Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
  • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid

Definitions

• the present invention relates to the use of bisphosphonic acid derivatives for the preparation of a medicament for the treatment of calcium pyrophosphate deposition disease (CPDD) primarily pseudogout and chondrocalcmosis, in a mammal. More specifically, the present invention relates to the use of bisphosphonic acid derivatives, said derivatives being especially adapted to be administered to subjects suffering from CPDD. The invention also relates to the use of bisphosphonic acid derivatives for the prevention or treatment of caries, such as secondary caries.
• CPDD calcium pyrophosphate deposition disease
• CPDD calcium pyrophosphate deposition disease
• CPPD Disease Calcium pyrophosphate dihydrate crystal deposition disease
• pyrophosphate gout pyrophosphate gout
• the calcium pyrophosphate crystal deposits are topologically confined to the hyaline cartilage, the fibrocartilage in the meniscus of the knee, the annulus fibrosus of the intervertebral disc, the synovial fluid, or the synovium and tendon insertions (Kenneth P.H. P ⁇ tzker et al., "Crystal-associated Arthropathies: What's New on Old Joints", J. American Geriatrics Society, 28 (1980) 439-445).
• the calcium pyrophosphate crystal deposits are also frequently known to form or precipitate in the articular cartilage, particularly in elderly people (Ryan, L.M. et al., "Calcium pyrophosphate crystal deposition disease, pseudogout and articular chondrocalcmosis", In: Arthritis and Allied Conditions, A Textbook in Rheumatology, 13 th edition, Vol, II; Ed. W.J. Kooperman, 1997, pp. 2103-2125).
• the calcium pyrophosphate crystal deposits are known to especially form in the synovial fluid, particularly in elderly people.
• EHDP ethane-l-hydroxy-l,l-b ⁇ sphosphon ⁇ c acid
• a series of similar bisphosphonates are used in the treatment of osteoporosis and for the prevention of bone fractures in connection to various cancer diseases.
• Such compounds are known under various trade names, e.g. "Didronel” or “Aredia” or “Fosamax”.
• EP 0924293 discloses a fabric care composition including the compound hydroxy-ethane- 1,1-d ⁇ phosphon ⁇ c acid (HEDP/EDHP) and its use in order to inhibit the formation of inorganic microcrystals.
• HEDP/EDHP hydroxy-ethane- 1,1-d ⁇ phosphon ⁇ c acid
• US 3 683 080 discloses a composition which may include effective amounts of polyphosphonates, such as ethane-l-hydroxy-l,l-b ⁇ sphosphon ⁇ c acid (EHDP), for the inhibition of anomalous deposition and mobilisation of calcium phosphates in animal tissue.
• EHDP ethane-l-hydroxy-l,l-b ⁇ sphosphon ⁇ c acid
• EP 563096 discloses anti-inflammatory compositions comprising salicylic acid-, phenylacetic acid-, anthranilic acid- based inflammation inhibitors and an amount of an organic phosphonic acid or one of its salts or esters, said compositions being suitable for treating rheumatoid arthritis, bone infections and bone degradation.
• US 4 812 304 discloses a method for treating or preventing osteoporosis in humans, the method amongst others comprising a bone resorption period during which ethane-1- hydroxy-l,l-d ⁇ phosphon ⁇ c acid (EHDP) is administered.
• EHDP ethane-1- hydroxy-l,l-d ⁇ phosphon ⁇ c acid
• US 5 882 656 discloses pharmaceutical compositions of bisphosphonic acids for the treatment of disturbances involving the calcium or phosphate metabolism.
• Suitable organophosphonate compounds include 4-am ⁇ no-l-hydroxybutyl ⁇ dene-l,l-b ⁇ sphosphon ⁇ c acid.
• US 6 221 861 discloses a method for the treatment of an animal with pyrophosphate gout comprising administering an effective amount of calcium antagonists, such as phenylalkylamines, dihydropy ⁇ dines or benzothiazepines.
• calcium antagonists such as phenylalkylamines, dihydropy ⁇ dines or benzothiazepines.
• JP 10017493 discloses an external anti-inflammatory or antiallergic skin composition containing at least one calcium ion blocking agent consisting of hydroxyethanediphosphonic acid (EHDP). Summary of The Invention
• a first object of the invention is directed to the use of a bisphosphonic acid derivative for the preparation of a medicament for the treatment of calcium pyrophosphate deposition disease (CPDD) in a mammal
• CPDD calcium pyrophosphate deposition disease
• a related aspect of the invention relates to a composition for the delaying the deposition of calcium pyrophosphate depots in hyaline cartilage, the fibrocartilage in the meniscus of the knee, the annulus fibrosus of the mtervertebral disc, the synovial fluid, or the synovium and tendon insertions, comprising a 1,1-b ⁇ sphosphon ⁇ c acid derivative.
