Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-09-21
2003-07-29
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S450000, C424S401000, C426S613000, C426S615000
Reexamination Certificate
active
06599533
ABSTRACT:
This application is a 371 of PCT/EP98/01789 filed on Mar. 26, 1998 which claims foreign priority to German Applications 19713093.3 filed on Mar. 27, 1997 and 19713094.1 filed Mar. 27, 1997.
The subject of this invention are homogeneous formulations containing glycerophospholipids and polar or lipophilic substances, and a method of producing a these formulations.
Glycerophospholipids play an important physiological role as building blocks for membranes, especially during compartmentation in biological systems. They are accordingly ubiquitous in animal, plant and microbial forms of life.
Chemically speaking, natural glycerophospholipids consist of glycerol which is esterified in the C
1
and C
2
positions with fatty acids and carries a phosphatide ester in the C
3
position. From the point of view of quantity, by far the most important natural glycerophospholipids are the phosphatidyl derivatives phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol and phosphatidic acid. In certain cell systems, however, there are, in addition, high concentrations of other phospholipids, eg, plasmalogens, cardiolipins or sphingomyelins.
In principle, it is possible to synthesise glycerophospholipids in vitro by means of chemical and/or enzymatic processes. The structure of the products obtained can correspond to that of natural glycerophospholipids, but can also be “synthetic”. However, at the present time, biological sources still take precedence in industrial-scale production because they are readily available. This applies especially to plant lecithins, eg, from soybeans, rape or sunflower seed. These lecithins are obtained as a mixture of various phospholipid classes, so-called “raw lecithin”, in the refining process during the production of cooking oils. The most important animal source of glycerophospholipids is the yolk from hens' eggs, which is characterized by a high phosphatidyl choline content. There are various methods available, eg, solvent extraction, with which it is possible to increase the proportion of certain glycerophospholipid classes in the naturally occurring mixtures, and/or, usually with the help of chromatographic separation methods, to obtain them in uniform form; here too, phosphatidyl choline is particularly important.
By means of chemical and/or enzymatic processes, eg, by means of hydrolysis, hydroxylation or hydrogenation, naturally occurring glycerophospholipids can be modified such that their surface-active properties, in particular, are changed.
The main reason why surface-active glycerophospholipids are used technologically is because of their emulsifying effect, which is exploited specifically to stabilise emulsions or suspensions, eg, traditionally in the food-processing sector, in industry, and in the pharmaceuticals sector. In addition, glycerophospholipids can also be used physiologically, because in vivo they fulfil important functions, especially as building blocks for membranes in biological cells. By virtue of this fact, and because they are toxically innocuous, natural glycerophospholipids in particular, especially phosphatidyl cholines and cephalins, are used for products or formulations which can be supplied directly or indirectly to humans. Of particular interest is their use in food and in pharmaceutical products. It is also known that the resorption, pharmacokinetics and/or the pharmacological effect of active ingredients used in drugs can be varied by formulating them with glycerophospholipids.
In the preparation of emulsions and dispersions, eg, in the formulation of pharmaceutical active ingredients, but also in other technical areas, it is often desirable for the active ingredients to be dispersed as finely and homogeneously as possible. This necessitates, eg, a small particle size. Formulations and methods of producing them with which the active ingredient can be more finely distributed by way of the formulation than was possible so far are accordingly of great interest and can be of far-reaching importance.
According to the prior art, there are three main methods of formulating glycerophospholipids with polar or lipophilic substances:
(1) formulation of the (dissolved) polar substances or (liquid or dissolved) lipophilic substances in membrane-forming glycerophospholipid vesicles or liposomes (“micellar system”),
(2) formulation by means of incorporating fine (micro-crystalline) particles of the solid polar or lipophilic substance in glycerophospholipids (“micro-crystalline system”), and
(3) formulation by means of binding the polar or lipophilic substance chemically to glycerophospholipids (chemical-bond system).
In “micellar-system” formulations, the polar substances are dissolved in polar solvents, usually water, and are surrounded by a single- or multi-layer membrane, eg, a bilayer membrane, consisting of surface-active glycerophospholipids. The lipophilic substances, in liquid form or dissolved in suitable solvents, are encapusulated in a similar way. A recent survey on this formulation technique is contained in H. Hauser, Phospholipid Vesicles in Cevc. G. (ed.), Phospholipid Handbook, Marcel Dekker, New York, 1993, pp. 603-637. Building up a micellar bilayer membrane for the formulation of polar substances in water or of lipophilic substances is, however, not unproblematic, and certain esters of phosphoric acid, eg, in the form of glycerophospholipids such as phosphatidyl choline, may have to be present in the membranes in order to impart the required stability.
The inclusion rates for the active ingredients to be formulated are often low, so that large active-ingredient losses have to be allowed for during production of the formulation. In addition, sterol derivatives such as cholesterol are often needed to stabilise the membrane. Attempts have also been made to stabilise the membrane by forming an adduct—by means of a chemical bond—between cholesterol and the substance to be formulated (eg, J. L. Murtha et al., J. Pharm. Sci 83 (9), 1222-8, 1994). Another approach has been to produce liposomal formulations using supercritical carbon dioxide, rendering the use of large volumes of organic solvent unnecessary (Frederiksen L. et al, J. Pharmaceutical. Sci. 86, 921-8, 1997). Formulations of active ingredients, eg, through use of the liposome technique, have resulted in great progress, eg, in many therapies used in modern medicine; however, there are two main disadvantages, eg, in parenteral applications: for one, liposomes—as artificial micelles—have only a limited lifetime in vivo because lipid exchange reactions, in particular, can take place at membranes and thus destabilise the membranous vesicle or liposome, or even cause it to disintegrate, before it reaches the actual place of intended therapy. For another, especially in the case of larger micelles, the mononuclear phagocyte system becomes active, and leads to undesired immunological side reactions. For physical reasons, it is impossible to reduce the size of vesicular liposomes arbitrarily and thus to avoid the immune response, because the surface of the membrane, depending on its composition, will tear open as from a certain micelle size.
In formulations where polar or lipophilic substances are incorporated in micro-crystalline form in glycerophospholipids, the problem likewise arises that according to prior art, the size of the microcrystals cannot be arbitrarily reduced. If a solvent system is used, for example, in which both the polar/lipophilic substances and the glycerophospholipids are dissolved, and this solution is subjected, eg, to spray drying, the solubility limits of the substances and the glycerophospholipids are reached at different solvent concentrations during removal of the solvent, and a “microcrystalline formulation” is obtained. As the time needed to remove the solvent approaches zero, the size of the particles could, in theory, be reduced still further, but this is technically unfeasible.
The patent specification EP-B-O 493 578 describes the use of supercritical carbon dioxide to try and overcome these problems.
Graefe Jürgen
Heidlas Jürgen
Wiesmüller Johann
Zirzow Karl-Heinz
Degussa - AG
Fulbright & Jaworski L.L.P.
Sharareh Shahnam
Travers Russell
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