Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-06-21
2001-09-11
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S012200, C530S300000, C530S324000, C530S350000, C530S380000, C424S184100, C424S400000, C424S489000, C424S491000
Reexamination Certificate
active
06288040
ABSTRACT:
The invention relates to drug carrier particles which are suitable for site-specific drug application, especially to the central nervous system (CNS).
The treatment of CNS diseases is made difficult by the blood-brain barrier, one of the most important and most impermeable physiological barriers in the body. The vascular endothelium of the brain capillaries is regarded primarily as a morphological substrate of the blood-brain barrier as the intercellular gaps between the endothelial cells are bridged by tight cell-cell-connections (“tight junctions”). The endothelial cells are surrounded moreover by an unbroken basal membrane. The lack of fenestration, the absence of pores and a low pinocytotic activity are typical of the tissue. In addition to this, the blood vessels are enclosed in a closely adjacent layer of glial cells in the area of the CNS (Thews, G., Mutschler, E., Vaupel, P.,
Anatomie, Physiologie und Pathophysiologie des Menschen
, 3
rd
Edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1989; Borchard, G., in: Müller, R. H., Hildebrand, G. (Ed.),
Pharmazeutische Technologie: Moderne Arzneiformen
. Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, 291-296). As a rule, therefore, the brain can be reached from the blood only by lipophilic drugs with a low molecular weight (MW<500) (Pardridge, W. M.,
J. Control. Rel
., 39, 281-286, 1996).
The blood-brain barrier is normally not permeable for very many active substances such as e.g. peptides, proteins and oligonucleotides as possible therapeutics for CNS diseases.
According to Pardridge (
J. Control. Rel
., 39, 281-286, 1996), the strategies for a drug delivery into the brain can be divided into
a) invasive
b) pharmacological and
c) physiological procedures.
With invasive techniques, the blood-brain barrier can be physically circumvented, e.g. by implanting a drug carrier system into the brain (Domb, A. J., Ringel, I., in: Flanagan, T. R., Emerich, D. F., Winn, S. R. (Ed.),
Providing Pharmacological Access to the Brain
. Academic Press, Inc., New York, 1994, 169-187; Friden, P. M.,
J. Control. Rel
. 46, 117-128, 1996). A disadvantage of these techniques is that they involve a surgical operation and for that reason have not established themselves as a common method of treatment.
The pharmacological strategies for a drug delivery through the blood-brain barrier include measures for increasing the lipophilicity of drugs (Chekhonin, V. P., Kabanov, A. V., Zhirkov, Y. A., Morozov, G. V.,
FEBS Lett
., 287, 149-152, 1991). Disadvantages of these procedures are that “new drug entities” form, for which extensive cost-intensive toxicological studies have to be carried out, that these procedures are practicable only for relatively small molecules and that they have a low efficiency (Friden, P. M.,
J. Control. Rel
., 46, 117-128, 1996; Pardridge, W. M.,
J. Control. Rel
., 39, 281-286, 1996).
Physiological strategies for a drug delivery into the brain are based on the knowledge of special active specific delivery mechanisms to the blood-brain barrier e.g. for nutrients (amongst other glucose and amino acids), peptides or proteins (Pardridge, W. M.,
Peptide Drug Delivery to the Brain
, Raven Press, New York, 1991; Pardridge, W. M.,
J. Control. Rel
., 39, 281-286, 1996; Friden, P. M.,
J Control. Rel
., 46, 117-128, 1996). An example is L-dopa as pro-drug of the neurotransmitter dopamine which the blood-brain barrier is not able to overcome. On the other hand, L-dopa is transported through the blood-brain barrier into the brain cells by an active transport mechanism for neutral amino acids (“neutral amino acid carriers”), where the actual active form dopamine is formed (Mutschler, E.,
Arzneimittelwirkungen, Lehrbuch der Pharmakologie und Toxikologie
, 7
th
Edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1996; Borchard, G., in: Müller, R. H., Hildebrand, G. (Ed.),
Pharmazeutische Technologie: Moderne Arzneiformen
, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, 291-296). But this approach has not been widely implemented either, due to the following disadvantages:
1. the active transport mechanisms are very substrate-specific, i.e. only a few drugs very similar to the substrate are delivered, which greatly limits the usability of this strategy.