• a further aspect of the invention relates to the use of etidronate, pamidronate, alendronate, tiludronate, ⁇ sedronate, zoledronic acid, clodronic acid or ibandronic acid for the preparation of a medicament for the treatment of calcium pyrophosphate deposition disease (CPDD) in a mammal.
• CPDD calcium pyrophosphate deposition disease
• a second object of the invention relates the use of a bisphosphonic acid derivative for the manufacture of a medicament for the prevention or treatment of secondary caries or for the treatment of persons suffering form primary caries.
• An interesting aspect of the invention related to the use of etidronate, pamidronate, alendronate, tiludronate, ⁇ sedronate, zoledronic acid, clodronic acid or ibandronic acid for the preparation of a medicament for the prevention or treatment of secondary caries or for the treatment of a mammal suffering from primary caries.
• EHDP ethane-l-hydroxy-l,l-b ⁇ sphosphon ⁇ c acid
• bisphosphonate acid derivatives such as alkyl-1,1- bisphosphonic acids (EHDP)
• EHDP alkyl-1,1- bisphosphonic acids
• a particular embodiment of the present invention is the ability to severely retard the spontaneous precipitation of various forms of calcium pyrophosphate crystals from solutions supersaturated with respect to calcium pyrophosphate. Rates of dissolution are however unchanged.
• bisphosphonates can be used in yet another context, namely for the manufacture of a medicament for the prevention or treatment of secondary caries, i.e. caries that forms at the interface between the natural dental material (enamel, dentine, cementum and root material) and the filling material.
• secondary caries i.e. caries that forms at the interface between the natural dental material (enamel, dentine, cementum and root material) and the filling material.
• EHDP acts as a chelatmg agent and thereby reduces or inhibits the dissolution of tooth minerals beneath or in the vicinity of the "primary" caries under repair.
• the present invention provides use of an effective amount of a bisphosphonic acid derivative, for the preparation of a medicament for the treatment of calcium pyrophosphate deposition disease (CPDD) in an animal.
• the animal is preferentially a human.
• CPDD includes pseudogout, chondrocalcmosis, and any other disease caused by the deposition of calcium pyrophosphate crystals in the body.
• the invention relates, in one aspect, to a method of treating or preventing calcium pyrophosphate deposition disease (CPDD), such as pseudogout and chondrocalcmosis in a mammal.
• bisphosphonic acid derivative when referred to herein are intended to mean bisphosphonic acid derivatives, salts thereof, esters thereof or hydrates thereof.
• bisphosphonic acid derivatives of the present invention are discussed more fully hereinafter.
• the term "bisphosphonic acid derivative” is intended to mean a compound having two phosphonic acid groups bound to the same carbon atom, namely 1,1- bisphosphonic acid derivative (gemmal bisphosphonic acid derivatives), as well as salts or hydrates thereof
• the invention relates to the use of a compound comprising a - C(P0 3 H 2 ) 2 - moiety, or a pharmaceutically acceptable salt or hydrate of said compound
• R 1 and R 2 may be independently selected from hydrogen, halogen, COOH, optionally substituted C 12 -alkyl, optionally substituted aryl, optionally substituted C 3 9 - cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted 12 -alkyl-aryl, optionally substituted 12 -alkyl-C 3 9 -cycloalkyl, optionally substituted Ci 12 -alkyl-heteroaryl, heteroaryl, heterocyclyl, optionally substituted 12 - alkyl-heterocyclyl, ammo, optionally substituted 12 -alkyl-am ⁇ no, optionally substituted amino-Ci ⁇ 2 -alkyl, optionally substituted am ⁇ no-C 3 9 -cycloalkyl, optionally substituted 12 - alkyl-hahde, optionally substituted 12 -alkyl-OH, optionally substituted Cj 12 -alkyl-
• optionally substituted 12 -alkyl in itself or when used as a moiety within a group, is intended to mean an optionally substituted alkyl chain of 1-12 carbons in length
• the optionally substituted C t 12 -alkyl is a Cj 6 -alkyl having 1-6 carbon atoms
• a substituted 12 -alkyl may have a substituent any position along the alkyl chain
• a substituent may be of any array known to the person skilled in the art, such as a halogen, COOH, optionally substituted Ci 1 -alkyl, optionally substituted aryl, optionally substituted C 3 g-cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted d 12 -alkyl-aryl, optionally substituted Cj ⁇ 2 -alkyl-C 3 g-cycloalkyl, optionally substituted d 12 -alkyl-heteroaryl, heteroaryl, heterocyclyl, optionally substituted Ci 12 -alkyl-heterocyclyl, ammo, optionally substituted Ci 12 -alkyl-am ⁇ no, optionally substituted am ⁇ no-d ⁇ 2 -alkyl, optionally substituted d 12 -alkyl-hal ⁇ de, optionally substitute
• An amine may be optionally substituted in any manner known to the person skilled in the art, such as with a COOH, optionally substituted 12 -alkyl, optionally substituted aryl, optionally substituted C 3 9 -cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted Ci 12 -alkyl-aryl, optionally substituted d 12 - alkyl-C 3 9 -cycloalkyl, optionally substituted d 12 -alkyl-heteroaryl, heteroaryl, heterocyclyl, optionally substituted C x 12 -alkyl-heterocyclyl, ammo, optionally substituted Ci 12 -alkyl- ammo, optionally substituted amino-d 12 -alkyl, optionally substituted Ci 12 -alkyl-hal ⁇ de, optionally substituted d 12 -alkyl-OH, optionally substituted d ⁇ 2 -alkyl-SH, optionally substituted
• Ci 12 -alkyl-am ⁇ no is intend to mean an optionally substituted alkyl chain of 1-12 carbons in length with an ammo group within or at the end of said chain.
