EP0665756A1 - Process and device for producing liquid, dispersed systems - Google Patents

Process and device for producing liquid, dispersed systems

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Publication number
EP0665756A1
EP0665756A1 EP19930922883 EP93922883A EP0665756A1 EP 0665756 A1 EP0665756 A1 EP 0665756A1 EP 19930922883 EP19930922883 EP 19930922883 EP 93922883 A EP93922883 A EP 93922883A EP 0665756 A1 EP0665756 A1 EP 0665756A1
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Patent type
Prior art keywords
characterized
liquid
process
systems according
disperse systems
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Ceased
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EP19930922883
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German (de)
French (fr)
Inventor
Georg Rössling
Andreas Sachse
Thomas Schneider
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.)
Rossling Georg
SACHSE Andreas
SCHNEIDER Thomas
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RÖSSLING, Georg
SACHSE, Andreas
SCHNEIDER, Thomas
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1277Processes for preparing; Proliposomes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations
    • A61K49/0433X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461Dispersions, colloids, emulsions or suspensions
    • A61K49/0466Liposomes, lipoprotein vesicles, e.g. HDL or LDL lipoproteins, phospholipidic or polymeric micelles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/06Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1806Suspensions, emulsions, colloids, dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/06Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1806Suspensions, emulsions, colloids, dispersions
    • A61K49/1812Suspensions, emulsions, colloids, dispersions liposomes, polymersomes, e.g. immunoliposomes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/70Nanostructure
    • Y10S977/788Of specified organic or carbon-based composition
    • Y10S977/797Lipid particle
    • Y10S977/798Lipid particle having internalized material
    • Y10S977/799Containing biological material
    • Y10S977/801Drug
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/902Specified use of nanostructure
    • Y10S977/904Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/906Drug delivery
    • Y10S977/907Liposome
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/902Specified use of nanostructure
    • Y10S977/904Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/927Diagnostic contrast agent
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/902Specified use of nanostructure
    • Y10S977/904Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/927Diagnostic contrast agent
    • Y10S977/928X-ray agent
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/902Specified use of nanostructure
    • Y10S977/904Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/927Diagnostic contrast agent
    • Y10S977/929Ultrasound contrast agent

Abstract

The description relates to a continuous process for producing liquid, dispersed systems in which a pre-dispersion is sequentially extruded at high pressure of 6.6 to 250 MPa through 1 to 8 filter stages with decreasing pore sizes between 0.01 and 35 νm. There may be up to 20 passages per filtering stage. The description also relates to a device which may be used to implement the process of the invention.

Description

Method and apparatus for the production of liquid, disperse systems

The invention relates to a method and an apparatus for the production of liquid, disperse systems.

In addition to the cosmetic industry, there is, especially in the pharmaceutical industry a great need for methods and apparatus for producing dispersed systems. This is especially true for the reason, because they (drug designation delivery system) developed, known as drug carrier systems in the search for new possibilities of drug transport, the disperse systems (especially solid / liquid or liquid / liquid) represent. to mention among these are, for example, emulsions (liquid / liquid) for parenteral nutrition or administration of poorly water soluble drugs, and particularly liposomes suspensions which can be used as targeted drug carriers use.

Because of the hydrophobic interactions spontaneously closed lipid vesicles, which are called liposomes formed after dispersion of phospholipids in water. In these it is spherical or elliptical hollow body having one or more lipid bilayers ( "bilayer"), which include an aqueous phase. According to their size one distinguishes small unilamellar (small unilamellar vesicles [SUV] with radii of 25 to 50 nm) and large unilamellar vesicles (large unilamellar vesicles [LUV] with radii greater than 50 nm to 10 microns) (Weiner, N ., Martin, F., Riaz, M., Drug Dev. Ind. Pharm. 15_, 1523- 1554 (1989)).

There are other known multilamellar liposomes (multilamellar vesicles [MLV]), in which there are a plurality of concentrically arranged bilayer and multivesicular liposomes (multivesicular vesicles [MW]), which in turn comprise vesicular structures in their lumen.

The liposomes are suitable for inclusion hydrophilic and lipophilic drugs wherein the level and location of the inclusion of the physicochemical properties of the drug and the lipid composition of the liposomes is dependent.

All methods for the preparation of liposomes include, as main step, the dispersion of the lipid or lipid mixture in an aqueous phase. Proceeding from this, one can divide all of the production method of the three main principles dispersion. A distinction is "mechanical

1 ERSATΣBLATT dispersion "(mechanical dispersion)," two-phase dispersion "(two-phase dispersion) and" detergent solubilization "(detergent solubilization) (New, RRC (eds), Liposomes:. A practical approach, Oxford University Press, New York, 1990, p 33).

For methods that include a "two-phase dispersion" are mainly the limited solubility of certain lipids in organic solvents and the high costs in the removal of the solvent used (such as chloroform, methanol, diethyl ether), to reduce the residual solvent concentration to tolerable concentrations (toxicity), disadvantageous. The "detergent-Solubilisationsmethoden" have the disadvantage of only difficult to remove from the preparation Restdetergenzgehalts.

In so-called "mechanical dispersion method", in contrast, dispenses with the use of organic solvents or detergents during the dispersion of the lipid in the water phase. In general, a lipid film is thereby formed first by rotary evaporation of an organic solution of the lipid or lipid mixture (for example, in chloroform, methanol or diethyl ether). then often a 12-24 hour lyophilization at high vacuum is done to completely remove the residual solvent. By subsequent addition of an aqueous phase and mere shaking (the so-called hand-shake method by Bangham, Bangham, AD, Standish, MM, Watkins, J. C., J. Mol. Biol. 12, 238-252 (1965)), one obtains a MLV suspension which is extremely heterogeneous in terms of liposome size and lamellarity.

For further processing of corresponding MLV suspensions are several method in which generally receive SUV or LUV.

The oldest and most widely used method for the production of SUV is the "sonication method" (sonication method). Here MLV are crushed by sonication (ultrasonic probe or ultrasonic). The liposomes thus obtained have an average diameter of 20 to 60 nm and a Einschlußkapazität below 1%. The disadvantages of this method are mainly in the high heat, which can lead to decomposition of the lipid and the drug as well as the difficulty to process larger amounts of sample reproducible. In use, the ultrasonic rod is, moreover, the disadvantage of contamination of the sample with titanium chips as well as the formation of an aerosol (see the already cited publication by RRC New).

