Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-05-29
2003-12-30
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S900000, C514S902000
Reexamination Certificate
active
06670343
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an agent for periodontal disease, which comprises, as an active component, a methanebisphosphonic acid derivative or a hydrate thereof.
BACKGROUND ART
Periodontal disease is the disease of tissues that surround and support teeth. These include the gingiva, cementum, periodontal ligament, alveolar process bone, and dental supporting bone. Specifically, periodontal disease also includes a disease in the pulp tissue such as early stage of apical periodontitis which occurs subsequent to the inflammation or necrosis of the dental pulp, in addition to so-called “periodontal disease” including gingivitis or periodontitis.
Periodontal disease involves the inflammation, destruction and degeneration of periodontal tissues that surround and support mammalian teeth. These periodontal tissues include the crevicular epithelium, junctional epithelium, external marginal epithelium, gingiva, alveolar bone, periodontal ligament, and cementum. The loss of supporting bone in periodontitis is the latest stage of this progressive disorder and is the major cause of tooth loss in adults.
The periodontal disease is classified as gingivitis and periodontitis according to the progress of disease. The term “gingivitis” means a condition in which inflammation is localized within the gingiva and no lesion occurs in the bone and periodontal ligament, and a pocket is relative pocket. In principle, it indicates a condition in which the base of pocket is on the dental crown side upward from the cementum-enamel junction and there is no attachment loss. The term “periodontitis” means a condition in which the inflammation of gingiva reaches the periodontal ligament and alveolar bone, the pocket becomes a periodontal pocket, and the attachment level (the position of attachment) is on the root apex side downward from the cementum-enamel junction. The inflammation prolongs and proceeds toward deep parts with a deepening periodontal pocket.
Initiators of these “periodontal diseases” include dental plaque and dental calculus. Factors to enhance the initiator or to modify inflammation caused by the initiator include the promoting factors of dental plaque and dental calculus, and abnormal occlusion.
The destruction of tissue due to periodontal disease is predominantly caused by dental plaque attached between the teeth and gingiva. Specifically, a histolytic enzyme or toxin produced by bacteria in the plaque directly induces the destruction of tissue, or such a substance produced by the plaque bacteria induces inflammation and immunoreaction in the periodontal tissue, and immunoreacive cells, such as leukocytes, secondarily cause the destruction of tissue. In the early stages of periodontal disease, the tissue to be destructed is mainly gingival epithelium, junctional epithelium and gingiva, and the aforementioned condition of gingivitis is exhibited. With continuous invasion of a harmful substance from the plaque, the inflammation proceeds toward deep parts and the gingival tissue is destructed, reduced and recessed to thereby cause the shift of the junctional epithelium toward the root apex side. The junctional epithelium is then peeled off from the tooth plane to cause attachment loss to thereby form a periodontal pocket. When the periodontal pocket increases in depth, a subgingival plaque increases to thereby make further progress of the lesion. When the inflammation reaches the deep parts, it exhibits the condition of periapical periodontitis associated with the destruction of periodontal ligament fiber, and additionally, the activity of osteoclasts around the alveolar bone increases to thereby make progress of bone resorption. Factors that directly induce the tissue destruction include collagenase, hyaluronidase, protease and other enzymes, and endotoxin, leukotoxin and other toxins which are produced by the plaque bacteria. Additionally, there is a secondary destruction of tissue through the mediation of inflammation and/or immunoreaction. Specifically, when the product of the plaque bacteria intrudes into the gingival connective tissue, it is captured by macrophages, and, concurrently, a lysosomal enzyme is released. Additionally, a B lymphocytes stimulated by macrophages produce antibodies to thereby form an antigen-antibody complexes (immunocomplexes). This complexes activate a complement to increase vascular permeability and induce the chemotaxis of neutrophils. The neutrophils englobe such an immunocomplex, but it concurrently releases lysosomal enzymes to the surrounding tissues to thereby make further progress of the destruction of tissue. It is considered that LPS and other toxins released from the plaque bacteria, prostaglandin E
2
(PGE
2
) produced by the macrophage,as an inflammatory cell (immunoreactive cell), osteoclast-activating factor released from T lymphocyte, and interleukin-1 and interleukin-6 released from the macrophage induce the activation of osteoclast. When the destruction of the alveolar bone proceeds, the supporting power of the teeth is ultimately decreased to thereby induce tooth loss.
Alternatively, the teeth can be lost by apical periodontitis in which inflammation occurs in the apical area of infected dental root. Such apical periodontitis is caused by infection from the dental pulp via the root apex hole, external injury, hematdgenous infection, as well as mechanical or chemical stimuli.
Antibiotics are used for the treatment of periodontal disease in order to suppress the plaque bacteria, but this is not effective for long term treatment. Home care such as gargling, brushing or the use of dental floss aids the suppression of the periodontal disease. Additionally, the combination use of gingival massage with brushing to enhance local blood supply is also effective to suppress the progress of periodontal disease. Another prophylactic treatment is hydrogen peroxide gargle. (3% H
2
O
2
in warm water). Likewise, carbamide peroxide (urea-hydrogen peroxide, CH
6
N
2
O
3
) is also used for the local treatment of inflammation in slight infection and periodontitis.
An additional approach to the treatment of periodontal disease includes the use of non-steroidal anti-inflammatory agents to suppress disease progression. It is known according to U.S. Pat. No. 4,667,132 that the analgesic and anti-inflammatory agent Etodolac may inhibit bone resorption and bone loss associated with periodontal disease. U.S. Pat. No. 4,440,779 describes the use of novel tricyclic analgesic and anti-inflammatory agents as being useful in the-treatment of pain and inflammatory conditions associated with, for example, arthritis, spondylitis, gout, and periodontal diseases.
The use of several bisphosphonic acid derivatives in the treatment of broad range of calcium metabolism disorders including periodontal diseases is known. European Unexamined Patent Application Publication No. 320,455 discloses the use of a N-aralkylamino-1-hydroxyalkane-1,1-bisphosphonic acid derivative, as being effective for the treatment of inflammatory/degenerative articular disease, osteoporosis, periodontitis and hyperthyroidism. Japanese Unexamined Patent Application Publication No. 1-197495 discloses the use of an aromatic-substituted azacycloalkylalkanebisphosphonic acid for a disease in which calcium metabolism disorder or the abnormal deposition of an insoluble calcium salt is observed, and refers to periodontitis or periapical periodontitis.
Additionally, the effects of bisphosphonic acid derivatives on tooth loss due to the destruction of the alveolar bone, which occurs in periodontitis, are known. For example, U.S. Pat. No. 5,283,057 discloses the use of 1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid, as being effective for the suppression of alveolar bone resorption or tooth migration after surgical orthodontics. U.S. Pat. No. 5,270,365 discloses the use of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, as being effective for alveolar bone loss or tooth loss. However, it has been reported that 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is not effective f
Ito Masatoshi
Kawabe Norio
Kawai Yuriko
Okazaki Seiji
Piper Rudnick LLP
Rose Shep K.
Toray Industries Inc.
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