Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1996-03-07
2003-12-16
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
Reexamination Certificate
active
06663885
ABSTRACT:
The present invention relates to an aqueous liposome system with the characteristic features of the preamble of claim 1 and a method for the preparation of such a liposome system.
Different use are known for aqueous liposome systems. Such systems may for instance be used in cosmetics or for the preparation of pharmaceutical products. They are characterised by the fact that they contain hollow vesicles, also known as liposomes, which have an inner sphere containing an aqueous phase. Depending on the respective use the aqueous phase in the inner part of the hollow vesicles may contain a pharmaceutically or cosmetically active ingredient in a dissolved, a dispersed or a suspended form. The system described by EP-A 0 315 457 is an example of such a liposome system whereby these liposome systems contain the drug pentamidine in the inner part of the vesicles.
Furthermore aqueous liposome systems are known, which contain in the inner part of the vesicles only the aqueous phase, such liposome systems being called an unloaded liposome system which can, if needed, be loaded subsequently with a pharmaceutically or cosmetically active product.
Both types of the above-described aqueous liposome systems have as a barrier to the outer phase a lipid double membrane.
The liposome systems known from the prior art have a frequent disadvantage, that they show the tendency to form unwanted sediments after a short time.
The object of the subject invention is to provide an aqueous liposome system which comprises besides a non-toxic organic solvent at least one phospholipid, which possesses a particularly high stability and does not lead to unwanted sedimentation.
The inventive aqueous liposome system which comprises optionally besides a non-toxic organic solvent at least one phospholipid, comprises besides said phospholipid constituting the liposome system a further substance, which is not a phospholipid. This further non-phospholipidic substance is a bile acid, a bile acid salt, a bile acid derivative and/or a salt of a bile acid derivative, the mass ratio between said phospholipid and said further non-phospholipidic substance varying between 1:0.001 and 1:0.1.
The inventive liposome system has a number of advantages. So, it could be observed, that the inventive liposome system even at a storage period of several months or years did not show any tendency to form sediments or deposits on the inner walls of the vessels. Furthermore, the inventive liposome system has a high transparency and does not show any opalescence as do the liposome systems known in the art. Due to the lack of sedimentation and deposit formation and the high transparency the inventive liposome system can be inspected quite easily on the presence of foreign particles, since such an inspection may be simply performed by looking through the same.
The above advantageous properties of the inventive liposome system are thought to depend on a synergistic effect brought about by the presence of the small amounts of the further non-phospholipidic substance (a bile acid, a bile acid salt, a bile acid derivative and/or a salt of a bile acid derivative), which is not present in natural phospholipid systems.
Particularly good properties in respect to the before-mentioned advantages are shown by a first embodiment of the inventive aqueous liposome system, in which the mass ratio of the phospholipid to the further non-phospholipidic substance (a bile acid, a bile acid salt, a bile acid derivative and/or a salt of a bile acid derivative) is between 1:0.03 and 1:0.1.
As mentioned before, the inventive phospholipid preparation comprises at least one further non-phospholipidic substance. This concerns in particular a salt, in particular a sodium and/or an ammonium salt, of cholic acid, deoxycholic acid, ursodeoxycholic acid and/or chenodeoxycholic acid but may also be the salt, in particular a sodium and/or an ammonium salt, of a bile acid derivative, preferably glycocholic acid and/or taurocholic acid.
A further particularly suitable embodiment of the inventive liposome system provides, that the inventive liposome system contains as the further non-phospholipidic substance glycocholic acid, a salt of glycocholic acid and/or a derivative of glycocholic acid within the previously mentioned range of mass ratios.
The concentration of the at least one phospholipid varies between 5% by weight and 25% by weight, in particular between 8% by weight and 18% by weight, these concentration values relating to the final liposome system or to a liposome system as is offered commercially. It is obvious, that depending on the respective intended type of treatment or the intended case to be treated, higher as well as lower phospholipid concentrations as the above values are possible.
A particularly high stability and a particularly homogeneous distribution of the liposomes with respect to their diameter is found at another embodiment of the inventive liposome system, when it contains phosphatidylcholine, in particular such a phosphatidylcholine (3-sn-phosphatidylcholine, soya) which is gained from soybean. In particular in cases where the phospholipid in the inventive liposome system constitutes to at least 90% by weight and preferably to at least 95% by weight of phosphatidylcholine, then such a liposome system possesses the advantages which were mentioned previously in even more pronounced form. Additionally, such a special liposome system can with essentially less effort and for that reason in about half of the usual time be reduced in a homogeneous way by extrusion, high pressure split homogenisation or ultrasound treatment to a wanted mean particle diameter of between 30 and 100 nm, in particular of between 35 and 90 nm. Also such a special liposome system which contains mostly unilamellar to bilamellar liposomes of the said dimension, to be filtrated easily, whereby preferably 0.2 &mgr;m filters are being used.
A further advantage of the inventive liposome system is the fact, that it possesses a pH value which varies around neutrality and lies preferably between 6.0 and 8.0 and more preferably between 6.2 and 7.4.
As stated previously, the inventive liposome system comprises mostly unilamellar or bilamellar liposomes with a particle diameter between 30 nm and 100 nm, preferably between 35 nm and 90 nm.
The inventive liposome system can be used for pharmaceutical as well as cosmetic purposes, this use covering the unloaded liposomes as well as such liposome systems loaded with a respective pharmaceutically or cosmetically active ingredient.
If the inventive liposome system was used in the form of an unloaded liposome system without any encapsulated active ingredient, it could be observed that said unloaded system is perfectly suited for the treatment of atherosclerosis, increased blood lipid values as well as the treatment of liver diseases of any type. Said unloaded liposome system comprises preferably besides water and eventually an alcohol between 5% by weight and 20% by weight of a mixture of phosphatidylcholine of the before-mentioned purity and the further non-phospholipidic substance (bile acid, a bile acid salt, a bile acid derivative and/or a salt of a bile acid derivative of the afore-mentioned type) in the mass ratio as mentioned previously. Such a pharmaceutical product is particularly suitable for injection.
As has been mentioned before, the inventive liposome system may contain an encapsulated cosmetic or pharmaceutical active ingredient. It has been observed, that such an encapsulated active ingredient has a greater therapeutic efficacy in particular with respect to its duration, in comparison with conventional application form, like e.g. a tablet, a sugar-coated tablet or the like. This greater efficacy enables as a rule the reduction of the amount of the active ingredient, without this having a negative effect on the therapeutic efficacy. This depot effect may be explained by a regular and long-lasting release of the encapsulated active ingredient from the liposome system. As a result any unwanted side effects do not appear, or at least in a
Dürr Manfred
Hager Jörg-Christian
Löhr Josef-Peter
A. Natterman & Cie GmbH
Finnegan Henderson Farabow Garrett and Dunner, LLP
Kishore Gollamudi S.
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