Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-10-01
2004-01-13
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S450000, C514S937000, C514S938000
Reexamination Certificate
active
06676956
ABSTRACT:
This application is a 371 of PCT/EP/99/10106 filed Dec. 18, 1999.
DESCRIPTION
The invention relates to an oil-in-water emulsion exhibiting a protective action against damages to human organs resulting from peroxidation, containing &agr;-tocopherol, the main component of vitamin E, as an active ingredient whose content considerably exceeds that of vitamin E, as usually contained in multi-vitamin solutions. This emulsion is especially directed against peroxidation which occurs when organs are exposed to a deficient blood supply, or even a complete cessation of the blood supply, followed by a renewed complete blood supply. This condition can occur with any type of closure of a blood vessel serving to supply an organ, with the renewed blood supply mostly being restored by surgical intervention. However, it is also deliberately produced in the course of operations on organs, such as the kidneys, liver, intestines or heart, by clamping the blood vessel carrying the blood supply in order to be able to carry out a surgical intervention on the organ. Once the operation is finished, the blood supply is then restored. This solution can likewise be used successfully during the course of an organ transplantation. As a rule this emulsion is applied exclusively intravenously, especially as an infusion. However it is also suitable for use as an additive to organ preservation solutions in the course of organ transplantations.
Vitamin E is an essential, fat-soluble vitamin that can effectively combat peroxyl radicals of lipids even in relatively low concentrations. It is moreover highly effective in the protection of cell membranes against peroxidation, it being also assumed in this case, that this effectiveness is also based on protection against lipid oxidation, i.e. double bonds of lipids present in the cell membrane are protected against destruction by peroxidation, the cell membrane remaining intact in its structure and strength. &agr;-Tocopherol is the main component of vitamin E. The term vitamin E also covers the other tocopherols such as &bgr;, &ggr;, and &dgr;-tocopherols, and further tocol and tocotrienol derivatives. The &agr;-tocopherol has the formula 2, 5, 7, 8 tetramethyl-2- (4′,8′,12′-trimethyltridecyl)chroman-6-ol, it has 3 chiral centres in the positions 2, 4′ and 8′, and there are therefore 8 stereoisomeric forms (RRR, SSS, RRS, SSR, RSR, SRS, RSS and SRR). Only the RRR form occurs in nature, and this is also the most strongly effective. In addition there are the other stereoisomers which can be obtained synthetically, like the racemate form, all-rac-&agr;-tocopherol, which is a mixture of equal proportions of all 8 stereoisomers. It is usual to relate the effectiveness of all the stereoisomeric forms, as well as that of the all-rac form to the effectiveness of the RRR form. Thus for example, the effectiveness of 1 g of the all-rac-&agr;-tocopherol corresponds to that of 0.74 g of the RRR-stereoisomer, and that of 1 g of the SRR-stereoisomer to that of 0.31 g RRR-&agr;-tocopherol. The anti-oxidant effect is ascribed to the phenolic OH group on the chroman ring.
It is usual to administer vitamin E perorally in multi-vitamin preparations; vitamin E is also frequently contained in the form of esters of the a-tocopherol in multi-vitamin solutions which can be administered parenterally or also intravenously, so that any vitamin E deficiency can be eliminated or prevented.
