JPH1160489A - Medicine for preventing/treating osteoporosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine for preventing/treating osteoporosis which enhances density and strength of bone without elevating the concentration of calcium in blood, by including an active type vitamin D and bisphosphonic acid as active ingredients. SOLUTION: The medicine is obtained by including (A) one or more active type vitamin Ds selected from the group comprising 1α-hydroxyvitamin D, 1α-24-dihydroxyvitamin D, 1α,25-dihydroxyvitamin D, 1α,24,25-trihydroxyvitamin D, 24,24-difluoro-1α,25-dihydroxyvitamin D, and 26,26,26,27,27,27-hexafluoro-1α,25- dihidroxyvitamin D, and (B) one or more bisphosphonic acids selected from the group comprising alendronic acid, pamidronic acid, etidronic acid, and licedronic acid, as active ingredients. It is preferable to administrate active type vitamin Ds at, a rate of 0.1-20 μg/d and bisphosphonic acids at a rate of 1-20 μg/d.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention relates to a drug containing active vitamin Ds and bisphosphonic acids as active ingredients for use in the prevention or treatment of osteoporosis.

[0002]

2. Description of the Related Art 1α-hydroxyvitamin D ₃ (1α-O
Active vitamin D such as H-D ₃ ), 1α, 24 (R) -dihydroxyvitamin D ₃ and 1α, 25-dihydroxyvitamin D ₃ have a calcium absorption promoting action in the small intestine, and a bone resorption in bone. Since it has an effect of regulating bone formation, it is used as a therapeutic drug for various diseases based on abnormalities of calcium metabolism such as osteoporosis. However, although the therapeutic agent containing only the active vitamin D as an active ingredient is almost satisfactory in improving bone density and bone strength, it has a side effect of increasing blood calcium levels in patients. There were drawbacks.

[0003] On the other hand, bisphosphonic acids specifically act on activated osteoclasts, and are thought to inhibit bone resorption by inhibiting the activity thereof. Thus, treatment of diseases based on abnormal calcium metabolism such as osteoporosis is considered. It is used as a medicine.

[0004] However, the therapeutic agent containing only bisphosphonic acids as an active ingredient has no side effect of increasing the blood calcium concentration of a patient, unlike the therapeutic agent containing only the active vitamin D as an active ingredient, but has a bone mineral density. In terms of improving bone strength, it did not reach the therapeutic agents containing only the active vitamin D as an active ingredient.

[0005]

Therefore, the present inventors have been able to improve bone density and strength to a level equal to or higher than those of conventionally known therapeutic agents for osteoporosis, and to improve blood density. An object of the present invention is to provide a drug that does not increase the calcium concentration in the medium. Also,
An object of the present invention is to provide, as a preventive agent for osteoporosis, a drug capable of suppressing a decrease in bone density and bone strength and not increasing blood calcium concentration.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies on components effective as a therapeutic agent for osteoporosis, and found that active vitamin D and bisphosphonic acid, which were conventionally used alone, were used in combination. By doing so, it has become possible to provide a therapeutic agent for osteoporosis, which is well-balanced in that it improves bone density and strength and does not increase blood calcium concentration. Furthermore, according to the study of the present inventors, the combined use of the active vitamin Ds and bisphosphonic acids not only improves the reduced bone density and strength, but also reduces the bone density and strength. The present invention has been found to have an inhibitory effect, and has made it possible to provide an osteoporosis preventive agent.

[0007] That is, the present invention is an agent for preventing or treating osteoporosis, comprising active vitamin Ds and bisphosphonic acids as active ingredients.

Hereinafter, the present invention will be described in detail.

The active vitamin D used in the present invention is distinguished from the vitamin D itself which has no physiological action, and refers to the vitamin D which has a physiological action such as calcium and bone metabolism regulation. Vitamin D ₂ , activated vitamin D ₃ and their derivatives.
Specific examples thereof include, for example, 1α-hydroxyvitamin D, 1α, 24-dihydroxyvitamin D, 1α, 25
-Dihydroxyvitamin D, 1α, 24,25-trihydroxyvitamin D, 24,24-difluoro-1α,
25-dihydroxyvitamin D, 26, 26, 26, 2
7,27,27-hexafluoro-1α, 25-dihydroxyvitamin D and the like. Among them, 1α-hydroxyvitamin D ₃ , 1α, 24 (R) -dihydroxyvitamin D ₃ and 1α, 25-dihydroxyvitamin D ₃ are preferred. Further, the active vitamin Ds in the present invention may be one or a mixture of two or more of these, and the mixing ratio is appropriately determined.

