JPH10236977A - Orthodontic medicine containing pth - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare an effective orthodontic medicine containing a PTH (parathyroid hormone), capable of enhancing the movement of tooth in orthodontics and actually utilized in clinic by using the PTH or a derivative thereof as an active ingredient. SOLUTION: This orthodontic medicine containing a PTH contains one or more kinds of the PTHs or a derivative thereof as an active ingredient. The PTH or the derivative thereof is preferably the recombinant human PTH produced by a gene engineering method and comprising 34 amino acid residues. The dosage form of the objective medicine is, for example, an injection, a microcapsule, a mouth mucosal preparation, etc., and preferably the noninvasive one. The administration method is preferably a topical administration when a specific tooth is intended to move. The topical administration is preferably carried out by allowing the objective medicine to be successively absorbed from the surface of the mucosa or successively infusing the objective medicine to the limited part by using a sustained release basis. When the whole teeth are moved, the whole body administration is convenient and preferable. The dose amount in the case of the whole body administration is preferably 10μg to 1mg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an orthodontic treatment containing parathyroid hormone (PTH) or a PTH derivative as an active ingredient.

[0002]

2. Description of the Related Art Parathyroid hormone (PTH) is known as one of the important hormones in bone metabolism. Conventionally, many effects of PTH on bone have been reported.
In orthodontic practice, tooth movement is considered to enhance bone remodeling due to mechanical forces applied to the teeth.
Histologically, this adaptation of the alveolar bone to mechanical forces
It has been demonstrated as increased bone resorption on the compression side of periodontal tissue and increased bone formation on the tension side of periodontal tissue.
These histological changes to mechanical forces in periodontal tissue are due to the tension hypothesis.
(Oppenheim, 1911), but the exact mechanism of cellular response to mechanical forces is unclear (Sandy, Farndale and Me).
ikle, 1993).

[0003] Bone turnover (bon) during tooth movement
Increased e turnover has been considered important for tooth movement in orthodontics. The reason is that an increase in turnover shortens the treatment period. PGE ₁ (Yamasaki, Miura and Suda, 1980; Lee, 1990), PGE ₂
(Yamasaki, Miura and Suda, 19
80; Chao et al., 1988) and 1α, 25- (O
H) ₂ D ₃ (Collins and Sinclair, 1
988; Takano-Yamamoto et al., 199.
Local administration of chemicals such as 2) or PGE
₁ (Lee et al., 1988) has been reported to enhance bone resorption during experimental tooth movement.

[0004] It is well known that parathyroid hormone (PTH) is one of the essential systemic factors in bone remodeling. PTH in vivo
Intermittent injections were performed in ovariectomized (OVX) rats (Hock
Liu et al., 1991; Ibbottso.
n, 1992) or healthy rats (Hock and Ge)
ra, 1992; Dobnig, 1995). Therefore, osteogenic stimulation is considered as one of the physiological roles of pulsatile secretion of PTH in vivo. On the contrary, parathyroidectomized rats receiving continuous infusion of PTH (Kitazawa et al.,
1991) or healthy dogs (Mallache et al., 198).
Bone morphometry in 2) showed a simultaneous increase in bone formation and bone resorption, but no net increase in bone mass. According to data obtained from various in vivo studies, osteoclastogenesis (Takahashi et al., 1988; Kurihara
1991) and osteoblast proliferation (Somjen).
1990) have been shown to be stimulated by PTH. In addition, since periodontal tissue is systemically affected by PTH administration, it has been reported that the alkaline phosphatase reaction in the periodontal ligament and the distribution of osteoclasts differ from the findings in the non-administration group (exit). Toshio,
Journal of the Japanese Orthodontic Society, Vol. 28, No. 1,19
69, pp. 1-7).

