mean the phases with the nomenclature according to Luzzati, as shown in Section II.6 of D. Marsh, Handbook of Lipid Bilayers:
  • - L one-dimensional lamellar ("one-dimensional, lamel- lar ");
  • - P two-dimensional oblique or centered ("two-dimensional oblique or centered (rippled)");
  • the phases can be identified, for example, by X-ray diffraction, Freeze-Fracture Electron Microscopy or 31 P-NMR.
  • the first fluid is in a lamellar phase before, particularly preferably in a one-dimensional lamellar ( "one-dimensional lamallar") phase. If the first fluid is present in an ge ⁇ associated phase, particularly in a one-dimensional lamellar phase, the preparation is carried out of vesicles immediacy ⁇ bar of the lamellar phase of the first fluid.
  • the vesicles of the desired diameter and / active ingredient (s) contained therein directly and not, as in other methods of the prior art via one or more intermediate steps is formed which often lead to large multilamellar vesicles which, in turn, do not rearrange to the desired smaller unilamellar vesicles in a subsequent step
  • the multilamellar vesicles may deliver the active agent to the environment or exchange it with the solvent that unilamellar vesicles are ununiform Ier loading in relation to the active ingredient and the amount of the same.
  • the temperature and / or the pH and / or the number of ions and / or the ionic strength of the first fluid and / or the concentrations of the ingredients in the first fluid is preferably adjusted such that the formation of vesicles in step be ⁇ réellet (d) becomes.
  • the temperature and / or the pH and or the number of ions and / or the ionic strength of the f ⁇ th fluid can be adjusted such that the first fluid to ⁇ present least before carrying through the pore in a lamellar phase.
  • the first fluid may have a time-variable flow rate ⁇ .
  • inertial forces are acting, which influence the formation of vesicles and in particular can facilitate.
  • they may affect the formation of droplets from the first fluid described below and their separation to form vesicles.
  • the porous material may be, for example, a sintered metal, a membrane or a porous glass.
  • suitable sintered metals, membranes and porous glasses having a desired pore size or pore size distribution is well known to those skilled in the art.
  • Suitable porous sintered metals are playing, obtainable from ⁇ by the company Portec Ltd., 8355 Aadorf, Switzerland un ⁇ ter the brand name METAPOR®.
  • suitable po ⁇ Roese Sintermetalle bronze are Sinterme by the company Meyer ⁇ tall AG, 2557 Studen, Switzerland available.
  • Other suitable nanoporous metal membranes were developed by the Institute of Materials of the Technical University of Braunschweig, Germany.
  • Suitable nanoporous glass membranes are approximately from the CPI - is offered ⁇ Chemical Park Institute GmbH 06749 Bitterfeld, Germany.
  • membranes for example, conventional sterile filter of a suitable pore size can be used.
  • WEI Suitable porous materials include, for example, porous plastics.
  • At least one pore preferably at least 30% of the pores, more preferably min ⁇ least 50% of the pores, particularly preferably at least 75% of the pores have a diameter of 50 nm to 10000 nm, preferably 250 nm to 1000 nm, more preferably 450 nm to 550 nm.
  • Derarti ⁇ ge diameter are particularly suitable for the production of unilamellar vesicles, in particular in the inventive presence of the first fluid in an ordered phase.
  • At least one pore preferably at least 10% of the pores, more preferably at least 50% of the pores, more preferably at least 80% of the pores Ver ⁇ ratio of length of the pore and the diameter of the pore harnesss ⁇ least 500, preferably at most 200, more preferably at most 50.
  • the pores may be coated with at least one hydrophobic or at least one hydrophilic substance, so that the mechanical stress of the vesicles can be adjusted during their formation.
  • the thickness of the porous material, in particular the membrane is at most 10 ⁇ m, preferably at most 5 ym, more preferably at most 2 ym.
  • vesicles of defined dimensions and small deviation from the average size are obtained by carrying out the fluid containing the starting materials required for vesicle formation through pores of certain defined dimensions.
  • a porous material having pores whose diameter is between 6% and 14%, more preferably between 7% and 13%, between 8% and 12%, between 9% and 11% and most preferably at 10% above the desired one is used Diameters of the vesicles are. As a result, vesicles of a relatively narrow size distribution can be generated.
  • a porous material with different pore diameters can be used to make vesicles of other, wider size distribution. This may be of interest, for example, in the simultaneous encapsulation of drugs of various sizes.
  • step (b) The passage of the first fluid through the at least one pore in step (b) may be accomplished by techniques known to those skilled in the art. These include, for example, centrifugation and the use of pressure gradients. In some embodiments, step (b) is performed by centrifugation. The first fluid is thereby pressed by centrifugal forces through the Po ⁇ re or pores of the porous material.
  • the second fluid may be conducted past the second side of the porous material in a second flow space.
  • a controlled laminar flow can be achieved.
  • turbulence which in turn can lead to vesicles of various sizes.
  • the second fluid may have a time-variable flow rate ⁇ .
  • the flow rate is understood here as a vectorial size; Also, a Strömungsge ⁇ speed, in which only the direction, but not the amount of time changes, so is considered to be variable over time.
