JPH1192379A - Preventive or therapeutic agent for osteopathy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent capable of suppressing bone quantity decrease and of considerably promoting osteogenesis, and useful for preventing or treating osteopathy including osteoporosis and fracture, by including a specific xanthine derivative (salt) as active ingredient. SOLUTION: This agent contains, as active ingredient, a xanthine derivative (salt) of the formula (R1 is a 1-3C straight-chain or branched-chain alkyl) such as 1-(5-oxohexyl)-3,7-dimethylxanthine or 1-(5-oxohexyl)-3-methyl-7-propylxanthine. The daily dose of the active ingredient is pref. 50-1,200 mg per adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a preventive or therapeutic agent for bone diseases. More specifically, the present invention relates to a prophylactic or therapeutic agent for a bone disease containing a xanthine derivative as an active ingredient, and the therapeutic agent is used for preventing or treating a bone metabolic disorder such as osteoporosis, or for preventing or treating a fracture. Can be done.

[0002]

2. Description of the Related Art It is said that bone metabolism is established by a well-balanced repetition of bone resorption by osteoclasts and bone formation by osteoblasts. In healthy adults,
A dynamic equilibrium is maintained between this formation process and the resorption process, thereby maintaining bone mass and structure. Many bone metabolic disorders represented by osteoporosis are thought to be caused by an imbalance between these two processes.
Active vitamin D is used as a therapeutic agent for such bone diseases.
_Three preparations, calcitonin preparations, bisphosphonic acid preparations, estrogen preparations, ipriflavone preparations, calcium preparations and the like are used. It has been reported that many of these preparations have an effect of suppressing bone resorption. However, in osteoporosis cases, especially in women in their 50s,
The so-called post-menopausal bone loss is significant, some leading to fracture risk zones. Many of the conventional drugs do not always have a sufficient effect as a therapeutic agent for surely recovering the bone mass in a case where the bone mass has decreased to the fracture risk area. Therefore, there is a need for the development of a drug that substantially increases the bone mass even in the treatment of bone diseases, particularly in cases where the bone mass has decreased to the risk of fracture.

[0003] On the other hand, when a fracture occurs, blood vessels in the medullary cavity, bone cortex, periosteum, and soft tissues are damaged, forming hematomas and infiltrating inflammatory cells. Disruption of blood flow causes tissue degeneration and necrosis, and it is said that bone cells are necrotic up to 1 to 2 mm from the fracture end 2 to 4 days after the fracture. After such an inflammatory phase, the phase shifts to a repair phase. Hematomas are replaced by granulation tissue by the emergence of mesenchymal cells from the periosteum and endosteum, and new blood vessel invasion. At this time, callus composed of fibrous tissue, cartilage tissue and fibrous bone tissue is formed, and progresses to bone union within a few weeks after the fracture mainly due to endochondral ossification. However, the new bone tissue at this time is coarse reticulated and does not have sufficient support for weight bearing. The last phase of fracture healing is called the remodeling phase, in which the formed callus is resorbed and a continuous lamella straddling the fracture stump is returned to its original shape. This period is very long, from months to years. In addition to these fresh fractures, infections, impaired blood circulation, bone displacement,
In some cases, prolonged healing fractures or pseudoarthritis may not be obtained due to malnutrition, metabolic abnormalities, etc., and normal bone union cannot be obtained ("Science of Bone", Medical and Dental Medicine, pp. 212-221). For the treatment of such fractures, casts, bracing, external fixation devices and, if necessary, intramedullary nails and bone plates are used by surgery. However, such treatment does not shorten the fracture healing period, but aims at preventing bone displacement in the early stage of injury and enhancing fragile bone support. Although anti-inflammatory agents and antibiotics are also used, these are administered for the purpose of preventing excessive inflammation and infection after injury, and do not promote healing. Therefore, no drug has been used for the purpose of accelerating the healing of fractures, and there is a demand for the development of a drug that enables early weight bearing.

