JP2001213780A - Periodontal disease medical trreatment composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a local dose medicine effective as alveolus bone absorption restraint agent. SOLUTION: The periodontal disease medical treatment composition for local injection by an alveolus mucous membrane piercing method with bisphoshonic acid derivative or its salt as the effective component is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition for treating periodontal disease, which contains a drug, particularly a bisphosphonic acid derivative or a salt thereof, as an active ingredient for local injection of periodontal tissue.

[0002]

2. Description of the Related Art Periodontal disease is a disease in which chronic gingivitis progresses and inflammation spreads to periodontal tissues other than gingiva, accompanied by progressive destruction of periodontal tissues. Clinically, chronic gingival inflammation, bleeding from periodontal pockets, resorption of alveolar bone, etc. are observed, and tooth sway and movement occur due to the progress of destruction. It is known to occur. Treatment of periodontal disease includes removal of plaque and calculus, which are causative substances, root planing for reattachment of gingiva, and removal of degenerated necrotic tissue by periodontal surgery (Medicine Dental Publishing Co., Ltd.) Published Periodontology (Second Edition) 215
226 (1992)). Drug treatment for periodontal disease
Tetracycline antibiotics are mainly used for the purpose of removing periodontitis-related bacteria. However, there is currently no drug that directly affects the alveolar bone resorption, which is an important clinical picture of periodontal disease, and a drug with such an effect is expected to be useful as a new therapeutic agent for periodontal disease. You.

[0003] Bisphosphonate (hereinafter referred to as BP) is a structural analog of pyrophosphate that is stable in vivo and has biological effects such as an ectopic calcification inhibitory action and a bone resorption inhibitory action. BP is hypercalcemia associated with malignant tumor, bone Page
Although it has already been used clinically as a remedy for t-disease and osteoporosis, its pharmacological action is expected to have an effect on alveolar bone resorption due to periodontal disease. BP has been reported to inhibit periodontal tissue destruction in rats (J. Dent. Res. 11, 14).
30-1433 (1988)) It has recently been reported that alendronate, a second-generation BP, inhibited alveolar bone destruction by oral administration in monkey and dog periodontal disease models.
(J. Periodontol. 63, 825-830 (1992); J Periodonto
l. 66 (3), 211-217 (1995)). Incadronate disodium (chemical name disodium c
ycloheptylaminomethylenediphosphonate monohydrat
e; hereinafter abbreviated as incadronate) is a third-generation BP having a strong bone resorption inhibiting action (Japanese Patent Publication No. 7-6)
No. 29), the effect of inhibiting alveolar bone retraction in a hamster periodontal disease model (Journal of the Japanese Society of Fundamental Dentistry 36 (5), 510-519)
(1994)), and it has been reported that subcutaneous or oral administration of alveolar bone suppresses alveolar bone regression and improves attachment levels, respectively, in a dog periodontal disease model (J. Periodont. Res. 33, 196-). 204 (1998)).

