JPH0692847A - Therapeutic agent for osteoporosis - Google Patents

Abstract

PURPOSE:To obtain a therapeutic agent for osteoporosis, useful for inhibiting the onset of the osteoporosis, preventing deterioration, improving and treating the osteoporosis and excellent in safety. CONSTITUTION:This therapeutic agent for osteoporosis comprises ethyl all- cis-5,8,11,14,17-icosapentaenoate as an active ingredient. The therapeutic agent is especially useful for I type osteoporosis frequently found in women mainly of 50 to 70 or more years old, i.e., the osteoporosis causing reduction in bones due to bone resorption exceeding the osteogenesis in spite of a high metabolic turnover type in which both bone resorption and osteogenesis are accelerated as compared with the normal state. This therapeutic agent has hardly any side effects found in medicines such as an estrogen pharmaceutical preparation or an active type vitamin D3 which are used at present.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel therapeutic agent for osteoporosis,
Specifically, ethyl icosapentate (hereinafter referred to as “EPA-E”)
(Also sometimes abbreviated) as an active ingredient.

[0002]

2. Description of the Related Art Osteoporosis has a high frequency and causes bone fractures in various parts of the body, leading to the so-called "bedridden elderly". Not only is it attracting attention as a social problem. Osteoporosis is mainly age 5
Type I osteoporosis that is common in women aged 0 to 75
It is mainly classified into two types, i.e., osteoporosis type II, which is found in elderly people over 70 years old (Riggsby
Riggs BL et al, The New England Journal of Medicine (The)
New England Journal of Me
dicine), 314, 1676, 1986
Year). Here, type I osteoporosis is basically a high turnover type in which bone resorption and bone formation are both higher than normal, but since bone resorption exceeds bone formation. It causes bone loss. A decrease in female hormones associated with menopause is often the cause of increased bone resorption. On the other hand, type II osteoporosis is a low turnover type in which metabolism of bone resorption / bone formation is lower than normal, and induces differentiation of osteocyte with age and its function decline, lack of exercise such as bedridden and bone. In addition to the decreased formation ability, the etiological factors such as decreased intake of calcium and decreased production of vitamin D due to decreased renal function are considerably diverse.

On the basis of the above etiology and pathological condition, at present, drugs for the purpose of suppressing bone resorption are mainly used for type I osteoporosis, and promotion of bone formation for type II osteoporosis. The intended drug is mainly used. Estrogen preparations are a representative therapeutic agent used alone for type I osteoporosis, but uterine bleeding and the onset of thrombosis and cancer due to long-term administration have been reported. Thrombosis and estrogen dependence such as breast cancer and uterine cancer Contraindicated in patients with suspected metastatic tumor. Further, calcitonin preparations, active vitamin D3 preparations, ipriflavone and the like are also used for the treatment of osteoporosis, but side effects such as gastrointestinal disorders such as nausea and vomiting, shock symptoms and hypersensitivity have been recognized. Since osteoporosis is a disease for which the treatment period is extremely long, it is an important task to develop a safe therapeutic drug that does not cause such side effects.

Recently, whole-cis-obtained from refined fish oil
A patent application was filed for an osteogenesis promoter containing 5,8,11,14,17-eicosapentaenoic acid (hereinafter abbreviated as "EPA") as an active ingredient (JP-A-1-157912).
issue). However, this specification shows the bone formation-promoting effect of EPA-free bodies on isolated osteoblasts of animals, and there is no suggestion of the effect on osteoclasts or suppression of bone resorption, and clinically. There is no description about the effectiveness in. As described above, in the treatment of type I osteoporosis, the bone resorption must first be suppressed. Therefore, the osteogenesis promoters disclosed in the prior art are considered to suggest the treatment of type II osteoporosis. This is also clear from the description in the section (Effect of the invention) of JP-A-1-157912.

Morita et al., The inventor of the above patent application,
The effect of EPA-free body in an osteoporosis model in which a low Ca diet was given to ovariectomized rats has been reported (Journal of the Japanese Society for Bone Metabolism Vol. 9, No. 3, pp. 307, 1991).
The report suggests that EPA has a pro-osteogenic effect under specific conditions in an experimental model, but there is no mention of actual treatment.

[0006] However, the EPA used in these two prior arts is a free form, there is no disclosure of its use in the form of other derivatives such as salts, esters, amides, etc., and its usefulness, and clinically. There is no mention of the effectiveness of. E
It is known that the free form of PA has strong mucosal irritation, and clinically, side effects such as ulcer induction are concerned.

[0007] In addition, residents of the Far North (Dyerberg J et al., American Journal of Clinical Nutrients), Vol. 28, p. ), There is also a report that bone loss is observed (Masess RB et al.
et al), American Journal of Clinical Nutrients (Am J ClinNut)
r), Vol. 42, No. 1, p. 143, 1985), E
The usefulness of PA for osteoporosis in humans has not been known so far.