• the ammo group may be a free ammo or optionally substituted
• optionally substituted am ⁇ no-d 12 -alkyl is intended to mean an ammo group bound to the central carbon of the bisphosphonic acid moiety, said ammo group further bound to an optionally substituted alkyl chain of 1-12 carbons in length
• Ci 12 -alkyl-C 3 9 -cycloalkyl is intended to mean an optionally substituted alkyl chain of 1-12 carbons in length with an optionally substituted C 3 9 -cycloalkyl at the end.
• substituents are to be understood in the same manner as defined for the term "optionally substituted Ci 12 -alkyl-C 3 9 -cycloalkyl"
• halogen is intended to mean that R 1 and R 2 may be independently selected from CI, Br, F and I.
• R 1 may be selected from hydrogen, halogen, -COOH, optionally substituted d 12 - alkyl, optionally substituted C 3 9 -cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted Ci 12 -alkyl-aryl, optionally substituted Ci 12 - alkyl-heteroaryl, heteroaryl, heterocyclyl, optionally substituted Ci 12 -alkylheterocyclyl, optionally substituted d d i 2 -alkyl-C 3 9 -cycloalkyl, ammo, optionally substituted d 12 -alkyl- amino, optionally substituted am ⁇ no-d 12 -alkyl, optionally substituted Ci 12 -alkyl-hal ⁇ de, optionally substituted d 12 -alkyl-OH, alkoxy, and optionally substituted d i 2 -alkyl-0-alkyl; and R 2 may be selected from hydrogen, halogen
• R 1 is selected from hydrogen, halogen, -COOH, alkoxy, d 12 - alkyl, optionally substituted d ⁇ 2 -alkyl-am ⁇ no, optionally substituted amino-Ci 12 -alkyl, optionally substituted Ci 12 -alkyl-0-alkyl, optionally substituted Ci 12 -alkyl-hydroxy, and optionally substituted d ⁇ 2 -alkyl-hal ⁇ de
• R 2 is selected from hydroxy, halogen, COOH, ammo, optionally substituted Ci 12 -alkyl-am ⁇ no, am ⁇ no-C 3 .
• R 1 is selected from the group consisting of halogen, hydroxy, ammo, and R 2 is a halogen, such as a chloro group. In a further suitable embodiment one or both of R 1 and R 2 is a hydroxy group. In a further suitable embodiment one or both of R 1 and R 2 is an optionally substituted alkyl ammo group. In a combination of suitable embodiments, one of R 1 and R 2 is hydroxy and the other and R 2 is a substituted ammo alkyl group, such as in ibandronic acid (l-hydroxy-3[methyl(pentyl) am ⁇ nopropyl ⁇ dene] l,l-b ⁇ sphosphon ⁇ c acid) or salts or hydrates thereof.
• ibandronic acid l-hydroxy-3[methyl(pentyl) am ⁇ nopropyl ⁇ dene] l,l-b ⁇ sphosphon ⁇ c acid
• R 1 and R 2 is a d- 12 -alkyl-heterocyclyl such as an i 12 -alkyl-pyrrol ⁇ dene, such as a d 6 -alkyl-pyrrol ⁇ dene such as a propyl-pyrrohdene, such as [l-Hydroxy-3-(l-pyrrol ⁇ d ⁇ nyl)propyl ⁇ dene]b ⁇ sphoshonate or salts or hydrates thereof.
• a d- 12 -alkyl-heterocyclyl such as an i 12 -alkyl-pyrrol ⁇ dene, such as a d 6 -alkyl-pyrrol ⁇ dene such as a propyl-pyrrohdene, such as [l-Hydroxy-3-(l-pyrrol ⁇ d ⁇ nyl)propyl ⁇ dene]b ⁇ sphoshonate or salts or hydrates thereof.
• the bisphosphanate is (6-Am ⁇ no-l- hydroxyhexyl ⁇ dene)b ⁇ sphosphonate (ne ⁇ dronate) or salts or hydrates thereof.