[0004] In the case of such systemic administration such as oral administration, subcutaneous injection and intravenous injection, it is considered that BP at a concentration exhibiting a medicinal effect is transferred to the affected area of the alveolar bone, thereby exerting a bone resorption inhibiting action. At the same time, B
When P is transferred, the bone resorption inhibitory action may be exhibited similarly in the whole body bone tissue, and an undesirable action may be exhibited. On the other hand, attempts have been made to locally administer BP. For example, topical administration of risedronate near the periosteum adjacent to the first molar, and topical administration of pamidronate below the palatal mucosa have been studied in rat molars. It has been reported to be effective for mobile models (J. Den
t. Res. 73 (8) 1478-1484 (1994); Orthod. Waves 57
(5) 307-317 (1998)). However, to date, there has been no report on an alveolar bone resorption inhibitor for local administration of BP which is clinically available in humans. In fact, there is a difference in the shape, size, irritation, etc. of the periodontal tissue between rats and humans. Based on the above-mentioned findings of rats, the appropriate local administration concentration, dosage, administration method, etc. around the human periodontal tissue are considered. It was difficult to predict. Japanese Patent Application Laid-Open No. 7-502506 discloses a therapeutic agent for alendronate for periodontal disease, and its main administration method is systemic administration by oral or intravenous injection. Although there is a statement that topical administration can be directly attached to the inflamed site of teeth and gingiva, there is no specific disclosure of the dose, administration site, etc., and it merely suggests the possibility. Moreover, this method of directly attaching to the site of inflammation of the teeth and gingiva not only has low BP translocation to the alveolar bone, but also suggests that it may be orally administered together with saliva. It was something I could not expect at all. There is also a report that BP having an amino group has local irritation (Lanc
et., 348, N0.9023, 345-346 (1996); Br. Med. J., 295, N
o. 6609, 1301-1305 (1987)), that is, it is completely unclear whether it is actually possible to treat periodontal disease by local administration of BP around the periodontal tissue in humans.

[0005]

As an alveolar bone resorption inhibitor containing BP as an active ingredient, it has a selective alveolar bone inhibitory effect on bone resorption, is easy to administer, and has high clinical utility in humans. The creation of useful topical medicaments is eagerly awaited.

[0006]

Means for Solving the Problems The present inventors used incadronate, which has been confirmed to have a therapeutic effect on periodontal disease by oral administration in a dog periodontal disease model having periodontal tissue similar to humans, Investigations on the treatment of periodontal disease for topical administration revealed that, surprisingly, BP was injected into the gingival alveolar mucosa using the alveolar mucosal puncture method, which has been used as a conventional method of injecting an anesthetic in the dental field. It has been found that BP can be selectively transferred to the alveolar bone by local injection, and a good alveolar bone resorption inhibiting action and a periodontal disease treating action can be exhibited, thus completing the present invention. Moreover, this administration method is the first local administration method of a BP-containing periodontal disease therapeutic agent to human periodontal tissue, which is simple in operation and less burdensome on patients, and has high clinical utility. That is, the present invention relates to a pharmaceutical composition for treating periodontal disease comprising a bisphosphonic acid derivative or a salt thereof as an active ingredient, which is for local injection by alveolar mucosal puncture. . The injection amount per administration site of the pharmaceutical composition for local injection by the alveolar mucosal penetration method of the present invention is preferably 100 to 300 μL.

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
The “bisphosphonic acid derivative or salt thereof” of the present invention is a structural analog of pyrophosphoric acid that is stable in a living body.
It means a compound having two phosphonic acid residues and having a bone resorption inhibiting action, and a salt thereof. Bisphosphonic acid derivatives known as bone resorption inhibitors include, for example, clodronate, tiludronate, neridronate, pamidronate, incadronate, alendronate, olpadronate, EB-1053, risedronate, ibandronate, zoledronate, YM5
29 (1-hydroxy-2- (imidazo [1,2-a]
Pyridin-3-yl) ethane-1,1-bisphosphonic acid), and salts thereof. Preferred are incadronate, alendronate, olpadronate, EB-1053, risedronate, ibandronate, zoledronate, and YM529.

The present inventors have studied a practical administration method capable of selectively transferring BP to alveolar bone using incadronate. The administration method usually used for periodontal disease treatment, for example, when attached to or attached to the gingiva, the transferability of BP to the alveolar bone is low, and there is concern about gingival irritation.
Administration into the periodontal pocket was less practical because of the further distance from the alveolar bone, and there was concern that the drug would leak out of the pocket into the oral cavity, making it impractical. The present inventors, as a method of transferring the drug to the alveolar bone most, periodontal tissue around the alveolar bone, namely, gingiva,
It has been found that local injection into the alveolar mucosa, sublingual mucosa, palate, and the like is most preferable. However, the periodontal tissue near the alveolar bone where the drug can be locally injected is very small, the volume that can be administered is limited, and there is concern about pain to the patient, so further improvement is desired. there were.