2 ERSATΣBLATT Another method for the production of small uni- or oligolamellar liposomes the "french press method" whose name used to it is high jerk apparatus (french press) back. This system consists of an electric, hydraulic press and a high pressure cell having a maximum volume capacity of 4 or 40 ml, depending on Ausführun (New RRC; see above). A disadvantage of this method is above all the fact that the final liposome suspensions in a proportion not crushed MLV are generally contaminated with abrasion residues of the pressure chamber ode and the difficulty is to control the temperature rise in the chamber in addition to the limited volume of the z manufacturing dispersions.

Recently, also found so-called high-pressure homogenizers entrance to di

Liposome technology. Thus, the production of SUV was a

Kleinstmengenringspalthomogenisator from MLV or lipid dispersions (ohn previous film formation) described (Brandl, M., Bachmann, D., turners, M., Farmer,

KH, Drug Dev Ind Pharm... Eat, 2167-2191 (1990)).

This method permits the reproducible production of small quantities of homogeneous

SUV dispersions with very small average diameters (<50 nm).

but is disadvantageous especially the occurrence of abrasion devices (annular gap etc.) as well as the difficult control of the product temperature.

In addition to the previously described method for the production of SUV there are several mechanical methods for preparation of LUV, which also operate unte using predispersions (liposomes or lipid). The oldest of these methods is the so-called "extrusion method". In this method, a MLV dispersion by hand sequentially through filter holder with polycarbonate filters of decreasing pore size (3.0, 1.0, 0.8, 0.6, 0.4 and 0.2 microns) at pressures up to 0.35 MPa filtered (Olson, F., Hunt, CA, Szoka, F. C, Vail, WJ, Papahadjopoulos, D., Biochim. Biophys. Acta SSZ, 9-23 (1979)).

A further development of these extrusion methods, the so-called "LUVET- method" (Large unilamellar vesicles by extrusion) is (WO86 / 00238, 1986, and Hope, M. J "Bally, MB, Webb, G., Cullis, PR, Biochim. Biophys. Acta fi 12, 55-65 (1985)). In this batch process, a rough ode lipid liposome dispersion at pressures below 3.5 MPa is extruded several times through two superimposed polycarbonate filters with pore sizes smaller than / equal to 100 nm. In this case, we obtain unilamellar liposomes with a diameter of 6 to 100 nm and a trap volume 1-3 I aqueous phase per mole of lipid. If the liposome suspension below a lipid concentration of about 200 μmo

3 SUBSTITUTE SHEET ml per addition (some freeze-thaw cycles of freezing the suspension and subsequent thawing - Cullis, PR, Mayer, LD, Baliy, MB, Madden, TD, Hope, MJ, Adv Drug Delivery Rev. 3, 267-282 (. 1989 subject)), then increasing the trapping efficiency can be established. When using pressures up to 5.5 MPa very high lipid concentrations could be processed. In the technique used in this pressure filter devices, the pre-dispersion is placed in a lying directly over the membranes Aufgußraum closed the pressure vessel, and then built up by means of compressed air or nitrogen necessary for the filtration pressure. The filtrate is removed through an outlet and then back out again up to 20 times in the Aufgußraum. A drawback of the extrusion method is in the discontinuous mode of operation, the small working volumes and low filtration pressing the commercially available devices.

A relatively new method provides for the high-pressure homogenization with the so-called Microfluidizer ™ is (Mayhew, E., Lazo, R., Vail, WJ, King, J., Green, AM, Biochim. Biophys. Acta 775, 169-174 (1984) ).

In this method, a MLV dispersion or a coarse aqueous lipid dispersion is first introduced into a reservoir and pressed by means of a high-pressure pump via a prefilter (5 microns) in a so-called interaction chamber in which the liquid flow is split into micro-channels into two separate streams which subsequently combined with high speed. After exiting the interaction chamber, the obtained dispersion can either be removed or recirculated.

A disadvantage of this method is mainly the occurrence of metal abrasion in the finished preparations as well as the fact that sometimes, a loss or degradation of the lipid is observed (Talsma, H., Ozer, AY, van Bloois, L., Crommelin, DJA , Drug. Dev. Ind. Pharm. 15: 197-207 (1989)). In addition, the size and lamellarity of the liposomes can be set reproducibly only over a limited range.

In the preparation of emulsions find simple, high-speed stirrers, shaker, stirrer with rotor and stator (for example Ultra Turrax) and colloid mills use. Due to various device-related disadvantages and the poor reproducibility and low Dispersitätgraden that are achieved with these devices have in addition to the ultrasound treatment (laboratory scale) especially the Hochdruckhomogenisationsverfahren, enforced despite the associated disadvantages in emulsion preparation (Praveen, T. ( eds). Specialized drug delivery system, drugs and the pharmaceutical sciences, Vol. 41,

4 SUBSTITUTE SHEET Marcel Dekker, Inc., New York, Basel 1990, pp 317 et seq.). Here, especially the Ringspalthomogenisator APV Gaulin (Luebeck, Germany) to name or the Microfluidizer ™, the application is already described, for example for the production of emulsions for parenteral nutrition (Washington, C., Davis, SS, Int. J. Pharm. 44, 169-176 (1988) and Mukhtar, S., Jacobs, GP, Benita, S., Tenside Surf. Det. 20, 347-351 (1989)).

The continuous process according to the invention for producing liquid dispersions does not have the above-mentioned disadvantages of the previously known methods. It is characterized in that extruding a pre-dispersion under a high pressure of 6.6 to 250 MPa sequentially 1 to 8 filter stages of decreasing pore size from 0.01 to 35 microns, wherein up to 20 passages may be used per filtration step.

The inventive method is preferably carried out at a working pressure of 7 to 80 MPa. The extrusion can be implemented on each filtration stage via one or a combination of 2 - 4 carried filters of the same or different pore size. Here membrane filter (Tübingen) are usually such as polycarbonate membranes (surface filters) about the company Nucleopore® used.