[0008]

The present invention is a therapeutic agent for osteoporosis, which contains EPA-E as an active ingredient.

[0009] The present inventor has conducted diligent research on a safe therapeutic drug for osteoporosis. As a result, EPA-E is clinically extremely useful for preventing and ameliorating the progression of osteoporosis, particularly in type I. I found it useful. The treatment in the present invention also includes prevention of the disease.

The present invention will be described in detail below.

EPA-E in the present invention means ethyl all-cis-5,8,11,14,17-ethyl icosapentate (ethyl all-cis-5,8,11,14,
17-icosapentaenoate), which can be obtained by purifying and esterifying fish oil by a known method in addition to commercially available products.

In the active ingredient of the therapeutic agent of the present invention, EP
As AE, not only pure products thereof but also EPA-E having a fatty acid content of 50% by weight or more, preferably 85% by weight or more can be used.

The therapeutic agent of the present invention may be prepared by administering the active ingredient alone, or by using a suitable carrier or vehicle generally used, for example, an excipient, a binder, a lubricant, a coloring agent, a flavor. Agent, sterilized water or vegetable oil if necessary, and harmless organic solvent or harmless solubilizer (eg glycerin, propylene glycol), emulsifier, suspending agent (eg Tween 80, gum arabic solution), etc. It can be combined to prepare a suitable pharmaceutical preparation.

Since EPA-E is highly unsaturated, the above formulations further contain antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, pharmaceutically acceptable quinones and α-tocopherol. It is desirable to include it.

The dosage form of the preparation includes tablets, capsules,
Granules, fine granules, powders, oral liquid preparations, suppositories, syrups, inhalants, ointments, injections (emulsion, suspension, non-aqueous), or emulsions or suspensions before use Although it is administered to a patient in the form of a solid injection whether orally or parenterally, oral administration in a capsule such as a soft capsule is preferable. The high-purity ethyl ester form of EPA (EPA-E) is already on the market as a safe drug with few side effects.

The dose of the therapeutic agent of the present invention is sufficient to treat the target osteoporosis. The dosage form of the therapeutic agent, the method of administration, the number of administrations per day, the degree of symptoms, the body weight, The amount varies depending on age and the like. Generally, 0.
The dose is 3 to 6 g / day, preferably 1 to 3 g / day in three divided doses, and may be administered once or in several divided doses as needed.

The action of the therapeutic agent of the present invention will be described below with reference to specific examples.

Experimental Example 1 Effect of EPA-E in type I osteoporosis model rat (1) Female Wistar rats (8) as type I osteoporosis model
Age of 5 weeks, body weight 250-300g) 5 groups (each group 5
The experiment was carried out by dividing into 8 animals. 1) control group (sham operation group), 2) ovariectomy (OVX) group, 3) OVX +
EPA-E 30 mg / kg administration group, 4) OVX + EPA
-E 300 mg / kg administration group, 5) Control + EP
AE 300 mg / kg administration group. In the other 3 groups except sham ope, the ovaries were extracted at 8 weeks after birth and bred on a diet containing no fat, cocoa butter, and 0.5% Ca. EP
Each of A to E was suspended in gum arabic water and orally administered daily. After 8 weeks, the rats were sacrificed, tibias were collected, and their specific gravities were compared. The results are shown in Table 1.

Table 1 ─────────────────────────────────── n Specific gravity (g / cm ³ ) ─ ────────────────────────────────── Control (sham operation) 8 1.580 ± 0.012 *** OVX 8 1.476 ± 0.009 OVX + EPA-E 30 mg / kg 5 1.531 ± 0.016 ** OVX + EPA-E 300 mg / kg 7 1.532 ± 0.006 *** Control + EPA-E 300 mg / kg 6 1.564 ± 0.015 *** ──────────── ──────────────────────── **: p <0.01, ***: p <0.001 (vs. OVX group) EPA-E Significantly suppressed the decrease in the bone specific gravity of the type I osteoporosis model rat due to ovariectomy.

Experimental Example 2 Effect of EPA-E in type I osteoporosis model rat (2) Female Wistar rats (8) as type I osteoporosis model
Weekly age, body weight 250-300g, the following 3 groups (each group 8
The experiment was carried out by dividing them into 1) control group (sham operation group), 2) ovariectomy (OVX) group, 3) OVX + E
PA-E 300 mg / kg administration group. After switching from the normal diet to the F-1 diet without fish meal + 0.5% Ca diet, ovariectomy was performed 2 weeks later and the animals were bred on the same diet. Others were the same as in Example 1. The results are shown in Table 2.