Therefore, the present inventors have proposed that the alveolar mucosal puncture method, which has not been used at all except for the infiltration anesthesia method in the dental area, can reduce the percutaneous density of the alveolar bone by 10% per one place.
0 to 300 μL of the BP-containing periodontal disease therapeutic agent can be easily injected locally, and an effective amount of BP can be transferred selectively to the alveolar bone as described later. We found that it was simple and less burdensome on patients, and that a good alveolar bone resorption inhibitory effect or a periodontal disease treatment effect could be obtained. That is, the alveolar mucosal puncture method is highly clinically practical,
It has been found that this is the first method in the world to locally administer a BP-containing therapeutic agent for periodontal disease to human periodontal tissue.

The “alveolar mucosa puncture method” in the present invention is defined as
A needle is inserted into the movable oral mucosa (alveolar mucosa or sublingual mucosa shown in FIG. 1) adjacent to the gingiva, preferably in the vicinity of the border with the gingiva, so that the needle is laid down rather than vertically,
This means a method of injecting a drug solution between the alveolar bone periosteum and the alveolar mucosa. Specifically, when the injection is performed on the buccal side of the tooth, the alveolar mucosa shown in FIG. 1, preferably near the border of the gingival alveolar mucosa, and on the lingual side, the sublingual mucosa, preferably on the part close to the jaw bone,
The needles are laid down and the drug solution is injected. The angle at which the needle is inserted is as close as possible to the horizontal as much as possible. It is preferable to pierce the mucous membrane portion while lying down at 10 degrees or less. However, on the palatal side of the upper jaw, there is no alveolar mucosa or a movable mucosa similar to it, so a needle is inserted into a site about 1 cm away from the tooth jaw to inject the drug. It is included as one aspect of the alveolar mucosal penetration method of the present invention.

The alveolar mucosal puncture method is also known as a horizontal method or a submucosal injection method, and is a known injection method conventionally used as one type of infiltration anesthesia method used in the dental field. This method is an extremely simple method, because the anesthetic is injected into the movable alveolar mucosa, such as the gingival-buccal junction, instead of the gingiva, so that it takes no time and pain is caused at the time of the first puncture. Because it is only a point, it is known as a method that is less burdensome for both the practicing doctor and the patient (Periodontal Therapy (2nd edition) published by Medical and Dental Medicine Publishing Co., Ltd. (second edition), pages 325 to 326 (1992)).
An injection method called an alveolar mucosal puncture method, a horizontal method, or a submucosal injection method, which has been performed as one type of the infiltration anesthesia method, is a preferable embodiment of the "alveolar mucosa puncture method" of the present invention.

A preferred operation method of the alveolar mucosal puncture method is disclosed in Periodontology (2nd edition), pp. 325-326 (1992), published by Medical and Dental Drug Publishing Co., Ltd. However, the method of penetrating the alveolar mucosa of the present invention is not limited to this description. "In practice, the lips or cheeks are first evacuated with a finger or mirror to expose the oral vestibule, and the loose mobile mucosa of connective tissue (alveolar mucosa)
Make sure that the needle is not horizontal but horizontal, and only a few millimeters are inserted. Here, the release of the liquid is slowly started, and a blister is first formed under the mucous membrane, and then the discharge is continued while continuing the centrifugal movement with the needle still in place, thereby forming a levee-shaped bulge. (Omitted) On the lingual side, a similar bulge is created by piercing the sublingual mucosa near the jawbone. On the palatal side of the upper jaw, there is no movable mucous membrane, so normal infiltration anesthesia is performed at intervals of 1 cm at a site approximately 1 cm away from the tooth jaw. "