Regarding the role of PTH in bone remodeling in relation to tooth movement in orthodontic practice, the induction of osteoclasts on the compression side during experimental tooth movement is completely suppressed by parathyroidectomy, Previous reports have demonstrated that it was restored by injection of body extracts (Kam
ata, 1972). This fact indicates that PTH plays an important role in the formation of osteoclasts during experimental tooth movement. However, the practical application of PTH in orthodontic clinical settings has not been revealed at all.

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an effective and effective orthodontic treatment in orthodontic clinic.

[0007]

The present inventors have made intensive studies and found that tooth movement in orthodontics is increased by administration of one or more parathyroid hormone (PTH) or PTH derivatives. And completed the present invention based on this finding. That is, the present invention
The present invention relates to an orthodontic treatment agent containing one or more parathyroid hormone (PTH) or a PTH derivative as an active ingredient. In addition, the present invention relates to human PTH (1-84)
Or an orthodontic treatment agent containing one or more of its derivatives as an active ingredient. Furthermore, the present invention relates to an orthodontic treatment agent containing one or more of human PTH (1-34) or a derivative thereof as an active ingredient. In addition, the present invention relates to an orthodontic treatment agent comprising parathyroid hormone (PTH) as an active ingredient. Furthermore, the present invention relates to human PT
The present invention relates to an orthodontic treatment agent containing H (1-84) as an active ingredient. Furthermore, the present invention relates to human PTH (1-3
The present invention relates to an orthodontic treatment agent containing 4) as an active ingredient. In addition, the present invention relates to parathyroid hormone (PT
H) or a dental composition containing one or more of PTH derivatives as an active ingredient. In addition,
The present invention relates to a non-PTH invasive preparation characterized by continuously administering an effective amount of one or more of parathyroid hormone (PTH) or a PTH derivative.

[0008] In the specification of the present application, "orthodontics"
And "orthodontics" are used interchangeably.

[0009] In the present invention, the term "orthodontic treatment agent" means an agent used for correcting abnormalities in teeth, upper jaw and / or lower jaw. The orthodontic treatment agent of the present invention is preferably used as an agent for correcting orthodontics, that is, an orthodontic treatment agent. In the present invention, an “orthodontic treatment agent” refers to an irregular dental arrangement, that is, an abnormality in the form of the dental arch due to an abnormal interdental distance or abnormal tooth position (lip (buccal) or lingual metastasis). Means an agent used to bring the dental arch into a normal configuration by moving and fixing the specific or all of the abnormal teeth to normal positions when they are coming.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Parathyroid hormone (PTH) in the present invention includes natural PTH, recombinant PTH produced by genetic engineering techniques, and chemically synthesized PTH. Is human PTH consisting of 84 amino acid residues (human PTH (1-84)), in particular, recombinant human PTH (1-84) produced by genetic engineering techniques
Is mentioned. The PTH derivative is a partial peptide of the above PTH, PTH itself or a partial amino acid of the partial peptide substituted with another amino acid, PTH itself or a partial amino acid of the partial peptide is deleted. And all peptides having the same activity as PTH itself or a peptide obtained by adding one or more amino acids to a partial peptide thereof. Examples of partial peptides of PTH include human PTH (1-34), human PTH (1-64), human PTH (35-84), bovine PTH (1-34), and the like. PTH (1-34) refers to a partial peptide of PTH consisting of 34 amino acids from the N-terminal to the 34th amino acid of PTH. Examples of preferred partial peptides of PTH include human PTH consisting of 34 amino acid residues (human PTH (1-34)), particularly recombinant human PTH (1-34) produced by genetic engineering techniques.

Preferred examples of the amino acid substitution include substitution of a constituent amino acid at position 8 with leucine or norleucine, substitution of a constituent amino acid at position 18 with leucine or norleucine, and substitution of a constituent amino acid at position 34 with tyrosine. Is raised.

Preferred examples of the parathyroid hormone (PTH) or PTH derivative used in the present invention as an orthodontic treatment, a dental composition or a PTH non-invasive preparation are human PTH (1-84) and human PTH ( 1-3
4), human PTH (1-38), human PTH (1-3)
7), human PTH (1-34) -NH _{2 and the} like, more preferably human PTH (1-84), human PTH
TH (1-34), and most preferred is human PTH (1-34).

