Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2000-11-08
2003-11-25
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S725000, C514S451000, C514S732000
Reexamination Certificate
active
06652877
ABSTRACT:
BACKGROUND OF THE INVENTION
A very large number of diterpenoids possessing a labdane skeleton (FIG. 1)
occur in nature (Connoly, J. D.; Hill, R. A Dictionary of Terpenoids, Chapman and Hall: London 1991). The interest in studying labdanes is heightened due to the wide range of biological activities of these compounds (Singh, M.; Pal, M.; Sharma, R. P. Planta Med., 1999, 65, 2-8.). They comprise a decalin system and a C-6 ring, which may be open or closed with an oxygen atom, as in manoyl oxide and its derivatives. Labdanes have been isolated from several plant families, such as Asteraceae, Labiateae, Cistaceae, Pinaceae, Cupressaceae, Taxodiaceae, Acanthaceae, Annonaceae, Caprifoliaceae, Solanaceae, Apocynaceae, Verbenaceae and Zingiberaceae. In addition they have been isolated from marine algae of the genus Laurence, from Taonia atomaria and from the red alga Chondria tenuissima.
The conifers are an important source of diterpenoids. Several labdanes have been detected in the neutral fraction of the oleoresin of Araucaria excelsa, including manool as well as nor-labdanes (Caputo, R.; Mangoni, L.; Monaco, P. Phytochemistry, 1972, 11, 839-840). A variety of biological activities have been associated with labdane diterpenes including antibacterial, antifungal, antiprotozoal, enzyme induction, anti-inflammatory modulation of immune cell functions, as well as cytotoxic and cytostatic effects against human leukemic cell lines. (K. Dimas et al. Planta Med. 1998, 208-211; K. Dimas et al. Leukemia Res. 1999, 217-234; K. Dimas et al. Anticancer Res. 1999, 4065-4072). In addition to the (antimicrobial, enzyme and endocrine related) properties mentioned above, it is interesting that many labdane type diterpenes also exhibit significant properties against cancer cells. A number of labdane type diterpenes tested exhibited remarkable antiproliferative and cytotoxic activities (Itokawa, H. et all. Planta Med. 1988, 311-315; K. Dimas et al. Planta Med. 1998, 208-211; K. Dimas et al. Leukemia Res. 1999, 217-234; K. Dimas et al. Anticancer Res. 1999, 4065-4072).
Labdane furanoids, and forscolin derivatives are the subject of several patents and applications, including European Patent Application 93103605.7; International Patent Publication No. WO 97/45099; International Patent Publication No. WO 91/02525; and International Patent Publication No. WO 85/03637.
Liposomes, or phospholipid vesicles, are self-assembled colloidal particles that occur naturally and can be prepared artificially (Lasic, D. D. Liposomes: from Physics to Applications. Elsevier), as shown by Bangham and his students in the mid-1960s (Bangham, A. D. ed. (1983) Liposomes Letters, Academic Press). At first, they were used to study biological membranes; several practical applications, most notably in drug delivery, emerged in the 1970. Today, they are a very useful model, reagent and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry and biology. Liposomes were introduced as drug-delivery delivery vehicles in the 1970s. Early results were, however, rather disappointing, owing mainly to their colloidal and biological instability, and their inefficient and unstable encapsulation of drug molecules. Their utility was improved following basic research that increased our understanding of their stability and interaction characteristics.
In the scientific literature, there is reference to a great number of liposomic pharmaceutical forms. Many of these are in the clinical study stage and some other have been already registered and marketed. Among the medicines formulated in liposomic form, are econazole, amfotericin B, minoxidyl and some anticancer and antiviral medicines, which are in the clinical study stage.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that naturally occurring labdanes, such as labd-13-ene-8&agr;, 15-diol, labd-14-ene-8, 13-diol, and 3&bgr;-hydroxy-labd-14-ene-8, 13-epoxy, exhibit biological properties in their pure state (Dimas et al., Planta Med. 1998) and may be useful as novel pharmaceutical and medicinal agents. The present invention deals with preparation of hydrated lipidic lamelar phases or liposomes particularly conventional and/or PEGylated and/or protein conjugated, containing the above compounds and their derivatives or plant extracts containing them, which are part of this invention. The compositions of the invention are useful for the treatment of neoplastic diseases.
As used herein the term “alkyl” refers to a straight or branched, saturated hydrocarbon containing from one to about twelve carbon atoms such as, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl, wherein one or more of the hydrogen atoms may be substituted.
As used herein the term “alkenyl” refers to a straight or branched hydrocarbon containing from one to about twelve carbon atoms where at least one carbon-carbon bond is unsaturated such as for example, vinyl, allyl and butenyl, wherein one or more of the hydrogen atoms may be substituted.
As used herein the term “alkynyl” refers to a straight or branched hydrocarbon containing from one to about twelve carbon atoms where at least one carbon-carbon bond is doubly unsaturated such as for example, acetylene, propynyl and butynyl, wherein one or more of the hydrogen atoms may be substituted.
As used herein the term “cycloalkyl” refers to a cyclic hydrocarbon containing from three to about twelve carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein one or more of the hydrogen atoms may be substituted.
As used herein the term “aralkyl” refers to a straight or branched, saturated hydrocarbon containing from one to about twelve carbon atoms, which is substituted with an aromatic ring such as, for example, benzyl and phenethyl, wherein one or more of the hydrogen atoms may be substituted.
As used herein the term “heterocyclyl” refers to a cyclic hydrocarbon, wherein at least one carbon atom has been replaced by a heteroatom such as, for example, nitrogen, oxygen or sulfur, containing from three to about twelve atoms such as, for example, furan, pyran and imidazole.
As used herein the term “dialkylaminoalkyl” refers to a straight or branched, saturated hydrocarbon containing from one to about twelve carbon atoms, which is connected to a tertiary amino group containing two alkyl groups such as, for example, diethylaminoethyl. Preferably, the dialklyaminoalkyl group is present as the acid addition salt resulting from reaction with either an inorganic or organic acid.
As used herein the terms “alkylthioketones”, “alkenylthioketones”, “alkynylthioketones”, “cycloalkylthioketones”, “aralkylthioketones” and “heterocyclothioketones” refer to a thioketone connected to a further radical.
As used herein the terms “alkylcarbonyl”, “alkenylcarbonyl”, “alkynylcarbonyl”, “cycloalkylcarbonyl” and “aralkylcarbonyl” refer to a carbonyl connected to a further radical.
As used herein the term “sugars” refers hexoses or pentoses in their pyranose or furanose state or disaccharides containing hexose-hexose, pentose-pentose, hexose-pentose or pentose-hexose in their pyranose or furanose state. These sugars may be substituted with amino or halogen groups, preferably chlorine, bromine or iodine.
1. Labdanes of the Invention
The labdanes of the present invention include:
A. Formula I,
LABD-13-ENE-8&agr;,15-DIOL (I)
Wherein R wherein R is selected from the group consisting of H, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, aralkylcarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, dialkylaminoalkyl, alkylthioketones, alkenylthioketones, alkynylthioketones, cycloalkylthioketones, aralkylthioketones, heterocyclylthioketones and sugars.
B. Formula II
LABD-14-ENE-8, 13-DIOL (II)
Wherein R is selected from the group consisting of H, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, aralkylcarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, dialkylaminoalkyl, alkylthioketones, alkenylthioketones, alkynylthio
Anastassaki Thalia
Angelopoulou Demetra
Demetzos Constantinos
Dimas Constantinos
Kokkinopoulos Demetrios
Kishore Gollamudi S.
P.N. Gerolymatos S.A.
Pennie & Edmonds LLP
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