[0004] Xanthine derivatives have been used as central nervous system stimulants and cerebral circulation and metabolism improving agents. Some of the active ingredients of the present invention are actually used as pharmaceuticals,
1- (5-oxohexyl) -3,7-dimethylxanthine is a cerebral microcirculation improving agent, 1- (5-oxohexyl) -3
-Methyl-7-propylxanthine is used as a remedy for motivational and emotional disorders due to sequelae of cerebral infarction and sequelae of cerebral hemorrhage. Until now, it has been reported that xanthine derivatives may be useful for inflammatory diseases by inhibiting the production of TNF-α (Tumor necrosis factor-α) in a dose-dependent manner (Journal of Cardiovascular Pham).
acology Vol.25, p.30-33, 1995). TNF-α was discovered as a factor that induces hemorrhagic necrosis at a tumor site, but is now recognized as a cytokine widely involved in inflammation-based biological defense and immune mechanisms. TNF
Sustained and excessive production of -α causes tissue damage,
It is thought to be the cause of various diseases and the cause of exacerbation. 1- (5-oxohexyl) -3,7-dimethylxanthine, which is one of the active ingredients of the present invention, is suitable for the treatment of shock due to sepsis, adult respiratory distress syndrome, lung injury due to cardiopulmonary bypass, and cardiopulmonary injury due to reperfusion. It has been suggested that tissue damage caused by the sphere can be reduced (Infect. Immun. 56 (7): 1722-1729, 1988).
Japanese Unexamined Patent Publication No. 7-500085 discloses that the compound is TN
It is described that F-α has effects such as reduction of tumor cell proliferation, and hematopoietic stem cells promote differentiation into erythrocytes, platelets and granulocytes. But,
The active ingredient of the present invention is useful for prevention or treatment of abnormal bone metabolism, or prevention or treatment of bone fracture, and has an effect of restoring the bone mass in a case where the bone mass is reduced to a fracture risk area. It is not described. As described above, simply increasing bone mass is not enough for healing of a fracture, and it is necessary to progress to bone union to such an extent that weight can be finally loaded. In fact, estrogen (Obstet. Gynecol) is a treatment for osteoporosis.
48 (3): 351-352, 1976), calcitonin (J. Orthop. Res.
7 (1): 100-106, 1989), bisphosphonic acid preparation (J. Orth
op.Res.14 (1): 74-79, 1996, Pharmacol. & Toxicol.75
(6): 384-390, 1994) has no effect on promoting fracture healing. Furthermore, it has been reported that transforming growth factor β2 (TGF-β2), which has an osteogenesis promoting effect, also has no fracture healing promoting effect (Bone 16 (5): 5).
21-527, 1995). There has not yet been described that the active ingredient of the present invention is effective for fracture healing.

[0005]

SUMMARY OF THE INVENTION Accordingly, the present invention provides a highly specific osteogenic effect, reliably promotes osteogenesis, and reduces the amount of bone to the risk of fracture. It is another object of the present invention to provide a compound capable of restoring the bone mass and a compound capable of effectively promoting the fracture healing process and enabling early weight bearing. The present inventor has made intensive efforts to achieve the above object, and as a result, the following xanthine derivatives inhibit bone loss in a state where bone resorption is promoted, and particularly increase bone cortex, even in a normal state. The present inventors have found that they have a strong bone formation promoting action to increase bone mass and bone cortex, and more interestingly, have a bone fracture healing promoting action, and have completed the present invention. The therapeutic agent for bone disease of the present invention is used not only for treating bone metabolic disorders such as osteoporosis in which the bone mass is reduced to a fracture risk area,
The present invention can be used for the prevention or treatment of bone diseases, which are widely predicted to shift to osteoporosis and the like, and for the prevention or treatment of pathological fractures such as prolonged healing fractures, false joints, and bone defects as well as fresh fractures. These treatments include those in the field of veterinary surgery. The therapeutic agent for bone disease of the present invention can be used for the prevention or treatment of bone diseases such as osteoporosis and fracture, particularly in cases where the bone mass has decreased to a fracture risk area.