[0013] The purity of parathyroid hormone (PTH) or a PTH derivative used in the present invention as an orthodontic treatment, a dental composition or a non-invasive preparation of PTH does not necessarily have to be 100%. (PTH) or the PTH derivative may be substantially pure. In the present invention, “substantially pure” means a substance which has been purified so as to show at least a single peak by HPLC, and is preferably further purified by combining techniques such as SDS-DAGE and capillary electrophoresis. Means that has been confirmed to be. Such PTHs can be prepared by the method described in JP-A-6-87897, or by using JP-A-4-505259 and J.P. Bio
l. Chem. , 265, 15854 (1990) or a modified method thereof.

[0014] The dosage form of the drug of the present invention includes injections (for example, liquids,
In addition to lyophilized preparations), oral and mucosal preparations, for example, encapsulation in microcapsules or contained in a gel-like sheet, are also possible.
Upon formulation, pharmaceutically acceptable auxiliary components can be added. A formulation modified with polyethylene glycol for the purpose of increasing the half-life in blood is also possible.
Preferably, it is a non-invasive preparation.

[0015] Oral mucosal preparations have been put to practical use with drugs such as nitroglycerin, nicotine and nifedipine. As a non-invasive preparation of peptides and proteins, the advantage of oral mucosal preparations is that no special administration depises are required,
It is easy to administer, is not affected by degradation in the gastrointestinal tract or first-pass effect in the liver, and the like.
However, hydrophilic substances such as peptides and proteins, unlike these low molecular weight compounds, require the use of enhancers to cross physicochemical and enzymatic barriers in the oral mucosa. Bile acids, dihydrofusidic acids, cyclodextrins, surfactants, chelating agents and the like are used as enhancers.

[0016] The auxiliary components of the drug of the present invention include a base,
Stabilizers, preservatives, preservatives, emulsifiers, suspending agents, solubilizers,
Dissolution aids, lubricants, flavoring agents, coloring agents, fragrances, soothing agents, excipients, binders, thickeners, buffers and the like,
Specifically, for example, calcium carbonate, lactose, sucrose,
Examples include sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, cocoa butter, distilled water for injection, aqueous sodium chloride, Ringer's solution, glucose solution, human serum albumin and the like.

In preparing the drug of the present invention using these auxiliary components, for example, a pharmaceutical excipient list (Tokyo Pharmaceutical Manufacturers Association Medical Law Regulation Committee and Osaka Pharmaceutical Industry Association Medical Regulation Research Committee) As described in (Issue), the auxiliary component may be appropriately selected and used. The amount of the auxiliary component to be used may be appropriately selected according to the dosage form and the like within a pharmaceutically acceptable range.

The method of administering the medicament of the present invention can be performed either locally or systemically. In particular, when only a specific tooth (for example, an anterior tooth) is to be moved, the local administration method is excellent. For local administration, continuous local administration is desirable. As a method for sustained local administration, it is preferable to inject PTH locally using a sustained-release base or to continuously absorb PTH from the mucosal surface. As a specific example of a sustained release base, as direct injection under the mucosa or subperiosteum,
(1) collagen pellets, (2) polylactic acid base,
(3) hydroxyapatite cement (hydroxy)
appointment cement), (4) alginate gel, and the like. It can also be absorbed as a patch from the mucosal surface. On the other hand, an advantage of the systemic administration method is that PTH can be administered without invasion if the administration method is devised. Preferred examples of systemic administration include systemic administration such as subcutaneous administration, intravenous administration, intranasal administration, and pulmonary administration. When all teeth are to be moved quickly, systemic administration is considered to be simpler and superior to local administration over a wide range.

The administration period is based on the period necessary for the movement of the teeth and the fixation of the moved alveolar bone, and is determined by the judgment of the clinician according to the etiology. The administration frequency can be from once every 3 months to daily administration, preferably from once a month to about 5 times / week or daily. In particular, continuous administration is preferred.

