JP2003292453A - Medicinal agent composition for treating bone disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal agent composition useful for the treatment of bone diseases such as osteoporosis, etc. <P>SOLUTION: This medicinal agent composition is provided by using a calcitonin derivative with a bisphosphonate simultaneously. By using the calcitonin derivative with the bisphosphonate simultaneously, bone strength increases synergistically. Thereby, it is possible to perform the treatment of the bone diseases effectively by a low dose. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to prevention and / or prevention of bone diseases.
Alternatively, it relates to a pharmaceutical combination agent containing at least calcitonin or a calcitonin derivative and a bisphosphonate as active ingredients for treatment.

[0002]

Bone mass is maintained by maintaining a balance between bone resorption by osteoclasts and bone formation by osteoblasts. Various basic and clinical studies have revealed that bone resorption and bone formation uncoupling in bone remodeling results in loss of bone mass. Such bone diseases include osteoporosis, osteomalacia, aplastic bone, fibrous osteomyelitis due to hyperparathyroidism, cancer such as dialysis osteosis, multiple myeloma, and bone loss due to administration of drugs such as steroids. Such as systemic bone diseases such as, or arthritis due to inflammation, periodontal disease, fracture due to surgical damage, re-fracture, osteoarthritis, bone defect due to surgical operation, and the like.

[0003] Among them, osteoporosis is defined as "a systemic disease in which bone fragility is increased as a result of low bone mass and deterioration of the fine structure of bone tissue and bone fracture is likely to occur". It is divided into subtypes, and is classified into, for example, primary osteoporosis in which no underlying disease exists and secondary osteoporosis associated with other diseases such as various endocrine diseases and blood diseases.

Primary osteoporosis further includes postmenopausal osteoporosis called regressive osteoporosis, ie, type I osteoporosis, or senile osteoporosis classified as type II osteoporosis. On the other hand, secondary osteoporosis further includes immobility osteoporosis caused by long-term bed rest and weightless stimulation, drug-induced osteoporosis caused by long-term administration of corticosteroids, Cushing's syndrome and other gonadal dysfunction mainly due to excessive secretion of endogenous steroids. , Osteoporosis caused by endocrine disorders such as primary hyperparathyroidism, secondary hyperparathyroidism, hyperthyroidism, hypoparathyroidism, renal osteodystrophy, and diabetes, multiple bone marrow It includes osteoporosis caused by hematological diseases such as tumor and malignant lymphoma, osteoporosis caused by rheumatoid arthritis, and osteoporosis caused by genetic disorders such as osteogenesis imperfecta, homocystinuria, and Marfan syndrome.

With the rapid aging of the population, the number of patients with osteoporosis has been increasing, and in 2000 it was 10 in Japan.
It is estimated that there are 0.9 million people and 75 million people worldwide (New Current CONTENTS, 2
001.1.10), osteoporosis is attracting attention as a particularly serious social problem compared to other diseases, because the bone fracture caused by osteoporosis, especially the femoral neck fracture, causes the patient to become bedridden and Quality of li
This is due to many incidents such as a decrease in fe, an increase in medical expenses, and lack of social care.

Currently, as a therapeutic agent for such bone diseases,
Calcium agents, estrogen preparations, anabolic steroid preparations, active vitamin D3 preparations, calcitonin preparations,
Bisphosphonate preparations, vitamin K2 preparations, ipriflavone preparations, etc. are clinically used. For example, a calcitonin preparation is a bone disease therapeutic agent whose main component is a peptide consisting of 32 amino acids secreted by thyroid C cells in mammals such as humans. Calcitonin has a blood calcium lowering effect in the rat thyroid in 1963. Was discovered as a certain substance (Hirsch et al., “Thyroid
hypercalcic principle a
nd current larnagener
ve injure as factors affe
cting the response to par
athyroidomy in rats "En
docology. 73.244-252.19
63. ). Its pharmacological action is a bone resorption inhibitory action that directly acts on osteoclasts, and is said to be particularly effective in a pathological condition in which bone resorption is markedly enhanced. At the same time, it has a remarkable analgesic effect, and since it has a bone resorption suppressing action, it is also widely used especially in patients with osteoporosis. At present, as a natural type calcitonin or a derivative thereof showing a bone resorption inhibitory effect, including calcitonin having a human type amino acid structure, calcitonin having each amino acid structure of eel, salmon, chicken, pig and the like, and natural type calcitonin Elcatonin, which is a derivative of eel calcitonin, and hybrid (chimera) type calcitonin, which has a partial amino acid structure of salmon and human, are known.