• R 1 and R 2 is an optionally substituted alkyl ammo group, such as an alkyl (d ⁇ alkyl)am ⁇ no group, such as the bisphosphonate is [3-(Dimethylamino)-l-hydroxypropylidene]bisphosphonate (olpadronate) or salts or hydrates thereof.
• alkyl ammo group such as an alkyl (d ⁇ alkyl)am ⁇ no group
• the bisphosphonate is [3-(Dimethylamino)-l-hydroxypropylidene]bisphosphonate (olpadronate) or salts or hydrates thereof.
• R 1 and R 2 is a C ⁇ - 12 -alkyl-heteroaryl, such as [l-Hydroxy-2-imidazo-( l,2a)pyridin-3-ylethylidene]bisphosphonate (minodronate) or salts or hydrates thereof.
• R 1 and R 2 is an optionally substituted amino-C 3 .
• 9 -cycloalkyl such as [(Cycloheptylamino)-methylene]bisphosphonate, (incadronate) or salts or hydrates thereof.
• R 1 is selected from hydrogen, halogen, amino, and C ⁇ - 12 -alkyl
• d- ⁇ -alkylamino and R 2 is selected from hydrogen, halogen, hydroxy, amino, d_ ⁇ 2 -alkylamino, -CH 2 COOH, -CH 2 P0 3 H 2 and - CH 2 CH 2 P0 3 H 2 .
• R 1 is selected from hydrogen and d-- 12 -alkyl
• R 2 is selected from hydroxy, amino, -CH 2 COOH, -CH 2 P0 3 H 2 and - CH 2 CH 2 P0 3 H 2 .
• R 1 is selected from d. 12 -alkyl and R 2 is selected from hydroxy.
• R 1 is selected methyl and R 2 is selected from hydroxy.
• one aspect of the invention is directed to a composition for the delaying the deposition of calcium pyrophosphate depots in hyaline cartilage, the fibrocartilage in the meniscus of the knee, the annulus fibrosus of the intervertebral disc, the synovial fluid, or the synovium and tendon insertions, comprising a bisphosphonic acid derivative, as defined supra.
• one aspect of the invention is directed to a composition for the treatment of pseudogout or chondrocalcinosis.
• a general aspect of the invention relates to the use of compounds of a bisphosphonic acid derivative for the inhibition of growth or delaying of growth of calcium pyrophosphate, in vivo or in vitro.
• one or both of R 1 and R 2 is a halogen, such as a chloro group.
• one or both of R 1 and R 2 is a hydroxy group.
• one or both of R 1 and R 2 is an optionally substituted ammo alkyl group.
• one of R 1 and R 2 is hydroxy and the other and R 2 is a substituted alkylamino group, such as in ibandronic acid (l-hydroxy-3[methyl(pentyl)am ⁇ nopropyl ⁇ den]l,l-b ⁇ sphosphon ⁇ c acid).
• Suitable embodiments of bisphosphonates approved by the Food and Drug Administration, U.S. Department of Health and Human Services are, e.g. Didronel (etidronate), Aredia (pamidronate), Fosamax (alendronate), Skelid (tiludronate), Actonel (risedronate), Zometa (zoledronic acid), Bonefos (clodronic acid), (Bondronate) ibandronic acid, neridronate, olpadronate, mcadronate, l-Hydroxy-3-(l-pyrrol ⁇ d ⁇ nyl)propyl ⁇ dene]b ⁇ sphoshonate, or [1- Hydroxy-2- ⁇ m ⁇ dazo-(l,2a)pyr ⁇ d ⁇ n-3-ylethyl ⁇ dene]b ⁇ sphosphonate.
• These compounds are, according to the present invention, useful for the treatment of CPDD or, as discussed infra, for the prevention or treatment of secondary caries or
• the medicament comprises a compound of formula I in combination with etidronate, pamidronate, alendronate, tiludronate, risedronate, or zoledronic acid, clodronic acid or ibandronic acid, neridronate, olpadronate, mcadronate, l-Hydroxy-3-(l-pyrrol ⁇ d ⁇ nyl)propyl ⁇ dene]b ⁇ sphoshonate, or [l-Hydroxy-2- ⁇ m ⁇ dazo-(l,2a)pyr ⁇ d ⁇ n-3-ylethyl ⁇ dene]b ⁇ sphosphonate or salts thereof.
• the bisphosphonates of the present invention may further be selected such that R 1 and R 2 are as outlined
• One further interesting aspect of the invention relates to the use of Didronel (etidronate) for the preparation of a medicament for the treatment of CPDD.
• a further embodiment of the invention relates to the use of Aredia (pamidronate) for the preparation of a medicament for the treatment of CPDD.