[0013] The BP concentration in the pharmaceutical composition for local injection by the alveolar mucosal puncture method of the present invention is low enough to make the local irritation clinically acceptable and the local injection Is a concentration at which a sufficient alveolar bone resorption inhibiting action is exhibited. For example, in incadronate, the concentration is 3.33 to 100 μg / mL. The optimum BP concentration can be determined by local injection of BP using an animal model having periodontal tissue similar to humans, such as dogs and monkeys, preferably by local administration tests using the alveolar mucosal puncture method. It can be found by confirming the effect of inhibiting bone resorption. At this time, the number of administrations and the interval between administrations are related to the development of local irritation, and should be appropriately considered.
The pharmaceutical composition of the present invention is 100 to 300 μm per administration site.
L, preferably 150-200 μL local injection.
It is preferable that the administration be performed on one of the buccal side and the lingual side, preferably both (2 places) per tooth. This is administered once or two to ten times at intervals of one day to several weeks.
Preferably, administration is performed 2 to 10 times at intervals of 3 to 14 days. A more preferable administration form should be appropriately selected depending on the drug concentration, and it is preferable that the administration interval is narrow and the number of times is high at a low concentration, while the administration interval is long and the frequency is small at a high concentration. .

The alveolar bone resorption inhibitor for topical administration of the present invention comprises:
Contains sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble liquid include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, solubilizing, and isotonic agents (eg, xylitol, mannitol, sorbitol, ethylene glycol). May be. These may be sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide or irradiation, or are produced under aseptic conditions. They can also be used in the preparation of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use. It is preferable for clinical use that the alveolar bone resorption inhibitor of the present invention is provided particularly in a dental cartridge preparation.

The effects of the alveolar bone resorption inhibitor and the agent for treating periodontal disease of the present invention and examples of prescription thereof will be described below in Examples. In addition,
The scope of the present invention is not limited by the following examples.

[0016]

EXAMPLES Example 1: Dog periodontal disease model test (method) Female beagle dog (1 to 2 years old, at the time of grouping) which had been given soft food containing water to Gain's Packon (AGF) from the day before ligation Thirty animals (weight: 7.9-13.7 kg) were used. Under xylazine hydrochloride (Bayer) and pentobarbital anesthesia, the lower left and right second premolars (P2) / third premolars (P)
3), the gingiva between P3 / 4th anterior molar (hereafter, P4) and the gingiva between P4 / the first molar (hereafter, M1) are cut with a scalpel, and P3
And periodontal pockets were created in P4. Double ligations of silk thread (Surgical Suture Nescosture (3-0), Morita) were applied to the cervical region of P3 and P4 to create a periodontal disease model. At this time, fixed points were made on the buccal and lingual sides of the crown at the gingival margin of P4 with a dental drill. Since the periodontal local state (calculus adhesion state and periodontal state) was almost uniform, the animals were divided into the following five groups according to their general state (body weight and age) without performing scaling and brushing. 1) control group: saline, 2) incadronate 0.5μg / site
Group, 3) incadronate 1.5 μg / site group, 4) incadronate 5.0 μg / site group, and 5) incadronate 15
μg / site group.

Administration was started immediately after surgery in each group. Incadronate (injection solution, Yamanouchi Pharmaceutical Co., Ltd.) was dissolved and diluted with physiological saline to prepare a dose of 150 μL / site. Administration was performed three times immediately after ligation, 1 and 2 weeks after ligation. The administration was carried out by attaching a 27G injection needle to a glass microsyringe and using the alveolar mucosal puncture method. Insert the injection needle horizontally from the alveolar mucosa border to the alveolar mucosa of the ligated tooth (gingival alveolar mucosal boundary), and apply the drug between the alveolar mucosa and the alveolar mucosa.
0 μL was injected. Administration was performed on both buccal and lingual sides (total of 4 sites per jaw, total 600 μL). Thirteen weeks after the final administration, the animals were sacrificed by exsanguination, and the lower jaw and ribs including P3 and P4 were sampled and used for bone density measurement.