On the other hand, it was clarified that bisphosphonate, which was initially developed as a calcification inhibitor, shows a bone resorption inhibitory action at a low dose, and various bisphosphonates which specifically enhance the bone resorption inhibitory action are found. It is used as a therapeutic drug for bone resorption-promoting conditions such as osteoporosis.
Currently, as bisphosphonates having a strong bone resorption inhibitory action, etidronate, clodronate, tiludronate, pamidronate, alendronate, incadronate, zoledronate, minodronate, risedronate, ibandronate, etc. are known.

[0008] As described above, many drugs have been used and tried for the treatment of bone diseases such as osteoporosis, but it cannot be said that the bone diseases are sufficiently treated by these drugs (Masataka Shiraki “ Concept of therapeutic drug for osteoporosis "Latest osteoporosis (edited by Hajime Orimo) pp522-527, Life Science Publishing Co., Tokyo, 1999.". For example, as of 1990, the number of femoral neck fractures that develop as osteoporosis progresses is estimated to be 1.7 million worldwide, and it is predicted that the number will increase to 6.3 million by 2050 (New Curren).
t CONTENTS, 2001.1.10). In this way, the ever increasing number of femoral neck fractures is due in part to lifestyle changes, but it is also an undeniable fact that this fracture is based on osteoporosis, and from this point Then, the therapeutic effects of the current therapeutic agents for osteoporosis are not yet fully satisfactory.

The main purpose of treating bone diseases, particularly osteoporosis, is to prevent bone fractures, and it is necessary to maintain and improve bone strength.
For that purpose, it is important to comprehensively improve the mass, quality, and structure that define the strength of bone. From these viewpoints, not only in increasing bone mass but also in improving bone quality and trabecular structure, the development of new drugs that exceed the efficacy of existing drugs, or the combined use of multiple existing drugs, results in a single drug It has been desired to develop a new pharmaceutical combination agent that exceeds the above.

[0010]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a pharmaceutical combination agent which is extremely useful for treating bone diseases including osteoporosis.

[0011]

[Means for Solving the Problems] As a result of intensive studies conducted by the present inventors, when calcitonin or a calcitonin derivative and bisphosphonate were administered at low doses, the administration of each single agent was not effective in improving bone strength. On the other hand, it was discovered that the co-administration of both agents significantly increased bone strength and showed an improving effect. Until now, it has been considered that calcitonin and bisphosphonate act directly on the same osteoclast, that is, the point of action of each drug is the same. It was a real discovery.

That is, the present invention prevents and / or prevents bone diseases.
Alternatively, the present invention relates to a pharmaceutical complex comprising at least the following (a) and (b) as an active ingredient for treatment. (A) Calcitonin or a calcitonin derivative. (B) Bisphosphonate. This particular combination of compounds provides a synergistic therapeutic effect on bone disease compared to the individual administration of each drug.

The present invention also relates to a pharmaceutical combination agent for preventing and / or treating osteoporosis, which comprises a combination of (a) and (b). The present invention relates to a pharmaceutical complex for treating bone diseases, which is a form in which (a) and (b) are administered simultaneously.
The present invention relates to a pharmaceutical composite agent for treating bone diseases, which is a form in which (a) and (b) are sequentially administered. The present invention relates to a pharmaceutical complex for treating bone diseases, wherein the calcitonin derivative is elcatonin. The present invention relates to a pharmaceutical combination agent for treating bone diseases, wherein the bisphosphonate is alendronate.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Calcitonin in the present invention may be any peptide hormone having at least a serum calcium lowering action, and a part of it is clinically treated for hypercalcemia, Paget's disease of bone and osteoporosis. It is used as a drug and includes at least natural calcitonin or a derivative thereof having a serum calcium lowering action. Examples of natural calcitonin include eel, salmon, chicken, pig, and calcitonin having a human amino acid structure.