  • the detachment of the drops can be controlled by a shear flow or an expansion flow or a superposition of the flow forms in the second fluid.
  • the second fluid may for example contain water or represents ⁇ consist.
  • the second fluid may at least one buffer and / or at least one surfactant and / or at least one salt and / or at least one acid and / or Minim ⁇ least comprise a liquor.
  • the conditions that are required for the amphiphilic substance can be adjusted.
  • amphiphilic substance is covered.
  • this separation surface is quickly covered by a double layer of the amphiphilic substance, so that a stable vesicle is formed.
  • the temperature and / or the pH and or the number of ions and / or the ionic strength of the second fluid is preferably adjusted such that the formation of vesicles in step (c) be ⁇ This favors.
  • the formation of the vesicle in step (d) can also be achieved or promoted, for example, by applying a shear flow or a stretch flow or their combination in the second fluid.
  • step (d) also by means of a mechanical device, in particular by means of ei ⁇ ner shear plate, to be performed.
  • a first side of the shear plate along the second side of the porö ⁇ sen material can be passed, whereby, for example Trop ⁇ fen are separated by the shear plate along the second side of the porö ⁇ sen material.
  • the second fluid is passed along a second side of the shear plate.
  • the first fluid and / or the second fluid and / or the porous material in mechanical vibration and / or are acted upon by me ⁇ chanical waves it is advantageous if the frequency of the oscillations or waves is close to a natural frequency of the vesicles to be formed.
  • the second fluid can thus have a resonating flow field.
  • the first fluid and / or the second fluid and / or the porous material are mechanically vibrated and / or mechanically driven by ultrasound.
  • the ultrasound can be generated with a per se be ⁇ known ultrasonic resonator.
  • the amphiphilic substance the first fluid comprises min ⁇ least one amphiphilic block copolymer may consist of two or meh ⁇ eral different blocks. At least one of these blocks must be hydrophobic and at least one must be hydrophilic be.
  • the combinations AB, ABA or BAB are possible, where A is a hydrophobic block and B is a hydrophilic block.
  • the hydrophobic properties must be
  • hydrophilic predominate In hydrophobic media this is reversed.
  • hydrophilic blocks are polyalkylene oxide, polymethyl oxazoline, polyacrylic acid, polysaccharides and polyhydroxyethyl methacrylate.
  • the polyalkylene oxide can be at ⁇ play as polyethylene oxide.
  • hydrophobic blocks are polyalkylcaprolactone, polyisobutylene, polyalkylacrylate, polybutadiene, polyethylene, polyisoprene, polydimethylsulfoxide, polystyrene.
  • the polyalkyl ⁇ caprolactone may, for example, be Polymethylcaprolacton.
  • the block copolymer comprises at least one ester functionality and / or at least one ether functionality, which are responsible for the amphiphilic character of the block copolymers.
  • the amphiphilic block copolymer is selected from the group consisting of Po ⁇ poly (alkylene oxide) n _ poly (alkylcaprolacton) m and poly (isobutylene) n - poly (ethylene oxide) m.
  • poly (alkylene oxide) s preferred " ⁇ Po ly (ethylene oxide) n”
  • poly (alkylcaprolacton) m before Trains t ⁇ "poly (methylcaprolactone) n".
  • Poly (alkylcaprolacton) m in particular poly (ethylene oxide) n _ poly (methylcaprolactone) m, n is preferably in the range of 10 to 50, and m is preferably in the range of 20 to 80.
  • n is preferably in the range of 10 to 50, and m is preferably in the range of 20 to 80.
  • ⁇ Po ly (isobutylene) n - Poly (ethylene oxide) m is preferably in the range from 30 to 100, and m is preferably in the range of 10 to
  • n is preferably in the range of 10 to 50 and m is preferably in the range of 20 to 80.
  • the poly (isobutylene) n -poly (ethylene oxide) m has a structure of the following formula II:
  • poly (ethylene oxide) 10-50 poly (methylcaprolactone) 20-80 and poly (isobutylene) 30-100 poly (ethylene oxide) 10-50 are particularly suitable for vesicle formation because of the adjustable chain lengths these from ⁇ transition materials, both the variable length of the hydrophobic radicals, the branch of the hydrophobic residues (which determines the mobility of the molecule in the lamellar phase) and the size of the hydrophilic heads of the formation of defined unilamellar vesicles size with only small deviations from the lamellar phase allows.
  • the poly (ethylene oxide) is preferably io-so _
  • polymers with small polydispersities can be prepared (Mw / Mn ⁇ 1.3).
  • the polydispersity is understood as the quotient of the weight average Mw to the number average Mn of the molecular weight of the polymer.
  • (ethylene oxide) was 2o so _ poly (methylcaprolactone) 30 for Poly - found 100 that the type of vesicles formed by both the final concentration of the block copolymer in the second fluid and the ratio of poly (ethylene oxide) and Po ⁇ ly (methylcaprolactone).
  • the length of the hydrophobic block increases, the size of the vesicles formed increases. This means that block copolymers with a larger ratio between hydrophobic and hydrophilic groups form larger vesicles.