That is, the present invention provides:

Embedded image (Wherein R ₁ is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms) or a salt thereof, as an active ingredient. .

Examples of such xanthine derivatives include 1- (5-oxohexyl) -3,7-dimethylxanthine (hereinafter, this compound is referred to as its general name pentoxifylline), 1- (5 -Oxohexyl) -3
-Methyl-7-propylxanthine (this compound is hereinafter referred to as its general name, propentofylline), and the like, but is not limited thereto. In addition, examples of the bone disease include osteoporosis, fresh fracture, prolonged healing fracture, pseudoarthritis, bone defect, osteogenesis imperfecta, and root / alveolar defect.

[0008] Examples of the linear or branched alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an isopropyl group and an n-propyl group.

The above compounds contained in the bone disease agent of the present invention can be produced, for example, by the methods described in JP-B-45-21308 and JP-B-52-33120. The manufacturing method is not limited to these methods.

The bone disease agent of the present invention contains the above compound in free form or in the form of a pharmacologically acceptable salt as an active ingredient. Examples of the pharmacologically acceptable salt include a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an amine salt and the like. The bone disease agent of the present invention may contain a combination of two or more of the above compounds. In addition, active vitamin D ₃
Agents, known vitamin D derivatives, calcitonin preparations, bisphosphonic acid preparations, estrogen preparations, ipriflavone preparations, calcium preparations, and other therapeutic agent components. The above-mentioned compound contained in the bone disease agent of the present invention has a strong bone formation promoting action, and by using it as a therapeutic agent for bone diseases such as osteoporosis, it significantly promotes bone formation, thereby In addition, since it has the effect of forming a tough bone qualitatively, it is possible to prevent a fracture even in a case where the fracture reaches a fracture risk area. In addition, by using as a therapeutic or preventive agent for various bone metabolic disorders in which bone mass is reduced, fracture can be prevented. Furthermore, by using it as a therapeutic agent for fresh fractures, it is possible not only to accelerate the healing process and obtain bone fusion at an early stage, but also to prevent pathological fractures such as prolonged healing fractures, false joints, and bone defects. it can. By using it as a therapeutic agent for such pathological fractures, it is possible to effectively promote bone formation, to escape from the pathological state and to cure the pathological state.

The dosage form of the therapeutic agent for bone disease of the present invention is not particularly limited, but it can be administered orally or parenterally. Examples of formulations suitable for oral administration include, for example,
Tablets, capsules, powders, fine granules, granules, solutions, syrups and the like can be mentioned. Formulations suitable for parenteral administration include, for example, injections, suppositories, inhalants, ointments, patches and implants.
The therapeutic agent for bone disease of the present invention may be produced by adding a pharmacologically or pharmaceutically acceptable additive as necessary. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, diluents, bases, Agents, solubilizing agents, tonicity agents, pH regulators, stabilizers, propellants, adhesives and the like.

Formulations for oral administration include glucose, lactose, D
Excipients such as mannitol, starch or microcrystalline cellulose; disintegrants or disintegrants such as carboxymethylcellulose, starch or calcium carboxycellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or gelatin; stearic acid Lubricants such as magnesium or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol or titanium oxide can be used. Formulations for transdermal or transmucosal administration include vaseline, liquid paraffin,
Bases such as polyethylene glycol, gelatin, kaolin, glycerin, purified water or hard fat;
Propellants such as diethyl ether or compressed gas; adhesives such as sodium polyacrylate, polyvinyl alcohol, methylcellulose, polyisobutylene, and polybutene; base fabrics such as cotton cloth or plastic sheet can be used. Injectable preparations include dissolving agents or solubilizing agents which can constitute aqueous or ready-to-use injections such as distilled water for injection, physiological saline and propylene glycol; glucose, sodium chloride, D-mannitol, glycerin and the like. Isotonizing agents; pH adjusters such as inorganic acids, organic acids, inorganic bases and organic bases can be used. As a method of topical administration, there is a method in which the surface of a bone or a tooth is covered with the compound of the present invention using collagen paste, fibrin glue or another adhesive. Among these, the bone used for bone transplantation can be used not only for natural bone but also for conventionally used artificial bone. The artificial bone means a bone made of a natural material such as metal, ceramics, and glass, or an artificial inorganic material. Preferably, the artificial inorganic material is hydroxyapatite. For example, metal is used for the inner material of the artificial bone and hydroxyapatite is used for the outer material.