Further, examples of the calcitonin derivative include
Based on the structure of calcitonin, a synthetic derivative in which the disulfide bond at the 1- and 7-positions of the calcitonin is substituted with an ethylene bond with aminosperic acid is exemplified.
u ^1,7 ] eel calcitonin), [Asu ^1,7 ] salmon calcitonin, [Asu ^1,7 ] chicken calcitonin, [A
Su ^1,7 ] porcine calcitonin, [Asu ^1,7 ] human calcitonin, etc. are known, and a hybrid (chimera) type calcitonin having a partial amino acid structure of salmon and human is exemplified. These substances and synthetic methods are described in British Patent No. 1516947. Calcitonin other than the above is also included in the scope of the present invention as long as it is a peptide hormone having at least a serum calcium lowering action. These calcitonin or calcitonin derivatives have extremely low toxicity,
For example, elcatonin intravenously in mice and rats,
13500 or 740 by intramuscular, subcutaneous or oral routes
No lethal toxicity was observed even after administration of 0 unit / kg (body weight).

Further, the bisphosphonate in the present invention has a strong affinity for hydroxyapatite, which has a P--C--P structure as a basic structure, and has at least one action for bone, for example, an osteoclastic bone resorption inhibitory action. All compounds are included as the bisphosphonate of the present invention. Bisphosphonates used for the purpose of the present invention are also included in the present invention in addition to the examples below. As a preferable example of such a bisphosphonate, etidronate:
((1-hydroxythylidene) bis
Phosphonic acid), Clodronate: (dichlorometh
ylene) bisphosphonic aci
d), tiludronate:
[[(4-chlorophenyl) thio] me
stylene] bisphosphonic aci
d), pamidronate ((Pamidronate: 3
-Amino-1-hydropropylide
ne) bisphosphonic acid), alendronate: (4-ami
no-1-hydroxybutylidene) bi
sphosphonic acid), incadronate: [(cyclohept
ylamino) methylene] bisphos
phonic acid), zoledronate (Zole
dronate: [1-hydroxy-2- (1H-
imidazol-1-yl) ethylidene]
Bisphosphonic acid), Minodronate: (1-hydroxy
-2-imidazo (1,2-a) pyridin-
3-ylethylidene) bisphosphon
ic acid), risedronate (Risedron)
ate: [1-hydroxy-2- (3-pyrid
inyl) Ethylidene] bisphosph
onic acid), Ibandronate (Iband
ronate: [1-hydroxy-3- (meth
ylpentylamino) propyliden
e] bisphosphonic acid) and the like, and more preferably alendronate (Alen).
dronate: (4-amino-1-hydrox
ybutylidene) bisphosphonic
acid).

These bisphosphonates can also be prepared by established methods detailed in the following articles and patents: Etidronate (Bayer et al., US Pat. No. 3,468,935, issued 1969).
No.), clodronate (Quimby et al. J. Org.
Chem. 32.4111.1967), tiludronate (Brelier et al., European patent Appl. 100718, issued in 1984), pamidronate (Blum et al., U.S. Pat. No. 4,327,039, issued in 1982), alendronate (1987). US Pat. No. 470, issued to Staibano et al.
5651), incadronate (European patent No. 325482 issued to Isomura et al. In 1989),
Zoledronate (Jaeggi, published in 1990)
Et al., US Pat. No. 4,939,130), risedronate (European patent App. 186405 by Benedict et al., 1986), ibandronate (US Pat. No. 4, Gall, et al., 1990).
927814).