  • concentration of block copolymers in the second fluid increases, their packing density also increases.
  • Lamellar structures can be found from a concentration of about 10% by weight, while at lower concentrations, the block copolymers as individual vesicles and isolated as a rod-shaped micelles vorlie ⁇ gen. From a concentration of 40 wt .-% are the block copolymers predominantly in the form of lamellar structures.
  • the poly (isobutylene) 3o-ioo _ poly (ethylene oxide) 10-50 shows a ähnli ⁇ ches behavior. Below a concentration of 10% by weight in water, the polymer is present almost exclusively in the form of vesicles or micelles. Above a concentration of 50% by weight, lamellar structures are formed, while in the concentration range between 10% by weight and 50% by weight, a mixture of lamellar structures and hexagonal rods is formed. A particularly preferred final concentration of the block copolymers is present at about 5 wt .-%, since the block copolymers are predominantly at such a concentration as densely packed vesicles before ⁇ .
  • Another aspect of the invention relates to a total composition, holding a carrier fluid and at least one vesicle ⁇ ent.
  • the vesicle may have been prepared by a method as described above.
  • the second fluid may form the carrier fluid.
  • the vesicles in the total composition, preferably substantially all the vesicles in the RescueZusammenset ⁇ wetting one or more of the properties described above.
  • the vesicles may comprise at least one of the above-described block copolymers.
  • the chemical composition of the vesicle is different from the chemical composition of the carrier fluid.
  • the vesicles contains at least one ingredient in a first concentration, while the carrier fluid containing the contents ⁇ material in a second concentration that is different from the first concentration.
  • the ingredient may be, in particular, an active ingredient.
  • the ingredient, into ⁇ particular the active ingredient may be present in the enclosed layer of this inner region of the vesicle in which the amphiphilic substance-containing outer layer of the vesicle and / or.
  • the second concentration may be less than the first concentration.
  • the pH levels in the interior of the vesicle and in the carrier fluid may be substantially the same. This is understood to mean that the pH values differ from one another by at most 0.15, preferably at most 0.1, particularly preferably at most 0.05.
  • Another aspect of the invention relates to an apparatus for producing vesicles.
  • the device comprises
  • At least one porous material in particular a Memb ⁇ ran, and / or a receptacle for a porous material, in particular a membrane, said material having a first side and a second side and at least one pore, which second from the first side to the Side stretches;
  • vesicles can be produced, in particular in the inventive method.
  • a in the second flow space on the second side of the porous Materials passing over the second fluid so drops of a first fluid can be separated, which was passed from the first flow space through the porous material in the second flow space.
  • the layer of the amphiphilic substance closes around the drop to be separated by the second fluid, so that, for example, no disordered structures are formed, but vesicles with a closed layer of the amphiphilic substance ,
  • At least one dimension of the second adjustable Strö ⁇ mung space namely at least by means of a BEWE ⁇ supply at least one second flow space bounding surface. This movement should take place relative to the second side of the porous material. It is not excluded that an adjustability of the dimension of the second flow space can also be done in addition by movement of the porous material.
  • the dimension of the second flow space is adjustable only by means of a movement of at least a second flow space bounding surface without the porous Mate ⁇ rial must be moved. This simplifies the supply of the fluid ers ⁇ th considerably.
  • the complete installation and / or removal and / or conversion of Schika ⁇ nen in or out of the second flow space is not understood as a movement of at least one of the second flow space limiting surface; a device in which the dimensions of the second flow space can be achieved only by such an installation and / or removal and / or conversion is therefore not covered by this formulation.
  • At least one dimension of the second flow space in the region of the second side of the porous material and substantially perpendicular to the second side adjustable at least by means of a movement of at least one second flow space bounding surface.
  • the width of a gap of the second Strö ⁇ mung space may be adjustable in the region of the second side of the porous material.
  • the porous material and in particular the pore contained therein, may have one, several or all of the properties discussed above in connection with the method.
  • the device can be used in particular for the production of vesicles with the method according to the invention.
  • the device comprises further means for separating drops of the first fluid (1) formed on the second side of the porous material to form vesicles.
  • the other means for separating are also used as means for producing a shear flow, an expansion flow mung or any combination thereof formed in the second fluid.
  • the device includes a hollow body, in particular a hollow cylinder, and a rotatable shaft disposed within the hollow body.
  • the hollow body comprises
  • the shaft with particular variable motivatesgeschwin ⁇ speed is rotatable relative to the hollow body. Furthermore, the shaft relative to the hollow body, in particular with respect to a longitudinal axis of the hollow cylinder, eccentrically displaceable. As a result, the shaft forms means for producing a shear flow, a stretch flow or any combination thereof in the second fluid. By selecting the peripheral speed and / or the ex ⁇ centric shift, the ratio of expansion flow and shear flow can be adjusted. Thus, an eccentric Ver ⁇ displacement of the shaft relative to the hollow body leads to adjustment of a dimension of the second flow space.
  • the surface of the shaft forms the movable, second Strö ⁇ mung space bounding surface in the sense of the invention.