Unlike the prior art methods, however, other filter ent speaking differential pressure resistance of different materials and in different geometries (such as filter disks, or Cups - candles) suitable for carrying out the method. Suitable filters are metal or polymer membranes or inorganic materials such as glass fiber or R Anopore membranes (Fa. Anotec, Banbury Oxon, England). Examples of suitable polymer materials are filter made of polytetrafluoroethylene (PTFE), polypropylene (PP), polyvinylidene fluoride or cellulose esters such as cellulose acetate.

It has already been mentioned that the invention not only relates to a process for the production of liquid dispersions, but also a device for performing this method. This device, which can be referred to as continuously operating the high-pressure extrusion apparatus (s. Fig. 1), is characterized by a storage vessel (1), whose discharge line to a high-pressure pump (2) results, which is designed to build working pressures of up to 250 MPa. On the output side, this pump is equipped with a compartment intended for containing the filter according to the invention the filter holder (6) from which the product via

5 is SUBSTITUTE SHEET a discharge line (7) is either recycled to the storage vessel and / or removed.

Preferably, the high-pressure pump for building up working pressures is adapted to a maximum of 80 MPa. Between the high pressure pump and a filter holder pre-filter may be mounted, if desired, which is intended to contain filters with an average pore size of 2 to 35 microns. Furthermore, the device according to the invention can still be provided with venting means and / or temperature and pressure gauges.

Suitable pumps for the inventive device are, for example pneumatic or hydraulic piston pumps (for example MAXIMATOR®, Fa. Schmidt, Kranz & Co., Zorge, Germany). Suitable pumps are usually those which have a Umspannfaktor of about 50 to 750 and thus can produce working pressures between 5 and 300 MPa from 0.1 to 0.4 MPa inlet pressure (air or nitrogen). Suitably, devices of the invention with a control valve (3) are provided, may be selectively adjusted by means of which the applied pressure in the present process. At high pressure, then large amounts of dispersion with high concentrations of disperse phase can (gel-like) can be extruded (e.g., 500 mg lipid per ml of aqueous phase) and, accordingly, high viscosity, which is not possible with the prior art methods as a rule. The hereby resulting product flows are generally between 0.1 and 10 liters per minute, preferably at 0.15 to 3 liters per minute.

Due to the high pressures in the inventive method applicable that occurs with other methods problem of clogging of the filter is also eliminated, thereby interruptions of the process for changing the filter omitted.

The storage vessel used in the inventive device may be designed so that it is temperature-controllable, the lines may be metal tubes or hoses. Alternatively, the product recycling can also be done via a two-chamber storage container or a liquid spiral where appropriate, with heat exchange.

When the apparatus for producing pharmaceutical preparations to be used, all wetted parts must be the same sterilizable and resistant to the solvent used in it. Preferably, the apparatus is made from such materials, which allow a heat sterilization.

6 SUBSTITUTE SHEET In contrast to most prior art devices allows the high-pressure extrusion apparatus di invention, liquid dispersions and kontinuierlic produce in large quantities, whereby the manufacturing cost of di dispersions thus the economic efficiency of the method is significantly improved and significantly reduced.

Thus, the apparatus used in the embodiments for setting filter holder, allowing the use of membrane filters of 47 mm diameter. The pressure holding capacity of the filter holder used for this beträ 80 MPa. This device allows the rapid preparation of dispersions in Bereic from 100 to 1000 ml (dead volume of the system approximately 10 ml). When using vo two filters with 47 mm diameter having a pore size of less than / equal to 100 n can be achieved with this device flows that are significantly above 150 ml pr minute.

With an appropriate design of the apparatus but also the production i pilot plant and production scale without negatively affecting de product features is possible. With an appropriate design of the Vorrichtun (pump capacity, filter geometry, pipe connections, etc.) can be increased with de corresponding systems the achievable flow rate to well over 3 L per minute Alternatively, however, a design of such facilities for very small amounts of products is possible where this as is erwünsch for economic reasons.

In devices in which is to be a feedback de product after the first dispersion, it is often advantageous that the dispersion is first collected in a two-chamber system, in order to then again return them by merely opening a ent speaking valve in the system. This bicameral system has the advantage over direct recirculation, as always, first, the total amount of the dispersion is subjected to the shearing process and no mixing of undispersed and dispersed phase occurs. De same effect can also take place via the recirculation of Disperison via a liquid spiral, which grasps the total volume of the processing approach. Here, take place simultaneously controlling the temperature of the dispersion over the outer walls of the respective spiral.

The inventive device is not only suitable for performing the method according to the invention, but may be even with use of lower pressures in the range of 1 to 6.6 MPa useful.

7 SUBSTITUTE SHEET feasible by means of the inventive device, the inventive methods for preparing liquid dispersions are of particular importance in the pharmaceutical and cosmetic liposome technology, since they economical production of large liposomes amounts with reproducible properties (such as occlusion, liposome size and -lamellarität) pharmaceutical grade ( for example, allow sterility and pyrogens).

The inventive method allows the production of uni- or multilamellar liposomes over a wide limit range (average diameter typically 25 nm to 5 microns). The size and homogeneity of the size distribution and lamellarity of the liposomes obtained here is, inter alia, a function of the type of filter used, and pore size of the filtration pressure (working pressure), the number of passages through the device, the lipid species and concentration and the nature and amount of drug employed. By the usual preliminary tests, as they are known to the expert, can be obtained by a suitable choice of these parameters formulations with a very narrow size and Lamellaritätsverteilung.

In the formation of liposomes using the method of the invention, the same lipid components can be used, as in the other methods of this type. Such lipids are usually Phosphoiipide such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, phosphatidylinositol or sphingolipids. Moreover, such as Choiesterol or other components such as fatty acids (eg stearic acid, palmitic acid), dicetyl phosphate or cholesterol hemisuccinate are used as further constituents of sterols. With the use of amphiphilic substances such as Hexadecylpoly (3) glycerol, Dialkylpoly (7) glycerol ether, and alkyl glucosides, so-called niosomes, liposomes, these are made of non-ionogenic Vesikelbildnern obtained.