As used herein, the term "patient" refers to
It means living vertebrates, such as mammals including humans and birds, which are suffering from bone diseases and which are to be treated with a pharmaceutical complex containing calcitonin or a calcitonin derivative and a bisphosphonate as active ingredients.

The term "bone disease" as used herein means a pathological condition caused by various causes of uncoupling of bone resorption and bone formation in bone remodeling (remodeling). As the disease name, cancers such as primary osteoporosis, secondary osteoporosis, osteomalacia, aplastic bone, fibrous osteomyelitis due to hyperparathyroidism, dialysis osteosis, and multiple myeloma,
Systemic bone disease such as bone loss due to administration of drugs such as steroids, or arthritis due to inflammation, periodontal disease, fracture due to surgical injury, re-fracture, osteoarthritis, surgery Includes bone defects.

Primary osteoporosis further includes postmenopausal osteoporosis, senile osteoporosis. Secondary osteoporosis is
Immobility osteoporosis due to long-term bed rest and weightlessness stimulation, drug-induced osteoporosis due to long-term administration of corticosteroids, Cushing's syndrome and other gonadic dysfunction mainly due to excessive secretion of endogenous steroids, primary hyperparathyroidism, Secondary hyperparathyroidism, hyperthyroidism, hypoparathyroidism, renal osteodystrophy, osteoporosis caused by endocrine disorders such as diabetes, and blood disorders such as multiple myeloma and malignant lymphoma And osteoporosis caused by rheumatoid arthritis, osteogenesis imperfecta, homocystinuria, and osteoporosis caused by genetic diseases such as Marfan syndrome.

Calcitonin or calcitonin derivatives,
The bisphosphonate and the bisphosphonate can be administered to the patient simultaneously as separate compositions or as a single composition. Therefore, in the present invention, the dosage form of the pharmaceutical composition is preferably such that both can be administered simultaneously or both can be administered sequentially. When calcitonin or calcitonin derivative and bisphosphonate are sequentially administered, the administration interval of both may be appropriately selected depending on the dosage form of each drug and the symptoms sought by the patient.For example, the number of administrations of calcitonin or calcitonin derivative is 1 day. It may be 1 to 2 times, or 1 to 3 times daily or weekly. In addition, bisphosphonate is used every day to once a week, or every 2 days, every 3 days, 4
It may be administered daily, every 5 days or every 6 days. In addition, the dose can be appropriately changed within the safe dose range, such as administration in 2 to 4 times a day. As used herein, the term "pharmaceutical complex" refers to an intimate admixture of the components of the invention, as in a typical composition, as well as non-mixing agents in which each component is administered separately from its container. It also includes the meaning of the combination.

Calcitonin or calcitonin derivatives,
The bisphosphonate and bisphosphonate may be administered as a formulation to which a pharmaceutically acceptable auxiliary component is added. However, under normal use conditions calcitonin or calcitonin derivatives,
The selection of adjunct ingredients and admixture with the active ingredient (s) must be adapted so that there are no interactions that would substantially reduce the pharmaceutical efficacy of bisphosphonates and bisphosphonates. In addition, the pharmaceutically acceptable auxiliary component must, of course, have both a sufficiently high degree of purity and a sufficiently low toxicity such that there are no safety concerns when administered to a patient.

Examples of some of the auxiliary components include sugars such as lactose, glucose and sucrose, starch such as corn starch and potato starch, cellulose derivatives such as cellulose and sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powder tragacanth, gelatin, and the like. Vegetable oils such as talc, stearic acid, magnesium stearate, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobro oil,
Polypropylene such as propylene glycol, glycerin, sorbitol, mannitol, polyethylene glycol, agar, alginic acid, isotonic solution, buffer such as phosphate buffer, wetting agent and lubricant such as sodium lauryl sulfate, coloring agent, flavoring agent , Preservatives, stabilizers, antioxidants, preservatives, antimicrobial agents and the like.

