Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-08-03
2003-11-04
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S103000
Reexamination Certificate
active
06642214
ABSTRACT:
The present invention relates to spacer-bridged cyclodextrin oligomers, and to complexes of such cyclodextrin oligomers with pharmaceutically active substances.
Cyclodextrins are circular glucose polymers which are referred to as &agr;-, &bgr;- or &ggr;-cyclodextrins, depending on the number of glucose units (6 to 8, respectively). A lipophilic cavity exists inside the oligoglucose ring. It is known that lipophilic substances can be enclosed within this cavity. Cyclodextrins are used, inter alia, for converting compounds having low solubility to a soluble complex by complex formation with cyclodextrin.
In Tetrahedron, Vol. 51, 2 (1995), p. 377-388, R. Breslow et al. describe cyclodextrin dimers which are capable of binding substrates having the correct geometry in aqueous solutions.
In the Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, 27 (1997), p. 69-84, A. Ruebner et al. describe dimeric cyclodextrins having high binding affinities for porphyrinoid photosensitizers as a carrier system for the application of drugs in photodynamical cancer therapy.
In Tetrahedron Letters 25 (1984), p. 5533-5536, K. Fujita et al. describe the preparation of ditosylates of &bgr;-cyclodextrin and their purification by reversed-phase chromatography.
In Tetrahedron Letters 18 (1977), p. 1527-1530, I. Tabushi et al. describe the specific bifunctionalization of cyclodextrin.
In Arch. Microbiol. 165 (1996), p. 206-212, R. Feederle et al. describe the purification and characterization of the enzyme cyclodextrinase from
Klebsiella oxytoca.
In an electronic publication which is accessible under http://antas.agraria. uniss.it/electronic_papers/eccc3/bcd/welcome.htm, B. Manunza et al. describe a molecular dynamics study of the structure and internal movement of solvated &bgr;-cyclodextrin.
In the Journal of Pharmaceutical Sciences 84 (1995), p. 1223-1230, U. S. Sharma et al. describe the pharmaceutical and physical properties of paclitaxel (taxol) complexes with cyclodextrins.
In SPIE Biomedical Optics 3191 (1997), p. 343-353, A. P. Savitsky et al. describe an avidin-biotin system for the selected transport of photosensitizers and other cytotoxic agents into tumor tissue.
In Eur. J. Nucl. Med. 20 (1993), p. 1138-1140, F. Fazio & G. Paganelli describe that such biotin-avidin systems enable a highly specific labeling of tumors.
It has been the object of the present invention to provide cyclodextrin oligomers which are suitable for the inclusion of pharmaceutically active substances due to their geometry.
The cyclodextrin oligomers according to the invention are two cyclodextrins connected through a spacer at the secondary side, the spacer comprising the unit B which is a rigid and preferably hydrophilic structural element. In one embodiment, the cyclodextrin oligomers have the general formula
CD—X—A—X—B—X—A—X—CD
where
each X is independently selected from —NH—, —O—, —S—, —CO— or a covalent bond;
each A is an aliphatic C
2
to C
4
residue or a covalent bond;
B is a rigid and preferably hydrophilic structural element; and
each CD represents a cyclodextrin bound through its secondary side.
Preferred compounds for the unit B include melamine, trimesic acid, alizarintetracarboxylic acid or tetraaminoalizarin, and cyclodextrins, such as &agr;-cyclodextrin, &bgr;-cyclodextrin or &ggr;-cyclodextrin, the cyclodextrins being preferably bound through their primary sides.
As examples of the cyclodextrin oligomers according to the invention, there may be mentioned the compounds:
di-&bgr;-CD(—NH—(C
8
H
16
)—NH—);
di-&bgr;-CD(terephthaldiamide);
di-&bgr;-CD(—NHCO(trimesyl)CONH—);
di-&bgr;-CD(—NH—(C
3
H
6
)—NHCO—(C
3
H
6
)—CONH—(C
3
H
6
)—NH—);
di-&bgr;-CD(—NH—(C
2
H
4
)—NHCO(trimesyl)CONH—(C
2
H
4
)—NH—);
di-&bgr;-CD(—NH—(C
2
H
4
)—SH—[6-&agr;-CD-6]—SH—(C
2
H
4
)—NH—);
di-&bgr;-CD(—NH—(C
4
H
8
)—NHCO—(C
3
H
6
)—COHN—(C
4
H
8
)—NH—);
di-&bgr;-CD(—NH—(C
2
H
4
)—SH-[6-(&bgr;,&ggr;)-CD-6]-SH—(C
2
H
4
)—NH—); or
di-&bgr;-CD(—NH—(C
3
H
6
)—NHCO(trimesyl)COHN—(C
3
H
6
)—NH—).