By means of the inventive device and the inventive method it is possible to encapsulate both hydrophilic and iipophile liposomal drugs. Suitable active ingredients are, for example, vitamins, hormones, antifungal agents, anti-allergic agents, Antphlogistica, antihypertensives, Antiarrhytmica, antibiotics, antivirals, anxiolytics, cytostatics, immunomodulators, contraceptives, peptides, proteins and sedatives.

8 SUBSTITUTE SHEET In the case of hydrophilic drugs, these usually solved in the preliminary dispersion used to prepare the aqueous phase and subjected to preparation of the predispersion to the inventive method. Here, surprisingly liposomes with particularly high inclusions can be obtained.

Thus, the novel process, among other especially suitable proves for the encapsulation of contrast agents for X-ray (or CT) and NMR diagnostics, which were encapsulated adequately with the previously known mechanical dispersion methods. With the inclusion of iodinated contrast media (RCM) can thus be achieved even with small liposomes diameters and relatively low lipid concentrations high inclusion capacities. By combination with one or more freeze-thaw cycles (freezing and thawing), a further Einschlußerhöhung can be achieved. Particularly suitable examples of the type of the corresponding RKM triiodobenzoic acid are iopromide, iohexol, iopamidol, ioversol, lopentol, loxaglat, 3- carbamoyl-5- [N- (2-hydroxyethyl) acetamido] -2,4,6-triiodo-benzoic acid - [(1 RS, 2SR) - 2,3-dihydroxy-1-hydroxymethylpropyl] amide and iotrolan.

In the case of inclusion of contrast agents for NMR diagnostics, the inventive method proves superior in terms of the achievable inclusion capacities compared to all previously described mechanical method. By mere high-pressure extrusion, extremely high inclusions can be obtained which can not be increased much further surprisingly, by additional freeze-thaw cycles. Particularly suitable for the encapsulation NMR contrast agents here are Gd-DTPA, Gd-EOB-DTPA, Gd-BOPTA, Gd-DOTA, Mn-DPDP and Gadobutrol (US-A 4,957,939, US-A 5,021,236 and Schuhmann Giampieri, G., Inv. Radiol. 28, (1993) in press).

Alternatively, suitable water-soluble substances can be encapsulated with so-called active ioading techniques (remote loading). For this purpose, drug-free liposomes, for example, first produced by the high-pressure extrusion technique, then, for example, be loaded over a pH gradient, with the substance to be encapsulated (Cullis, PR, Mayer, L D., Bally, MB, Madden, TD, Hope, MJ , Adv. Drug Delivery Rev. 3, 267-282 (1989)).

For the encapsulation of lipophilic substances in the novel process of the corresponding active substance by dissolving or dispersing in the lipid pre-dispersion and by subsequent stirring may be encapsulated in a final liposome suspension. For such drugs it may also be modified

9 act SUBSTITUTE SHEET drug molecules (amphiphiles) that can act by appropriate chemical modification directly as a liposome membrane constituents. Consistent with the previously existing liposome preparation methods can be expected from a quantitative encapsulation of the respective component for lipophilic drugs as long as a critical drug / lipid ratio is not exceeded. In this respect, the inventive method also proves to be particularly suitable, because by the processability extremely high lipid concentrations (> 400 mg / ml) and extremely high levels of lipophilic drugs may be dispersed.

The method according to the invention is distinguished from the previously described production methods by a very good reproducibility of the liposomes are some produced from. As can be detected in the multiple production of contrast medium-containing liposomes under identical conditions, for example, that the liposomes produced have only slight variations in their characteristics (especially including, size and size distribution). This reproducibility of the process is not adversely affected by the enlargement of the production scale.

The inventive process is also particularly suitable for carrying out under aseptic conditions. This is significant especially in such cases where the desired liposomes can be subjected because of their size no terminal sterile filtration (0.2 micron). For aseptic manufacturing sterilized, depyrogenated devices and sterile and pyrogen starting materials are to be used and it is to work in clean rooms of the respective cleanroom classes. In all other cases (that is, last extrusion less than / equal to 0.6 microns) can usually sterilized by filtration (eg, 0.2 microns) are the final product. Moreover, the method of the invention offers the possibility, by extrusion using filters of suitable pore size (less than / equal to 0.6 microns) to effect removal of germs from the beginning, whereby a subsequent sterile filtration could be omitted.

The inventive method is also suitable especially for the production of storage-stable liposomes. In the case of storage of iopromide-containing liposomes in which the unencapsulated lopromidanteil is not separated, no decrease of the pH value and the inclusion as well as no change in the average diameter can be determined as, for example, after three months of storage in the refrigerator.

10 SUBSTITUTE SHEET with regard to the preparation of emulsions, the inventive method for the first time offers the possibility of continuous production of large quantities of emulsion with reproducible properties. Essentially, the advantages (liposome preparation) of the high-pressure extrusion process of the invention listed above come into play even with the emulsion preparation. The use of filter extrusion in this area previously described, which was only opened by the inventive high-pressure extrusion method, enables the flexible production of emulsions over a wide size range (100 nm - 20 microns average diameter of the dispersed phase) without major expenditure on apparatus. The method is also characterized in this application by the processability of large volumes of internal phase out, and in most cases also a direct manufacture is possible (without pre-dispersion).

Depending on the intended application can be by this process Zwei¬ or multiphase emulsions (for example W / O, O / W, W / O / W or O / W / O) can be prepared. can be used, for example, vegetable oils such as soybean, castor, safflower or olive oil as the oil phase. Suitable emulsifiers are, for example, egg and soy lecithin or pure Phospholipe from such fractions. Further, nonionic surfactants such as higher fatty alcohols, sorbitan fatty acid esters or polyethylene glycol ethers and esters can be used, for example. The water phase may contain pure water (or pure pi.) And aqueous solutions of various buffers or salts (for example NaCl, KCl) are made and also additives such as glycerol. Furthermore, emulsions may additionally contain sugars such as glucose and xylitol, and other salts such Natriumdihydrogenphospnat, magnesium chloride or zinc acetate for parenteral nutrition. Furthermore, fats, such as medium-chain triglycerides in the emulsion may be present.

