Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-02-26
1996-11-19
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31335
Patent
active
055763456
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE94/00371 filed Apr. 26, 1994.
The present invention is related to the field of ophthalmology and more specifically to a composition and its use for preventing secondary cataract, a long term complication after extracapsular cataract extraction with or without intraocular lens (IOL) implantation.
A great number of intraocular lens models have been developed and commercialised over the years and these as well as the techniques for IOL implantation have been improved so that extracapsular cataract extraction with intraocular lens implantation are nowadays well established procedures with a high success rate. Opacification of the posterior capsule in the optical axis is however still a significant long-term complication reported, within 3 to 5 years after surgery, in as much as 50% of the cases. This condition is the result of deposition or in-growth of cells, mainly remnant lens epithelial cells (LEC) which proliferate on the posterior lens capsule resulting in blocking of incoming light. The direct consequence is the need for posterior capsultomy, which has a comparatively high incidence (1-3%) of serious complications.
A number of different ways to prevent secondary cataract have been tested over the years, both with regard to the intraocular lens as such and the technique used in surgery. So has for instance Hoffer in U.S. Pat. No. 4,244,060 described a lens that has a barrier ridge on the side facing the capsule wall. The intention is to create a mechanical barrier inhibiting migration of residual lens epithelial cells and their derivatives into the optical zone behind the IOL.
Administration of various types of drugs during surgery for preventing opacification is another approach that has been found to be of potential importance. Examples of such drugs are colchicine and 5-fluorouracil.
Colchicine is a mitosis-inhibiting phenanthrene derivative isolated from Colchicum autumnale. Colchicine arrests mitosis at metaphase by binding to a protein present in microtubules, hence interfering with the structure of the mitotic spindle. The substance has been shown to be a potent inhibitor of lens epithelial cell proliferation and migration. However, colchicine has a low therapeutic index with a lot of potential side effects, including a temporary toxic effect on the optic nerve when used for preventing posterior capsule opacification in primates.
5-Fluorouracil is a potent anti mitotic drug affecting the DNA replication and is widely used in the treatment of epithelial tumours. Ruitz et al (Inhibition of posterior capsule opcification by 5-fluorouracil in rabbit; Ophthalmic Res. 22 (1990) 201-208) have also shown that this substance reduces posterior capsule opacification in vive in rabbits.
Since 1982 subconjunctival administration of 5-fluorouracil has been utilized in patients at high risk of failure of glaucoma filtering surgery. Although beneficial effects of the substance have been clearly demonstrated, disadvantages have included corneal epithelial defects and other ocular complications.
In spite of the different approaches tested, opacification is still a considerable problem. We have now found that the substance taxol that is obtained from the bark of Western yew (Taxus brevifolia) constitutes a very promising drug candidate for preventing opacification after extracapsular cataract extraction. The substance is known to promote the formation of microtubule bundles, which deform the cytoskeleton and interfere with mitosis. Taxol is used as a broad spectrum antitumour agent in many different forms of tumours.
Chemical as well as certain therapeutic properties of taxol and some derivatives of taxol have been described in the literature, see for instance "The Chemistry of Taxol, a Clinically Useful Anticancer Agent" by Kingston et al in Journal of Natural Products 53(1) (1990) pages 1-12. With taxol derivatives for use according to the invention is meant functional analogues which are effective in preventing secondary cataract by inhibiting epithelial cell proliferation and m
REFERENCES:
patent: 5252319 (1993-10-01), Babcock et al.
Chem. Abstract of Barza et al. (abstract No. 107:12808) 1987.
Chem. Abstract of Van Bockxmeer et al. (abstract No. 103:154095) 1985.
Graefe's Archive of Clinical and Experimental Ophthalmology, vol. 228, 1990, Stewart A. Daniels et al., "Taxol treatment of experimental proliferative vitreoretinopathy".
Ophthalmic Res, vol. 22, 1990, J. M. Ruiz et al., "Inhibition of Posterior Capsule Opacification by 5-Fluorouacil in Rabbits".
STN, EMBASE, Accession No. 93309059, Jampel H. D. et al: "Glaucoma filtration surgery in nonhuman primates using taxol and etoposide in polyanhydride carriers". Invest. Ophthalmol. Visual Sci., (1993)34/11 (3075-3083).
M.ang.nsson Per
Rolfsen Wenche
Wickstr om Kerstin
Henley III Raymond
Pharmacia & UpJohn AB
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