WO1996028166A1

WO1996028166A1 - Osteoporosis remedy and osteogenesis accelerator

Info

Publication number: WO1996028166A1
Application number: PCT/JP1995/000425
Authority: WO
Inventors: Kazuyoshi Iwai; Hitoshi Arita; Hisato Kakushi; Masahiro Toukin
Original assignee: Shionogi & Co., Ltd.
Priority date: 1994-02-02
Filing date: 1995-03-15
Publication date: 1996-09-19

Abstract

An osteoporosis remedy and an osteogenesis accelerator each containing at least either mepitiostane or epitiostanol as the active ingredient and having an excellent therapeutic effect exceeding the known drugs.

Description

Details 誊

Osteoporosis treatment and bone formation promoter

The present invention relates to an osteogenesis promoting agent and a treatment for osteoporosis containing mepithiostan represented by the following formula (I) or ebitiostanol represented by the following formula (II) which is a metabolite thereof in the body: Agent.

Background art

Osteoporosis is a disease in which bone fracture or destruction occurs almost without warning due to abnormally low bone mass. Osteoporosis is the most common disease in the Japanese population, and most of it occurs in people after middle age, so it is considered to be a particular problem in the future aging society due to the prolongation of the average age. Attention has been paid.

It is known that bone is in vivo, and osteoblasts that make bone and osteoclasts that break bone work in parallel to remodel bone by remodeling bone formation and bone resorption. _c Bone resorption is initiated when the surface of a quiescent bone is stimulated by a stimulant such as the hormone ゃ a cytokine, by which unknown information is transmitted to the osteoclast by an unknown mechanism. On the other hand, bone formation is caused by these osteoclasts. This is done by repairing the bone that has been absorbed and broken down by osteoblasts. In a normal body, the amount of bone resorption and the amount of bone formation are in equilibrium, and this harmony in the body causes the bones to be reborn while maintaining the status quo.

However, after middle age, physiologically, the amount of bone resorption exceeds the amount of bone formation for some reason, and this accumulates or the amount of bone resorption abnormally exceeds the amount of bone formation due to other factors. Osteoporosis develops. Therefore, it was expected that suppression or inhibition of bone resorption would be useful for treatment of osteoporosis, and that promotion of bone formation would be useful for treatment of osteoporosis. Furthermore, it was expected that a drug having both the effect of inhibiting bone resorption and the effect of promoting bone formation would be extremely useful for treating osteoporosis.

Osteoporosis treatments are already on the market.For example, to reduce bone loss caused by low calcium intake, to increase calcium intake, for example, alphacalcidol Activated vitamin

D is used.

However, the above-mentioned active vitamin D merely had the effect of efficiently ingesting calcium, and was merely a scavenging therapy for a deficiency in the amount of vitamin D consumed as food or impaired calcium absorption in the intestinal tract. In addition, when the dose was increased, toxicity such as (1) calcidiaemia and (2) nephrotoxicity became a problem.

Calcitonin, a peptide existing in the body, is known as a drug that acts to suppress the release of calcium from the osteoclasts into the blood (ie, bone resorption). In addition to calcitonin derived from humans, salmon calcitonin derived from salmon, as well as porcine and persimmon types are also on the market. However, human calcitonin is difficult to purify. It is in the stage of searching for production using the biotechnology method. Studies on chimeric calcitonin, which is similar to human calcitonin, are also being conducted, but have not yet achieved any definite results. In addition, calcitonin other than human calcitonin has a strong antigenicity, and has a problem that side effects such as vomiting and weight loss occur.

Parathyroid hormone (PTH) is a biological substance secreted from the parathyroid gland due to a decrease in blood calcium concentration, and is a single-chain protein that has long been known to have the effect of increasing bone mass. Butid. However, although it increases bone mass when intermittently administered, continuous administration significantly increases bone resorption.

According to recent studies on osteoporosis, osteoporosis is viewed from bone biopsy, and high-speed osteoporosis, in which bone resorption and bone formation are actively performed, and low rotation in which bone absorption and bone formation are poor It has been found to be classified as type osteoporosis. The above-mentioned PTH has an effect of increasing bone turnover and increasing bone mass, and is therefore considered to be applicable only to low-rotation osteoporosis.

