Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-05-07
2003-05-13
Lovering, Richard D. (Department: 1712)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S757000, C514S824000, C514S832000, C514S833000, C516S076000, C516S929000
Reexamination Certificate
active
06562872
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the field of medical industry and is concerned with a composition of and a process for the preparation of a medicinal form of emulsions of perfluoroorganic compounds (PFOC) with gas-transporting properties, intended, in particular, for intravenous administration when compensating for blood losses and for treating various diseases accompanied by hypoxic or ischemic lesions, and also as contrast and perfusion media.
STATE OF THE ART
Though the range of possible applications of gas-transporting PFOC emulsions keeps on extending, on the whole the application of these preparations is still limited in view of the following factors.
The delivery of oxygen is not sufficiently effective, particularly because of insufficient oxygen capacity of PFOC emulsions compared with whole blood, which makes those engaged in developing PFOC emulsions increase the concentration of gas-transporting components, for example, up to 65 vol. % [European Patent No. 0307087B1, publication dated 08.06.1994]. However, an increase of the PFOC concentration in the emulsion is inevitably accompanied by a sharp increase in the viscosity of the preparations. As a result, emulsions with a high PFOC concentration, in spite of a high absolute oxygen capacity, do not provide sufficiently effective oxygen delivery to the tissues due to the small dynamic oxygen capacity determined by the absolute oxygen capacity/viscosity ratio. When the viscosity of the preparation is high, the compensatory reactions of the cardiovascular system, directed to increasing the minute volume and raising the rheological properties of blood, can provide neither sufficient perfusion of large vessels nor effective circulation, and, consequently, the delivery of oxygen to the tissues is disturbed.
The reactogenicity of PFOC emulsions is relatively high. The reactogenicity is associated, in the first place, with the formation of peroxide radicals in the stabilizing agent [L. E. McCoy, C. A. Berker, T. H. Goodin, M. J. Barnhart, //Scann. Electron. Microscopy, 1984, v. 1, p. 311] which forms an adsorption layer of the PFOC particles, and, in the second place, with the presence of large particles in the emulsion, which are recognized by the immune system of the organism as foreign agents [S. I. Vorob'ev et al., “Comparative study of some perfluorocarbon emulsions”, in: Physiological Activity of Fluorine-containing Compounds (Experiment and Clinic), Pushchino, 1995, pp. 33-41 (in Russian)].
The possibility of manifestation of toxicity of the emulsions, caused by the effect of lipophilic perfluorocarbons rapidly eliminable from the organism, traditionally used for producing gas-transporting blood substitutes, on biological structures, and by possible aggregation and coarsening of emulsion grains in the blood flow. Rapidly eliminable perfluorocarbons easily interact with enzymatic systems and biological membranes, formed elements and proteins of blood, and, as is shown by a number of investigations, Induce an anaphilactogenic reaction and delayed death (in 50-80 days) of large laboratory animals having a low blood flow rate, comparable with that in humans (A. N. Sklifas, V. V. Obraztsov, K. N. Makarov, D. G. Shekhtman, N. I. Kukushkin, “Investigation of the Toxicity Mechanism of Perfluorodecalin Emulsion for Rabbits”, in collected articles: “Perfluorocarbon Active Media for Medicine and Biology. New Aspects of Research”. Pushchino, 1993, pp. 129-135 (in Russian)].
High cost of PFOC emulsion preparations, associated with the necessity of preparing individual PFOCs and high requirements to their purification from admixtures, which makes them difficult of access for users.