Examples of the drug form of calcitonin or calcitonin derivative in the present invention include injections, rectal absorbents, vaginal absorbents, nasal absorbents, transdermal absorbents, pulmonary absorbents, buccal absorbents and oral administrations. Agents and the like. These dosage forms are not limited in any way.

When the calcitonin or calcitonin derivative of the present invention is administered as an injection, it is preferably used for intramuscular administration or intravenous administration, and when administered as a rectal or vaginal absorption agent. Is generally used in the form of suppositories, and when administered as a nasal or transdermal agent, it is used in the form of a formulation to which an appropriate absorption promoter is added, and when administered as a pulmonary absorbent, Used in the form of an aerosol composition containing a suitable dispersant or water and a propellant. When administered as an oral absorbent, it is used in the form of, for example, a sublingual tablet with the addition of a suitable absorption promoter. When administered as an oral administration, it is used for oral administration such as ribosome preparations and microcapsule preparations. Used in the form.

When the calcitonin or calcitonin derivative in the present invention is formulated as an injection, for example, elcatonin is dissolved in distilled water for injection in which an appropriate amount of a buffer, a tonicity agent, and a pH adjusting agent are dissolved, and the solution is passed through a sterilizing filter. It can be prepared by dispensing sterilized ones into ampoules. Rectal and vaginal absorbents are, for example, absorption promoters having a chelating ability such as sodium becnate and sodium alginate with elcatonin, and hypertonic agents such as sodium chloride and glucose are appropriately selected for use in distilled water or an oil solvent. It is dissolved or dispersed to prepare a rectal / vaginal injection suppository or suppository (see British Patent Nos. 2092002 and 2095994).

When the calcitonin or calcitonin derivative of the present invention is administered as a nasal absorbent, for example, elcatonin is a water-soluble organic acid glucuronic acid,
It is prepared as a liquid or powder formulation to which an absorption promoter such as succinic acid or tartaric acid is added (JP-A-63-24303).
3, JP-A-63-316737, JP-A-1
-230530, JP-A-2-111, JP-A-2-104531). Further, for example, an emulsion may be appropriately added to elcatonin to obtain a nasal absorbent (JP-A-4-99729).

When the calcitonin or calcitonin derivative of the present invention is administered as a percutaneous absorption agent, for example, a method of adding absorption enhancer such as Azone to salmon calcitonin to promote absorption from the skin has been reported. (Annual NY Acad. Sci. 507, 3).
2, 1988), a percutaneous absorption agent of calcitonin or a calcitonin derivative may be obtained.

When the calcitonin or calcitonin derivative according to the present invention is formulated as a transpulmonary absorbent, the calcitonin or calcitonin derivative is ground and ground together with a dispersant such as Arlacel or Span 80 to form a homogeneous paste, and then this paste is prepared. Is dispersed in a cooled propellant such as Freon 11 or Freon 12, and then filled in a container equipped with a valve (Japanese Patent Laid-Open No. 60-
161924).

When the calcitonin or calcitonin derivative according to the present invention is formulated as an oral absorbent, the calcitonin or calcitonin derivative may contain, for example, ascorbic acid, acidic amino acid, citric acid, unsaturated fatty acid, salicylic acid, etc. Alternatively, a combination of two or more kinds, an excipient such as glucose, a flavoring agent such as menthol, etc. is added, and a troche, a sublingual tablet,
It can be obtained as a powder or the like (JP-A-56-14).
0924). Furthermore, for oral administration, for example, W / O / W
Method Using Emulsion (Endocrinol. J
pn. 23.493.1976) to prepare calcitonin or a calcitonin derivative, and a method for ribosome preparation (Hormone Res. 16.24).
9.1982), calcitonin or calcitonin derivatives may be formulated.

The bisphosphonate of the present invention can also be used in humans as an oral preparation, a rectal absorption preparation, an injection preparation (subcutaneous, intravenous, intramuscular, intrasternal, etc.). It is determined according to the form. These dosage forms are not limited in any way.
When the bisphosphonate according to the invention is formulated as an oral preparation, it may be in the form of discrete units such as hard or soft capsules, tablets, troches or lozenges, each containing a predetermined amount of active ingredient, a dispersible powder or granules. It can be in the form of a solution or suspension of an aqueous or non-aqueous liquid, a syrup or elixir, or an oil-in-water emulsion or a water-in-oil emulsion.