The dose of these active vitamin Ds is an amount effective for the prevention or treatment of osteoporosis, and the patient's age, weight, type of combination therapy, frequency of treatment,
Since it depends on the kind of desired effect or the method of administration, it cannot be unconditionally determined, but when it is generally used as a therapeutic agent, it is usually 0.01 μg to 100 μg / day, preferably 0.1 μg to 20 μg / day. In the case of an external preparation, the amount is usually 0.01 μg to 100 μg / day, preferably 1 μg to 20 μg / day. When used as a prophylactic agent, it is usually 0.05 μg to 5 μg / day, preferably 0.1 μg to 5 μg.
0.5 μg / day.

The bisphosphonic acids used in the present invention include alendronic acid, pamidronic acid, etidronic acid, tiludronic acid and risedronic acid. Of these, alendronic acid is preferred. These may be used alone or in combination of two or more at an arbitrary ratio.

The dose of bisphosphonic acids is an amount effective for the prevention or treatment of osteoporosis, and the patient's age, body weight, type of combination therapy, frequency of treatment, type of desired effect, or administration method, etc. However, when it is generally used as a therapeutic agent, it is generally 5 mg to 400 mg / day, preferably 10 mg to 20 mg.
0 mg / day. 0.01 μg for external preparations
１００100 μg / day, preferably 1 μg to 20 μg / day. When used as a prophylactic, usually 1 mg to 1 mg
0 mg / day, preferably 2.5 mg-5 mg / day.

[0013] The preventive or therapeutic agent for osteoporosis of the present invention comprises:
What is necessary is just to contain these active vitamin Ds and bisphosphonic acids as active ingredients. They can be mixed and administered at the same time, or they can be separately and sequentially administered in a chain.

The number of daily administrations of the prophylactic or therapeutic agent for osteoporosis of the present invention can be once or divided into two or three times.

Here, when the agent of the present invention is used as a prophylactic agent, it is preferable to administer it in a chain before the bone density and the like are significantly reduced, and in particular, to administer bisphosphonic acids → active vitamin D in this order. Is preferred. On the other hand, when the agent of the present invention is used as a therapeutic agent, simultaneous administration is preferred.

The agent for preventing or treating osteoporosis of the present invention not only can improve bone density and strength but also does not increase blood calcium concentration. This is a conventionally known therapeutic agent for osteoporosis,
When only active vitamin D is used as an active ingredient, it has an effect of improving bone density and bone strength, but has a side effect of increasing blood calcium concentration. However, when only bisphosphonic acids are used as the active ingredient, there is no side effect of increasing blood calcium concentration, but the effect is insufficient in terms of improving bone density and strength. The osteoporosis preventive or therapeutic agent of the present invention can be used as an active ingredient by using two types of active vitamin Ds and bisphosphonic acids having different mechanisms of action in combination with each other to obtain a osteoporosis preventive or therapeutic agent equivalent to or better than a conventionally known osteoporosis therapeutic agent. The present invention is characterized in that it has an effect of improving bone density and strength and can provide a well-balanced drug free of the side effects.

The active vitamin Ds and bisphosphonic acids of the present invention can be formulated by known methods alone or together with appropriate excipients as described below. Specific examples of such dosage forms include oral preparations such as soft capsules, hard capsules, tablets, and syrups, injections, and external preparations.

Such excipients include vegetable oils (eg, corn oil, cottonseed oil, coconut oil, almond oil,
Peanut oil), oily esters such as medium-chain fatty acid glycerides, mineral oil, petrolatum, animal fats and oils, cellulose derivatives (for example, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), polyvinylpyrrolidone,
Dextrin, lactose, mannitol, sorbitol, starch and the like. If necessary, additives such as an antioxidant, a wetting agent, a viscosity stabilizer, and a coloring agent may be added.

The oral preparations such as soft capsules, tablets and granules for dry syrup of the preventive or therapeutic agent for osteoporosis of the present invention are specifically described, for example, in JP-B-57-45415 and JP-B-63-46728. , Tokiko 63-6000
No. 7, JP-A-61-87619.

[0020]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below with reference to embodiments.

[0021]

Example 1 and Comparative Examples 1-3 Rats aged 40 weeks (Sp
(Rague-Dawley strain, female). 1
After leaving for 5 weeks and bone loss, alendronate disodium salt (dose 0.2 mg / kg body weight) and 1α-
Hydroxyvitamin D ₃ (dose 0.02 μg / kg body weight, indicated as “one alpha” in the figure) was orally administered alone or in combination for 12 weeks as shown below. After the administration, the rats were euthanized, the vertebral bodies were isolated, and the bone density (BMD, g / cm 2) of the fourth to sixth vertebral bodies (L4-L6) was measured by a dual energy X-ray absorption method. The results are shown in FIG. Comparative Example 1: Ovariectomized group (control) Comparative Example 2: Alendronate-administered group Comparative Example 3: One-alpha-administered group Example 1: Alendronate + One-alpha combined group From FIG. The improvement in bone density was confirmed as compared with 1 to 3.