Furthermore, can be those described in the literature, incorporated analogous in one or both phases are dissolved or drugs prior to preparation of the emulsion or suspended after the completion of the emulsion preparation. The corresponding hydrophilic or lipophilic active ingredients can, for example, the above (liposome preparation) belong to classes of substances listed.

11 ERSATΣB The following examples serve to further illustrate the apparatus and method of the present invention.

The abbreviations used in this case are as follows:

Chol: cholesterol, powdered cholesterol, E. Merck, Darmstadt

DCP: dicetyl phosphate, Sigma, St. Louis, MO, USA

EPC: egg phosphatidylcholine, lipid E ​​100, Lipoid KG, Ludwigshafen

EPS: Eiphosphatidylserin, lipid EPS, Lipoid KG

PCS: Pnotonenkorrelationsspektroskopie- method for measuring

Particle sizes below 1 micron

SPA: Sojaphosphatidsäure, lipid SPA, Lipoid KG

SPC: soy phosphatidylcholine, Lipoid S 100, Lipoid KG

SPE: soy phosphatidylethanolamine, lipid SPE, Lipoid KG

SPG: Sojaphosphatidylglycerol, lipid SPG, Lipoid KG

SS: stearic acid, Fluka, CH-Buchs

A.) embodiments concerning the inventive apparatus

Example A 1:

The device is a schematically depicted in Figure 1 continuously operating high-pressure extrusion apparatus.

It consists of a temperature-controlled storage vessel (1) which is connected via a pipe connection with a pneumatic piston pressure air pump (2) having a Umspannfaktor of about 250th The piston pressure air pump is operated by means of nitrogen, the inlet pressure is adjusted via an inlet valve (3). From the high-pressure pump via a tube connection, a venting valve (4) and a pressure gauge (5) to a high pressure filter holder (6), which is suitable for holding membrane filter discs with a diameter of 47 mm. Exiting the holder Filters dispersion is discharged via a hose connection (7) which is used optionally for product withdrawal or recirculation of product in the storage vessel (1).

Example A 2:

This device shown schematically in Figure 2 is also a continuously operating high-pressure extrusion apparatus.

It differs from the embodiment shown in Figure 1 apparatus by the fact that still a Metalltassenvorfilter (6) is installed with a pore diameter of 35 microns, for example, behind the pressure gauge (5).

A further difference to the method described in Figure 1 apparatus is that the from the filter holder (7) emerging hose connection to a

12

SUBSTITUTE SHEET dual chamber storage vessel (1) leads. The outlet of the upper of the two vessels (1a) is a three-way valve (1c) is provided which allows therein to remove or located dispersion wholly or partly over the lower vessel (1b) supplying RETRY the high-pressure extrusion process.

B.) embodiments concerning the inventive method

Preliminary remarks: In the following embodiments of the mid vesicle diameter by PCS (. Submicron particle sizer model autodilute 370, Nicomp Instr Fa Corp., Goleta, CA) is determined.

Example B 1 Preparation of a liposome suspension containing 50 mg of SPC / ml

5 g SPC are dissolved at 50 ° C on a rotary evaporator in ethanol and connect the film evaporated.

The film obtained is treated with 100 ml 20 mM Tris-HCl buffer (pH = 7.5) and NAC 15 minutes of swelling replaced by at least 2 minutes shaking by hand. Di preliminary dispersion thus obtained with the inventive apparatus at a working pressure of between 3 and 10 MPa respectively 5 times through 2 polycarbonate membranes of decreasing pore size (5.0, 1.0, 0.4, 0.2, 0.1, 0.05 to 0:03 micron) filtered sequentially. The liposome suspension obtained is slightly opalescent and the liposomes have an average diameter of 64 nm.

Example B 2: Preparation of a liposome suspension containing 200 mg of SPC / ml

Preparation as in example B 1, but using 20 g of SPC in the film formation.

The liposome suspension obtained is slightly opalescent and the liposomes have an average diameter of 73 nm.

Example B 3: Preparation of a liposome suspension of 400 mg SPC / ml

Preparation as in example B 1, but using 40 g of SPC in the film formation.

The liposome suspension obtained is of gel-like consistency and the liposomes have an average diameter of 74 nm.

13 ERSATΣBLATT Example B 4: Preparation of a liposome suspension containing 50 mg of SPC / Chol / SPG (molar ratio 6: 3: 1) per ml

Preparation as in example B 1, but using 5 g of the lipid mixture to form a film. The liposome suspension obtained is highly transparent to slightly opalescent and the liposomes have an average diameter of 72 nm.

Example B 5: Preparation of a liposome suspension having a reduced number of extrusion steps

Manufacturing and composition as in Example B 4, however, reduction in the extrusion steps to 0.4, 0.1 and 0:03 microns. The liposome suspension obtained is highly transparent to slightly opalescent and the liposomes have an average diameter of 68 nm.

Example B 6 - B 18: Use of different lipids and lipid mixtures

Placebo liposomes with different lipid compositions are produced as described below:

-The manufacture of a lipid film is carried out by rotary evaporation of an organic lipid solution (ethanol, methanol or chloroform / ethanol - according to

Solubility) at elevated temperature (eg 50 ° C).

-The lipid film with the buffer solution above the phase transition temperature of the lipid mixture used is dispersed (swelling time at least 15 min, shaking by hand - min. 2 min.)

-The sequential extrusion of the predispersion (MLV) via filter Descending

Pore ​​size (5.0, 1, 0, 0.4, 0.2, 0.1, 0.05 and 0.03 microns, where appropriate - depending 5

Filter passages - optionally at elevated temperature).

In these examples, (B 6 - B 18) are each two superimposed polycarbonate filter per filter size is used, with the last extrusion is carried out through 0.05 micron filters. After completion of the extrusion, the Liposomen¬ suspensions are sterilized by filtration (cellulose acetate membrane, 0.2 micron). The lipid concentration employed is from 50 mg / ml. There are approaches 100 ml in buffer (20 mM Tris (hydroxymethyl) aminomethane, pH 7.5, hereinafter referred to as Tris-buffer) was prepared.