The dose of the PTH of the present invention varies depending on the moving distance of teeth, the type of teeth, the number of moving teeth, and the like.
For systemic administration, the dose is about 0.1 μg to 10 mg, preferably 10 μg to 1 mg.

[0021]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Materials used : The types and sources of animals and drugs used in each example are as follows. Male Wi
Ster rats (350-400 g) were obtained from Oriental Yeast Co., Ltd. (Tokyo). The PTH used in Example 1 was recombinant human PTH (1-84).
9 and JP. Biol. Chem. 265,15
854 (1990). The PTH used in Example 2 was recombinant human PTH (1-34).
H (1-34) is a peptide institute (Peptide Institute)
Inc. , Mino) was used. (Example 2
Please consider whether or not to describe the PTH used in. ) Osmotic pump (Alzet 2ML1) is A
Iza (Palo Alto, CA, USA). Tween-80 was purchased from Wako Pure Chemical Industries, Ltd. (Tokyo). Orthodontic elastic bands (Quik-Stik, A-1) were purchased from Unitek (Monrovia, CA, USA).

Experimental method of moving teeth: a method of inserting an elastic band (rubber) between teeth and a closed coil spring for orthodontics.
Is used. Orthodontic closed coil springs are super elastic Ni of Tommy International Co., Ltd.
-Made of Ti (Sentalloy closed coi
With lspring, light, 509-21), a traction force of about 30 g can be obtained almost constant in the range of 2-3 mm in spring extension. Therefore, unlike the conventional spring, the traction force does not increase in proportion to the extension amount. This means that if the initial extension amount is adjusted to this range and attached to the tooth, a constant force acts regardless of the amount of movement of the tooth. In the method of inserting rubber between the molars, an extremely large force acts immediately after insertion, but when the tooth moves by 0.5 mm, almost no force acts. Therefore, for a short-term tooth movement experiment, a method of inserting an elastic band (rubber) or a method of extending with a closed coil spring can be used, but for a long-term tooth movement experiment, the first method of extending the closed coil spring can be used. The method of moving the molars mesially may be appropriate. In the first embodiment, the elastic band (rubber)
, And a closed coil spring was used in Example 2.

[0024]

Example 1 Experiment 1: Dose Dependence of PTH Infusion on Experimental Tooth Movement
Effect Eighteen rats were divided into one control group and three PTH injection groups (six rats as control group, four rats in each of three injection groups). PTH dissolved in citrate buffered saline containing 0.05% Tween 80 was placed in the osmotic pump. This osmotic pump was implanted in the posterior neck region of rats under ether anesthesia. For rats, 1,
PTH was continuously infused in amounts of 3 and 10 μg / 100 g body weight / day and fed a standard pellet feed (Oriental Yeast Co., Ltd.). The control group of rats received only vehicle. 48 hours after burial,
Wong and Rothbl as shown in FIG.
According to the att method (1954), upper first molars and second molars (M ₁ and M ₂ ) on the right side of rats under ether anesthesia
A piece of elastic band (thickness 0.8 mm) was inserted between them. Rats were sacrificed by ether inhalation on the third day of interdental separation. After incising the upper jaw, 50, 100 and 15
By using a combination of a contact gauge having a thickness of 0 μm (manufactured by Sandental Corporation, Osaka), M ₁ and M _{2 can be obtained.}
Was measured (FIGS. 1B and 1C). Since the control group was able to insert a 50 μm contact gauge between M ₁ and M ₂ , the amount of interdental separation was determined by subtracting 50 μm from each measured diameter value. The results are shown in FIG. In FIG. 2, “*” means that a significant difference was recognized at a 5% risk ratio with respect to the control group (0 μg / 100 g body weight / day (day)). FIG. 2 shows that the effect is most effective when the injection amount is 10 μg / 100 g body weight / day. The maxilla was fixed in 4% paraformaldehyde, decalcified in 4% formic acid, and embedded in paraffin. They were cut into serial microcentrifuge sections 8 μm thick and stained with hematoxylin and eosin. All histological examination is performed at the pressure side of the septum in between roots M _1, 300 × 700μ of that portion
The number of osteoclasts in the area of m ² was counted (FIG. 1).
(C)). Osteoclasts are large multinucleated cells, stained with eosin, and counted based on their proximity to the bone surface. The statistical difference between the control group and the experimental group was evaluated by Wilcoxon rank sum test.
All results were expressed as mean ± SEM. P values less than 0.05 were considered statistically significant.