  • the first inlet opening is arranged at the location of the narrowest gap between the hollow body and the shaft. Through this first inlet opening, the first fluid can flow into the second flow space.
  • the second inlet opening is arranged at a location upstream of the flow direction of the lateral surface.
  • the second outlet opening is preferably at one arranged downstream of the flow direction of the lateral surface. Through this second outlet, the second Flu ⁇ ID can be led out with vesicles suspended therein from the second flow space.
  • the further means for separating the drops are formed as means for applying mechanical vibrations and / or waves to the first fluid and / or the second fluid and / or the porous material.
  • these means may be at least one tubular resonator and / or at least one piezoelectric film and / or at least one unbalance generator and / or at least one electromagnet.
  • the device may include a channel having at least one wall surface, the channel including the first flow space and the second flow space.
  • the porous material may be formed as a membrane and separate the first flow space from the second flow space.
  • the membrane may be arranged substantially parallel to the wall surface.
  • the first inlet port for the first fluid may be integrally ⁇ arranged on the wall surface, wherein the first inlet port in communication with the first flow space.
  • the means for producing vibrations and / or waves can be designed as
  • At least one unbalance generator and / or at least one electromagnet in particular on at least one wall of the channel and / or on the membrane.
  • the tube resonator is excited at a frequency in the range of 2 Hz to 100 Hz, preferably from 10 Hz to 20 Hz.
  • the further means for separating can be formed as a means for shearing off the drops along the second side of the porous material, in particular as at least one shear plate.
  • the device comprises
  • a first block in particular an upper block
  • a second block in particular a lower block
  • Block which forms the second flow space
  • An adjusting device for adjusting the width of the gap An adjusting device for adjusting the width of the gap.
  • the width of the gap forms the adjustable dimension of the second flow chamber, and the gap defining upper ⁇ surface of the first block and / or the gap-limiting 0- ber measurements of the second block is movable, the second flow space defining surface.
  • the width of the gap can be adjusted approximately by the axial force on the rotor and / or by the volume flow of the second fluid.
  • the first inlet opening has the shape of a Ringka ⁇ nals.
  • the rotation of the first block relative to the second block generates a shear flow in the region of the gap which corresponds to the flow in a thrust bearing.
  • the shear rate that is the ömli ⁇ che change in the flow velocity in a direction perpendicular to the flow rate resulting from the rotation ⁇ number of the first block relatively to the second block and of the width of the gap.
  • the device comprises
  • Hollow body substantially uniformly spaced and in particular conical membrane which forms the porous material
  • a particular conical inner body, which is at least partially enclosed by the membrane and insbesonde ⁇ re coaxial with the hollow body is arranged;
  • a second inlet opening for the second fluid in particular arranged in the top surface
  • the distance between the conical inner body and the membrane forms within the meaning of the invention, the adjustable dimension of the second flow space, while the conical surface of the conical inner body is the movable, the second flow space limiting surface.
  • the axial force can be minimized on the cones.
  • the shear rate results from the distance between the conical inner body and the diaphragm and the speed of the rotor.
  • the conical inner body has a first opening angle
  • the membrane has a second Publ ⁇ opening angle which is smaller than the first opening angle. This narrows a gap between the conical inner body and the membrane.
  • the conical hollow body is additionally rotatable relative to the shaft.
  • the peripheral speed of the Hohlkör ⁇ pers is variable.
  • both directions of rotation can be the same.
  • a large number of flow states can be set in the flow space.
  • only the hollow body is rotatable relative to the conical inner body. This prevents the formation of so-called Taylor vertebrae, which are perpendicular to the rotation axis. These vortices are caused by the liquid accelerated outward by the centrifugal force, which urges on the inner surface of the hollow body.
  • the invention further relates to the use of a device for producing vesicles and / or for producing a total composition as described above.
  • the device may be used in a method as described above.
  • a device inserted ⁇ sets comprising the following:
  • porous material in particular a Memb ⁇ ran, and / or a receptacle for a porous material, in particular for a membrane, wherein the porous material having a first side and a second side and at least one pore extending from the first side (16; 22; 33) extends to the second side (17; 23; 34);
  • the device may also have one, several or all of the features described above.
  • Another aspect of the invention relates to the use of vesicles which have been produced by a device of the invention with a method and / or according to the invention, as or in a drug, a cosmetic, a food product, egg ⁇ ner color, a fuel or an anti-corrosion agent.
  • the anticorrosion agent contained in vesicles can be released, for example, upon weathering and / or exposure to UV light and then develop its desired effect.