14 SUBSTITUTE SHEET Table 1: Average diameter hochdruckextrudierter liposomes of different lipid composition (Examples B 6 - B 18)

Example B 19 - B 22: approaches with different lipid concentrations

There are approaches of pure SPC and Tris buffer containing the lipid concentrations 50 made 100, 200 and 400 mg / ml as described in Example B 6- B 18. The final stage of extrusion was carried out at a pore size of 0.03 microns. The values ​​obtained are listed in Table 2 below.

Table 2: liposome size as a function of the used lipid concentration (Examples B 19 - B 22)

15 SUBSTITUTE SHEET Example B 23 - B 29: Influence of the resulting Vesikeldurchmesse by the pore size of the filters used

It can be as prepared in Example B 6- 18 B and characterized, but with the modification that the pore size of the last extrusion step is varied in each run approaches. The last pore sizes are 5.0, 1, 0, 0.4, 0.2, 0.1, 0.05 and 0.03 microns. (3: 1: 6) as a lipid, a mixture of SPC, Chol and SPG is used in Tris-poufs. The results are summarized in Table 3 below.

Table 3: vesicle diameter, depending on the filter pore size (Examples B 23 - B 29)

Example B 30 - B 33: Influence of the number passages on the average vesicle diameter

There are four approaches described under Example B 6 - B 18 described, but each having a different number of passages (1, 3, 5 and 10) is formed on each extrusion step and characterized. (3: 6: 1) in Tris buffer, a mixture of SPC, Chol and SPG is used as lipid. All mixtures are subjected to a 3-stage extrusion process through membranes with 0.4, 0.1, and 0.03 micron pore size. The results are shown in Table 4 below.

Table 4: Effect of passage number (Examples B 30 - B 33)

16 ERSATΣBLÄTT Example B 34 Preparation of a liposome suspension previously without film formation (direct dispersion)

It is a 100-ml batch of SPC: Chol: SPG (6: 3: 1) prepared in Tris buffer with a lipid concentration of 50 mg / ml. Without film formation di lipids are weighed directly into a 100 ml graduated cylinder and hot at 70 ° C was added Tris Puffer. After swelling (30 min), they are treated with an Ultraturrax 30 ml with 13,500 U / min at the same temperature and then dispersed as unte Example B 6 - B 18 described extruded. The final product has a mean diameter of 60 nm with a variation coefficient of 25%.

Example B 35: Extrusion using a filter pore size (0.1 micron)

It is a 100-ml batch of EPC in Tris buffer with a Lipidkonzentratio of 100 mg / ml. Without film formation, the lipid is weighed directly into a 100 ml graduated cylinder and at room temperature with Tris buffer was added After swelling (15 min) the mixture is homogenized with an Ultraturrax for 10 min at 1350 U / min at the same temperature dispersed, and then every 10 times extruded over zwe superimposed 0.1 micron polycarbonate filter. The final product has an average diameter of about 120 nm at a coefficient of variation of 32%.

Example B 36 Preparation of a bulk approach (1 I liposome suspension) mi high flow

It is a 1000 ml great approach of SPC in Tris buffer with a Lipidkonzentratio of 100 mg / ml. Without filming the lipid is directly into a

weighed 1000 ml graduated cylinder and admixed at room temperature with Tris-buffer.

After swelling (15 min) the mixture is homogenized with an Ultraturrax for 10 min at 1350

U / min dispersed at the same temperature, and then 10 times each sequentially practice two superimposed polycarbonate filters (1.0 to 0.2 and 0.1 microns) extruded.

The flow rate in this case is independent of the pore size of the used

Membranes about 500 ml / min.

The obtained after 10 passages over the last combination of filters (0.1 micron)

Liposomes have an average diameter of about 110 nm at a

Coefficient of variation of 30%.

17 ERSATZBLÄTT Example B 37 Preparation of a batch of high lipid concentration (500 mg / ml)

It is a 100-ml batch of SPC in Tris buffer with a lipid concentration of 500 mg / ml. Without film formation, the lipid is weighed directly into a 100 ml graduated cylinder and admixed at room temperature with Tris-buffer. After swelling (30 min) the mixture is homogenized with an Ultraturrax for 10 min with 13500 U / min at the same temperature dispersed with a gel-like consistency is obtained. This gel is then 2 times each sequentially over two superimposed polycarbonate filters (1 0 - 0.2 and 0.1 microns) extruded without the membranes clogged.

After 2 passes through the last filter combination (0.1 microns), liposomes (gel) obtained have an average diameter of about 180 nm at a coefficient of variation of 41%.

Example B 38 Preparation of an approach using polytetrafluoroethylene (PTFE) filters

It is a 100-ml batch of SPC in Tris buffer with a lipid concentration of 100 mg / ml. Without film formation, the lipid is weighed directly into a 100 ml graduated cylinder and admixed at room temperature with Tris-buffer. After swelling (15 min) the mixture is dispersed using an Ultraturrax for 10 min at the same temperature with 13500 U / min. Subsequently, this pre-dispersion is 10 times each sequentially over two superposed PTFE-filter (5.0 to 1.2 and 0.2 microns) extruded.

After 10 passages over the last filter combination (0.2 microns) obtained liposomes have an average diameter of about 210 nm at a coefficient of variation of approximately 30%.

Example B 39 Preparation of an approach using a metal (cups) (5 micron) filter

It is a 1000 ml great approach of SPC in Tris buffer with a lipid concentration of 100 mg / ml. Without film formation, the lipid is weighed directly into a 1000 mL graduated cylinder and admixed at room temperature with Tris-buffer. After swelling (15 min) the mixture is homogenized with an Ultraturrax for 10 min with 13500 U / min dispersed at the same temperature and then extruded 10 times each over a metal (mugs) filter with a nominal pore size of 5 microns. The liposomes obtained after 10 passages have a mean diameter of about 1, 4 .mu.m with a coefficient of variation of approximately 80%.