The composition for oral use can be manufactured by a method known in the technical field of manufacturing any pharmaceutical composition, and is appropriately selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. It may contain one or more auxiliaries. Further, it can be mixed with a pharmaceutically acceptable non-toxic excipient to produce a tablet.

Excipients used include, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate, (2) granulating and disintegrating agents such as corn starch or alginic acid, (3 )
Binders, such as filter dust, gelatin or acacia (4)
Lubricants such as magnesium stearate, stearic acid or talc are mentioned.

The tablets may be uncoated or they may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example glyceryl monostearate,
Alternatively, a time delay material such as glyceryl distearate may be used. Also, to prepare them as sustained release osmotic therapeutic tablets, US Pat.
It can also be coated by the method described in No. 52, No. 4256108, and No. 4265874.

An oral preparation further containing bisphosphonate is
The bisphosphonate can be formulated in the form of hard gelatin capsules mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin.
The bisphosphonates may also be formulated in the form of soft gelatin capsules mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions containing bisphosphonates are usually formulated in admixture with excipients suitable for their preparation. Such excipients include (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, (2) (a) lecithin, etc. Natural phospholipids, (b) condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate,
(C) Condensation products of ethylene oxide with long-chain aliphatic alcohols, such as hebutadecaethyleneoxycetanol, (d) Condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, such as polyoxyethylene sorbitol mono. Oret, (e)
Mention may be made of condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example dispersants or wetting agents such as polyoxyethylene sorbitan monooleate.

Also included in such aqueous suspensions are one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and sucrose or One or more sweeteners such as saccharin may also be included.

Oily suspensions containing bisphosphonates include active ingredients such as vegetable oils such as peanut oil, olive oil,
It can be formulated in suspension in sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Furthermore,
A sweetener, a flavoring agent, and an antioxidant such as ascorbic acid may be appropriately added for production.

Dispersible powders and granules containing bisphosphonates are suitable for preparing aqueous suspensions. They are provided in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Examples of suitable dispersants, wetting agents and suspending agents are those already mentioned above. The above-mentioned excipients such as a sweetener, a flavoring agent, and a coloring agent may be appropriately further added to these.

The bisphosphonates according to the invention can also be formulated in the form of oil-in-water emulsions. The oily phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or mixtures thereof. Suitable emulsifiers include (1) natural gums such as acacia gum and tragacanth gum, (2) natural phospholipids such as soybean lecithin, (3)
Esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate,
(4) A condensation product of the partial ester and ethylene oxide, for example, polyoxyethylene sorbitan monooleate.

The emulsion may optionally contain a sweetening agent and a flavoring agent. In addition, sweeteners such as glycerin, propylene glycol, syrup and elixir,
It can be prescribed using sorbitol, sucrose or the like. Such formulations may also contain protectants, demulcents, preservatives, flavoring agents, coloring agents and the like.

The bisphosphonates according to the invention can also be formulated in the form of injectables, for example sterile injectable aqueous or oleaginous suspensions or solutions. The suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils, such as any mild non-volatile oil, including synthetic mono- or diglycerides, can be used as the solvent or suspending medium.
In addition, fatty acids such as oleic acid are also used as solvents for injectable formulations.

The bisphosphonate in the present invention also includes
It can also be administered as a suppository for rectal administration. These compositions are solids at normal temperatures, but can be prepared by mixing with suitable non-irritating excipients which become liquid at rectal temperatures and thereby melt in the rectum to release the active ingredient. . Examples of such a material include cocoa butter and polyethylene glycol.

Furthermore, for topical administration of the bisphosphonates according to the invention, liquid or semi-liquid preparations such as rubs, lotions, liniments, creams, ointments, pastes containing jelly or tooth paste, or drops. It can be formulated as a simple solution or suspension.