  • the following uses are conceivable:
  • vesicles according to the invention Preference is given to the use of the vesicles according to the invention and / or the vesicles which are obtained according to the method according to the invention for encapsulation / encapsulation of active ingredients, drug prodrug, active substance prodrug or excipients for human medicines, veterinary drugs, vaccines, enzymes, coenzyme me, isoenzymes, vitamins, hormones, proteins, peptides, Carbohydrate ⁇ rate, natural substances, fragrances, structurally related odorants such as pheromones and flavorings in medicine, in cosmetics, as dental care products, skin and hair care products, sebum and detergents, in food or food additives , Fut ⁇ feedingstuff, preservatives and other additives, products used for agricultural ⁇ economic purposes, such as fertilizers, Bi ⁇ ozide such as pesticides, herbicides or fungicides, Mizellensentner (detergents), disinfectants, metal products, non-
  • Preferred pharmaceutical applications include a treatment treatment of cardiovascular diseases with active ingredients such as isoflavone, vitamin E, vitamin C and folic acid. Another application is the treatment and / or prevention of osteoporosis with a combination of vitamin D3, zinc, magnesium and / or calcium. Yet another application is in the treatment and / or prevention of indigestion with fructooligosaccharide and / or partially hydrolyzed guar gum. It should be understood that these are only exemplary pharmaceutical applications in which one or more drugs may be in encapsulated form.
  • suitable dosage forms include as rectal and vaginal dosage forms, transdermal, subcutaneous and transdermal Arzneifor ⁇ men, medicinal forms for application to the eye, medicinal forms for use in the nose and the ear, oral dosage forms with rapid-release oral dosage forms with slow-release peroral drug forms with controlled drug release, dental application or topical Applikati ⁇ onsformen.
  • the vesicles, methods, and devices of the invention find use in the encapsulation of active ingredients in liquids or beverages. Another use is the encapsulation of components of natural products.
  • nutritionally relevant components can be encapsulated, such as vitamins, for which targeted, controlled release is of interest.
  • protective components may be sensitive to a variety of influences, such as light, oxygen, water, pH.
  • they can be volatile components or components which taste unpleasant and / or have a bad taste, and which are thus to be masked.
  • they may be components that are needed only in small amounts, such as vitamins, minerals or phytochemicals.
  • flavorants Preferably, flavorants, redoxaggans, enzymes, artificial sweeteners, fermentants, antioxidants, colorants, drugs with unpleasant odor or taste, essential oils, amino acids, vitamins and minerals are encapsulated.
  • active substances such as phytin can be encapsulated in order to enable release only in the large intestine.
  • Other applications include the encapsulation of lycopene and its derivatives for use in anti-aging products.
  • a depot application with slow release of the active ingredients is possible.
  • the drug dosage can be varied at a constant vesicle dose. Bioavailability should therefore be independent of drug dosing.
  • a slow or controlled release of the drug is possible by the choice of Ve sikel supportive.
  • the vesicles or vesicles according to the invention which have been prepared by the process according to the invention have a high active ingredient content with an inclusion rate of at least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80% preferably at least 90%, or even more preferably even at least 95%.
  • Such vesicles can increase the half-life of a pharmaceutical in the blood by more than tenfold
  • the vesicles may be used in mixture with natural and / or synthetic polymers of all kinds such as starch, and in particular quizhydrolyse- starch degradation products, polyethylene glycol and other lösli ⁇ Chen, sparingly soluble and / or insoluble polymers are used.
  • the vesicle preparation in or on the membrane of the vesicles contains a polymer, preferably polyethylene glycol having an average molecular weight (MW) of 2,000 to 10,000, which protects the active ingredient at the vesicle surface from interactions with body components.
  • the body components include in particular blood be used as a pharmaceutical, acid when used as a cosmetic and food (acid mantle of the skin or gastric acid).
  • both water-soluble and water-insoluble active substances can be included in the vesicle structure.
  • the vesicles are used in many fields of therapy and Diagnos ⁇ tik (Knight, EC ed, Research monographs in cell and tissue physiology, vol 7, Liposomes:.. From physical structu- re to therapeutic applications, Elsevier, North Holland, Biomedical Press, Amsterdam, New York, Oxford 1981). Because of Mög ⁇ friendliness to encapsulate a lot of different drugs in vesicles over time a very broad application spectrum ⁇ emerged with a focus in the parenteral administration (iv, sc, im, ip) is located. Further fields of use of vesicles are in cosmetics, food industry or corrosion treatment.
  • the vesicle dispersions of the invention are also suitable for inclusion of active ingredients and transport these active ingredients through the skin and therefore represent a valuable support system for application of cosmetic and pharmacological agents, in particular they are suitable to enclose water ⁇ soluble drugs in the area enclosed by the vesicles aqueous phase.
  • lipid-soluble and water-insoluble active ingredients can be a ⁇ built.
  • Water-soluble or lipid-soluble cosmetic or pharmazeuti ⁇ specific and nutritional ingredients may be incorporated into the vesicles, by mixing the vesicle-forming molecules with the lipid-soluble active substances and optionally with a water-soluble solvent dissolves the water-soluble active compound ⁇ fe in water and the lipid phase dispersed in the aqueous phase ,
  • water-soluble agents z.
  • water ⁇ soluble vitamins, minerals and proteins eg. As salts of ascorbic acid, amino acids and water-soluble polypeptides, which ⁇ serlösliche dyes, antibacterial substances, inflammation- substances and many others.
  • B. oil-soluble vitamins, eg. As tocopherols, UV filter substances or other water-soluble active substances are included.
  • water-soluble refers to those active ingredients which are clearly dissolved in water at 20 ° C. to at least 1% by weight.