Binary PFOC emulsions are known (see, e.g., USSR Patent No. 797546, publ. in Bull. “Otkrytiya, Izobreteniya, . . . ”, No. 2, 15.01.1981, or RF Patent No. 2088217, publ. in Bull. “Izo-breteniya . . . (Zayavki . . . ,)”, No. 24, 27.08.1997), in which, for lowering the toxicity, in addition to rapidly eliminable perfluorocarbons, slowly eliminable substances are contained, for instance, perfluorinated tertiary amines, which possess expressed lipophobic properties and do not interact in any manner with biological objects. For example, it has been shown that the presence in the composition of the emulsions and even long-term acctmulation in organs of slowly eliminable perfluorotributylamine, which is retained in macrophages of different organs for a period commensurable with the life time of animals (and which is therefore not used for medical purposes) does not bring about any pathological changes. This is confirmed by more than 30 years of investigations aimed at finding toxicity and probable cancerogenicity and by 16 years of experience in medical uses of emulsions of perfluoroorganic compounds, containing other relatively slowly eliminable perfluorinated tertiary amines [Biomaterials, artificial cells, and artificial organs. 1988, vol. 16, No. 1-3, Special Issue from III International Symposium on “Blood Substitutes”; A. M. Golubev, Advances in and Prospects of Studying the Influence of Fluorocarbon Blood Substitutes on Biological Systems./Perfluorocarbon Active Media for Medicine and Biology (New Aspects of Research). Pushchino: ONTI of Pushchino Research Center, Russian Academy of Sciences, 1993, pp. 88-93 (in Russian)].
The binary PFOC emulsion according to RF Patent No. 2088217 is the closest to the claimed emulsion with regard to the formulation of its components. It comprises a mixture of a rapidly eliminable lipophilic perfluorocarbon perfluorodecalin (PFD) or perfluorooctylbromide and a slowly eliminable lipophobic perfluorinated tertiary amine perfluoro-N-(4-methylcyclohexyl)-piperidine (PFMCP) in a ratio of 40-50 vol. % to 1-10 vol. %, and is stabilized by phospholipids the amount of which is from 2 to 6%. Upon intravenous administration of such emulsion, 100% of rabbits survive during 60 days of observations. However, this emulsion has a high viscosity (14-16 cP), which, as indicated above, in spite of the high absolute oxygen capacity of the preparation, leads to a sharp drop of the dynamic oxygen capacity and does not provide efficient delivery of oxygen.
Furthermore, the use of such sharply differing in their physical properties PFOC as the lipophilic PFD and lipophobic PFMCP leads to clustering of the fluorocarbon phase inside the emulsion particles, which complicates the choice of the stabilizing agent and impairs the emulsion stability. As a result, the emulsion dispersity changes both during storage and when the emulsion enters the blood flow.
Finally, in this invention individual highly purified perfluorodecalin and perfluoro-N-(4-methycyclohexyl)-piperidine are used for preparing the emulsion, which, as already indicated, makes the PFOC emulsion appreciably more expensive.
A PFOC emulsion is known, which is closest to the claimed one in the composition and in the ratio of the components [see RF Patent No. 2070033, publ. in Bull. “Izbreteniya . . . (Zayavki, . . . )”, No. 34, 27.08.97]. This emulsion contains perfluorocarbon in the form of cis- and trans-isomers of perfluorodecalin and perfluorinated tertiary amine perfluoro-N-(4-methylcyclohexyl)-piperidine in lower concentrations of both components: 7 vol. % and 3.5 vol. %, respectively, and it is stabilized by a polyoxyethylene-polyoxypropylene copolymer with a molecular mass of 6-8 thousand Dalton (Da) with a mean size of emulsion particles of 0.08-0.1 &mgr;m. This composition, with a comparatively small value of the absolute oxygen capacity (7 vol. % of oxygen at pO
2
of 760 mm Hg), ensures owing to its small viscosity (3.5 cP) a higher dynamic oxygen capacity than other known PFOC emulsions (see Table 1 in the specification to said RF Patent), i.e., it ensures better oxygen delivery to the tissues. Owing to the high proportion of the slowly eliminable PFMCP (the PFMCP/PFD ratio=1:2) in the PFOC formulation and the high degree of monodispersity of the particles along with their size, this emulsion
Arkhipov Vladimir Viktorovich
Ivanitsky Genrikh Romanovich
Ivashina Albina Ivanovna
Kulakova Galina Mikhailovna
Maevsky Evgeny Iliich
Lovering Richard D.
Otkrytoe Aktsionernoe Obschestvo Naucho-Proizvodstven-Naya Firma
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