Further, when the calcitonin or calcitonin derivative and the bisphosphonate according to the present invention are administered as one composition, the pharmaceutical efficacy of each is substantially determined by referring to the formulation of each active ingredient suitable for each drug form. It may be prepared by a production method that does not cause an interaction that decreases. For example, calcitonin or a calcitonin derivative and a bisphosphonate are buffered, isotonic, and pH.
An injection prepared as one composition can be obtained by dissolving an appropriate amount of a regulator in distilled water for injection and sterilizing it through a sterilization filter and dispensing into an ampoule. The drug form is not limited in any way.

The thus-prepared calcitonin or calcitonin derivative is, for example, in the case of an injection of elcatonin, a single dose of elcatonin is 0.5 to
5000 units are administered, preferably 1 to 400 units. In the case of other preparations and other calcitonin or calcitonin derivatives, it may be administered according to the titer unit of elcatonin. The administration frequency of calcitonin or a calcitonin derivative may be once or twice a day, or once a day or once a week. Furthermore, Solita T
An appropriate amount of calcitonin or a calcitonin derivative may be dissolved in an appropriate infusion solution such as -3, and then intravenously administered, for example, over 1 to several hours. The amount of calcitonin or calcitonin derivative in the drug is appropriately determined, but it is sufficient to determine the amount of calcitonin activity per single administration to be 0.5 to 5000 units of the injection.

The dose of the bisphosphonate prepared is, for example, in the case of oral alendronate preparation, the body weight k
The dose is in the range of about 0.5 μg / g to about 1 mg / g, and more preferably in the range of 1 μg-800 μg / kg of body weight, and the dose can be administered up to four times daily. Furthermore, the daily dose of the alendronate oral preparation for the purpose of preventing bone disease is about 5 μg / kg to about 200 μg / kg of body weight.
μg, more preferably 20 μg to 10 per kg body weight
It is in the range of 0 μg. The daily parenteral dose of alendronate for treating bone diseases is about 5 per kg body weight.
0 μg to about 3 mg, more preferably kg body weight
It is in the range of 200 μg to 1.5 mg. Bisphosphonates other than alendronate are also appropriately determined depending on the specific activity and the degree of patient symptoms. The bisphosphonate may be administered every day to once a week, or every 2 days, every 3 days, every 4 days, every 5 days or every 6 days. In addition, the dose may be appropriately changed within a safe dose range such as administration in 2 to 4 times a day.

Further, when calcitonin or a calcitonin derivative and bisphosphonate are administered as a single composition, the above single agents should be appropriately combined and administered according to the effective dose and the administration frequency. You can Further, it is possible to prepare calcitonin or a calcitonin derivative and bisphosphonate at a dose at which a single drug administration does not show a sufficient drug effect, that is, a dose smaller than the above dose. It will be apparent from the examples below that the effects can be seen by combining doses which are not effective with each single agent. As a result, it is considered that side effects that may occur when an effective amount is administered by each single agent administration are reduced by the combined use and the respective amounts can be reduced, and the administration can be continued.

The administration period of the pharmaceutical combination agent in the present invention is
As a general rule, it is possible to continue the administration even after recovery, depending on the condition of the disease, based on the period of clinical judgment that the patient is clinically affected by the bone disease.

The present invention also provides kits, packages, and documents for conveniently and effectively carrying out the method of the present invention. Such a kit is a medical kit for administration of a pharmaceutical combination for preventing and / or treating a bone disease, which comprises a compartmentalized carrier for storing and carrying one or more containers in a stationary manner. And (c) the first container contains calcitonin or a calcitonin derivative,
(D) The second container contains bisphosphonate. Such a kit facilitates the understanding and implementation of the methods of the invention and facilitates the therapist to accurately administer the appropriate active ingredient to the patient in the correct dosage.