  • Oil-soluble substances are understood to be those which are clearly soluble in paraffin oil at 20 ° C. to at least 1% by weight.
  • the aqueous phase may contain the solutes up to the saturation limit.
  • the lipid phase which consists essentially of the membrane lipids, should not contain more than 10% by weight of the lipid phase, preferably not more than 5% by weight, of the lipid phase of oil-soluble active ingredients.
  • Flow rate of a second fluid is constant in time
  • FIG. 1 a schematic diagram of a sixth embodiment ⁇ form of the method according to the invention, in which a second fluid is fluidized;
  • FIG. 1 a schematic diagram of a seventh embodiment ⁇ form of the method according to the invention, in which the direction of the flow velocity ei ⁇ nes first fluid is variable in time;
  • ⁇ S with an upper block, a lower block and a gap therebetween;
  • a third embodiment of erfindungsge ⁇ MAESSEN device with a tube resonator A fourth embodiment of the erfindungsge ⁇ MAESSEN device with a hollow cylinder designed as a hollow body and a shaft.
  • a centrifuge 10 is used.
  • the centri fuge ⁇ 10 includes a horizontally oriented plate 18 and a ro-mountable ⁇ arm 13 with a first passage 12 forming a first flow chamber.
  • One of the starting materials for vesicle formation and one or more active substances containing first fluid 1 is supplied via a first inlet opening 11 into the first channel 12.
  • a porous Ma ⁇ material which has been formed as a membrane fourteenth
  • the membrane 14 has a first side 16 and a second side 17. It contains pores with a substantially uniform diameter of 500 nm, which extend from the first side 16 to the second side 17.
  • the first fluid 1 is present in an ordered phase, in particular in a one-dimensional lamellar phase.
  • This ordered phase was adjusted by a suitable choice of temperature and / or pH and / or ion number and / or ionic strength of the first fluid (1) and / or by the concentrations of the ingredients in the first fluid (1).
  • the suitable parameters can be determined by the expert by routine tests.
  • the presence of an ordered phase, in particular a one-dimensional lamel ⁇ stellar phase, such as by using X-ray diffraction, Freeze-Fracture Electron Microscopy or 31 P-NMR can be determined.
  • the plate 18 penetrating inlet opening ⁇ a second fluid can be transported from below to the top of the plate 18.
  • the second fluid forms a radially outwardly flowing film.
  • the plate 18 can rotate about the vertical axis, where ⁇ is supported by the radial flow.
  • the space area above the plate 18 thus forms a second flow space.
  • the arm 13 and in particular the membrane 14 immerse in this film.
  • the first fluid 1 Upon rotation of the arm 13, the first fluid 1, as viewed in detail in FIG. 1b, becomes, due to centrifugal forces, the peripheral region of the arm 13 and the pores from the first side 16 to the second side 17 of the membrane 14, where it enters the second fluid 2.
  • the first fluid 1, upon exiting the pores of the membrane 14 and entering the second fluid 2 forms vesicles (not shown) of uniform size and uniform loading with the active ingredient.
  • FIGS. 2 a to 2 c show a second embodiment of the method according to the invention.
  • two shear plates 20, 20 ' are used.
  • Each of the two shear plates 20, 20 'in each case contains at least one pore 21 or 21'.
  • the lower shear plate 20 ' forms a porous material according to the invention and has a first side 22 and a second side 23.
  • a first fluid 1 containing the starting materials for vesicle formation and the one or more active substances is pressed through the two pores 21, 21 'according to FIG. 2a.
  • a droplet 4 is initially formed from the first fluid 1.
  • FIG. 3 shows a third embodiment of the method according to the invention is visualized, which is carried out by means of extrusion.
  • the starting materials for vesicle formation and the one or more active substances containing first fluid 1 is pressed in egg ⁇ NEN channel 30 forming a first flow chamber.
  • a porous material which is formed as a membrane 31.
  • the membrane 31 has ei ⁇ ne first side 33 and a second side 34 and contains pores having a substantially uniform diameter of 500 nm.
  • the first fluid 1 is pressed by means of a pressure gradient through the pores from the first side 33 to the second side 34.
  • On the second side 34 of the membrane 31 there is a second flow space 32, in which a second fluid 2 flows.
  • the first fluid 1 Upon exiting the pores of the membrane 31 and entering the second fluid 2, the first fluid 1 forms vesicles (not shown) of uniform size and loading with the drug.
  • the pressure pl of the first fluid 1 is in this case greater than the pressure p 2 of the second fluid and, for example, matched to the pore size of the membrane 31 and / or the viscosities of the first fluid 1 and / or the second fluid 2 that the first fluid 1 the Membrane can happen in a desired throughput.
  • FIGS. 4a to 4d show a fourth embodiment of the method according to the invention.
  • the starting materials for vesicle formation and the one or more active substances containing first fluid 1 is according to figure 4a by one or several ⁇ re in a porous material 40 existing pores 41 upward ge ⁇ pressed.
  • a drop 4 is initially formed.
  • the droplet is separated in FIG. 4d to form a vesicle 3.
