Drug – bio-affecting and body treating compositions – Dentifrices
Reexamination Certificate
2002-05-23
2004-01-27
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Dentifrices
C514S108000, C514S102000
Reexamination Certificate
active
06682718
ABSTRACT:
TECHNICAL FIELD
This invention relates to medicaments, particularly a pharmaceutical composition for periodontitis treatment as periodontal tissue local injection, which comprises a bisphosphonic acid derivative or a salt thereof as an active ingredient.
TECHNICAL BACKGROUND
Periodontitis is a disease in which chronic gingivitis progresses and inflammation is also spread to periodontal tissues other than gingiva, which accompanies progressive destruction of periodontal tissues. Clinically, chronic inflammation of gingiva, bleeding from periodontal pockets, alveolar bone resorption and the like are observed, and it is known that mobility and movement of teeth occur as the destruction advances, finally causing spontaneous loss of a tooth or a necessity of tooth extraction. The treatment of periodontitis includes removal of dental plaque and dental calculus as causal substances, and removal of degenerative, necrosed tissues by root planing and periodontal surgery and the like for the purpose of effecting reattachment of gingiva (Periodontal Therapy (2nd edition), pp. 215-226 (1992), published by Ishiyaku Shuppan). In the drug therapy of periodontitis, tetracycline antibiotics are mainly used with the aim of removing periodontitis-associated bacteria. However, a drug that directly acts upon alveolar bone resorption, which is an important clinical manifestation of periodontitis, does not exist to date, so that a drug having such an action is expected to have usefulness as a novel therapeutic agent for periodontitis.
Bisphosphonate (hereinafter, BP) is a structural analog of pyrophosphoric acid, which is stable in the living body, and has biological actions such as heterotopic calcification inhibitory action, bone resorption inhibitory action and the like. BP has already been used in the clinical field as a therapeutic agent for hypercalcemia accompanied by a malignant tumor, Paget's disease, osteoporosis and the like, and its action on alveolar bone resorption caused by periodontitis is also expected due to its pharmacological actions. An action of BP to inhibit periodontal tissue destruction in rats has been reported (
J. Dent. Res
., 11, 1430-1433 (1988)), and it has been reported in recent years that alendronate, which is a second generation BP, inhibited alveolar bone destruction in monkey and dog periodontitis models by its oral administration (
J. Periodontol
., 63, 825-830 (1992),
J. Periodontol
., 66(3), 211-217 (1995)). Also, it has already been reported that incadronate disodium (chemical name disodium cycloheptylaminomethylenediphosphonate monohydrate; to be referred to as incadronate hereinafter) is a third generation BP having potent bone resorption inhibitory action (Japanese Patent Publication No. 629/1995) and exerts alveolar bone loss inhibitory action in a hamster periodontitis model (
Dentistry Basic Medicine Journal
, 36(5), 510-519 (1994)) and alveolar bone loss inhibitory and attachment level improving actions in a canine periodontitis model, by its subcutaneous or oral administration respectively (
J. Periodont. Res
., 33, 196-204 (1998)).
In such oral administration, subcutaneous injection, intravenous injection and the like systemic administrations, it is considered that bone resorption inhibitory action is exerted by the transfer of drug effect-inducing amount of BP into an affected part of the alveolar bone, and there is a possibility that BP is simultaneously transferred into other tissues in the same manner, and express bone resorption inhibitory action particularly in systemic bone tissues in the same manner, thus inducing undesirable actions.
On the other hand, attempts have been made to administer BP topically; for example, it has been reported that topical administration of risedronate to the sub-periosteum area adjacent to the first molar and topical administration of pamidronate to sub-mucasa on palate-side are effective in rat molar experimental tooth movement models (
J. Dent. Res
., 73(8), 1478-1484 (1994);
Orthod. Waves
, 57(5), 307-317 (1998)).
However, there are no reports to date on alveolar bone resorption inhibitors for use in the topical administration of BP, which are clinically usable in human. Actually, since there are differences in the shape, size, stimulation property and the like of periodontal tissues between rats and human, it is difficult to predict suitable topical administration concentration, dose, administration method and the like at human periodontal tissues or their periphery from the above information in rats.
WO 93/11774 discloses a periodontitis-treating agent of alendronate, but its main administration method is a systemic administration by oral administration or intravenous injection. Regarding its topical administration, it is described that it can be directly applied to inflammatory parts of teeth and gingiva, but there are no illustrative disclosures on its dose, administration site and the like, merely suggesting a possibility. What is more, in this method for directly applying it to inflammatory parts of teeth and gingiva, not only transfer rate of BP into alveolar bone is low but also a possibility of orally systemic administration with saliva is suggested, so that its alveolar bone-selective administration cannot be expected at all.
In addition, there are reports stating that a BP having amino group has a local irritative property (
Lancet
, 348, No. 9023, 345-346 (1996);
Br. Med. J
., 295, No. 6609, 1301-1305 (1987)), that is, it is completely unclear whether or not the treatment of periodontitis by topical administration of BP to periodontal tissues or adjacent tissues thereof in human is actually possible.
Great concern has been directed toward the creation of a topical administration medicament useful as a periodontitis treating agent containing BP as the active ingredient, which has an alveolar bone-selective bone resorption inhibitory action, is convenient as the administration method and has high practical values clinically in human.
DISCLOSURE OF THE INVENTION
The present inventors have carried out examinations on the periodontitis treating agents for topical administration using a canine periodontitis model having periodontal tissues bearing resemblance to those of human, making use of incadronate whose periodontitis treating action had been confirmed by oral administration, and found unexpectedly that BP can be transferred alveolar bone-selectively and good alveolar bone resorption inhibitory action and periodontitis treating action can be expressed, when BP is topically injected using an alveolar mucosa injection method conventionally used as a method for injecting anesthetic drugs in the field of dentistry, thereby accomplishing the invention. What is more, this administration method was a topical administration method, which is easy to handle, has less burden to patients and has clinically high practical value.
Accordingly, the invention relates to a pharmaceutical composition for treating human periodontitis, which comprises a bisphosphonic acid derivative or a salt thereof and a pharmaceutically acceptable carrier, characterized in that it is for topical injection by an alveolar mucosa injection method. The injecting volume of the pharmaceutical composition of the invention for topical injection by an alveolar mucosa injection method is preferably from 100 to 300 &mgr;l per one administrating site. Also, a pharmaceutical composition in which the bisphosphonic acid derivative or a salt thereof is incadronic acid or a salt thereof is desirable, and a pharmaceutical composition in which concentration of incadronic acid or a salt thereof is from 3.33 to 100 &mgr;g/ml is more desirable. Dose of incadronic acid or a salt thereof is preferable from 0.5 &mgr;g to 15 &mgr;g per one administrating site.
In addition, according to the inventors' studies, canine periodontal tissues were apt to undergo influence of local irritation by BP, and good therapeutic effects could not be obtained due to the local irritation at a concentration of topical dose capable of achieving an alveolar bone concen
Iwai Takaya
Kanoh Hiroyuki
Motoie Hiroyuki
O'Uchi Naoto
Yoshino Taiji
Rose Shep K.
Sughrue & Mion, PLLC
Yamanouchi Pharmaceutical Co. Ltd.
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