[0022]

Examples 2 and 3 and Comparative Examples 4 to 6 Ovariectomy was performed on 48-week-old rats (Sprague-Dawley strain, female). The drug was administered for 20 weeks or less as shown below from the day before bone mass and bone strength began to decrease. Comparative Example 4; Ovariectomized group (control); Vehicle Comparative Example 5; Alendronate administration group; Alendronate disodium salt (dose 0.5 mg / kg body weight) Comparative Example 6; One alpha administration group; 1α-hydroxyvitamin D ₃ (dose 0.05 μg / kg body weight) Example 2; one alpha → alendronate administration group; 1α
-Hydroxyvitamin D ₃ (dose 0.05 μg / kg body weight) (10 weeks) → alendronate disodium salt (dose 0.5 mg / kg body weight) (10 weeks) Example 3: alendronate → onealpha administration Group: alendronate disodium salt (dose 0.5 mg / kg body weight) (10 weeks) → 1α-hydroxyvitamin D ₃ (dose 0.05 μg / kg body weight) (10 weeks) After termination of administration, rats were euthanized The lumbar vertebra was isolated, and the bone density (BMD, g / cm2) of the third lumbar vertebra (L3) was measured by a dual energy X-ray absorption method, and the maximum load (N) was measured by a vertebral body compression test. The results are shown in FIG. 2 and FIG. FIG. 4 shows the serum calcium concentration.

As is clear from FIGS. 2 and 3, Examples 2 and 3 show the same effect of suppressing the decrease in lumbar spine bone density and bone strength (measured by maximum overload) as compared with Comparative Examples 4 to 6. Was. Also, when compared with Examples 2 and 3, Example 3, that is, the group to which alendronic acid was initially administered, had improved bone density and strength than the group to which one alpha was initially administered.

Further, as is apparent from FIG.
Sample No. 3 had a lower serum Ca concentration than Comparative Examples 4 to 6, which revealed that there was no side effect.

[0025]

The prophylactic or therapeutic agent for osteoporosis according to the present invention can improve bone density and strength to a level equivalent to or higher than those conventionally known therapeutic agents for osteoporosis, and can be used in blood. It is a well-balanced drug that does not increase calcium concentration. Furthermore, it is a well-balanced drug that can suppress a decrease in bone density and bone strength and that does not increase blood calcium concentration as a preventive agent for osteoporosis. It is.

[Brief description of the drawings]

FIG. 1 shows the effect of drug administration on rats from which ovaries have been removed and bone density has decreased.

FIG. 2 shows the effect of suppressing the decrease in bone density by administering a drug to rats before the ovaries were removed and the bone density was reduced.

FIG. 3 shows the effect of suppressing the decrease in bone strength by administering a drug to a rat before the ovary was removed and showing a decrease in bone density and measuring the maximum load.

FIG. 4 shows the results of administration of a drug to rats before the ovaries were removed and bone density decreased, and the serum calcium concentration was measured.

[Explanation of symbols]

* And ** represent P <0.05 and P <0.01, respectively, for the ovariectomized group as a result of Dunnett's multiple comparison test.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Tomohiro Ota 4-2-2 Asahigaoka, Hino-shi, Tokyo Teijin Tokyo Research Center Co., Ltd.

Claims (3)

[Claims] 1. An agent for preventing or treating osteoporosis, comprising an active vitamin D and a bisphosphonic acid as active ingredients. 2. The active vitamin D, wherein 1α-hydroxyvitamin D, 1α, 24-dihydroxyvitamin D,
1α, 25-dihydroxyvitamin D, 1α, 24,2
5-trihydroxyvitamin D, 24,24 difluoro-1α, 25-dihydroxyvitamin D, 26,2
6,26,27,27,27-hexafluoro-1α,
2. The preventive or therapeutic agent for osteoporosis according to claim 1, which is one or more active vitamin Ds selected from the group consisting of 25-dihydroxyvitamin D. 3. The osteoporosis according to claim 1, wherein the bisphosphonic acids are one or more bisphosphonic acids selected from the group consisting of alendronic acid, pamidronic acid, etidronic acid, tiludronic acid, risedronic acid. Prophylactic or therapeutic agent.