Experiment 2: Effect of PTH injection on experimental tooth movement
Time course of the effect of the entry 32 rats were divided into two experimental groups of 16 rats each. Since the results of the interdental separation in Experiment 1 showed that the dose of 10 μg / 100 g body weight / day was most effective, these rats were injected with PTH at a rate of 10 μg / 100 g body weight / day. For the control rats,
Only vehicle was administered. And 2 days after osmotic pump buried, it was inserted an elastic band between M ₁ and M ₂ on the right side of each rat. On days 0, 1, 3, and 5 of interdental separation (PTH
At 2, 3, 5 and 7 days after injection), the rats were each sacrificed. Subsequently, the same operation as in Experiment 1 was performed. Result 1. Effect of PTH (1-8) on separation between teeth by elastic band
4) Effect of injection: FIG. 2 shows the dose-dependent effect of PTH injection on interdental separation. As reported in many papers, insertion of this elastic band for 3 days
Interdental separation between ₁ and M ₂ was caused. 10μ
g / 100 g of body weight / day rats injected with PTH at a rate of, compared to control rats showed a marked increase in the distance between M ₁ and M _2. FIG. 3 shows the effect of 10μ on interdental separation.
The time course of the effect when PTH is injected at a rate of g / 100 g body weight / day is shown. In FIG. 3, “*” means that a significant difference was recognized at a 5% risk ratio with respect to the control group on the third day. On day 1, there was no significant difference between the control group and PTH-treated rats, but on day 3, the separation distance was significantly increased.
In rats treated with PTH on the 5th day of interdental separation, the separation appeared to be almost critical. The experiment was discontinued on day 5 in the PTH-treated rats as little friction could be observed between the teeth and the elastic band.

2. Effect of continuous infusion of PTH (1-84) on the number of osteoclasts on the compression side of periodontal tissue: FIG. 4 shows the dose-dependent effect of PTH infusion on the appearance of osteoclasts in interdental separation. Show. In FIG.
“*” Means that a significant difference was recognized at a 5% risk ratio with respect to the control group (0 μg / 100 g body weight / day).
As reported in many papers, insertion of this elastic band for 3 days increased the number of osteoclasts on the compression side of the periodontal tissue. Unlike the results for interdental separation, all three experimental groups showed a significant increase in osteoclast numbers compared to the control group.

FIG. 5 shows the time course of the effect of PTH injection at 10 μg / 100 g body weight / day on the appearance of osteoclasts on the compression side. In FIG. 5, “*” means that a significant difference was observed at a 5% risk ratio with respect to the control group in each number of days. The number of osteoclasts was significantly increased from day 1 by PTH injection. A significant difference in the number of osteoclasts between the control group and PTH-treated rats was 5
It was not recognized on the day.

3. PTH (1-84) for continuous infusion of decorated with oppressed periodontal tissue histological changes in rat: tissue remodeling oppressed periodontal tissue in the interdental separation mesial visor of M ₁ The surface was concentrated in the mesial region of the root. On day 1 of interdental separation, rats treated with vehicle (control group rats) and 10 μg / 100 g
Necrotic tissue was observed in the compression area in any of the rats treated with PTH bw / day. However, on day 3 of interdental separation, necrotic tissue was still observed in the compression area of the rats treated with the vehicle, but the same area of rats treated with 10 μg / 100 g body weight / day of PTH was observed. In, the necrotic tissue disappeared. 1μ
In rats treated with g / 100 g body weight / day and 3 μg / 100 g body weight / day PTH, bone resorption appeared to be more extensive than in rats treated with vehicle. However, areas of necrotic tissue were also observed in these two groups of rats.