• a still further embodiment of the invention relates to the use of Fosamax (alendronate) for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of Skelid (tiludronate) for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of Actonel (risedronate) for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of Zometa (zoledronic acid or salts thereof) for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of Bonefos (clodronic acid or salts thereof) for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of Bondronate (ibandronic acid or salts thereof) for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of neridronate for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of olpadronate for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of mcadronate for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of l-Hydroxy-3-(l- pyrrol ⁇ d ⁇ nyl)propyl ⁇ dene]b ⁇ sphoshonate for the preparation of a medicament for the treatment of CPDD.
• a yet still further embodiment of the invention relates to the use of or [l-Hydroxy-2- ⁇ m ⁇ dazo-(l,2a)py ⁇ d ⁇ n-3-ylethyl ⁇ dene]b ⁇ sphosphonate for the preparation of a medicament for the treatment of CPDD.
• organophosphonates further encompassed by formula I are methane- hydroxybisphosphonic acid and ethane-l-am ⁇ no-l,l-b ⁇ sphosphon ⁇ c acid.
• An even more preferred organophosphonate according to the present invention is ethane-l-hydroxy-1,1- bisphosphonic acid, with the formula CH 3 C(OH)(P0 3 H 2 ) 2 (abbreviated EHDP).
• EHDP formula CH 3 C(OH)(P0 3 H 2 ) 2
• any pharmaceutically acceptable salt of ethane-l-hydroxy-l,l-b ⁇ sphosphon ⁇ c acid can be used in the practice of the present invention, the t ⁇ sodium hydrogen salt, the disodium hydrogen salt, the monosodium hydrogen salt, and mixtures thereof are preferred, e.g. :
• the cation selected in salts of compounds of formula I may be any cation known to the person skilled in the art, such as mineral salts such as sodium, potassium, calcium, ammonium, typically sodium, or organic salts.
• the cation selected in salts of compounds of formula I may be selected for allowing or improving the solubility of the compound of formula I, particularly in vivo or for improving the release of the compound of formula I for the medicament or disintegration of the medicament.
• salts of phosphonic acids such as those described herein, may crystallise as solvates, especially hydrates, which are sometimes preferred forms of the solid phosphonic acid salts due to increased stability.
• the compounds of the present invention as defined by formulas I, II and elsewhere herein, may form different solvates, such as hydrates, depending on the conditions of manufacture.
• the invention is intended to encompass all such solvates, including for instance mono-, d ⁇ -, tri-, tetra-, penta-, and hexahydrates, as well as hydrates of other stoichiomet ⁇ es, such as hemihydrates, and the like.
• the CPDD may be due to any morphology of any form of calcium pyrophosphate such as columnar crystals, needle crystals (acicular) morphologies.
• the calcium pyrophosphate may be of any hydration such as the mono-, d ⁇ -, tri-, or tetrahydrate.
• the calcium pyrophosphate may be selected from the group consisting of t ⁇ clinic and monoclinic.
• Preferred forms of the t ⁇ clinical morphology is the dihydrate, most preferably in the form of the needle or columnar crystals.
• Preferred forms of the monoclinic morphology is the dihydrate or tetrahydrate. With regards to the tetrahydrate, the ⁇ - form is most preferred.
• the medicament may be formulated according to conventional pharmaceutical practice, see, e.g., Remington's - The Science and Practice of Pharmacy, 20th Ed. Alfonso R.Gennaro (Ed.), Lippmcott, Williams & Wilkins; ISBN: 0683306472, 2000, and in
• the compounds defined herein are formulated with (at least) a pharmaceutically acceptable carrier or excipient.
• Pharmaceutically acceptable carriers or excipients are those known by the person skilled in the art.
• the term "pharmaceutically acceptable carrier” denotes a solid or a liquid filler or an encapsulating substance.
• Such substances may be selected from the group consisting of sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; gelatine, talc, malt, stearic acid, vegetable oils, polyols such as propylene glycol, polyethylene glycol, agar as well as other non-toxic compatible substances used in pharmaceutical compositions.
• the administration route of the compounds as defined herein may be any suitable route which leads to a concentration in the blood or tissue corresponding to a therapeutic concentration.
• the following administration routes may be applicable although the invention is not limited thereto: the oral route, the parenteral route, the buccal route, the intravenous route, the cutaneous route or the nasal route.
• the choice of administration route depends on the physico- chemical properties of the compound together with the age and weight of the patient and on the particular the condition and the severity of the same.
• the bisphosphonic acid derivatives as defined herein, or a pharmaceutically acceptable salt or hydrate thereof may be contained in any appropriate amount in a pharmaceutical composition, the pharmaceutical composition comprising an amount of about 1-95% by weight of the total weight of the composition.
• the composition may be presented in a dosage form which is suitable for the oral route, the parenteral route, the cutaneous route or the nasal route.