(Evaluation of suppression of alveolar bone regression by standard X-ray photography) The X-ray irradiation direction and film position to the subject are always kept constant, and X-rays under the same conditions are always obtained even when the same part of the same individual is repeatedly photographed. To obtain photographs, standard radiography (J. Periodontol. 33, 164-171 (1962)) was used. This time, in order to evaluate the retraction of the alveolar bones of the left and right P3 and P4, a cap was formed using acrylic resin between the incisors of the left and right mandibles and M1, and a film holder was combined with this cap and a fixture was used. Produced. Under anesthesia with xylazine hydrochloride and ketamine hydrochloride (Ketalal, Sankyo), a dental film (Ultraspeed DF58: Kodak) is attached to the film holder on the fixture, and a dental X-ray apparatus (Supermax 70, model HD- 1, Morita Manufacturing). In addition, the height of the alveolar bone crest was measured using the evaluation method shown in FIG. That is, measure the X-ray film under a stereoscopic microscope (object x 1, eyepiece x 10), cover the x-ray film with an OHP sheet, and
By writing line a, line b and line c on the HP sheet, two points, b, b 'and c, c', respectively, on line b and line c were obtained. The distance between b-b 'and c-c' is defined as the reference point (b and b, respectively).
It was defined as the distance from point c) to the alveolar bone crest. The length of alveolar bone regression was determined by b-b 'and c-c'
The sum was calculated by subtracting the sum of the distances b-b 'and c-c' at the time of the ligation from the sum of the inter-distances.

(Measurement of clinical score) (1) Depth of pocket (Probing Depth; PD) The method of measuring the depth of periodontal pocket is described in J. Clin. Periodont.
ol. 4, 173-190 (1977) by a four-point measurement method. (2) Gingival regression The length of gingival retraction was measured at the buccal and lingual sides of P4 at each individual individual week, measured from the fixed point on the crown created during ligation to the gingival margin. And the average value was used.

(3) Attachment level (Attachment
Level; AL) The attachment level is an index that measures where the gingival sulcus bottom (pocket bottom) is located, and is expressed as the distance from the pocket bottom to a fixed point on the crown. That is, the sum of the depth of the pocket and the length of the gingival retraction was used as the attachment level. (4) Gingival Index (GI) The site of gingival inflammation and the degree of symptoms were evaluated according to J. Periodontol. 38, 602-610 (1967). (Measurement of Alveolar Bone Concentration and Intracostal Concentration) For the left fourth molar, the root was pulled out with pliers, the whole including the jawbone and the alveolar bone was divided into upper and lower parts, and the upper half was defined as the alveolar bone. Also,
For the concentration in the rib, the end of the rib that had been cryopreserved at -40 ° C after dissection was used. From these, incadronate was extracted by the calcium precipitation method, and the concentration in the bone was measured by the HPLC method.

(Results) For each data, the left and right teeth were calculated as separate values. SAS for all statistical analyses
(EXSAS-STAT) was used. FIG. 3 shows the results of the alveolar bone retraction suppressing effect. Alveolar bone regression was observed over time in the control group after ligation, and this was suppressed in any of the groups receiving incadronate, and the effect was 5 μg / si.
The strongest at the te dose.

Further, in the group to which incadronate was administered, deterioration of the clinical score of periodontal disease was suppressed. The clinical scores are as follows. (1) Pocket depth In the control group, a transient increase in the depth of the pocket, which peaked at 2 weeks after ligation, was observed. Incadronate significantly inhibited the increase in pocket depth at a dose of 1.5 μg / site or more at 2 and 4 weeks after ligation. (2) Gingival regression In the control group, gingival retraction due to ligation was enhanced over time. Incadronate significantly inhibited gingival regression at 4 and more weeks after ligation at a dose of 5 μg / site or more, and at 1.5 μg / site, it significantly suppressed only at 15 weeks after ligation.