Pyrophosphoric acid was known as a substance having a calcification-inhibiting action, but bisphosphonate derivatives obtained by replacing oxygen with a substituted carbon

PO _a H ₂ -C (R ¹ ) R ² -PO s H _£

(R ¹ and R ^J independently represent a hydroxyl group, a halogen, a substituted alkyl, a substituted amino, a octafluorothio, etc.) has a calcification-suppressing action and a bone-loss-reducing action. Although it is expected to be a therapeutic agent for osteoporosis, it has a problem that it causes osteomalacia because the half-life of bone concentration is extremely long. In addition to the above, there has been an attempt to apply vitamin K, which is believed to have the effect of activating bone vitamin K-dependent protein produced from osteoblasts to suppress calcium excretion, as a therapeutic agent for osteoporosis. Plant purple coconut palm Lipiflavone, a synthetic derivative of the active ingredient (flavonoids) of (Alpha alpha), has also been used as an auxiliary treatment for the improvement of bone S loss, and is further administered with fluorine, vitamin D, calcium, etc. Ru attempts like mower, while _£ not getting it is an effective means to fundamentally treat osteoporosis, has been pointed out for a long time for the association between hormone and osteoporosis is a biological substance. For example, it was well known that estrogen, a female hormone, has a therapeutic effect on osteoporosis. However, estrogen is known to have the side effects of abnormal irregular bleeding after menopause, and is involved in the occurrence of endometrial pain and breast cancer. ing.

Since estrogen has a therapeutic effect on osteoporosis, steroid hormones whose chemical structure is similar to estrogen and derivatives thereof have a therapeutic effect on osteoporosis and substances that reduce the side effects of estrogen Was expected. However, practically, such research has not yet been materialized.

Anabolic hormones such as androgens and insulin have the effect of increasing nitrogen accumulation and promoting protein synthesis, and are thought to have the effect of increasing bone mass by suppressing the production of urinary calcium excretion. No effective osteoporosis treatment has been identified.

Japanese Patent Application Laid-Open No. 4-3252795 discloses that a bisphosphonate derivative having a steroid hormone as a part of its chemical structure is useful for treating bone diseases. However, the publication does not disclose any test examples such as what kind of bone disease the compound is effective for, what specific compounds have a therapeutic effect on bone disease, and the like. Disclosure of the invention In view of the current state of the above-mentioned therapeutic agent for osteoporosis, the present inventors have attempted to create a drug having an excellent osteoporosis therapeutic action that surpasses the above-mentioned various vegetables. C The object of the present invention is here.

The present inventors accidentally found that mepithiostan represented by the formula (I) and ebitiostanol represented by the formula (II) have a powerful osteoporosis treatment, and completed the present invention. did. The gist of the present invention resides in that at least one of mebitiostan and epitiostanol is used as an active ingredient as a therapeutic agent for osteoporosis.

The mepithiostan according to the present invention is a compound known as an agent for oral renal anemia and an anti-mammary tumor agent. Mepithiostan exerts a hematopoietic effect by directly acting on bone 链 and exerts an antiestrogenic effect, thereby exhibiting a renal anemia treatment effect and a mammary tumor treatment effect.

Mepithiostan is metabolized in the body and is transformed into evithiosanol represented by the formula (II). Mebitiostan is an orally available drug as a so-called prodrug of epipistanol, and is considered to be converted to epipistanol in vivo to exert a pharmacological action. Epithiostanol is a known compound, and is used as an intramuscular injection, as well as mepithiostan, as an anti-diabetic agent and an anti-mammary tumor agent.

Mepithiostan and ebitiostanol are compounds that have already been marketed as drugs and have been shown to have side effects and clinically effective amounts, and are used effectively for the treatment of sexually transmitted blood and breast cancer during dialysis.

Although the above-mentioned pharmacological actions of mepithiostan and ebitiostanol are already known, the action mechanism of the osteoporosis treatment according to the present invention is completely different, and the action effect cannot be analogized. It could not be imagined at all from the action. The present invention provides a The present invention corresponds to the second pharmaceutical use invention relating to benzophenone and epithiostanol.

The mepithiostan and ebitiostanol according to the present invention markedly suppressed the reduction of the calcified femoral bone weight and the calcium content of the ovarian extraction rat, as will be described in detail later with examples of wiping. In addition, mebithiostane and epithiostanol according to the present invention significantly increased the femoral calcium content of the sciatic nerve transection rat. It is clear that the mepithiostan and epichostanol according to the present invention have a bone formation promoting action.