The dosage of the bone disease agent of the present invention is not particularly limited, but may be appropriately selected according to the administration form, age, body weight, symptoms and the like. For example, in the case of oral administration, 0.05 to 3000 mg, preferably 50 to 120 mg per day for an adult.
0 mg may be administered. The bone disease agent of the present invention may be administered once or several times a day. Also, the administration period can be arbitrarily determined according to the age, symptoms, and the like.

[0014]

The present invention will be described more specifically with reference to test examples.

[Test Example 1] LPS (lipopolysacaharid)
e, lipopolysaccharide) administration has already been reported to induce TNF-α production in macrophages and mast cells. In addition, as described above, the xanthine derivative inhibits the production of TNF-α. In this test, after confirming that TNF-α promotes bone resorption in vivo, the compound which is the active ingredient of the present invention inhibits the promotion of bone resorption by TNF-α, and It was examined whether the amount could be recovered. 4-week-old male DD with almost the same weight
Using 32 Y mice, 8 mice were classified into the following four groups. 1. LPS administration group (L in FIG. 1, FIG. 2 and FIG. 3)
12.5 mg / kg of LPS intramuscularly twice a week. 2. LPS, pentoxifylline administration group (indicated as LP in FIG. 1 and LPS + PTX in FIGS. 2 and 3) LPS 12.5 mg / kg twice a week and pentoxifylline 60 mg / kg twice a day intramuscularly. 3. Pentoxifylline administration group (indicated as P in FIG. 1 and PTX in FIGS. 2 and 3) 60 mg / kg of pentoxifylline intramuscularly once every two days. 4. A control group (C in FIG. 1 and Control in FIGS. 2 and 3) was intramuscularly injected with 0.9% physiological saline. Four weeks after the start of administration, each was fixed by perfusion, femurs were collected, bone images were taken with a soft X-ray apparatus (XP images), and in each group, the thickness of the cortical bone (CB) at the center of the femur / the whole bone Lateral diameter of
(TB) was measured. In addition, each group was divided into four animals at 0.4.
After decalcification of 6N-hydrochloric acid, the amount of calcium was measured using a chelate coloring method and a spectrophotometer.
/ G Body Wt.) Values were calculated. FIG. 1 shows a photograph taken by XP, and FIG. 2 shows a result of CB / TB measurement. FIG. 3 shows the value of the amount of calcium in the femur. In the photograph taken by XP, dark bones indicate small bone mass, and bright bones indicate large bone mass. As a result of the test, the LPS-administered group showed clear osteoporosis on the XP photograph, and the CB / TB value was smaller than the control group. The CB / TB value of the LPS and pentoxifylline administration group was larger than that of the LPS administration group, and was larger than that of the control group. The CB / TB value of the pentoxifylline-administered group was the largest, and a clear increase in bone cortex was observed in the XP photograph as compared with the control group. Comparing the femoral calcium content / body weight (mg / g Body Wt.) Value, the LPS-administered group was significantly lower than the control group. In the LPS and pentoxifylline administration groups, the amount of calcium in the femur was significantly increased as compared with the LPS administration group, and the pentoxifylline administration group was the most numerous.