• the composition may be in form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, creams, plasters, drenches, delivery devices, mjectables, implants, sprays, aerosols and in other suitable form.
• the pharmaceutical composition comprising said compound is formulated for oral administration.
• a medically relevant concentration of the bisphosphonic acid derivative is 0.1 to 35 ⁇ M when dissolved in the animal body, typically 5 to 35 ⁇ M.
• Other medical relevant concentrations may however be used, depending on the individual condition of the subject, i.e. the severity and course of the disease, the subjects health and response to the particular treatment.
• other medical relevant concentrations of the bisphosphonic acid derivative may be lower, such as 0 5-40 ⁇ M, or higher, such as 36- 50 ⁇ M.
• the medicament comprises the bisphosphonic acid derivative in an amount so as to achieve a concentration 0.1 to 200 ⁇ M in the body, such as 0.1 to 100 ⁇ M, such as 0.1 to 50 ⁇ M, typically 0.1 to 40 ⁇ M, more typically 1 to 30 ⁇ M, most typically 5 to 30 ⁇ M.
• the medicament of the invention may vary between high dosage and low dosage forms.
• the medicament comprises 5- 2000 mg of the comprises the bisphosphonic acid derivative, such as 10-1000 mg, such as 20- 500 mg, such as 50-500, such as 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg of the compound of formula I.
• the medicament comprises 50-250 mg of the comprises the bisphosphonic acid derivative.
• FIG. 1 For embodiments of the invention relate to the use of a bisphosphonic acid derivative for the treatment of CPDD in hyaline cartilage; for the treatment of CPDD in the fibrocartilage in the meniscus of the knee; for the treatment of CPDD in the annulus fibrosus of the intervertebral disc; for the treatment of CPDD in synovial fluid; for the treatment of CPDD in the synovium and tendon insertions; and wherein the CPDD is in the articular cartilage.
• the CPDD is confined to the hyaline cartilage, the fibrocartilage in the meniscus of the knee, the annulus fibrosus of the intervertebral disc, or the synovium and tendon insertions.
• the CPDD is especially confined to the synovial fluid or to the articular cartilage of the mammal, the mammal of which preferably is a human.
• the mammal to be treated has in one already suffering from deposits of calcium phosphate, and diagnosed as such.
• the mammal to be treated may have existing deposits, such as diagnosed as having CPDD.
• one interesting embodiment relates to the use of a compound of formula for the treatment of someone already diagnosed as having CPDD.
• the treatment may be to a mammal not presently suffering but deemed prone to suffer from CPDD, such as to a mammal taking a medicament which has as side effects an increased likelihood of CPDD; or to a mammal over 40 years old, such as over 50, such as over 60 years old; or to a mammal whose family has a history of CPDD thus having a genetic predisposition for CPDD; or to a mammal whose lifestyle increases the likelihood of having CPDD, such as due to dietary habits or professional occupation.
• a further embodiment of the invention relates to the use of a bisphosphonic acid derivative for the prophylactic treatment of CPDD.
• the invention further relates to a method of treating or preventing secondary caries.
• the invention relates to a method of treating a mammal suffering from primary caries.
• a further aspect of the present invention relates to the use of a bisphosphonic acid derivative for the manufacture of a medicament for the prevention or treatment of secondary caries in an animal, preferentially a human.
• second caries when used herein, is defined as caries that forms beneath, behind, in the vicinity of “primary caries”, i.e. beneath, behind or in the vicinity of caries that has already formed and subsequently been treated according to any conventional means known to the person skilled in the art.
• primary caries i.e. beneath, behind or in the vicinity of caries that has already formed and subsequently been treated according to any conventional means known to the person skilled in the art.
• aries is intended to mean “cavities” and may also relate to softened tooth material.
• An interesting aspect of the invention relates to a dental filling material, used in the treatment of caries, comprising a bisphosphonate derivative.
• the dental filling material may further comprise conventional materials used in tooth fillings,
• the secondary caries may be confined to the interface of the natural dental material (enamel, dentine, cementum and root material) and the filling material.
• the filling material is typically selected from the group consisting of amalgam and/or plastic but may be of any type used in dental care.
• a further embodiment of this aspect of the invention relates to the use of a bisphosphonic acid derivative for the treatment of mammal suffering from primary caries.
• the bisphosphonic acid derivative used for the manufacture of a medicament for the prevention or treatment of secondary caries or for the treatment of mammal suffering from primary caries may be selected from a bisphosphonic acid derivative as defined supra.
• any pharmaceutically acceptable salt of the compound of formula II may be used in the practice of the present invention, the t ⁇ sodium hydrogen salt, the disodium hydrogen salt, the monosodium hydrogen salt, and mixtures thereof are preferred.
• a further aspect of the invention is directed to a composition for the treatment or prevention of secondary caries comprising a bisphosphonic acid derivative of the formula I
• the medicament comprises a compound of formula I in combination with etidronate, pamidronate, alendronate, tiludronate, risedronate, or zoledronic acid.