It is not always clear what mechanism the therapeutic action of mebitiostan and ebitiostanol according to the present invention is based on, but it is clear that it has an action to promote bone formation. The mebithiostane and evithiostanol according to the present invention can therefore also be used as bone formation promoters. When the mebithiostane and ebithiosanol according to the present invention are used as a therapeutic agent for osteoporosis or an agent for promoting bone formation, they may be used alone or in combination. When mepithiostan and epithiostanol according to the present invention are administered as a medicament, they may be used as such or in a pharmaceutically acceptable non-toxic and inert carrier, for example, from 0.1% to 99.5%, preferably from 9% to 99.5%. , 0.5% to 90% as a pharmaceutical composition.

As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries are used. The therapeutic agent for osteoporosis is preferably administered in a unit dosage form. The therapeutic agent for osteoporosis of the present invention can be administered intravenously, orally, intravenously, topically (eg, eye drops, eye drops) or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. Oral administration is particularly preferred.

The dosage as a treatment for osteoporosis depends on the patient's condition, such as age and weight. It is desirable to set the dose taking into account the route of administration, the nature and degree of the disease, etc., but usually, the amount of the active ingredient of the present invention for an adult is 1 to 50 per day orally when administered orally. A range of m humans is preferred, preferably in the range of 5 to 20 mg. In some cases, lower doses may be sufficient and vice versa. It can also be administered in divided doses 2 to 4 times daily.

Oral administration is preferably carried out in solid or liquid dosage units.For example, powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets It can be performed by other dosage forms. Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance to a suitable finely divided form and then mixing with a similarly comminuted pharmaceutical carrier, for example, edible carbohydrates such as mannitol, and the like. If necessary, flavoring agents, preservatives, aromatics, coloring agents, spices and other substances may be mixed.

Capsules are produced by first filling a powdered powder, powder or tablet obtained as described above into granules and into a capsule made of forceps such as a gelatin capsule. Lubricants and fluidizers, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol, can be mixed with the powdered material and then filled. it can. By adding disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboquin starch sodium, calcium carbonate, sodium carbonate, etc. It can improve the effectiveness of the medicine when taken.

In addition, fine powder of this product is mixed with vegetable oil, polyethylene glycol, glycerin It can be suspended and dispersed in a surfactant and wrapped in a gelatin sheet to give a capsule. Tablets are made by preparing a powder mixture, granulating or slugging, adding a disintegrant or lubricant and compressing.

The powder mixture may be obtained by mixing the appropriately powdered substance with the above-mentioned diluents and bases and, if necessary, binding agents (eg, carboxymethylcellulose sodium, hydroxypropyl senorelose, methylsenorelose, Droxypropyl methylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), dissolution retarder (eg, paraffin, wax, hydrogenated castor oil, etc.), reabsorbent (eg, quaternary salt, etc.) and adsorbent ( For example, bentonite, kaolin, dicalcium phosphate, etc.) may be used in combination. The powder mixture can be first moistened with a binder such as syrup, starch paste, gum arabic, cellulose fibrous or polymeric solution, and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first apply the powder and then break the obtained incomplete slag into parent grains.

The granules thus produced can be prevented from adhering to each other by adding stearic acid, stearates, talc, mineral oil and the like as lubricants. The lubricated mixture is then tableted.

The uncoated tablets thus produced can be coated with a film coating and sugar coating.

Alternatively, the drug may be directly tableted after mixing with a fluid inert carrier without going through the steps of granulation and slag formation as described above. A transparent or translucent protective coating composed of a tightly closed shell of shellac, a coating of sugar or a polymer material, and a polishing coating composed of wax can also be used. Other oral dosage forms such as solutions, syrups, elixirs and the like can also be in dosage unit form so that the given quantity contains a certain amount of vegetable. Syrups are prepared by dissolving the compound in a suitable aqueous flavor solution, and elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohol アル, boroxyethylene sorbitol esters), preservatives, flavor enhancers (eg, ぺ oil, saccharin) Can be added.

Where necessary, dosage unit formulations for oral administration may be microcapsulated. The formulation can also provide extended duration of action and sustained release by coating or embedding in polymers, waxes, etc.

Administration into tissues can be carried out using liquid dosage unit forms for subcutaneous, intramuscular or intravenous injection, such as solutions and suspensions. In these, a fixed amount of the compound is suspended or dissolved in a non-toxic liquid carrier suitable for the purpose of injection, such as an aqueous or oily medium, and the suspension or solution is sterilized. It is manufactured by Alternatively, an aliquot of the compound may be placed in a vial, and then the vial and its contents sterilized and sealed. Spare vials or carriers may be provided with the powdered or lyophilized active component for dissolving or mixing immediately prior to administration. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. In addition, stabilizers, preservatives [J, emulsifiers, etc.] can be used in combination.