Another means of facilitating understanding and implementation of the method of the present invention is explanatory documentation and packaging. (A) Calcitonin or a calcitonin derivative. (B) Bisphosphonate. The means, the written document, and the described package, which describe that the bone disease can be prevented and / or treated by combining (a) and (b), facilitates understanding and implementation of the method of the present invention, and It facilitates the ability of the therapist to accurately administer the appropriate active ingredient to the patient at the correct dosage.

[0052]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Example 1 Effect of combined use of elcatonin and alendronate on bone strength of ovariectomized rats Material and method 1: animals used SD rats (Crj: CD (SD) IG 13 weeks old)
S, purchased from Japan Charles River Tsukuba Breeding Center) was used as 10 animals per group. 2: The test substances elcatonin (Asahi Kasei Co., Ltd.) and alendronate (Teijin Co., Ltd.) were both dissolved and diluted in 0.1 mM sodium acetate buffer containing 0.1% bovine serum albumin (Sigma) before use.

3: Group composition and experimental schedule Group composition was as follows: sham operation group (control group), ovariectomy group (pathological group), ovariectomy + elcatonin 5 unit / kg administration group (elcatonin alone group), ovariectomy + allen. Dronet 0.
A 6 μg / kg administration group (alendronate alone group) and an ovariectomized + elcatonin 5 unit / kg + alendronate 0.6 μg / kg administration group (elcatonin + alendronate combination group) were used. Elcatonin was subcutaneously administered 3 times a week and alendronate 7 times a week for 12 weeks immediately after ovariectomy. At the end of the experiment, the rat was sacrificed under ether anesthesia and the right femur was excised to measure the strength (AGS-
D, Shimadzu Corporation), the compression strength of the metaphyseal part was measured.

4: Experimental results (Table 1) In the pathological condition group, the maximum load (metaphyseal compressive strength) was significantly decreased as compared with the control group. In the drug-administered group, no significant improvement effect was seen in the elcatonin alone administration group and the alendronate alone administration group compared with the disease state group, but in the elcatonin + alendronate combination administration group compared to the disease state group The maximum load increased significantly.

[Table 1]

[0055]

As an active ingredient of the present invention for preventing and / or treating bone diseases, (a) calcitonin or a calcitonin derivative. (B) Bisphosphonate. The pharmaceutical combination agent comprising the combination of (a) and (b) can synergistically increase bone strength as compared with the case where each agent is administered alone, and is useful for preventing and / or treating bone diseases. Is.

Continued front page    F-term (reference) 4C084 AA02 BA01 BA08 BA19 BA24                       CA18 CA21 CA41 CA45 CA59                       DB31 MA02 MA17 NA05 NA14                       ZA962 ZA972                 4C086 AA01 AA02 DA34 MA02 MA04                       MA17 NA05 NA14 ZA96 ZA97

Claims (8)

[Claims] 1. A pharmaceutical combination agent comprising at least the following (a) and (b) as active ingredients for preventing and / or treating bone diseases. (A) Calcitonin or a calcitonin derivative. (B) Bisphosphonate. 2. The pharmaceutical composite agent according to claim 1, wherein the pharmaceutical composite agent is in the form of simultaneously administering (a) and (b). 3. The pharmaceutical composite agent according to claim 1, wherein the pharmaceutical composite agent is in the form of sequentially administering (a) and (b). 4. The pharmaceutical combination agent according to claim 1, wherein the bone disease is osteoporosis. 5. The pharmaceutical combination agent according to claim 1, wherein the calcitonin derivative is elcatonin. 6. The bisphosphonate is etidronate,
Clodronate, tiludronate, pamidronate, alendronate, incadronate, zoledronate,
The pharmaceutical combination according to any one of claims 1 to 5, which is at least one selected from minodronate, risedronate, minodronate and ibandronate. 7. The pharmaceutical combination agent according to claim 1, wherein the bisphosphonate is alendronate. 8. A pharmaceutical complex comprising at least the following (a) and (b) as active ingredients for preventing and / or treating osteoporosis. (A) Elcatonin (b) Alendronate