[0029]

Example 2 Experiment 1 Systemic continuous infusion of PTH affects experimental tooth movement
It has already been shown that PTH has different effects on bone in continuous administration and intermittent administration with respect to the effects of pilling . Therefore, it was examined how PTH affects the experimental tooth movement by each administration method. Twelve male Wistar rats weighing 350-400 g were used.
Osmoticpump (2M) was included in the PTH continuous administration group.
L2, Alzet, Palo Alto, Calif., USA) was implanted subcutaneously in the back and 0.4 or 4 μg
HPTH (1-34) (Pe
ptide Institute Inc. , Min
o) was continuously infused. As a control group, (1) ve
and only (2) 4 μg /
Two groups, an intermittent administration group in which PTH of 100 g body weight / day was injected subcutaneously into the back once a day, were used. From the day after the start of PTH administration, a superelastic closed coil spring (509) was placed between the upper incisor and the right first molar (M ₁ ).
-21, manufactured by Tommy International, Tokyo)
The mounting and the M ₁ with a force of about 30g to lead the mesial direction 12 days (Fig. 6-A, B). Every three days after the start of the movement, a precise impression of the upper jaw was obtained using a silicon impression material (Exafine, manufactured by GC, Tokyo), and the distance between the first and second molars (M ₂ ) on the cemented gypsum model Was measured (FIG. 6-C). At the end of the 12-day migration, arterial blood was collected from the inferior aorta and various serum parameters were measured. After the rats were sacrificed, the upper jaw and the right femur were removed. The upper jaw, including after demineralization, the cheeks aides Kokorone same centrifugal roots of M ₁ in the longitudinal direction 8μ
An m-thick paraffin section was prepared, and the tissue was observed by HE staining. The measurement of bone mineral density and bone mineral density of the removed femur was performed using dual-x-rayabsorbometry.
(DCS-600, manufactured by Aloka, Tokyo, Japan)
Japan).

Experiment 2 HPT with a sustained release dosage form
Shadow of local administration of H (1-34) on experimental tooth movement
As Hibiki topically administered PTH are sustained release, PT 0.2 and 2 [mu] g / [mu] l dissolved in saline
H solution is mixed with an equal volume of 4% methylcellulose, 0.1 and 1 μg / μl based on 2% methylcellulose
PTH agent (PTH-MC) was prepared. After preparation, PT
1 μl of H-MC every two days (in the same conversion as in Experiment 1,
0.0125 and 0.125 μg / 100 g / da
The y), was injected with a microsyringe (Hamilton (Hamilton) Ltd.) under palatal mucoperiosteal mesial palatal side of the M ₁ (FIG. 6-A). As a control group (1) 2% at the same site
A group in which only 1 μl of methylcellulose (MC) was injected every two days; (2) PTH was added to the same site with physiological saline at 1 μg /
μL (PTH-physiological saline) 1 μl every 2 days, and (3) PTH-
Three groups were used: a group to which 1 μg / μl of MC was administered every two days. Evaluation of tooth movement and histological observation were performed in the same manner as in Experiment 1.

Result 1. Systemic infusion of PTH is the impact on the movement of the experimental teeth (FIGS. 7, 8 and 9) move 12 day of the tooth, M ₁ is the control group to mesial 0.56
It moved ± 0.04 mm. On the other hand, in the PTH administration group, M ₁
Is promoted in a concentration-dependent manner by continuous infusion of PTH, and is 1.0% in the 4 μg / 100 g body weight / day continuous infusion group.
1 ± 0.09 mm, which was about twice that of the control group.