For rectal administration, use suppositories containing the compound, which is soluble or insoluble in low-melting water, such as polyethylene glycol, cocoa butter, higher esters (for example, myristyl palmitate), and mixtures thereof. To Therefore, it can be performed. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Formulation Examples of the compound according to the present invention.

Test example

1) Animal used

The animals used were Jc 1 -Wister and Jc 1 -Sprague Dawley (SD) 4- and 7-month-old female rats (Clea Japan) and were fed (commercially available). Products, CE-2, manufactured by Nippon Clea) and drinking water were allowed to be consumed freely.

2) Test drugs and comparative drugs

The test drugs mepithiostan and epichostanol were dissolved in sesame oil. The comparison drug testosterone 'propionic acid (Tokyo Kasei Kogyo Co., Ltd.) is broken down into sesame oil, and oxymetholone (Syntex Pharma cuetica 1s Internation al Ltd.) is suspended in sesame oil. did. Vitamin K ₂ is a commercial product (10 mg Zm 1; manufactured by Eisai Co., Ltd.) as it is, and 1 is 25. (OH) ₂ D, a commercial product (manufactured by Wako Pure Chemical Industries, Ltd.) is 1 mg / m 1 It was dissolved in ethanol to a concentration and diluted with distilled water for injection (Otsuka Pharmaceutical Co., Ltd.) at the time of use. Estradio 1 ルー 17 β (manufactured by Sigma) was suspended in physiological saline.

3) Administration method and administration method

Main Pichiosutan, Okishime preparative port emissions and vitamin K _f is once daily, continuous oral administration, S. Torajio one route 1 7 3 once a day, and continuous subcutaneous injection. Eviostanol and testosterone 'propionic acid were injected subcutaneously three times a week every other day, and 1α, 25 (OH) 1 DS was orally administered three times a week every other day. The dose volume of each drug was 1 m1Zkg.

4) Preparation of an experimental bone loss model

a) Ovariectomy model

The animals were intraperitoneally administered with pentobarbital'sodium (Somnopentyl; Pitman Moore), and bilateral ovaries were removed from the back under anesthesia.

For 4-month-old rats (Wistar and SD), ovariectomy was performed, and a test drug or comparator was administered once a day, 60 days continuously, or three times a week every other day for 9 weeks after 1 month .

For 7-month-old rats (SD), the test drug or the comparative drug is administered once daily for 3 months after ovariectomy, and after 3 months when the amount of calcium in the femur has decreased. Administered for 13 weeks. The day after the final administration, the femur was excised, the muscle tissue was removed, and the wet weight was measured.

b) Ovariectomy and sciatic nerve transection model

The bilateral ovaries of a 7-month-old rat (Wistar) were excised, and the right sciatic nerve was excised about 5 to 10 mm at the center of the femur. The test drug and control drug were administered once a day from the operation day for 90 consecutive days.

5) Measurement of ash weight and calcium content of femur

Femur black port Holm 'ethanol (2: 1) solution degreasing (3 hours, 2 times) after dried for 24 hours at 1 1 0 ^e C. The dried femur was ashed in an electric furnace (250 ° C. 400 ° C, 600 ° C, 1 hour each, 800 ° C for 5 hours), weighed, and then 1 N hydrochloric acid Was dissolved.

The amount of force on the femur was colorimetrically determined using a calcium determination reagent (Calcium C-Test Co .; manufactured by Wako Pure Chemical Industries, Ltd.). Knot

1 I 1) Effects of chestnut and comparative drugs on femoral calcium content in ovariectomized rats (4 months old)

Table 1 shows the results of oral administration of mebitiostan and oximetron for 60 days after oral ovariectomy of SD rats (body weight: 296-356 g) for 1 month.

table 1

Mepithiostan significantly inhibited the decrease in calcified femoral bone mass and lucidum content due to ovariectomy at doses of 0.2 mg / kg and 1 mg / kg / day. On the other hand, oximetron was also significantly suppressed at 10 and 50 mg / k days.

W istar system rats (body weight 228~273 g) E-bi Chio stanol after ovariectomy 1 month, testosterone, Burobion acid and 1 α, 2 5 (OH) 2 D 3 three times a week, when administered for 9 weeks Table 2 shows the results. Both drugs significantly reduced the decrease in ash weight and potash content of the femur due to ovariectomy.

