WO2005072747A1 - Bone resorption inhibitors - Google Patents

Bone resorption inhibitors Download PDF

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Publication number
WO2005072747A1
WO2005072747A1 PCT/JP2005/001252 JP2005001252W WO2005072747A1 WO 2005072747 A1 WO2005072747 A1 WO 2005072747A1 JP 2005001252 W JP2005001252 W JP 2005001252W WO 2005072747 A1 WO2005072747 A1 WO 2005072747A1
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WO
WIPO (PCT)
Prior art keywords
days
month
weeks
bisphosphonate
according
Prior art date
Application number
PCT/JP2005/001252
Other languages
French (fr)
Japanese (ja)
Inventor
Makoto Tanaka
Hiroshi Mori
Ryoji Kayasuga
Shohei Tanaka
Hironobu Asano
Masayuki Tanahashi
Original Assignee
Ono Pharmaceutical Co., Ltd.
Astellas Pharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Priority to JP2004024969 priority Critical
Priority to JP2004-024969 priority
Application filed by Ono Pharmaceutical Co., Ltd., Astellas Pharma Inc. filed Critical Ono Pharmaceutical Co., Ltd.
Publication of WO2005072747A1 publication Critical patent/WO2005072747A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/662Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/675Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Abstract

Bone resorption inhibitors containing bisphosphonates as the active ingredient, which inhibitors are minimized in the adverse effects on esophagus, stomach and bowel as observed in oral administration, that is, bone resorption inhibitors to be orally administered according to a dosage-regimen wherein bisphosphonates, or salts or hydrates thereof are administered four days per month or four weeks, namely, either four straight days per month or four weeks or every seventh days. The bone resorption inhibitors can be easily and simply administered to patients with little adverse effects on esophagus, stomach and bowel and attain effective inhibition of bone resorption, thus being efficacious in the prevention and/or treatment of osteoporosis, Paget disease, hypercalcemia, or bone lesions caused by metastasis of cancer to bone or multiple myeloma.

Description

Specification

Bone resorption inhibitors

Technical field

[0001] The present invention relates to a bone resorption inhibitor. Specifically, a bisphosphonate as an active ingredient, to bone resorption suppression agent characterized by being orally administered on a schedule of administering 4 days a month or four weeks.

BACKGROUND

[0002] In osteoporosis, for the treatment of such Pejietsuto disease Ya hypercalcemia, various bisphosphonates as agents which inhibit bone resorption, for example, alendronate, incadronate, clodronate, chilled port sulfonates, Echidoroneto, Ibando mouth sulfonates, risedronate, pyridinium Doroneto, pamidronate, zoledronate, olpadronate, neridronate is found using.

[0003] As a method of administering a bisphosphonate, currently, there intravenous and oral administration formulations. However, intravenous administration is very inconvenient to force the constraining pain and time to the patient. Furthermore, the oral dosage formulation, type periodically taken, for example for 2 weeks, after taking daily, there is a type in which followed by withdrawal from medication for 10 to 12 weeks, the type of a daily clothing does not require a withdrawal period. Type periodically taken are requiring washout period since the use is continued resulting in suppressed up to the formation of bone. While force, if these oral administration, medication method is taken with water 1 cup during severe tool fasting, which is then at least 30 minutes not laterally, and forced to fast for 30 minutes after taking from it is, go-between and to the patient is a medication how very inconvenient feel every time you take on a daily basis. This, when medication of bisphosphonate, or tablets accumulated in the esophagus, the reflux or the like of the gastric juice, by the upper digestive tract undergo long time stimulus, in order to have a possibility of inflammation and ulcers are caused. For example, alendronate has been reported esophageal irritation few examples in use, many of it had been associated with use in patients with improper administration or esophageal dysfunction have been reported. Thus, as long as daily doses of bisphosphonates to take to strict compliance method has been reported that sufficiently high tolerated is Les such protected medication method, comprising (e.g., not taken with water, next after taking etc.), or in raised and combed patient esophageal reflux, it is said to have a risk of causing upper gastrointestinal disorders.