  • the resulting vesicles 3 have a uniform size and loading with active ingredient.
  • FIGS. 5a to 5d show a fifth embodiment of the method according to the invention. This differs from the method illustrated in FIGS. 4a to 4d only in that the flow velocity of the second fluid 2 is constant in time (but not in space).
  • FIG. 6 shows a sixth embodiment of the method according to the invention.
  • One the starting materials for vesicle formation and the One or more active substances containing first fluid 1 is pressed through a plurality of pores 51 located in a porous material 55 (upwards) in a recess 52.
  • the recess 52 has a steep drop 56 in the flow direction of the second fluid 2 and increases in the further course 57 flat, so that upstream of the pores 51, a turbulence 53 gebil ⁇ det is.
  • At the boundary layer 58 of the formed with waves and / or oscillations ⁇ conditions applied flux field 54 vesicles 3 are transported away by the second fluid. 2
  • a seventh embodiment of the method according to the invention can be seen in FIG. ,
  • the starting materials for vesicle formation and the one or more active substances containing first fluid 1 with a time-variable (pulsating) flow rate is forced through a plurality of pores 51 of a porous material 55, thereby vesicles 3 separated and transported in a second fluid 2 from ⁇ .
  • the flow rate can temporarily drop to zero.
  • a variable Strö ⁇ flow velocity of the first fluid 1 can also be realized Schwingun ⁇ gene of the porous material 55, which may be generated at ⁇ play by means of an ultrasonic resonator.
  • FIGS. 8a and 8b an eighth embodiment of the method according to the invention is shown in FIGS. 8a and 8b.
  • a From the gear ⁇ materials for vesicle formation and the one or more active substances containing first fluid 1 is pressed by a plurality of pores located in a surface 60 of the 62nd
  • the surface 60 defines a tapering cavity 63, which tapers in an axial direction A.
  • the cavity 63 forms a second flow space, which flows through a second fluid 2 in the axial direction.
  • vesicles 3 are separated and removed in the second fluid 2.
  • Figure 8b shows.
  • FIG. 9 shows a first embodiment of a erfindungsge ⁇ MAESSEN device which is suitable for carrying out the inventive method.
  • the device comprises an upper block 73 and a lower block 74, between which a gap 71 is formed.
  • a shaft 75 arranged on the upper block, the width of the gap 71 can be adjusted.
  • the upper block 73 can be rotated by means of the shaft 75 in relation to the lower block 74 about a vertical axis of rotation D.
  • a first inlet port in the form of an annular channel 77 is provided through which a first fluid 1 to ei ⁇ ner first location can enter the gap 71st
  • a second inlet opening 76 for a second fluid 2 which is present centrally in the axial direction, via which the second fluid 2 can enter the gap 71 at a second location.
  • This second location is different from the first location and located radially further inward than the first location.
  • the gap 71 forms a second flow space for the second fluid 2.
  • the flow in the gap 71 corresponds to the flow in a thrust bearing.
  • the gap 71 as well as the lateral boundaries of the upper block 73 and the lower block 74 form a second outlet opening 70 for the second fluid 2.
  • membranes 78 are provided which form a porous material.
  • the width of the gap 71 forms an adjustable dimension of the second flow space and which upwardly delimits the gap 71.
  • Zende lower surface of the first block 73 forms a movable ⁇ bare, the second flow space limiting surface.
  • the width of the gap 71 can be adjusted by the axial force on the shaft 75 or by the volume flow of the second fluid 2. The shear rate results from the rotational speed and the adjustment of the width of the gap 71.
  • a conical hollow body 79 with base 80, top surface 81 and lateral surface 82 comprises a uniformly spaced to the inner circumferential surface 82 of the Hol stressess 79 membrane 72, and a represents ⁇ in arranged conical inner body 83.
  • the conical inner body 83 has an opening angle ⁇ on; the membrane 72 has an opening angle 2, which is smaller than ⁇ .
  • a first inlet port 84 arranged for a first fluid 1, while a second inlet opening 85 second in the top surface 81 for the Fluid 2 is arranged.
  • a second outlet opening 87 for the second fluid 2 is further arranged.
  • the first flow chamber 87 is Zvi ⁇ rule of the membrane 72 and arranged in the conical hollow body 79, and the second flow space 88 is arranged between the conical inner body 83 and the membrane 72nd
  • the base 80 includes a shaft 86 for shifting of the co ⁇ African inner body 83 along the horizontal axis of symmetry A to change the distance between the conical inner body 83 and the membrane 72nd
  • the distance between the conical inner body 83 and the membrane 72 forms an adjustable dimension of the second flow space in the context of the invention, while the conical surface of the conical inner body 83, the movable, the second flow space defining surface.
  • the diaphragm 72 does not have to be moved, which greatly simplifies the supply of the first fluid 1.
  • the conical inner body 83 by means of the shaft 86 is also rotatable about the axis of symmetry A, for example by means of a motor, not shown.
  • the axial force can be minimized on the cones.
  • the shear rate results from the distance between the conical inner body 83 and the diaphragm and the rotational speed of the shaft 86.
