Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-03-28
2004-02-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000
Reexamination Certificate
active
06692758
ABSTRACT:
The present invention relates to an implant attachment stabilizer, an interstitial tissue proliferation inhibitor and an osteolytic factor production inhibitor having, as an effective component, a methane-bisphosphonic acid derivative or hydrate thereof.
TECHNICAL BACKGROUND
In osteolysis or bone destruction occurring in acute or chronic inflammation involving bone, not only bone resorption by osteoclasts but also interstitial tissue proliferation or produced osteolytic factors are involved to a considerable extent, but no basic medication therefor has been discovered. Furthermore, in the case of the attachment of the implants such as artificial joints carried out in the orthopaedic surgery and dentistry fields, a problem which arises is that, following attachment, loosening occurs and detachment finally results. Consequently, the implant must be reattached by another surgical operation and this imposes an interim lowering in quality of life and a financial burden on the patient. The cause of implant loosening and detachment is considered to be the occurrence of damage to tissues such as bone present at the implant periphery. In particular, in bone tissue, bone resorption markedly increases and osteolysis occurs.
At present, in order to inhibit such bone resorption at the time of implant attachment, consideration is being given to the use of the oestrogen agents [
J. Clin. Invest
., 89 (1), 74-78 (1992)] and bisphosphonic acids employed as osteoporosis remedies in humans. In fact, a method for treating/preventing prosthesis peripheral bone loss using bisphosphonate bone resorption inhibitors such as Alendronate [(4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid], which is a bisphosphonic acid compound, has been disclosed [U.S. Pat. No. 5,646,134]. Furthermore, in the case of 1-hydroxyethane-1,1-bisphosphonic acid, there is a report that this inhibits the bone resorption occurring as a result of artificial joint wear debris produced at the time of artificial joint use [
Acta Orthopaedica Scandinavica
, 67 (3), 221-228 (1996)]. However, on the other hand there is also a report suggesting that 1-hydroxyethane-1,1-bisphosphonic acid inhibits the expression and activity of osteoblasts, which play a role in forming bone, so that difficulties arise in its use at the time of implant attachment [
Acta Histochemica
, 96 (2), 181-195 (1994)]. Furthermore, regarding Alendronate too, there is a report that it cannot prevent artificial joint loosening [
Acta Orthopaedica Scandinavica
, 70 (1), 67-70 (1999)] and it is unlikely that the manifestation of an adequate effect can be expected.
Furthermore, the use of the aforementioned compounds is in each case based on the fact that they have a direct inhibitory action on the osteoclasts which play a role in resorbing and breaking-down bone, and no mention is made of the effects on the proliferation of interstitial tissue such as granulation tissue and the production of the osteolytic factors produced by interstitial tissue, which occur prior to the bone tissue destruction. As known examples of osteolytic factors, there are interleukin-1, TNF&agr; and other such cytokines. For example, early in the 1980s it was proved using an organ culture of bone that interleukin-1 has a powerful osteolytic action [
Nature
, 306, 378-380 (1983)]. Furthermore, in a rat foetal bone organ culture system, it has been reported that TNF&agr; acts in osteolysis [
Nature
, 319, 516 (1986)] and that it acts synergistically with interleukin-1. There is also a report that Alendronate [(4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid] inhibits the production of interleukin-1, interleukin-6 and TNF&agr; from activated macrophage (
Journal of Bone and Mineral Research
, 11, 1719-1725 (1995)), but it is reported that it cannot prevent artificial joint loosening (
Acta Orthopaedica Scandinavica
, 70 (1), 67-70 (1999)). Thus, it is clear that the prevention of implant loosening is not simply linked to an inhibition of cytokine production. Furthermore, it has been reported that bisphosphonic acids such as Clodronate (dichloromethanebisphosphonic acid) inhibit the proliferation of granulation tissue around the antigen in delayed hypersensitivity, which is an allergic reaction condition (
Journal of Pharmacology and Experimental Therapeutics
, 266, 1691-1698 (1993)), but the non-allergic proliferation of granulation tissue formed as a result of implant attachment is not mentioned at all. Consequently, there are no disclosed examples of the use, as implant stabilizers, of drugs which inhibit the aforementioned interstitial tissue proliferation and production of osteolytic factors such as interleukin-1 and TNF&agr;, which occur prior to bone resorption at the periphery of implants and cause implant loosening and detachment. On the other hand, in JP-B-8-26048, there are disclosed methanebisphosphonic acid derivatives having an anti-inflammatory effect, an antirheumatic effect, a metabolic bone disorder improving effect, an interleukin-1 inhibiting effect and an antioxidation effect, but there is no disclosure at all relating to implant attachment stabilization efficacy.
An objective of the present invention lies in offering a novel implant attachment stabilizer for preventing the loosening and detachment of, for example, artificial joints and dental implants, and for extending the implant attachment period. Other objectives of the invention lie in offering an interstitial tissue proliferation inhibitor and an osteolytic factor production inhibitor.
DISCLOSURE OF THE INVENTION
As a result of painstaking study based on the aforesaid objectives, the present inventors have discovered that methanebisphosphonic acid derivatives represented by general formula (I), or hydrates thereof, inhibit interstitial tissue proliferation and inhibit osteolytic factor production, and, furthermore, they have discovered that by means of this inhibition of the proliferation of interstitial tissue accompanying implant attachment and the inhibition of the production of osteolytic factors such as interleukin-1 and TNF&agr; at the implant periphery, the implant attachment period may be extended, and it is on these discoveries that the present invention is based.
In order to realise the aforementioned objectives, the present invention has the following constitution. Specifically, the present invention offers an implant attachment stabilizer, an interstitial tissue proliferation inhibitor and an osteolytic factor production inhibitor having, as an effective component, a methanebisphosphonic acid derivative represented by general formula (I)
[where, in the formula, X represents a straight chain or branched chain unsubstituted, or nitrogen, oxygen or silicon atom substituent-containing, alkyl group with from 1 to 8 carbon atoms, a phenyl group or a naphthyl group (the phenyl or naphthyl group may also be substituted with a straight chain or branched chain alkyl group having from 1 to 8 carbon atoms, a straight chain or branched chain alkoxy group having from 1 to 8 carbon atoms, a halogen or a hydroxyl group), Y represents a straight chain or branched chain alkyl group having from 1 to 8 carbon atoms, a trifluoromethyl group, a straight chain or branched chain alkenyl group having from 2 to 8 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, an alkoxy group having from 1 to 8 carbon atoms or a halogen (excepting para-substituted chlorine), m and n represent 0, 1, 2 or 3,
represents a double bond or a single bond, A is —(D)
b
—(CH
2
)
C
— (where D is sulphur, oxygen or NR
5
(where R
5
represents hydrogen or a straight chain or branched chain alkyl group having from 1 to 8 carbon atoms), or CH
2
, b is 0 or 1, c is 0, 1, 2, or 3), or —(CH═CH)
d
—CH═ (where d is 0 or 1, and when A represents —(CH═CH)
d
—CH═, B is not present), B represents hydrogen, a straight chain or branched chain alkyl group having from 1 to 8 carbon atoms, a hydroxyl group or a trialkylsiloxy group (wher
Ito Masatoshi
Iwase Miho
Kawai Yuriko
Kim Kang Jung
Okazaki Seiji
Bennett Rachel M.
Page Thurman K.
Toray Industries Inc.
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