2. Changes over time in the effects of continuous and intermittent injection of PTH on experimental tooth movement (FIG. 1)
0) In the mobile day 3 of the tooth, continuous infusion of PTH, in both groups of intermittent injection, mesial movement of M ₁ was significantly accelerated slightly. The tooth movement promoting effect of PTH is
In the continuous infusion group, it was more prominent after day 9. However, the PTH intermittent administration group, the moving distance of the subsequent day 6 M ₁ is significantly different from the control group was observed.

3. Effect of local injection of sustained release PTH on experimental tooth movement (FIGS. 11, 12, 13, 1)
4) the mobile day 12 of the teeth, the only 2% methylcellulose was administered control group M ₁ is moved 0.54 ± 0.08 mm to the mesial. On the other hand, in the group to which PTH-MC was locally administered, M ₁
Transfer is promoted in a concentration-dependent manner, and 1 μg / 400 g / 1
In the group administered every other day, the value was 0.08 ± 0.11 mm, which was about 1.6 times that in the control group. In the group administered topically with PTH-saline or the group administered PTH-MC subcutaneously on the back, tooth movement was not promoted.

4. By local injection of sustained release PTH is local injection for time course of effects on experimental tooth movement (Figure 15) PTH-MC with 1 [mu] g / 400 g / 1 every other day, the mesial movement of M ₁ A tendency was observed from the third day of tooth movement. The effect of promoting tooth movement by PTH was more markedly observed after 9 days.

5. Histological findings of the effects of continuous infusion of PTH and local injection of sustained-release PTH on tooth movement (FIGS. 16, 17, and 18) Glass-like degeneration was observed in the periodontal ligament (Fig. 16-
A). On the other hand, in the continuous infusion group, remarkable bone resorption was observed in a wide range on the distal side of the alveolar septum, and no degenerated tissue was observed in the control group (FIG. 16-).
B). Furthermore, even in the mesial alveolar bone of M _1, the continuous infusion group compared with the control group, more vigorous bone absorption was observed. On the other hand, in the local injection group of sustained-release PTH, extensive alveolar bone resorption was not observed on the side of compression of the distal root as seen in the continuous systemic injection group (FIG. 18-B).

As described above, it was confirmed that the experimental tooth movement was promoted by continuous administration of PTH systemically or by local injection with a sustained-release dosage form.

[0037]

As described above, parathyroid hormone (PT)
H) or PTH derivatives have the effect of increasing tooth movement and are useful as orthodontic treatments.

[Brief description of the drawings]

FIG. 1 is a diagram illustrating a method for performing experimental movement of a tooth using an elastic band. (A) is Wong and Rothb
A method of inserting an elastic band between a first molar and a second molar by the latt method will be described. (B) and (C) show a method of measuring the moving distance of a tooth using a contact gauge.

FIG. 2 is a graph showing the dose dependent effect of PTH injection on interdental separation.

FIG. 3 is a fluff showing the time course of the effect of injecting PTH into rats at a rate of 10 μg / 100 g body weight / day on interdental separation.

FIG. 4. Effect of PT on the appearance of osteoclasts during interdental separation
4 is a graph showing the dose-dependent effect of H injection.

FIG. 5 shows the effect of 10μ on the appearance of osteoclasts on the compression side when an elastic band is inserted between the first and second molars.
4 is a graph showing the time-dependent change in the effect of PTH injection in g / 100 g body weight / day.

FIG. 6 is a view showing a method of performing an experimental movement of a tooth using a closed coil spring. (A) and (B) show a method of ligating and pulling a super elastic closed coil spring between the upper incisor and the right first molar.
(C) shows a method of measuring the moving distance of a tooth using a caliper under a stereomicroscope.

FIG. 7 shows the effect of hPTH (1-3) on mesial movement of the first molar.
4) A graph showing the dose-dependent effect of injection.

FIG. 8 shows the effect of hPTH (1-3) on the mesial movement of the first molar.
It is a figure which shows the influence of continuous injection of 4).