The cyclodextrin oligomers according to the invention can be obtained by the tosylation of the OH groups on the secondary side of cyclodextrins, followed by reaction with short bifunctional spacer groups. The thus obtained functionalized cyclodextrins can be converted to dimers with bifunctional reagents. The corresponding synthetic protocols can be found in A. Ruebner et al. (loc. cit.). Alternatively, carboxylic acid functions may also be introduced into the cyclodextrins by reacting the regiospecific tosylates with amino- or mercaptocarboxylic acids, such as 3-mercaptopropionic acid or 4-aminobutyric acid.
Binding constants can be determined in competition with 6-(p-toluidino)-2-naphthalenesulfonic acid (TNS). The measurement is performed by fluorescence spectroscopy according to Ruebner et al. (loc. cit.).
Preferably, the cyclodextrin oligomer additionally carries at least one and preferably two affinity groups which can interact with molecular target structures.
In principle, said at least one affinity group can have binding capability for a tissue-specific antigen as a molecular target structure. However, according to the polyphasic application route sought by Fazio & Paganelli (loc. cit.), an indirect tissue-specific binding is preferred: The affinity group recognizes a target structure which was previously attached at the desired site of action in a tissue-specific way.
For example, a possible site of action is a tumor. Thus, a tissue- or tumor-specific antibody which carries the target structure for the affinity group of the substance according to the invention can first be introduced into the organism once or several times to become enriched at the site of action, in terms of a polyphasic tumor therapy. Subsequently, a selective enrichment of the pharmaceutically active substance can be achieved at the site of action by the administration of a complex of a pharmaceutically active substance and the substance according to the invention having the affinity group. Then, the pharmaceutically active substance can be released at the site of action. This is effected, for example, by disrupting the cyclodextrin unit(s) at the site of action. Poly- or monoclonal antibodies, but also antibody fragments, such as Fab or F(ab)
2
fragments, and artificial antibodies such as scFv fragments, can be used as said antibodies. Suitable affinity groups and target structures include a wide variety of binding members, such as biotin/avidin, biotin/streptavidin or enzyme/inhibitor systems. Preferred affinity groups include biotinyl residues and digoxin/digoxigenin residues.
Therefore, the invention further relates to a complex of a pharmaceutically active substance and the cyclodextrin oligomers according to the invention. These physical inclusion complexes, which are highly hydrophilic externally, serve to prevent the uptake of the complexed pharmaceutically active substance into body cells for the purpose of reducing or excluding the side-effects of tumor therapeutics, for example. Preferably, the pharmaceutically active substance has a high potential for side-effects and can therefore be employed in its free form only in a limited way. Suitable pharmaceutically active substances include mitotic inhibitors, tumor therapeutics and photo-chemotherapeutics, especially taxol, a taxol derivative, coichicine, colchemide, 3
1
,8
1
-(di-t-butylphenoxy)porphyrin, chlorotrianisene, tamoxifene, vinblastin, vincristin, docetaxel.
If the cyclodextrin oligomers carry an additional affinity group, they can serve for the selective polyphasic application of a pharmaceutically active substance. Surprisingly, the side-effects of a therapy can be reduced by this method. In addition, a considerable dosage reduction of up to a factor of 10,000 is possible.
The invention also relates to medicaments which contain at least one cyclodextrin oligomer according to the invention or at least one complex according to the invention. Such medicaments are useful, in particular, for the treatment of tumor diseases, such as tumors of the bladder, carcinomas
BJ Associates
CeramOptec Industries Inc.
Crane Lawrence E
Skutnik Bolesh J.
Wilson James O.
LandOfFree
Detoxication of active pharmaceutical substances using... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Detoxication of active pharmaceutical substances using..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Detoxication of active pharmaceutical substances using... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3164824