(3) Attachment level In the control group, a decrease in attachment level due to the ligation was observed almost over time. Incadronate significantly suppressed the decrease in attachment level 2 weeks after ligation at a dose of 5 μg / site or more, and 1.5 μg / s.
The dose of ite significantly suppressed at 4 and 15 weeks after ligation. (4) Gingivitis index In the control group, transient exacerbation of the gingivitis index peaked at 2 weeks after ligation. Incadronate significantly inhibited exacerbation of the gingivitis index 2 weeks after ligation at a dose of 1.5 μg / site or more.

(Alveolar bone concentration and rib bone concentration) The results are shown in Table 1. In the 5 to 15 μg / site administration group, the concentration of incadronate in the ribs was almost 1/1 of the concentration in the alveolar bone.
0, indicating that the injection of the present invention achieves alveolar bone selective BP transfer.

[0025]

[Table 1]

Example 2: Formulation Examples Formulation Example 1 Incadronate 3.3, 10.0, 33.3 or 10
0 μg is dissolved in physiological saline to make 1 mL.
Filled into dental cartridge for L. Formulation Example 2 Incadronate 3.3, 10.0, 33.3 or 10
0 μg and 42.6 m of xylitol as tonicity agent
g, mannitol 51 mg, sorbitol 51 mg or glycine hydrochloride 21 mg was dissolved in distilled water for injection to make 1 mL. This was filled into a 1 mL dental cartridge. Formulation Example 3 7.5, 25 or 75 μg of incadronate, 42.6 mg of xylitol and 5 of mannitol as tonicity agents
1 mg, sorbitol 51 mg or glycine hydrochloride 21
mg was dissolved in distilled water for injection to make 1 mL.
This was filled into a 1 mL dental cartridge.

[0027]

The pharmaceutical composition comprising the bisphosphonic acid derivative of the present invention or a salt thereof as an active ingredient is locally administered by an alveolar mucosal puncture method instead of the conventional systemic administration. BP is selectively transferred, and is useful as an alveolar bone resorption inhibitor with less systemic side effects and as a therapeutic agent for periodontal disease. Therefore, it successfully inhibits alveolar bone resorption associated with periodontal disease, suppresses regression of alveolar bone crest and decrease in alveolar bone density caused by alveolar bone resorption, as well as gingivitis, bleeding,
Suppress deterioration of clinical score such as decrease in periodontal pocket depth and attachment level.

[Brief description of the drawings]

FIG. 1 shows a schematic diagram of a tissue around a gingiva.

FIG. 2 is a diagram illustrating a method of evaluating the height of alveolar bone crest according to the first embodiment. The symbols in the figure have the following meanings. line a: line connecting the crowns of P4 and P3, line
b and line c: perpendicular to line a passing through the most mesial side of the P4 crown and the most distal side of the P3 crown, b and c: line a and li
intersections (reference points) with ne b and line c, and b 'and
c ′: Intersection between the alveolar crest and line b and line c.

FIG. 3 is a diagram showing the effect of incadronate on alveolar bone regression in Example 1. The figure shows the mean value ± standard error of the length of alveolar bone retraction after ligation over time. () In the legend indicates the number of cases in each group. * and **
Indicates a significant difference from the control group (* p <0.05, ** p <0.
01, Dunnett's multiple comparison test).

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Taiji Yoshino 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Company Limited (72) Inventor Hiroyuki Kano 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Company Limited ( 72) Inventor Hiroyuki Honke 3-17-1 Hasune, Itabashi-ku, Tokyo Yamanouchi Pharmaceutical Co., Ltd. F-term (reference) 4C086 AA01 AA02 DA34 MA01 MA04 MA57 MA66 ZA67

Claims (1)

[Claims] (1) A pharmaceutical composition for treating periodontal disease which comprises a bisphosphonic acid derivative or a salt thereof as an active ingredient, wherein the pharmaceutical composition is for local injection by an alveolar mucosal puncture method.