  • the device includes a channel 91, which comprises a first flow space 93 for a first fluid 1 and a second flow space 90 for a second fluid 2. Between the first flow space 93 and the second flow space 90, a porous material is arranged, which is formed as a membrane 94. On a wall surface 92 of the channel 91 ei ⁇ ne first inlet opening 96 is arranged through which the first fluid 1 can enter the first flow chamber 93rd The first fluid 1 is guided through the pores of the membrane 94 from the first flow space 93 to the second flow space 90. In this case, initially droplets 4 from the first fluid 1 are formed.
  • these droplets 4 are separated to form vesicles 3.
  • the separation of the drops 4 is supported by a tube resonator 95, which is arranged in the second flow space 90.
  • the tube resonator 95 is in this case with a frequency between 2 Hz and 100 Hz, preferably between 10 Hz and 20 Hz excited.
  • FIG. 12 shows a side sectional view of a fourth embodiment of a device according to the invention for shearing off drops.
  • This device comprises a hollow body 101 designed as a hollow body and a disposed within the hollow cylinder 101 shaft 102, which is rotatable about a horizon ⁇ tal axis of rotation D.
  • the hollow cylinder 101 has a lateral surface 104 with a membrane 105, which is preferably arranged in the region of the narrowest gap between the shaft 102 and the hollow cylinder 101.
  • the shaft 102 is held at a Füh ⁇ approximately plate 111, which penetrates the lateral surface 104 of the hollow cylinder ⁇ one hundred and first
  • the guide plate 111 is movable in both directions R shown by the double arrow, ie perpendicular to the lateral surface 104. Between the diaphragm 105 and the shaft 102, a gap 110 is formed.
  • the width of the gap ⁇ ses 110 is adjustable. To adjust the width of the gap 110, the membrane 105 does not have to be moved, which greatly simplifies the supply of the first fluid 1.
  • the first fluid 1 is introduced.
  • the second fluid 2 is introduced on the lateral surface 104 at a second inlet opening 106 upstream of the flow direction.
  • the vesicles 3 suspended in the second fluid are then guided through the gap 110 and guided out of the cavity 108 between the lateral surface 104 and the shaft 102 at a second outlet opening 107 downstream of the flow direction.
  • This hollow space ⁇ 108 thus forms a second flow chamber for the second fluid 2.
  • the guide plate 111 prevents a direct flow of the second fluid from the second inlet port 106 to the second outlet port 107th
  • the shaft 102 is displaceable ⁇ eccentrically relative to the hollow cylinder 101 by means of movement of the guide plate 111 and can be rotated at the desired peripheral speed.
  • the desired expansion and shear flows in the second fluid 2 can be adjusted, which cause the separation of the drops 4 to form vesicles 3.

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Abstract

La présente invention concerne des procédés pour produire des vésicules (3). Un premier fluide (1) comprenant une substance amphiphile est guidé à travers un pore (21; 21'; 41; 51; 62) afin qu'il se forme au moins une goutte (4) du premier fluide (1). La goutte (4) est ensuite séparée en faisant passer un deuxième fluide (2). La composition chimique du deuxième fluide (2) est différente de la composition chimique du premier fluide (1). L'invention concerne également des compositions globales qui contiennent des vésicules (3). La présente invention concerne en particulier des vésicules (3) de copolymères à blocs amphiphiles, le copolymère à blocs comprenant notamment une fonctionnalité ester et/ou éther. L'invention concerne également des dispositifs pour la production de vésicules (3) ainsi que l'utilisation de tels dispositifs.
EP11712554A 2010-04-06 2011-04-06 Procédés et dispositifs pour la formation de vésicules, en particulier en utilisant des copolymères à blocs Withdrawn EP2555863A2 (fr)

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EP11712554A EP2555863A2 (fr) 2010-04-06 2011-04-06 Procédés et dispositifs pour la formation de vésicules, en particulier en utilisant des copolymères à blocs

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EP10159108A EP2374535A1 (fr) 2010-04-06 2010-04-06 Procédé et dispositifs de formation de vésicule, notamment en utilisant des copolymères en bloc
PCT/EP2011/055317 WO2011124589A2 (fr) 2010-04-06 2011-04-06 Procédés et dispositifs pour la formation de vésicules, en particulier en utilisant des copolymères à blocs
EP11712554A EP2555863A2 (fr) 2010-04-06 2011-04-06 Procédés et dispositifs pour la formation de vésicules, en particulier en utilisant des copolymères à blocs

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EP2402075A1 (fr) * 2010-06-28 2012-01-04 Bühler AG Procédé et dispositif destinés à la fabrication de vésicules
TR201818352A2 (tr) * 2018-12-02 2020-06-22 Bursa Teknik Ueniversitesi Mi̇kroenkapsülasyon yöntemleri̇nde parti̇kül boyutunu küçülten damlatma düzeneği̇
CN113125792B (zh) * 2021-04-22 2023-01-31 长春工业大学 一种用于测量转速的压电-电磁复合式传感装置

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WO2011124589A3 (fr) 2013-03-21
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