• one interesting aspect of the invention relates to the use of Didronel (etidronate) for the preparation of a medicament for the treatment of treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• a further embodiment of the invention relates to the use of Aredia (pamidronate) for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• a still further embodiment of the invention relates to the use of Fosamax (alendronate) for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• a yet still further embodiment of the invention relates to the use of Skelid (tiludronate) for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• Skelid titaniumudronate
• Actonel risedronate
• Zometa zoledronic acid
• a yet still further embodiment of the invention relates to the use of for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• a yet still further embodiment of the invention relates to the use of olpadronate for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• a yet still further embodiment of the invention relates to the use of incadronate for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• a yet still further embodiment of the invention relates to the use of l-Hydroxy-3- (l-pyrrolidinyl)propylidene]bisphoshonate for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• a yet still further embodiment of the invention relates to the use of or [ 1-Hydroxy- 2-imidazo-( l,2a)pyridin-3-ylethylidene]bisphosphonate for the preparation of a medicament for the treatment of secondary caries or the treatment of a mammal suffering from primary caries.
• the composition may be typically be formulated in the form of a depot, paste (such as a tooth-paste), putty, rinse solution, mouth-wash, lozenge or gum.
• a relevant concentration of the bisphosphonic acid derivative is up to the saturation point of the bisphosphonic acid derivative in the composition or solution, such as 0.001 to 50 M, such as 0.001 to 20 M, such as 0.001 to 10 M, such as 0.001 to 5 M, typically 0.01 to 5 M, more typically 0.01 to 1 M, such as 0.1 to 1 M.
• concentrations or amounts of bisphosphonic acid derivative in the composition depends on the nature of the composition and intended use. Solutions used as rinse by the dental practitioner before applying the filling (upon repair of a primary carie) may be of a different concentration than a depot to be applied between the tooth material and the filling material or of a dental filling material comprising the bisphosphonic acid derivative. Similarly, tooth pastes, lonzenges and gums are anticipated to have differing amounts or concentrations of the bisphosphonic acid derivative
• An interesting aspect of the invention relates to a dental filling material, a depot, toothpaste, rinse solution, mouth-wash, lozenge or gum comprising a bisphosphonic acid derivative, as defined herein.
• salts of phosphonic acids may crystallise as solvates, especially hydrates, which are sometimes preferred forms of the solid phosphonic acid salts due to increased stability.
• the salts of the compounds of the present invention may form different solvates, such as hydrates, depending on the conditions of manufacture.
• the invention is intended to encompass all such solvates, including for instance mono-, di-, tri-, tetra-, penta-, and hexahydrates, as well as hydrates of other stoichiometries, such as hemihydrates, and the like.
• the composition or medicaments of the invention are generally intended for the prevention of growth of calcium pyrophosphate depositions. The following Examples demonstrate, in a non-limiting fashion, the use of the compounds of formula I as a medicament as discussed supra.
• the prepared stock was mainly m-CPPD but with some t-CPPD, the most stable form of calcium pyrophosphate (CPP).
• the specific surface area of the m-CPPD stock is 1.35 m 2 /g.
• the prepared crystals have a short needle-like shape with the longest dimension measuring about 10 ⁇ m.
• Stock crystals of acicular t-CPPD for use in the following examples, were prepared according to the method of Ch ⁇ stoffersen et al. (Kinetics and mechanism of dissolution and growth of acicular t ⁇ clinic calcium pyrophosphate dihydrate), .R. Ch ⁇ stoffersen, T. Bahc-Zunic and J. Ch ⁇ stoffersen, Crystal Growth and Design, 2002, 2, 567-571.
• the specific surface area of these stock crystals is 2.8 m 2 /g.
• m-CPPT ⁇ Stock crystals of m-CPPT ⁇ , for use in the following examples, were prepared according to the method of Ch ⁇ stoffersen et al. (Growth and precipitation of a monoclinic calcium pyrophosphate tetrahydrate indicating auto-inhibition at pH 7, J. Crystal Growth, 212, 500- 506).
• the specific surface area of the m-CPPT ⁇ stock crystals is 6 m 2 /g
• the compound EHDP for use in the following examples, was in the form of a disodium salt and in the form of the tetra-acid.
• Example I The compound EHDP, for use in the following examples, was in the form of a disodium salt and in the form of the tetra-acid.
• the following examples serve to illustrate the effect that the presence of EHDP has on solutions that 1) are supersaturated (or unsaturated) with calcium pyrophosphate and 2) solutions that further comprise various stock crystals of calcium pyrophosphate dihydrate.
• the various stock crystals used in the following examples are: monoclinic CPPD (m-CPPD), columnar and acicular morphologies of tnclmic CPPD (t-CPPD), and monoclinic CPPT (m-CPPT ⁇ ).