Table 2 ─────────────────────────────────── n Specific gravity (g / cm ³ ) ─ ────────────────────────────────── Control (Sham Op) 8 1.615 ± 0.007 *** OVX 8 1.564 ± 0.006 OVX + EPA-E 300 mg / kg 8 1.585 ± 0.004 * ─────────────────────────────────── *: p < 0.05, ***: p <0.001 (vs. OVX group) Also in this experiment, EPA-E significantly suppressed the decrease in bone specific gravity of the type I osteoporosis model rat due to ovariectomy.

[0022]

EXAMPLES The effects of the therapeutic agent of the present invention on human osteoporosis patients will be shown and specifically described below.

High-purity EP for patients with regressive osteoporosis
A-E formulation (Epadel (trademark): Mochida Pharmaceutical 6 capsules (1800 mg as EPA-E) / day) was orally administered for 3 to 6 months in 2 to 3 divided doses. The vertebral bone densities before and after administration of the patient were measured, and the rate of change was compared with that of the control group (without EPA-E administration). When measuring bone density, DPX (L
UNER company, dual energy X-ray absorption method (D
The PXA), mean bone density of the second lumbar vertebra to the fourth lumbar vertebra (L2-L4BMD (mg / cm 2)) was measured.

Table 3 shows the bone density and the rate of change (%) (mean ± standard error) of each group before and after administration.

Table 3 ──────────────────────────────────── L ₂ -L ₄ BMD ── ─────────────────────── Before administration (mg / cm ² ) After administration (mg / cm ² ) Change rate (%) ────── ────────────────────────────── EPA-E administration group 0.862 ± 0.024 0.879 ± 0.026 1.90 ± 0.80 control group 0.995 ± 0.094 0.977 ± 0.095 −2.11 ± 0.75 ──────────────────────────────────── The increase / decrease in BMD well reflects the increase / decrease in cancellous bone in the vertebrae, and is a good indicator of the progression of osteoporosis.

The individual changes in vertebra BMD in the EPA-E-administered group were + 4.0%, + 2.2%, + 0.2% and + 1.2%, and BMD was clearly increased in all cases. On the other hand, in the EPA-E non-administration group, vertebra BM
D was significantly reduced. That is, high-purity EPA-E
By administration of the formulation, the change in BMD in patients with regressive osteoporosis turned from a significant decrease to an increase. In addition, no particular side effect was observed in the EPA-E administration group.

As a result of the above, the therapeutic agent of the present invention has a high efficacy rate (actually 100%) even in human osteoporosis.
Since it became clear that the above-mentioned reaction was observed and no side effect was observed, it was revealed that EPA-E is extremely useful in human osteoporosis. It is the first time that the present invention has demonstrated the utility of EPA-E in human osteoporosis. Furthermore, EPA-E has reduced toxicity upon oral administration as compared to EPA. In addition, since EPA (free form) is acidic, it causes irritation to the mucous membrane. On the other hand, when EPA is administered as a salt, ions such as sodium and potassium are also taken in at the same time. There is a risk of ingestion, but EPA-E does not have that concern. EPA-E is also excellent in this respect. EPA-E is used in Japan as a therapeutic drug for arteriosclerosis obliterans, which has excellent safety and extremely few side effects.

[0028]

INDUSTRIAL APPLICABILITY The therapeutic agent for osteoporosis of the present invention, which contains EPA-E as an active ingredient, not only significantly suppresses the decrease in bone specific gravity in an experimental animal model, but also actually reduces osteoporosis in humans. It is useful for prevention of onset, prevention and improvement of exacerbation, and treatment. EPA-E is superior to EPA in terms of safety, and has almost no side effects found in drugs such as estrogen preparations and active vitamin D3 currently used for the treatment of osteoporosis, and is suitable for an aging society. Since it is highly safe, the usefulness of this therapeutic agent is extremely large.

[Procedure amendment]

[Submission date] November 10, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0023

[Correction method] Change

[Correction content]

High-purity EP for patients with regressive osteoporosis
A-E formulation (Epadel (trademark): Mochida Pharmaceutical 6 capsules (1800 mg as EPA-E) / day) was orally administered for 3 to 6 months in 2 to 3 divided doses. The vertebral bone densities before and after administration of the patient were measured, and the rate of change was compared with that of the control group (without EPA-E administration). When measuring bone density, DPX (L
UNER company, dual energy X-ray absorption method (D
The PXA), mean bone density of the second lumbar vertebra to the fourth lumbar vertebra _{(L2-L4BMD (g / cm} 2)) was measured.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0025

[Correction method] Change

[Correction content]

[0025] The increase / decrease in BMD of the vertebrae measured by this method well reflects the increase / decrease in cancellous bone in the vertebrae, and is a good indicator of the progression of osteoporosis.

Claims (1)

[Claims] 1. A therapeutic agent for osteoporosis, which comprises ethyl icosapentatoate as an active ingredient.