Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1998-11-16
2002-09-24
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
Reexamination Certificate
active
06455514
ABSTRACT:
The present invention relates to a process for treating lameness with an osseous, articular or osteoarticular component in human or veterinary medicine, comprising the administration of a bisphosphonic acid derivative.
The term lameness is understood to refer to irregular gait caused by the perception of a pain by partially or fully bearing weight on one or more limbs during the functioning of limbs prompted into motion.
Lameness can manifest itself clinically in an intermittent or continuous manner for several days, several weeks or several months.
Lameness results more specifically from the appearance of painful lesions on the bone structure, the cartilages, the ligaments, the synovial membrane or the connective tissue or from an anomaly of local vascularization. Thus, lameness is generally associated with one or more of the following components:
an osseous component which is the result of a change in the bone architecture and/or in the bone growth cartilages at the site of the lameness, such as, for example, losses of bone substance, the formation of cysts, deformation of the bone or excessive thickening of the growth cartilages;
an articular component which is the result of a change in the structure of the articular cartilages, such as, for example, erosions of the cartilaginous surfaces and/or a change in the synovial membrane and/or a change in the articular ligaments;
a muscular component which is the result of a change in muscle development, such as, for example, a muscular atrophy; and
a vascular component which is the result of a change in local vascularization, such as, for example, a reduction in vascularization of the injured region.
The invention is directed towards providing a process for treating lameness with an osseous component and/or with an articular component which appear in a person or an animal not suffering from fractures or arthritis. Hereinbelow, lameness is referred to by the expression lameness with an osseous, articular or osteoarticular component. It should be understood, however, that the osseous, articular or osteoarticular component can be present alone or combined with a muscular component and/or with a vascular component.
Lameness with an osseous, articular or osteoarticular component appear in particular during osteoarthrosis, osteochondrosis, navicular disease or enthesopathy of the bony insertions of the tendons, of the ligaments or of the aponeurosis.
Among the factors which can bring about lameness with an osseous, articular or osteoarticular component, mention may be made of constant and/or intense mechanical stresses on the locomotor apparatus. In the case of a person or animal unprepared for physical exercise, the intensity of the mechanical stress capable of bringing about lameness may be relatively low.
In contrast, in the case of a person or animal prepared for physical exercise, lameness will appear when subjected to a mechanical stress whose force or repetitive nature exceeds the resistance capacities of the limbs. Certain animal species are more particularly inclined to develop lameness with an osseous, articular and/or osteoarticular component. This is especially the case for equidae animals.
In point of fact, in horses, the locomotor apparatus is stressed more frequently than it is in other animal species, either during sporting competitions or when the horse is used by people as a mount. In this animal species, lameness represents one of the main clinical conditions requiring veterinary consultation. Their clinical description is well known; a fairly exhaustive review on this subject is presented in the book “Les boiteries du cheval” [Lameness in horses] edited by O. R. Adams (published by Maloine, 1990). Lameness with an osseous, articular or osteoarticular component are the most common; descriptions have especially been given in the art for navicular disease or horse podotrochlear syndrome, bone spavin or osteoarthrosis of the distal stage of the tarsus in horses, horse osteochondrosis and enthesopathy of the bony insertions of the tendons, of the ligaments or of the aponeurosis in horses.
Thus, the invention relates to a process for treating lameness with an osseous, articular or osteoarticular component, comprising the administration, to a person or to an animal (for example a horse) not suffering from fractures or from arthritis, of a bisphosphonic acid derivative.
The bisphosphonic acid derivatives which can be used in the context of the invention have the general formula:
in which:
R
1
represents a hydrogen atom, a halogen atom, a hydroxyl, an amino, a mono(C
1
-C
4
)alkylamino or a di(C
1
-C
4
)alkylamino;
R
2
represents a halogen atom, a linear alkyl comprising from 1 to 5 carbon atoms which is unsubstituted or substituted with a group chosen from a chlorine atom, a hydroxyl, an amino, a mono(C
1
-C
4
)alkylamino, a di(C
1
-C
4
)alkylamino; a (C
3
-C
7
)cycloalkylamino,
or R
2
represents a phenoxy, a phenyl, a thiol, a phenylthio, a chlorophenylthio, a pyridyl, a pyridyl-methyl, a 1-pyridyl-1-hydroxymethyl, an imidazolylmethyl or a 4-thiomorpholinyl.
The salts of these compounds with pharmaceutically acceptable inorganic or organic acids or bases can also be used in the context of the invention. Examples of salts with acids are hydrochloride, hydrobromide, sulphate, acetate, hydrogensulphate, dihydrogenphosphate, methanesulphonate, methylsulphate, maleate, fumarate, sulphonate, 2-naphthalenesulphonate, glycolate, gluconate, citrate, isethionate, benzoate, salicylate, ascorbate, tartrate, succinate, lactate, glutarate, toluenesulphonate and ascorbate. As examples of salts with inorganic or organic bases, mention may be made of ammonium salts or alkali metal salts such as, for example, sodium salts.
The hydrates of these compounds can similarly be used according to the invention.
These compounds are described in particular in EP 623,347.
Among these bisphosphonic acid derivatives, mention may be made in particular of the following compounds:
1-hydroxyethylidenebisphosphonic acid, whose international nonproprietary name is etidronic acid, and its sodium salts;
2-pyrid-2-ylethylidenebisphosphonic acid, whose international nonproprietary name is piridronic acid, and its sodium salts;
dichloromethylenebisphosphonic acid, whose international nonproprietary name is clodronic acid, and its sodium salts;
3-amino-1-hydroxypropylidenebisphosphonic acid, whose international nonproprietary name is pamidronic acid, and its sodium salts;
4-amino-1-hydroxybutylidenebisphosphonic acid, whose international nonproprietary name is alendronic acid, and its sodium salts;
6-amino-1-hydroxyhexylidenebisphosphonic acid and its salts;
phenoxymethylenebisphosphonic acid and its salts;
thiomorpholinomethylenebisphosphonic acid and its salts;
4-chlorophenylthiomethylenebisphosphonic acid, whose international nonproprietary name is tiludronic acid, and its pharmaceutically acceptable salts, in particular the disodium salt;
1-hydroxy-2-(3-pyridyl)ethylidenebisphosphonic acid, whose international nonproprietary name is risedronic acid, and its sodium salts;
1-hydroxy-2-(2-imidazolyl)ethyl-1,1-bisphosphonic acid and its salts;
(cycloheptylamino)methylenebisphosphonic acid and its salts;
2-hydroxyethylidene-2-(3-pyridyl)-1,1-bis-phosphonic acid and its sodium salts.
According to the present invention, the administration of tiludronic acid and of its pharmaceutically acceptable salts, in particular the disodium salt, or of its hydrates is particularly preferred.
Bisphosphonic acid derivatives are known to inhibit bone resorption and to decrease the activity of osteoclasts, as is found in particular in the following articles:
“Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo”, Fleisch H., Russell R., Francis M., Science, 1969, 165, 1262-1264
“Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix”, Boonekamp P. M., Van Der Wee-Pals L. J. A., Van Wijk-Lennep, Thesing C. W., Bijvoet O. L. M., Bone Miner., 1986, 1, 27-39
“Dichloromethylene bisphosph
Bardon Thierry
Du Mesnil Philippe
Thibaud Dominique
Ceva Sante Animale
Criares Theodore J.
Jacobson & Holman PLLC
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