18 SUBSTITUTE SHEET Example B 40 Preparation of niosomes

It is prepared in Tris buffer, a 100 ml large scale with 4 g VolpoN3 (polyoxyethylene glycol Iaurylalkohol) and 1 g of cholesterol. Without film formation, the lipids are weighed directly into a 100 ml graduated cylinder and admixed at RT with Tris-buffer. After swelling (15 min), they are treated with an Ultraturrax for 10 min with 13500 U / min at the same temperature and then dispersed sequentially 5 times in each case two superimposed polycarbonate filters of decreasing pore size (5.0 to 0.2 and 0.05 microns) extruded , The final product has an average diameter of 53 nm with a variation coefficient of 33%.

Example B 41 - B 44: inclusion of iopromide by using various production methods

100 ml of liposome suspensions prepared B 18 described which contain the water-soluble, non-ionic X-ray contrast agent iopromide - are as in Example B. 6 The iodine concentration in the final product is 100 mg / g, the lipid concentration 160 mg / g. The lipids SPC, Chol and SPG at a molar ratio (6: 3: 1). As the starting solution with Tris buffer diluted Ultravist 370 ® is used. The pore size of the last extrusion step is 0.1 microns. The production methods differ as follows:

B 41. A method as in Example B 6 described, at room temperature (RT) extruded.

B 42. A method as described in Example B 41 described extruded at 70 ° C.

B 43. A method as in Example B 6 described after extrusion by

0.4 micron pore size, however, is subjected to the extension 3 freeze-thaw cycles (freeze-thaw). Dry ice is frozen in glass vials in methanol at -70 to -80 ° C, thawed in a water bath at + 70 ° C is extruded at room temperature.

B 44. The method as described under B 43 described, but extrusion at 70 ° C.

For characterization of the prepared liposomes of the inclusion is determined by equilibrium dialysis with photometric evaluation as well as the average vesicle diameter with PCS. The mean values ​​and coefficients of variation of the results from three approaches are summarized in Table 5 below.

19 SUBSTITUTE SHEET Table 5: Properties iopromide-containing liposomes

Example B 45 - B 49: lopromideinschluß and vesicle size depending vo of the pore size of the final extrusion step

There are approaches such as under Example B 43 prepared and characterized, however, mi, except that the pore size of the last extrusion step is varied at each Ansat. The last pore sizes are 1.0, 0.4, 0.2, 0.1 and 0.05 microns. Di freeze-thaw cycles are performed after extrusion through 5.0 microns. Di lipid concentration is 150 mg / ml. The mean values ​​and coefficients of variation de results of three approaches are summarized in Table 6 below.

Table 6: Properties iopromide-containing liposomes as a function of pore size

Example B 50 - B 53: lopromideinschluß and vesicle size depending on the lipid concentration

There are approaches such as under Example B 43 prepared and characterized, but with the modification that different lipid concentrations (50, 100, 150 and 160 mg / ml) are used. The mean values ​​and coefficients of variation of the results from three approaches are summarized in Table 7 below.

20

ERSATZBLAT Table 7: Properties iopromide-containing liposomes as a function of the lipid concentration

Example B 54: Three-month stability of lopromidliposomen

To assess the stability of lopromidliposomen a 3-fold mixture after 3 months' storage in the refrigerator in terms of pH, of the inclusion and the vesicle size is examined. The stored samples of unencapsulated lopromidanteil is not removed prior to storage, ie the extruded liposomes can be stored directly.

Table 8 below shows the properties of the corresponding liposomes to the respective time points.

Table 8: Stability of lopromidliposomen

Example B 55 B 57: entrapment of Gd-DTPA using various manufacturing methods

Are as described under Example B 6 - B 18 described 100 ml of liposome suspensions prepared containing the water soluble ionic MRI contrast agent Gadopentetsäure- dimeglumine salt (hereinafter referred to only Gd-DTPA) included. The Gd concentration in the final product is 180 .mu.mol / g, the lipid concentration of 150 mg / g. When lipids are SPC and Chol in the molar ratio (7: 3). As a starting solution with

21

SUBSTITUTE SHEET water 1: 1 diluted Magnevist ® used. The pore size of the last extrusion step is 0.1 microns. The production methods differ as follows:

B 55. A method as in Example B 6 describes extruded at room temperature.

B 56. A method as in Example B 6 describes extruded at 70 ° C.

B 57. A method as in Example B 6 described, after extrusion through 0.4 micron pore size, the mixture is, however, subjected to 3 freeze-thaw cycles (freeze-thaw). is frozen in glass vials in methanol / dry ice at -70 to -80 ° C, thawed in a water bath at + 70 ° C is extruded at room temperature.

For characterization of the prepared liposomes by the inclusion of equilibrium dialysis and inductively coupled plasma-atomic emission spectrometry (ICP-AES) and the average vesicle diameter with PCS is determined. The mean values ​​and coefficients of variation of the results from three approaches are summarized in Table 9 below.

Table 9: Properties Gd-DTPA-containing liposomes

Example B 58 - B 60: Gd-DTPA-inclusion and vesicle size depending on the pore size of the final extrusion step

It can be as prepared in Example 57 B and characterized, but with the modification that the pore size of the last extrusion step is varied in each run approaches. The last pore sizes are 0.2, 0.1 and 0.05 microns. The mean values ​​and coefficients of variation of the results from three approaches are summarized in Table 10 below.

22 SUBSTITUTE SHEET Table 10: Properties Gd-DTPA-containing liposomes as a function of pore size

Example B 61 - B 63: Gd-DTPA-vesicle size and including a function of the lipid concentration

There are approaches such as under Example B 57 prepared and characterized, but with the modification that different lipid concentrations (100, 150 and 200 mg / ml) are used. The mean values ​​and coefficients of variation of the results from three approaches are summarized in Table 11 below.

Table 11: Properties Gd-DTPA-containing liposomes as a function of the lipid concentration

Example B 64 Preparation of liposomes containing a lipophilic drug (Methyiprednisolonaceponat - MPA)

20 ml placebo liposomes consisting of 50 mg SPC / ml, which were Example 1, but prepared in accordance with 0.2 micron as the final extrusion step, are mixed with 50 mg

MPA and then stirred with a magnetic stirrer at room temperature for 24 h.

The liposomes thus obtained have an average diameter of 189 nm at a coefficient of variation of 30%. The MPA is fully encapsulated in the liposomes.