[0004] On the other hand, as a method of administration aims to overcome the drawbacks of the above methods of administration, the W099 / 04 773 pamphlet (Patent Document 1), once weekly dosing, twice weekly dosing, once in two weeks administration, the unit-dose according to a continuous schedule is selected from the group consisting of administration twice a month, alendronate, incadronate, clodronate, chilled port sulfonates, Echidoro sulfonates, Ino Ndoroneto, risedronate, piridronate, Bruno Midoroneto, zoledronate, a method of their salts and mixtures thereof administered orally is disclosed. The patent is alendronate, and have use pseudo stomach acid containing risedronate and chilled port sulfonates, upper gastrointestinal disorders by esophageal reflux model, compared with the administration high concentration weekly, low concentrations of daily administration it is shown that occurs in. However, once a week administration, twice a week administration, administered once every two weeks, in the administration twice a month, not really a good Teisu bone resorption inhibiting effect fact been specifically confirm that disclosure. (For example, see Non-Patent Document 1) later published clinical trial results, the in twice a week administration of weekly administration or 35m g of 70mg of alendronate, even therapeutic effect comparable to administration 10mg daily Thalassa was it has been reported.

[0005] According to general Each bisphosphonate, oral absorption, affinity to bone, the rate of metabolism 'excretion in vivo (e.g., percentage excreted by 4 weeks, alendronate (32%), Li Sedoroneto (70 %) report a), irritation to the gastrointestinal tract, the type and extent such side effects are known to be different, respectively, the optimal method of administration, dosage varies by each Bisuhosu Honeto.

On the other hand, minodronic acid, JP-02- one hundred and thirty-eight thousand two hundred eighty-eight Pat in (see Patent Document 2), a compound described in Example 5, having a bone resorption inhibiting effect. Furthermore, has an effect of suppressing hypercalcemia caused by bone resorption, Pejiwetto disease, hypercalcemia, describes that it is effective in bone metastases and the treatment of osteoporosis in cancer have been made. Patent Document 1: WO 99/04773 pamphlet

Patent Document 2: JP 02 - 138288 discloses

Non-Patent Document 1:.... Aging Clin Exp Res, Vol 12, No. 1, discloses the pp 1-12 invention.

Problems that the Invention is to you'll solve

[0006] esophagus by oral administration, to minimize adverse effects on the stomach and intestines, conveniently administrable bisphosphonates, especially minodronic acid, provide bone resorption suppressing agent comprising a salt thereof or a hydrate thereof as an active ingredient It is to be.

Means for Solving the Problems

[0007] The present inventors have esophagus, can be administered adversely small tool easily to the stomach and intestines, or than one excellent bone resorption inhibitory effect, i.e. intensively studied methods of administration to achieve the bone mineral content increasing effect , it found that to achieve this purpose by be subjected to oral administration in the schedule to be administered four days a bisphosphonate month or four weeks, and have completed the present invention.

That is, the present invention is,

(1) bisphosphonate and an active ingredient, a bone resorption suppressing agent characterized by being orally administered on a schedule of administering 4 days a month or four weeks,

(2) agent according to schedule, a schedule for administration 4 days of continuous month or 4 weeks (1),

(3) agent according to schedule, a schedule for administration 4 days every 7 days month or 4 weeks (1),

(4) agent according to the schedule of administering 4 days a month or four weeks is intended to repeat about 3- 150 times (2) or (3),

(5) agent according to be packaged in dosage component force calendar pack according one schedule to feature that is (4),

(6) agent according to the prevention and Z or therapeutic agent for osteoporosis (1) to (3),

(7) involved in the bone metastasis or multiple myeloma cancer, agent according to a preventive and / or therapeutic agent for bone disease (1) to (3),

(8) bisphosphonate, minodronic acid, alendronate, there incadronate, Kurodorone one preparative, Chinoredoroneto, Echidoroneto, Ino Ndoroneto, risedronate, piridronate, pamidronate, zoledronate, olpadronate, neridronate, a salt or hydrate thereof, agent according to (2), (9) bisphosphonate, agents according to a minodronic acid hydrate (2) or (3),

(10) agent according to a daily dose of minodronic acid hydrate is about 0. 5mg- 30mg (6),

Agent according to according to (11) the daily dosage of minodronic acid hydrate is about 5mg- 70mg (7),

