Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-04-10
2001-11-20
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C554S035000, C554S079000
Reexamination Certificate
active
06319952
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to branched chain fatty acids and their derivatives, useful to facilitate or enable the penetration or transport of active ingredients through bio-membranes, including the blood brain barrier, to pharmaceutical compositions comprising these fatty acids and to methods of using them to treat central nervous system lesions including tumors, infections, abscesses and degenerative disorders.
BACKGROUND OF THE INVENTION
It has long been recognized that there is a need for agents which can improve or enable the permeability of non-lipophilic bioactive substances through biomembranes. In particular it would be advantageous to have agents that permit the reversible or transient permeabilization of biomembranes, such that bioactive molecules can be transported into cells or organs that are not normally accessible to these molecules without adversely affecting the viability of the cells. By way of example, the transport of nucleic acids and many other non-lipophilic substances is hampered by the lipophilic barrier that constitutes the cell membrane. There is an even greater need for agents that would enable therapeutic molecules to cross the lipophilic barrier that constitutes the blood brain barrier.
In the normal situation the central nervous system (CNS) is separated by a barrier from the general circulation, thereby permitting rigorous control of the microenvironment required for complex neural signaling. In certain pathological situations this blood brain barrier (BBB) interferes with the transport of therapeutic substances into the brain, thus hampering treatment of central nervous system lesions, including tumors, infections, abscesses and degenerative diseases.
The BBB maintains the homeostatic environment of the brain so that it can function irrespective of fluctuations in the systemic concentrations of compounds in the body. Moreover, it protects the brain from toxic agents and degradation products present in the circulatory system. Paradoxically, this barrier, which normally protects the brain, may be the cause for inefficient drug delivery into the brain, though in the pathological situation drug availability is crucial.
Molecules that show high therapeutic value in vitro and ex vivo in treatment of malignant infections and genetic diseases of the central nervous system are frequently found to be inactive in-vivo. This effect is due to insufficient access of the agent to the diseased target. Treatment of brain tumors is therefore problematic and the patients have poor prognoses. The same diminished effect can be seen in treatment of acute cerebral bacterial and viral infections, as well as with neurodegenerative and enzyme-deficiency diseases, such as Parkinson's disease, Huntington's chorea and Tay-Sachs disease.
Theoretically, the bioavailability problem presented above can be dealt with in several ways. The problem of delivering water soluble compounds, and in particular anticancer drugs, can be overcome by altering the biophysical characteristics of the drug. The permeability of a drug depends on its lipophilicity; thus, increasing the lipophilic nature of the compound may increase the therapeutic effect. Modification of a hydrophilic drug with hydrophobic groups such as alkyl or aromatic groups is a common way to improve their bioavailability. However, not all drugs maintain their therapeutic value after chemical modification.
Another strategy for attacking the problem of BBB impermeability is to alter the BBB itself, to enable transportation of the therapeutic substance into the brain (reviewed by Abbott and Romero, Molecular Medicine Today, March 1996, pp. 106-113). The most conmmon method of opening the BBB is by osmotic treatment. Mannitol is in clinical use as an agent for osmotic modification of the BBB. It was shown that chemotherapy administrated after barrier opening results in enhanced drug entry to both brain-tumor and brain, however, the studies also showed evidence that osmotic BBB modification causes complications. The primary problems include clinical manifestation of stroke, seizures, immunological reaction and ocular toxicity. Moreover, the osmotic treatment affects BBB opening for a very short period (Greig in Implications of the Blood-Brain Barrier and its Manipulation. Vol. 1, pp. 311-367, Neuwelt, E. A. ed., Plenum Press, N.Y., 1989).
A variety of other treatments have also been disclosed that increase permeability of the blood brain barrier including: the use of bradykinin agonists (WO 91/16355 of Alkermes) and certain other peptides (WO 92/18529 of Alkermes); use of bacterial cell wall fragments (WO 91/16064 of the Rockefeller Univ.) or the use of antibody to Bordetella pertussis filamentous haemagglutinin or brain endothelial x-molecule (WO 92/19269 of the Rockefeller Univ.). Certain fatty acids such as oleic acid have also been reported to reversibly open the BBB (Sztriha and Betz, Brain Res. 336, 257-262, 1991).
It has also been shown that valproic acid and other short chain fatty acids have membrane disordering potency and it was proposed that this activity might be correlated with the known sedative and anti-convulsant activity of these compounds (Perlman and Goldstein, Mol. Pharmacol. 26, 83-89, 1984).
The usefulness of methods for reversibly increasing the permeability of the blood brain barrier prior to administration of diagnostic reagents (U.S. Pat. No. 5,059,415 of the Oregon Health Sci. U.) or therapeutic reagents (WO 89/11299 of the Oregon Health Sci. U.) have been disclosed.
Known compositions for the permeabilization of biological membranes have not gained widespread acceptance in the medical community due to their adverse side effects or to their very short duration of action. Clearly, there is an unmet medical need for less toxic treatments with longer duration of action that will enable known effective drugs or diagnostic reagents to penetrate into the brain.
SUMMARY OF THE INVENTION
The present invention provides a family of branched fatty acids and their derivatives, which improve and enable the penetration and transport of active ingredients through bio-membranes. The invention further provides pharmaceutical compositions comprising these branched fatty acids and methods of using these compositions to permeabilize biological membranes thereby improving the administration of bioactive or therapeutic substances to cells or organs. According to a more preferred embodiment of this invention the methods are particularly useful to treat certain kinds of CNS lesions and diseases including but not limited to tumors, infections, abscesses and degenerative or behavioral disorders.
According to one aspect of the invention certain novel compounds are provided of general formula I:
wherein R denotes a saturated or unsaturated chain of between 3 to 10 carbon atoms and R′ denotes a saturated or unsaturated chain of between 10 and 30 carbon atoms, their salts esters and amides.
The present invention further provides pharmaceutical compositions for permeabilization of biological membranes comprising a pharmaceutically effective amount of a branched fatty acid of the general formula II:
wherein R denotes a saturated or unsaturated chain of between 1 to 10 carbon atoms and R′ denotes a saturated or unsaturated chain of between 5 and 30 carbon atoms, their salts esters and amides.
Currently more preferred compositions according to the present invention comprise a compound selected from the group consisting of:
2-propyldodecanoic acid (denoted herein as M3/10)
2-propyltetradecanoic acid (denoted herein as M3/12)
2-propylhexadecanoic acid (denoted herein as M3/14)
2-heptylnonanoic acid (denoted herein as M7/7)
2-heptyldodecanoic acid (denoted herein as M7/10)
2-heptylhexadecanoic acid (denoted herein as M7/14)
2-decanyldodecanoic acid (denoted herein as M10/10)
2-decanylhexadecanoic acid (denoted herein as M10/14)
2-tetradecanylhexadecanoic acid (denoted herein as M14/14)
Within the scope of the p invention the fatty acids may be used as free carboxylic acids or their phys
Kozak Alexander
Shapiro Israel
Vinikova Marina
Carr Deborah D.
D-Pharm Ltd.
Davidson Davidson & Kappel LLC
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