Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2001-03-22
2004-04-13
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S400000, C424S489000, C514S075000, C514S102000
Reexamination Certificate
active
06719998
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with compositions capable of preventing, inhibiting or reducing restenosis (sometimes referred to in the art as “accelerated arteriosclerosis” and “post-angioplasty narrowing”).
PRIOR ART
The following references are considered to be pertinent for the purpose of understanding the background of the present invention.
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-
Cardiol
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Curr
-
Opin
-
Cardiol
., 11(6):583-90, (1996).
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Aviat
-
Space
-
Environ
-
Med
. 67(10):990-6, (1996).
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Fundam. Clin. Pharmacol
., 10(3):243-57, (1996).
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Semin
-
Interv
-
Cardiol
., 1(3):173-9, (1996).
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Interv
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Cardiol
., 2(2):83-8, (1997).
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Ann. Thorac. Surg
., 63:582-591, (1997).
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Eur. Heart J
., 16:33s-48s, (1995).
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Clin. Cardiol
., 19:347-356, (1996).
10. Herrman, J. P. R., Herrnans, W. R. M., Vos, J., Serruys, P. W.,
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, 46:18-52, (1993).
11. Leclerc, G., Voisine, P., Bouchard, M., Fleser, A., Martel, R.
Elsevier Science
, 722-724, (1995).
12. Topol, E.,
The NY Academy of Sciences
, 225-277, (1997).
13. Fleisch, H., in: Bisphosphonates in bone disease. Parthenon Publishing Group Inc., pp. 184-186 (1997).
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J. Drug Target
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., 42:562-572, (1978).
16. Braunwald, E.
Heart Disease
in: A textbook of cardiovascular medicine; 5th Ed., W. B. Saunders Company: Philadelphia, (1997).
17. Gennaro Alfonso, R. Remington, in: The Science and Practice of Pharmacy, Mack Publishing, Easton Pa., 19th ed., (1995).
18. Mönkkönen, J., and Heath, T. D.,
Calcif. Tissue Int
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19. M. Donbrow in: Microencapsulation and Nanoparticles in Medicine and Pharmacy, CRC Press, Boca Raton, Fla., p. 347.
The above references will be acknowledged in the text below by indicating their number (as shown in brackets) from the above list.
BACKGROUND OF THE INVENTION
Over the past decade, mechanical means of achieving revascularization of obstructive atherosclerotic vessels have been greatly improved. Percutaneous transluminal coronary angioplasty (PTCA) procedures include, but are not limited to, balloon dilatation, excisional atherectomy, endoluminal stenting, rotablation, and laser ablation. However, revascularization induces thrombosis and neointimal hyperplasia, which in turn cause restenosis in a substantial proportion of coronary arteries after successful balloon angioplasty and in aortacoronary saphenous vein bypass graft and other coronary grafts. Furthermore, intimal hyperplasia causes restenosis in many superficial femoral angioplasties, carotid endarterectomies, and femoro-distal vein bypasses. The introduction of endovascular stents has contributed to reduce the incidence of restenosis, but this problem still remains significant
(1-9)
. Despite extensive research on the incidence, timing, mechanisms and pharmacological interventions in humans and animal models, to date no therapy exists which consistently prevents coronary restenosis
(10-12)
. Compositions and methods for the reduction or prevention of restenosis are still today greatly desired.
Bisphosphonates (BP) (formerly called diphosphonates) are compounds characterized by two C-P bonds. If the two bonds are located on the same carbon atom (P-C-P) they are termed geminal bisphosphonates. The BPs are analogs of the endogenous inorganic pyrophosphate which is involved in the regulation of bone formation and resorption. The term bisphosphonates is generally used for geminal and non-geminal bisphosphonates. The BPs and pyrophosphates may at times form together polymeric chains. BPs act on bone because of their affinity for bone mineral and are potent inhibitors of bone resorption and ectopic calcification. BPs or pyrophosphate have been used clinically mainly as (a) antiosteolytic agents in patients with increased bone destruction, especially Paget's disease, tumor bone disease and osteoporosis; (b) skeletal markers for diagnostic purposes (linked to
99m
Tc); (c) inhibitors of calcification in patients with ectopic calcification and ossification, and (d) antitartar agents added to toothpaste
(13)
.
SUMMARY OF THE INVENTION
In accordance with the present invention, a BP or pyrophosphate (collectively herein: “active ingredient”) is used for the treatment or prevention of vascular restenosis. The term bisphosphonate (BP) as used herein denotes both geminal and non-geminal bisphosphonates. The term “active ingredient” encompasses in its scope also polymeric chains of the BPs or pyrophosphate, particularly such chains consisting of up to 40 BP monomers. Preferred active ingredients are compounds of the following formula (I):
wherein R represents O or a CR
1
R
2
group;
R
1
is H, OH or a halogen group; and
R
2
is halogen; linear or branched C
1
-C
10
alkyl or C
2
-C
10
alkenyl optionally substituted by heteroaryl or heterocyclyl C
1
-C
10
alkylamino or C
3
-C
8
cycloalkylamino where the amino may be a primary, secondary or tertiary; —NHY where Y is hydrogen, Cs-Cg cycloalkyi, aryl or heteroaryl; or R
2
is —SZ where Z is chlorosubstituted phenyl or pyridinyl.
The present invention thus provides the use of said active ingredient, a complex of said active ingredient or a pharmaceutically acceptable salt or ester thereof, for the preparation of a medicament for the prevention or treatment of vascular restenosis.
The present invention also provides a method of treatment of restenosis, comprising administering to an individual in need thereof an effective amount of said active ingredient, a complex thereof or a pharmaceutically acceptable salt or ester thereof.
The present invention still further provides a pharmaceutical composition for the prevention or treatment of restenosis, comprising as an active ingredient, an effective amount of said active ingredient, a pharmaceutically acceptable free acid, a complex or a salt thereof, optionally together with a pharmaceutically acceptable carrier or diluent. A particularly preferred carrier is a liposome preparation.
The term “effective amount” means to denote an amount of the active ingredient which is effective in achieving the desired therapeutic result, namely prevention or reduction of vascular restenosis. The effective amount may depend on a number of factors including: weight and gender of the treated individual; the type of medical procedure, e.g. whether the vascular restenosis to be inhibited is following balloon angioplasty, balloon angioplasty followed by deployment of a stent, etc.; the mode of administration of the active ingredient (namely whether it is administered systemically or directly to the site); the type of carrier being used (e.g. whether it is a carrier that rapidly releases the active ingredient or a carrier that releases it over a period of time); the therapeutic regime (e.g. whether the active ingredient is administered once daily, several times a day or once every few days); clinical factors influencing the rate of development of restenosis such as diabetes, smoking, hypercholesterolemia, renal diseases, etc.; anatomical factors such as whether there is severe preangioplasty stenosis, total occlusion, left anterior descending coronary artery location, saphenous vein graft lesion, long lesions, multivessel or multilesion PTCA; on the dosage form of the composition; etc. Moreover, procedural variables may also have bearing on the dosage such as greater residual stenosis following PTCA, severe dissection, intimal tear, appropriate size of balloon, and the presence of thrombus. The artisan, by routine type experimentation should have no substantial difficulties in determining the effective amount in each case.
The invention is applicable for the
Danenberg Haim
Golomb Gerson
Hartley Michael G.
Hughes, Esq. Christopher A.
Morgan & Finnegan L.L.P.
Yissum Research Development Company of the Hebrew University of
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