FIG. 9 shows the effect of hPTH (1-3) on the mesial movement of the first molar.
4) is a diagram showing the effect of intermittent injection.

FIG. 10 shows the effect of hPTH (1-
FIG. 34 is a graph showing the change over time of the effects of continuous infusion and intermittent injection in 34).

FIG. 11: Effect of sustained release hPTH on mesial movement of first molars
It is a graph which shows the influence of the local injection of (1-34).

FIG. 12 is a diagram showing the effect of local injection of hPTH (1-34) on movement of first molars.

FIG. 13 is a diagram showing the effect of local injection of hPTH (1-34) on movement of first molars.

FIG. 14 is a diagram showing the effect of systemic injection of hPTH (1-34) on the movement of first molars.

FIG. 15 shows the effect of hPTH (1-3) on the movement of first molars.
It is a graph which shows the time-dependent change of the influence of the local injection of 4).

FIG. 16 shows the effect of hPTH (1-3) on the movement of first molars.
It is a figure which shows the histological finding of the influence of systemic continuous injection of 4).

FIG. 17 shows the effect of hPTH (1-3) on the movement of first molars.
4) Tissue findings of the effect of intermittent injection.

FIG. 18 shows the effect of hPTH (1-3) on the movement of first molars.
It is a figure which shows the histological finding of the influence of the local injection of 4).

Claims (20)

[Claims] 1. Parathyroid hormone (PTH) or PT
An orthodontic treatment agent comprising one or more H derivatives as an active ingredient. 2. Parathyroid hormone (PTH) is a human PT
The orthodontic treatment agent according to claim 1, which is H (1-84). 3. Substantially pure human PTH (1-84)
The orthodontic treatment agent according to claim 2, comprising: 4. The method according to claim 1, wherein the human PTH (1-84) is a recombinant human P
The orthodontic treatment agent according to claim 2 or 3, which is TH (1-84). 5. The method according to claim 1, wherein the PTH derivative is human PTH (1-34).
The orthodontic treatment agent according to claim 1, wherein 6. A substantially pure human PTH (1-34).
The orthodontic treatment agent according to claim 5, comprising: 7. The method according to claim 7, wherein the human PTH (1-34) is a recombinant human P
The orthodontic treatment agent according to claim 5 or 6, which is TH (1-34). 8. The orthodontic treatment agent according to claim 1, comprising parathyroid hormone (PTH) as an active ingredient. 9. The method according to claim 9, wherein the parathyroid hormone (PTH) is human PT.
The orthodontic treatment agent according to claim 8, which is H (1-84). 10. The method of claim 1 wherein substantially pure human PTH (1-8
The orthodontic treatment agent according to claim 9, comprising 4). 11. The agent for orthodontic treatment according to claim 9, wherein the human PTH (1-84) is recombinant human PTH (1-84). 12. The orthodontic treatment agent according to claim 1, further comprising a parathyroid hormone (PTH) derivative as an active ingredient. 13. The orthodontic treatment agent according to claim 12, wherein the parathyroid hormone (PTH) derivative is human PTH (1-34). 14. Substantially pure human PTH (1-3)
The orthodontic treatment agent according to claim 13, which contains 4). 15. The orthodontic treatment according to claim 13, wherein the human PTH (1-34) is a recombinant human PTH (1-34). 16. Parathyroid hormone (PTH) or P
A dental composition comprising one or more TH derivatives as an active ingredient. 17. The method according to claim 17, wherein the parathyroid hormone (PTH) is human P.
17. The dental composition according to claim 16, which is TH (1-84). 18. The method according to claim 18, wherein the parathyroid hormone (PTH) is human P.
17. The dental composition according to claim 16, which is TH (1-34). 19. An effective amount of parathyroid hormone (PTH)
Alternatively, a PTH non-invasive preparation for continuously administering one or more PTH derivatives. 20. The non-invasive PTH preparation according to claim 19, wherein the non-PTH invasive preparation is the dental composition according to claim 16.