2. conjugates of natural substrate and drug are not, or not very efficiently, delivered because of the pronounced specificity of the transport system (chemical structure and three-dimensional structure and size of the substrate to be delivered).
Another approach to site-specific drug administration, e.g. into the CNS, is the incorporation of drugs into particulate drug carriers such as nanoparticles, microparticles, emulsions and liposomes as well as processing into particulate forms of drugs such as hydrosols, nanocrystals and nanosuspensions. For intravenously injected particles the crossing of the endothelia is generally even more difficult, due to their size (as a rule>>30 nm), than for drug molecules (size in the Angström range). Thus for example a very limited ability to penetrate through the blood-brain barrier is generally described for liposomes (Gennuso, R., Spigelman, M. K., Chinol, M., Zappulla, R. A., Nieves, J., Vallabhajosula, S., Paciucci, P. A., Goldsmith, S. J., Holland, J. F.,
Cancer Invest
., 11, 118-128, 1993; Boado, R. J.,
Adv. Drug Deliv. Rev
., 15, 73-107, 1995; Boado, R. J.,
Proceed. Intern. Symp. Control. Rel. Bioact. Mater
., 24, 223-224, 1997; Pardridge, W. M.,
J. Control. Rel
., 39, 281-286, 1996).
Alyautdin et al. (Alyautdin, R. N., Gothier, D., Petrov, V. E., Kharkevich, D. A., Kreuter,
J., Eur. J. Pharm. Biopharm
., 41, 44-48, 1995) published a first success as regards the application of a drug to the CNS with particulate carriers. They demonstrated, for i.v. administered polybutylcyanoacrylate (PBCA) nanoparticles, to the surface of which the analgesically effective substance dalargin was bound by adsorption, a dose-dependent analgesic effect in the “tail-flick-test” on mice. The hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) is a leu-enkephalin-analogon and has a centrally analgesic effect as opioid receptor agonist. Dalargin cannot normally overcome the blood-brain barrier.
An i.v. administration of dalargin does not lead to an analgesic effect in spite of the stability in the blood even in high dosage (20 mg/kg) (Kalenikova E. I., Dmitrieva, O. F., Korobov, N. N., Zhukova, S. V., Tischenko, V. A.,
Vopr. Med. Khim
., 34, 75-83, 1988).
In another study, an accumulation of the particles in the area of the brain was detected in the rat model after intravenous injection of surface-modified polymethyl methacrylate (PMMA) nanoparticles (Tröster, S. D., Müller, U., Kreuter, J.,
Int. J. Pharm
., 61, 85-100, 1990). But the authors ruled out the possibility that the particles are absorbed in brain cells, which rules out a drug administration into the brain.
It is disadvantageous that the phenomenon reported by Alyautdin et al. (
Eur. J. Pharm. Biopharm
., 41, 44-48, 1995) and by Schröder and Sabel (
Brain Res
., 710, 121-124, 1996) cannot be used for a targeted and controlled drug administration. The mechanism is not known. There remains only the “trial and error procedure” to detect whether an addition of a surfactant to a particulate carrier perhaps produces by chance an accumulation in the brain. The probability that this happens is low, as surfactants were often used in particle preparations (Couvreur, P., Dubernet, C., Puisieux, F.,
Eur. J. Pharm. Biopharm
., 41, 2-13, 1995) and up until now the above reports are the first data concerning an absorption of a drug in the brain.
For drug delivery specifically into the desired target tissue, in particular also into the brain, a form of drug would be optimal which
1. combines the specificity of a transport route for example via receptor-mediated transcytosis (physiological strategy) with the high delivery capacity of particulate drug carriers, e.g. liposomes, emulsions or nanoparticles,
2. facilitates the absorption of the drug into the tissue—e.g. the brain
Kreuter Jorg
Lück Martin
Müller Ranier H.
Davenport Avis M.
DSS Drug Delivery Service Gesellschaft zur Forderung der Foshung
Manelli Denison & Selter PLLC
Melcher Jeffrey S.
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