^ «Exposure

f, m o ¾t / \ c K fx ') m

(g)

mm go ^ ft 6 0.366 ± 0.009 m go ¾ 6 0.332 ± 0.012 eviciostanol 0.4 6 0.372 ± 0.009 *

2 5 0.373 ± 0.008 * Testosterone 0.45 0.368 ± 0.008 pieces Brobionic acid 2 6 0.393 ± 0.01 **

1 a. 25 (OH), D, 0.0002 6 0.368 ± 0.011 *

W «» out 5 ^ ¾ † T ru ^ «H * p <0. 05, ** p <0. 01

2) Effect of test drug and comparative drug on femoral calcium content in ovariectomized rats (7 months old)

Ovariectomized SD strain rats (body weight 33 3~4 6 8 g), femoral Cal Shiumu including I «the amount of reduced Mebichiosutan after three months, the Okishime Tron及beauty vitamin K ₂ 9 0 days RenMitsuru轾Ro administration, and the i α. 2 5 (OH) . D 3 showed three times a week, the Naruyoko when administered 1 3 weeks閭経port in Table 3. Table 3

ί <κ

m c l c * ¾ e a «G

-4 o +1 +, +1 4-1 +1 +1 +1 +1 +1 +1 -l

Uru —

=> —One

=> O o

+1 +! +1 +1 +1 +1 +1 +1 +1 +1 +1 +1

bo o co

t¾, CO t— O c ^ is

V

o.

X

. ヽ Ό

□

'ヽ Meviostan significantly increased the femoral calcium content in the ovariectomized control group at a dose of 1 mgZkg gZ. Okishime Tron (1 O mgZk g Roh day) and vitamin K _s (l OmgZk gZ day) also showed a significant increase, 1 a, increase in this dose of 2 5 (OH) Da was observed _c 3) Effects of test drugs and specific drugs on femoral calcium content in ovariectomized and sciatic nerve transection rats (7 months old)

The results of ovariectomy and right-side sciatic nerve transection of a Wistar rat (body weight: 248-298 g) when mepithiostan and Estradiol-1R 1 1β were administered in a 90-day continuous administration on the same day are shown. 4

^^ administration m ash (bfiflt calcium ¾

Ung / k ff) (g) (mg / b one) mm Sesame oil 6 0.355 ± 0.010 012 52.8 ± 4.0 0 + 6 o. 336 + 0000 リ 7, II 1 Io Q. q -o M go ¾ 6 0.303 ± 0.

mm 004 106.1 ± 1.5 Mevich stan 0.04 6 0.304 ± 0.005 106.7 ± 2.0

A 9 Ό 0.316 ± 0.004 1 10.9 ± 1.2 i 6 0.35 ± 0.0 I0 1 I 5.5 ± 3.6 *

6 0.363 ± 0.0 I 2129.6 ± 4.9

6 0.349 ± 0.01 01 2 123.2 ± 5.1

6 0.299 ± 0.008 105.2 ± 3.1 1 Estradiol 1 Ί β 0.01 6 0.330 ± O. 009 * 117.3 ± 3.5.5 * Eggs out ¾¾ * p <0.05

Mevithiostan significantly increased the femoral calcium content in the ovariectomized and sciatic nerve transection control group at a dose of 1 mg / k day. On the other hand, estradiol-1Ίβ (1 O xi gZkg / day) also showed a significant increase, similar to mepithiostan. Formulation Example 1

Mepithiostan 5.0 mg

Macrogol 4 0 0 1 3 4.7 mg

Ethyl paraoxybenzoate 0.2 mg

Propyl paraoxybenzoate 0.1 mg

Polyoxyethylene hydrogenated castor oil 600 10.0 mg

Total 1 50.0 mg

A solution prepared by adding mepithiostan to a solution prepared by dissolving ethyl ethyl paraoxybenzoate, propyl paraoxybenzoate, and boroxy hydrogenated castor oil in McGoal 400 was filled into a soft capsule by a conventional method to prepare capsules.

Formulation Example 2

Mepiciostan 5 mg

Lactose 5 3 0 mg

Mannitol 220 mg

Hydroxib mouth pill cellulose 40 mg

Hydrous silicon dioxide _ 10 mg

8 0 5 mg in total

Mix the above ingredients with the exception of hydroxypropylmethylcellulose. This was subjected to wet milling using an aqueous solution of 8% (/ w) of hydroquinone propylcellulose as a mixing agent to obtain fine granules.

1 6

Claims

The scope of the claims

1. A therapeutic agent for osteoporosis, comprising as an active ingredient at least one of mepithiostan represented by the following formula (I) and epithiostanol represented by the following formula (II).

2. Claims A bone formation promoter comprising at least one of mepithiostan and epichistanol in the war as an active ingredient.