(12) agents described in one or two oral administration (1) to (3) per day,

(13) about 3. 5 mg per dose, about 7 mg, and the amount of minodronic acid hydrate selected from about 14 mg, is to orally administered once or twice a day (10) of the agent,

(14) bisphosphonate and, histamine H2 receptor blockers, proton pump inhibitors, one or more and the combination becomes Te medicament selected from PGI2 receptor agonist and PGE2 receptor agonists,

(15) approximately per formulation minodronic acid hydrate as an active ingredient 3. 5 mg, prevention and Z or a pharmaceutical composition for the treatment of about 7mg or about 1 4 mg comprising at osteoporosis for oral administration,

(16) oral agent comprising bisphosphonate are arranged in four consecutive, or one for every seven total of four arranged month or 4 weekly calendar pack,

(17) four vertical columns and consists recess consisting of 7 horizontal rows, calendar pack according to its longitudinal is placed on the four consecutive first column (16),

(18) calendar pack according to the bisphosphonate is minodronic acid hydrate (16),

(19) an effective amount of a bisphosphonate to a mammal, inhibiting bone resorption wherein the oral administration according to schedule administered 4 times a month, or four weeks, and

(20) Use of a bisphosphonate for the manufacture of a bone resorption inhibitor for use in the oral administration according to the schedule of administering 4 days a month or four weeks,

On.

In the present invention, the bisphosphonate, minodronic acid, alendronate, Inkado port sulfonates, clodronate, Chinoredoroneto, Echidoroneto, Inoku Ndoroneto, Risedorone over preparative, piridronate, Bruno Midoroneto, zoledronate, salts thereof or a hydrate thereof is used .

In the present invention, suitable salts of bisphosphonates, e.g., alkali metal (potassium © beam, sodium, lithium, etc.) salts, salts of alkaline earth metals (calcium, magnesium etc.), Anmoniumu salt (tetramethylammonium Niu arm salts, tetra Petit Ruan monitor © beam salts), organic Amin (Toriechiruamin, Mechiruamin, Jimechiruamin, cyclopentyl Rua Min, Ben Jinoreamin, Fuenechiruamin, piperidine, monoethanolamine § Min, diethanol § Min, tris (hydroxymethyl) Mechiruamin, lysine, arginine, and salts N- methyl-D- glucamine, etc.). More preferably salts of alkali metals (potassium, sodium, lithium, etc.). The bisphosphonate or a salt thereof it may also be a hydrate Les,.

[0009] The minodronic acid, 1-hydroxy-2- (imidazo [1, 2-a] pyridine _3_ I le) and Echiriden bisphosphonic acid, including its salts or monohydrate thereof, JP-A-02- It is described in Patent 138,288 herein.

The alendronate, 4-Amino one 1-hydroxybutylidene-one 1, 1-bisphosphonic acid (§ Les Ndoron acid), or a monosodium salt or trihydrate THEREOF, for example, U.S. Patent No. 4,922,007 No. written are described in Les, Ru.

The incadronate, heptyl aminomethylene one 1 cyclohexane, 1- diphosphonic acid (Inkadoro phosphate), or a disodium salt or monohydrate thereof thereof, for example, as described in JP-A 1-3082 90 Pat It is is, Ru.

[0010] Clodronate, 1, 1-dichloromethylene one 1, 1-diphosphonic acid (clodronic acid), or its disodium salt, are described, for example, U.S. Pat. No. 3,404,178. The chilled port sulfonate, (4-black port phenylene Honoré) thiomethylene one 1, 1-diphosphonic acid (chilled port phosphate), or its disodium salt, for example, as described in JP-A-5-42395 specification It is.

The Echidoroneto, 1-hydroxy-1, 1-diphosphonic acid (Echidoron acid), or its disodium.

The Ibando port sulfonate, 1-hydroxy - 3_ (N_ methyl -N- Penchiruamino) Puropiride emissions - 1, a 1_ bisphosphonic acid are described in 63-23889 Pat Sho.

