Process and device for the production of liquid, disperse...

Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent

Reexamination Certificate

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C424S009300, C424S009100, C424S450000

Reexamination Certificate

active

06241967

ABSTRACT:

The invention relates to a process and a device for the production of liquid, disperse systems.
In addition to the cosmetics industry, there is a great need for processes and devices for the production of disperse systems, particularly in the pharmaceutical industry. This is especially true because so-called pharmaceutical carrier systems (“drug-delivery systems”), which represent disperse systems (especially solid/liquid or liquid/liquid), were developed in the search for new ways to transport pharmaceuticals. For example, emulsions (liquid/liquid) for parenteral feeding or administration of sparingly water-soluble pharmaceuticals and especially liposome suspensions, which can be used as targeted pharmaceutical carriers, can be cited among these.
Due to the hydrophobic interactions, spontaneously sealed lipid vesicles, which are referred to as liposomes, result after phospholipids are dispersed in water. These are spherical or elliptical hollow bodies with one or more lipid double layers (“bilayers”), which include an aqueous phase. Depending on their size, in this case small unilamellar vesicles ([SUV], with radii of 25 to 50 nm) and large unilamellar vesicles ([LUV], with radii of greater than 50 nm up to 10 &mgr;m) are distinguished (Weiner, N., Martin, F., Riaz, M., Drug Dev. Ind. Pharm. 15, 1523-1554 (1989)).
Further, multilamellar liposomes (multilamellar vesicles [MLV]) are known, in which several concentrically arranged bilayer liposomes as well as multivesicular liposomes (multivesicular vesicles [MVV]) are present, which in turn have vesicular structures in their lumens.
The liposomes are suitable for inclusion of both hydrophilic pharmaceuticals and lipophilic pharmaceuticals, in which the extent and site of the inclusion depend on the physicochemical properties of the pharmaceutical and the lipid composition of the liposomes.
As the most important step, all processes for the production of liposomes comprise the dispersion of the lipid or lipid mixture in an aqueous phase. Based on this, all production processes can be classified according to the three main dispersion principles. In this case, “mechanical dispersion”, “two-phase dispersion,” and “detergent solubilization” are distinguished (New, R. R. C. (Editors), Liposomes: A Practical Approach, Oxford University Press, New York, 1990, p. 33).
In the methods which comprise a “two-phase dispersion,” it is particularly the limited solubility of some lipids in organic solvents as well as the great expense involved in removing the solvents used (such as chloroform, methanol, diethyl ether) to lower the residual solvent concentration to tolerable concentrations (toxicity) that are disadvantageous. The “detergent solubilization methods” exhibit the drawback of the residual detergent content, which can be removed from the preparation only with difficulty.
In the so-called “mechanical dispersion process,” on the other hand, the use of organic solvents or detergents during the dispersion of the lipid in the water phase is unnecessary. Generally, in this case, first a lipid film is formed by rotary evaporation of an organic solution of the lipid or lipid mixture (for example, in chloroform, methanol or diethyl ether). For complete removal of the residual solvent, freeze-drying under high vacuum for 12-24 hours is then often done. By subsequent addition of an aqueous phase and simple shaking (the so-called hand-shaken method according to Bangham, Bangham, A. D.; Standish, M. M.; Watkins, J. C., J. Mol. Biol. 13, 238-252 (1965)), an MLV suspension is obtained that is extremely heterogeneous with respect to liposome size and lamellarity.
For further processing of corresponding MLV suspensions, there are several processes in which SUV or LUV are generally obtained.
The oldest and most popular method for the production of SUV is the so-called “sonication method” (ultrasonic irradiation method). In this case, MLV are crushed by ultrasonic irradiation (ultrasound wand or ultrasound bath). The liposomes thus obtained have an average diameter of 20 to 60 nm and an inclusion capacity of less than 1%. The drawbacks of these methods are particularly the high heat input, which can lead to decomposition of the lipid or of the pharmaceutical, as well as the difficulty in handling even larger sample amounts in a reproducible manner. With the use of the ultrasound wand, moreover, there exists the drawback of contamination of the samples with titanium fragments, as well as the formation of an aerosol (see the already cited publication by R. R. C. New).
Another method for the production of small unilamellar or oligolamellar liposomes is the “French press method,” whose name comes from the high-pressure apparatus (French press) used here. This unit consists of an electric, hydraulic press and a high-pressure cell, which has a maximum capacity of 4 or 40 ml depending on design (New, R. R. C.; see above). The disadvantage to this method is, in addition to the limited volume of the dispersions to be processed, particularly the fact that the finished liposome suspensions are generally contaminated with abrasion residues from the pressure chamber or a portion of uncrushed MNLV, as well as the difficulty in controlling the rise in temperature in the chamber.
So-called high-pressure homogenizers also recently were introduced in liposome technology. Thus, the production of SUV with a minimum-quantity ring slot homogenizer from MLV or lipid dispersions (without prior film formation) has been described (Brandl, M.; Bachmann, D.; Drechsler, M.; Bauer, K. H., Drug Dev. Ind. Pharm. 16, 2167-2191 (1990)).
This process allows the reproducible production of small amounts of homogeneous SUV dispersions with very small average diameters (<50 nm). But particularly the occurrence of equipment wear and tear (ring gap, etc.), as well as the difficulty in controlling the product temperature, are drawbacks in this regard.
In addition to the previously described processes for the production of SUV, there are also several mechanical processes for the production of LUV which also work with use of predispersions (liposomes or lipids).
The oldest of these processes is the so-called “extrusion method.” In this process, an MLV dispersion is filtered by hand sequentially through filter holders with polycarbonate filters of decreasing pore size (3.0, 1.0, 0.8, 0.6, 0.4 and 0.2 &mgr;m) at pressures up to 0.35 Mpa (Olson, F.; Hunt, C. A.; Szoka, F. C.; Vail, W. J.; Papahadjopoulos, D., Biochim. Biophys. Acta 557, 9-23 (1979)).
The so-called “LUVET method” (large unilamellar vesicles by extrusion) represents a further development of these extrusion methods (WO86/00238, 1986 and Hope, M. J.; Bally, M. B.; Webb, G.; Cullis, P. R.; Biochim. Biophys. Acta 812, 55-65 (1985)). With this discontinuous process, a coarse lipid or liposome dispersion is repeatedly extruded at pressures of less than 3.5 MPa with two polycarbonate filters, placed one above the another, with pore sizes of less than or equal to 100 nm. In this case, unilamellar liposomes with a diameter of 60 to 100 nm and inclusion volumes of 1 to 3 l of aqueous phase per mol of lipid are obtained. If the liposome suspension below a lipid concentration of about 200 &mgr;mol per ml is additionally subjected to several freeze-thaw cycles (freezing of the suspension and subsequent thawing—Cullis, P. R.; Mayer, L. D.; Bally, M. B.; Madden, T. D.; Hope, M. J., Adv. Drug Delivery Rev. 3, 267-282 (1989)), an increase in inclusion efficiency can be noted. With the use of pressures of up to 5.5 MPa, very high lipid concentrations have been processed. In the pressure filter devices used in this technology, the predispersion is added to an infusion chamber located directly over the membrane, the pressure vessel is closed, and then the pressure necessary for filtration is built up using compressed air or nitrogen. The filtrate is removed through a drain and then fed back to the infusion chamber again up to 20 times.
Drawbacks to the extrusion method are the discontinuous operating method, the

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