WO 97/03651 has also already described oil-in-water emulsions with a content of vitamin E in the oil phase, in which the vitamin E is the only vitamin present, but does not represent the active ingredient of the oil-in-water emulsion. Active ingredients are rather substances of low solubility such as, preferably, itraconazole, an antimycotic or the anti-cancer drug Taxol, and/or its derivatives, whose solubility in the lipid phase is understood to be improved by the addition of vitamin E, especially &agr;-tocopherols. The aim is to achieve the greatest possible vitamin E content in the lipid phase, also including emulsions containing vitamin E as the only component of the lipid phase. These requirements are primarily fulfilled by the choice of synthetic emulsifiers of the copolymer class (poloxamers and/or pluronic types). In this case, with a 10 and 20% lipids content in the emulsion, these lipids consisting of a mixture of soya oil and vitamin E in the weight ratio of 1:1, with a content of poloxamer 407/pluronic 127 in a quantity of 2 and/or 4% stable emulsions, which, especially in the case of an emulsifier content of 4% satisfy the solubility for Taxol. These synthetic emulsifiers could also be used for the production of oil-free vitamin E emulsions. On the other hand, if phospholipids, especially egg lecithin, are used as emulsifiers, oil-vitamin E ratios of 1:1 are not achieved in an emulsion which is sufficiently stable, and the production of vitamin E as emulsions containing a single lipid substance is not possible according to this publication, see example 7, according to which, when egg lecithin is used as an emulsifier with a vitamin E content of 10 or 50% and egg lecithin contents of 0.4 to 4%, no stable emulsions could be obtained. Examples in which stable emulsions were obtained with phospholipids, have, in all cases when the soya phosphatide epicuron is used, an oil content of 30% and a vitamin E content of 5%, the soya phosphatide content amounting to 4%.
The only example in which egg lecithin was used as an emulsifier is example 4, where, converted to 1000 ml, the soya oil content in the emulsion amounted to 330 ml, that of vitamin E amounted to 80 g and that of egg lecithin 66 g. The i.v. administration of such emulsions to susceptible patients is not possible.
A special problem is damage resulting from peroxidation occurring in the case of ischaemia and subsequent reperfusion, because these generally concern the most seriously ill patients, e.g. those undergoing serious operations on the liver, heart or kidneys, or even organ transplantations. The opinion has arisen that this damage can be mitigated by the administration of vitamin E, if it can be ascribed to lipidperoxidation. Animal experiments have therefore been carried out, e.g. on mice or rats, to see whether this damage can in fact be combated by vitamin E. In many cases, but not always, these experiments showed that peroxidation damage resulting from ischaemia and/or perfusion can be reduced by the administration of vitamin E/&agr;-tocopherol.
Amongst several application possibilities, such as oral or intraperitoneal administration to the experimental animals, intravenous application to experimental animals was also examined. Thus, for example, Ikezawa T., Nishikimi N. and Oba Y., in their work “Lipidperoxides in the mechanism of ischemia/reperfusion injury in skeletal muscle; experimental studies” VASC SURG 1993, 27, 191-201 established that on an ischaemia-reperfusion model, on skeletal muscles of dogs, the administration of 500 mg vitamin E (all-rac-tocopherolacetate, preparation with polyethylene glycol 400), given for a few minutes directly before reperfusion, the ischaemia-reperfusion damage to be expected was reduced. This was also manifested by the fact that the significant increase in serum creatine-phosphokinase, which is regarded as a sign of rhabdomylisis occurring, is suppressed during the reperfusion phase by the administration of &agr;-tocopherol, and also by the fact that the increase in lipid peroxides in the serum, measured as a coloured reaction product (TBARS, thiobarbituric acid reactive substances) of the reaction of the malonodialdehyde (MDA) produced with thiobarbituric acid, was prevented by this administration. Furthermore, in the case of rats which were given the vitamin E orally via a tube, and intravenously via a central vein catheter in each case for 3 days in doses of 1.0 mg/day orally or 0.5 mg/day intravenously, and were then exposed to oxidative stress, it was shown that by means of intravenous administration, a significant concentration of vitamin E in the plasma and ao
Eggenreich Udo
Feichtinger Norbert
Hofer Gerald
Nagel Eckhard
Schaupp Karin
Fresenius Kabi Austria GmbH
Gollamudi Sharmila S
Katten Muchin Zavis & Rosenman
Page Thurman K.
Sira Serge
LandOfFree
Oil-in-water emulsion for protecting human organs against... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Oil-in-water emulsion for protecting human organs against..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oil-in-water emulsion for protecting human organs against... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3230044