From the above results, when the XP images and the amount of bone calcium in each group were compared and examined, the LPS-administered group showed thinner bone cortex, reduced the amount of bone calcium, and reduced bone coarseness as compared with the control group. Porosis had occurred. In contrast, non-thinning of the bone cortex and decrease in the amount of bone calcium are suppressed by simultaneous administration of pentoxifylline, which is one of the active ingredients of the present invention, and the pentoxifylline alone administration group is different from the control group. In contrast, the bone cortex was thickened and the amount of bone calcium increased. From these results, it was confirmed that osteoporosis was caused by LPS administration, osteoporosis was suppressed by simultaneous administration of pentoxifylline, and that pentoxifylline had an effect of increasing bone mass when administered alone. Was. In addition, a test similar to that described above was conducted for propentofylline, which is one of the active ingredients of the present invention, and it was confirmed that the compound had an effect of suppressing osteoporosis and increasing bone weight. The active vitamin D ₃ agents, known bone disease therapeutic component of the calcitonin and the like, significant effects such as found in active ingredient of the present invention in this experimental system was observed.

Test Example 2 Male Sprague-Dawley rats (8 weeks old) were used as experimental animals, and fractures were made in both radial shafts under pentobarbital anesthesia. The fracture end was reduced and no fixation was performed. Dissolve pentoxifylline in physiological saline for injection, and add 2 mg /
A dose of kg or 10 mg / kg was administered subcutaneously. On the other hand, physiological saline as a solvent was subcutaneously administered to the healthy group and the fracture control group. Four weeks after the fracture, the patient was euthanized by exsanguination under pentobarbital anesthesia, and the right and left radii were removed. The surrounding soft tissue is removed, and the proximal and distal ends of the radius are embedded in a resin and attached to a bone strength measuring device MZ-500D (manufactured by Maruto), and the torsional strength at the fracture site (when the bone sample is broken) (Maximum torque value). As a result, as shown in FIG. 4, the fractured bone showed about 60% of the strength of the healthy bone and was in the process of healing. The pentoxifylline 2 mg / kg administration group showed a slight increase in bone strength compared to the control group, but was not statistically significant, but the 10 mg / kg administration group had significantly more bone strength than the fracture control group. And promoted bone fusion to such an extent that no significant difference was observed with healthy bone, and bone strength was restored.

[0018]

According to the above results, the active ingredients (for example, pentoxifylline and propentofylline) of the therapeutic agent for bone diseases of the present invention have a remarkable effect on the suppression of bone loss and bone formation. It is clear to show. Such effects of the present invention are remarkably remarkable as compared with existing osteoporosis therapeutic components, because they significantly promote bone formation to form strong bones both quantitatively and qualitatively. In addition, as an effect on fracture healing, by promoting bone union,
It can enable early weight loading, which is difficult with normal fracture healing. That is, it is useful as an agent for treating or preventing various bone diseases such as osteoporosis, fresh fracture, prolonged healing fracture, pseudoarthritis, bone defect, osteogenesis imperfecta, and further, root and alveolar defect.

[Brief description of the drawings]

FIG. 1 is a photograph of an XP photograph of a femur of a mouse obtained in a test example.

FIG. 2 shows the lateral diameter (T
It is a figure which shows the result of having measured the ratio (%) of thickness (CB) of cortical bone with respect to B).

FIG. 3 shows the amount of calcium in the mouse femur (mg /
g Body Wt.) values.

FIG. 4 is a diagram showing the rat radial torsional strength (kgf · cm) of each group 4 weeks after a fracture in Test Example 2.

Claims (4)

[Claims] 1. The following general formula (I): (Wherein R ₁ is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms) or a bone disease preventive or therapeutic agent containing a xanthine derivative or a salt thereof as an active ingredient. 2. The method according to claim 1, wherein the xanthine derivative is 1- (5-oxohexyl) -3,7-dimethylxanthine or 1- (5-oxohexyl) -3,7-dimethylxanthine.
The preventive or therapeutic agent for a bone disease according to claim 1, which is (5-oxohexyl) -3-methyl-7-propylxanthine. 3. The preventive or therapeutic agent for a bone disease according to claim 1, wherein the bone disease is osteoporosis. 4. The preventive or therapeutic agent for a bone disease according to claim 1, wherein the bone disease is a fracture.