• the supersaturation, S is defined as
• a is the mean ion activity
• IP the activity product
• K s the solubility product.
• the index s refers to a saturated solution.
• the supersaturation S is calculated using an ion speciation programme "Ionics" and "Kielland" activity coefficients, the calculation of which is known by the person skilled in the art.
• pH is kept constant at 6.5 by titration with 2.0 mM KOH.
• S 0 , t -c D 6.3.
• pH is kept constant at 7.0 by titration with 2.0 mM KOH.
• S 0,m -cpp ⁇ 3.1. *EHDP from Kasei Kogyo Co., Japan is used.
• Tables 5 and 6 below serve to illustrate the spontaneous precipitation of calcium pyrophosphate, CPP, at room temperature, with and without the addition of 10 ⁇ M EHDP.
• the initial calcium concentration, C Ca, o; is 0.9 mM in all the experiments.
• C PP is the calcium pyrophosphate concentration
• C EHDP is the concentration of the compound ethane-1- hydroxy-l,l-bisphosphonic acid.
• t p is the time, after mixing EHDP and m-CPPT ⁇ , at which the onset of precipitation is observed, i.e. as a clear decrease in the pH-value.
• the pH at time t p is pH p .
• S p , m . CP p T is the supersaturation of m-CPPT at time t p .
• a "clear decrease" is defined as a decrease in pH of 0.5-0.6 units over a relatively short time.
• Table 7 below serves to illustrate the spontaneous precipitation of calcium pyrophosphate, CPP, from solutions supersaturated with respect to CPP, but without the addition of crystals.
• the induction time, t p denotes the time, after mixing EHDP and the solution supersaturated with CPP, at which the onset of precipitation is observed, i.e. as a clear decrease in the pH-value.
• Example IV Use of EHDP in the context of calcium pyrophosphate deposition disease
• the required dosage of the bisphosphonic acid derivative will vary with the particular condition to be treated, the severity of the of the condition, the duration of the treatment and the specific bisphosphonic acid derivative employed.
• single oral dosages of the bisphosphonic acid derivative such as the salt of ethane-l-hydroxy-l,l-bisphosphonic acid
• Said oral dosages may be administered preferably up to two times daily, such as up to three times daily, preferably such as up to four times daily. Dosages greater than, e.g., 500 mg per kilogram of body weight may produce toxic symptoms and should be avoided.
• the active compound EHDP may be formulated in the form of capsules, tablets or granules, preferably prepared in unit dosage form together with a pharmaceutically acceptable carrier.
• the pharmaceutically acceptable carrier comprises from 0.1 to 95 percent by weight of the total composition, such as from 0.1 to 98 percent by weight of the total composition.
• the active compound EHDP may also be administered parentally in aqueous solution to the subject by subcutaneous, intradermal, intramuscular or intravenous injection.
• the dosage may range from 0.05 to 15 mg per kilogram of body weight or such as from 0.5 to 10 mg per kilogram of body weight.
• the following example serves to illustrate the physical impact (binding strength) when adding EHDP to dental enamel imbedded in a plastic matrix, and an appropriate means for applying said compound.
• the example serves to illustrate the binding strength between dental enamel and a plastic filling material, when said dental enamel is treated with EHDP.
• a form with a small cylindrical hole was placed on a specimen. 6.
• the hole was filled with a dental plastic filling material, that does not bind to the form, but which binds to the dental enamel.
• the dental plastic filling material was polymerised by treatment with ultraviolet light, with an lamp used to polymerise this type of plastic filling in normal dental
• the force per unit area required for the specimen not treated with EHDP was 16.5 15 MPa.
• the force per unit area required for the specimen treated with EHDP was 18.7
• the above example could well be expanded so as to include the measurement of other parameters such as, e.g., surface roughness and adhesion. It is further anticipated that the chemical stability is able to be measured over time. Hence, it is anticipated that the chemical stability between the dental enamel and the plastic material can be monitored over time, both with and without the addition of EHDP to the dental enamel. For example,
• EHDP may be applied, in an aqueous solution, onto a 30 tooth subject to primary caries. It is anticipated, that the solution is applied onto the enamel after the tooth has been treated for the primary caries, according to any conventional method known to the person skilled in the art, but prior to the filling of the primary caries with a filling material, such as amalgam or plastic.
• the required dosage in the present context is such that the concentration of EHDP in the aqueous solution is in the 35 range of from 0.001 to 5 M, preferably such as from 0.1 to 1 M.
• the amount administered to the caries should be in the range of from 0.5 to 5 droplets, e.g., such as from 0.0025 ml to 0.25 ml.
• the amount of droplets is determined by the size or extent of the caries; the requirement is that the entire surface of the caries is substantially covered by a thin layer of the aqueous solution.

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