23 SUBSTITUTE SHEET Example B 65 Preparation of a 5% O / W emulsion

1, 5 g Lipoid E 80 are suspended in about 50 ml of water and then 5 ml bidestiliiertem filtered soybean oil (both Lipoid KG, Ludwigshafen, Germany) were added. After addition of bidestiliiertem water ad 100 ml, the mixture is for 10 minutes with an Ultra-Turrax (13500U / min) pre-dispersed. Subsequently, this predispersion of 10 times over two superimposed polycarbonate filters (0.1 micron) is extruded. The droplet size of the thus obtained homogeneous, yellowish turbid O / W emulsion is about 430 nm.

Example B 66 Preparation of a 5% O / W emulsion using a PTFE filter

1, 5 g Lipoid E 80 are suspended in about 50 ml of water and then 5 ml bidestiliiertem filtered soybean oil (both Lipoid KG, Ludwigshafen, Germany) were added. After addition of bidestiliiertem water ad 100 ml, the mixture is for 10 minutes with an Ultra-Turrax (13500U / min) pre-dispersed. Subsequently, this pre-dispersion is extruded 10 times each on two superposed PTFE-filter (0.2 micron). The droplet size of the thus obtained homogeneous, yellowish turbid O / W emulsion is about 230 nm.

Example B 67 Preparation of a 20% O / W emulsion

1 g Cremophor S9 (BASF) is suspended in about 50 ml of water and then 20 ml bidestiliiertem filtered soybean oil (Lipoid KG, Ludwigshafen, Germany) added thereto. After addition of bidestiliiertem water ad 100 ml, the mixture is 1 min with an Ultra-Turrax (8000U / min) pre-dispersed. Subsequently, this predispersion of 10 times over two superimposed polycarbonate filters (0.1 micron) is extruded. The droplet size of the thus obtained homogeneous, milky-turbid O / W emulsion is about 880 nm.

24 SUBSTITUTE SHEET

Claims

claims:
1. A process for the preparation of liquid disperse systems, characterized gekennzeich¬ net that extruding a pre-dispersion under a high pressure from 6.6 to 250 MPa sequentially 1 to 8 filter stages from 0.01 to 35 microns.
2. A process for the preparation of liquid disperse systems according to claim 1, characterized in that the extruded Vordisperison through filters made of inorganic materials
3. A process for the preparation of liquid disperse systems according to claim 1, characterized in that the extruded Vordisperison through a membrane filter.
4. A process for the preparation of liquid disperse systems according to patent claim 3, characterized in that extruding the dispersions 2 to 4 superimposed membrane filter per filtration step.
5. A process for the production of liquid, disperse systems according to patent claim 4, characterized in that the superposed filters having different pore sizes.
6. A process for the production of liquid, disperse systems according to patent claim 1 to 4, characterized in that the extrusion is carried out continuously.
7. A process for the production of liquid, disperse systems according to patent claim 1 to 6, characterized in that the dispersion is extruded sequentially through filters of decreasing pore size.
8. A process for the production of liquid, disperse systems according to patent claim 1 to 7, characterized gekennzeichent that 1 to 20 filter passages are applied per filtration step.
9. A process for the production of liquid, disperse systems according to patent claim 1 to 8 characterized in that lying in a transition herzustellen¬ the product volumes above 100 ml.
25 ERSATZBL
10. A process for the production of liquid, disperse systems according to claim 1 bis.9 characterized in that the product flows lie above 150 ml per minute.
11. A process for the preparation of liquid disperse systems according to patent claim characterized in that the disperse system is an emulsion from 1 to 10.
12. A process for the production of liquid, disperse systems according to patent claim characterized in that the disperse system is a liposome suspension 1 to 10.
13. A process for the production of liquid, disperse systems according to patent claim 12, characterized in that said X-ray contrast agents.
14. A process for the production of liquid, disperse systems according to patent claim 13, characterized in that this, iopromide as X-ray contrast agent iotrolan or 3-carbamoyl-5- [N- (2-hydroxyethyl) acetamido] -2,4,6- triiodo-benzoic acid - [(1 RS, 2SR) -2,3-dihydroxy-1 -hydroxymethylpropyl] -amide included.
15. A process for the production of liquid, disperse systems according to patent claim 12, characterized in that said NMR contrast agents.
16. A process for the production of liquid, disperse systems according to patent claim 15, characterized in that they contain as NMR contrast agent Gd-DTPA, Gd-EOB or Gadobutrol.
17. A process for the production of liquid, disperse systems according to patent claim 11 and 12, characterized in that the dispersions obtained are sterile.
18. Apparatus for producing liquid, disperse systems characterized by a supply vessel, the outflow line leading to a high pressure pump, which is designed for the construction of working pressures up to 250 MPa, which in turn with a for receiving the filter according to the invention
26 ERSAT certain filter holder, is connected from the product via a discharge line either recycled to the storage vessel and / or is removed.
19. Apparatus for producing liquid, disperse systems according to claim 18, characterized in that the high-pressure pump for the construction of working pressures up to 80 MPa is designed.
20. Apparatus for producing liquid, disperse systems according to claim 18 and 19, characterized in that a pre-filter is between the high pressure pump and filter holder additionally mounted, which is intended to contain filters with an average pore size of 2 to 35 microns.
21. Apparatus for producing liquid, disperse systems according to patent claim 18 to 20, characterized in that it is additionally aus¬ allows even with venting means and / or temperature and pressure gauges.
27 ERSA
EP19930922883 1992-10-16 1993-10-13 Process and device for producing liquid, dispersed systems Ceased EP0665756A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE19924235381 DE4235381A1 (en) 1992-10-16 1992-10-16 Appts. for prodn. of dispersions for cosmetic, pharmaceutical use etc. - uses high pressure extrusion through membrane filters
DE4235381 1992-10-16
DE19934328331 DE4328331A1 (en) 1993-08-18 1993-08-18 Continuous high-pressure extrusion process for the production of liposomes and emulsions
DE4328331 1993-08-18
PCT/DE1993/000997 WO1994008626A1 (en) 1992-10-16 1993-10-13 Process and device for producing liquid, dispersed systems

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