[0011] The risedronate, 1-hydroxy _2_ pyridine _3_ I Rue dust diphthalic acid (Lise alendronic acid), or a monosodium salt or hemihydrate thereof that, JP-A-7- 28 Les is described in the 5976 Pat, Ru.

The piridronate, [2- (2-pyridinyl) Echiriden] _1, 1-bisphosphonic acid are described in JP-A-62-48627 specification.

The pamidronate, 3 - Amino - 1-hydroxy propylidene one 1- bisphosphonic acid (Pami alendronic acid), or a disodium salt or a pentahydrate thereof that.

The zoledronate, 1-hydroxy-one 2-(1H-imidazo Ichiru _1_ I le) Echiriden one 1, 1 - a bisphosphonic acid or monohydrate thereof, are described in JP-A-63-150291 Rere that

[0012] The olpadronate, 3_ (Jimechiruamino) _1- hydroxypropylidene -1, 1_ Bisuho Suhon acid.

The neridronate, 6-Amino xylidene one 1 into single 1-hydroxy, Ru der 1-bisphosphonic acid.

In the present invention, the bisphosphonate minodronic acid, its salt or is preferably a hydrate instrument particularly preferably monohydrate minodronic acid (minodronic acid hydrate).

[0013] The oral administration according to the schedule of administering 4 days a month or 4 weeks of the present invention, among either oral administration or month, or four weeks to four consecutive days of specifically, month or 4 weeks 7従Re to the dosing schedule for oral administration to a daily four days, is a method for oral administration repeatedly, these methods of administration conventional periodically way to saddle base to the method of administration and the daily administration, hard to take the number of small Gumata complex administration regimen necessary to note the Nag at doses Tadashikai IJ, i.e. taken on an empty stomach, then at least 30 minutes not laterally, and strong is the day force to be a fasting after taken daily, that is, four days to 28 a day 31 days force month, or 4 weeks in the month the number of days is very small. Further, since number of doses is very small, the esophagus, the frequency is extremely reduced adverse effects against the stomach and intestine, esophagus, may be caused inflammation and ulcers in the stomach or intestine becomes very low.

[0014] Among the oral administration according to the schedule of administering 4 days a month or 4 weeks of the present invention, the moon or the oral administration of 4 days of continuous of 4 weeks, the effective amount of a bisphosphonate to 1 month or 4 weeks in four of successive days means that the oral administration. The 1 month or 4 weeks and 1 Sukeji Yunore, until therapeutic benefit is seen, and preferably from about 3 times a about 150 times, or about 3 months one about 12 years half repeatedly orally administered. Four consecutive days is not particularly limited, one month either of the day or records of the month, record of the week of the shift, day of the week force of displacement, et al., Including also Yo les, but the date of each month is the same or 4 the corresponding four days of the corresponding week of the week is preferred. For example, it includes month, 2, 3, and consecutive 4 days 4 days. In addition, the administration is preferably once or went twice Yogu especially once a day.

[0015] Further, the oral administration of 4 days every 7 days a month or four weeks, meaning that orally administering an effective amount of a bisphosphonate to 1 month or 4 weeks 4 days every 7 days of. The 1 month or 4 weeks and 1 schedule, until therapeutic benefit is seen, preferably from about 3 times a about 150 times, there have is orally administered repeatedly about 3 months one about 12 years half. 4 days of every 7 days is not particularly limited, for example,% Ά 1, 8, 15, 4 days of 22 days, there Rere four weeks of the month H 翟日, fire H 翟日, every Wednesday, every Thursday, every Friday, every Saturday or include the four days of the week every day. In addition, the administration is preferably once or twice went to Yogu especially once a day.

[0016] The dosage will depend on the type of bisphosphonate to be used and the bisphosphonates are commonly used use has been that the range is preferred, in the administration method of the present invention, beyond the small amount or range thereof than that range it may be administered Te. Moreover, the dosage age, body weight, symptom, different forces normal administration schedule, etc., per adult, for example, dosages per day when using minodronic acid hydrate as a preventive and / or therapeutic agent for osteoporosis about 0 · 5mg- about 30mg, preferably from about lmg- about 15 mg, more rather preferably is about 3. 5Mg- about 14 mg, 1 time to about 3. 5 mg as dose per was about 7mg or about 14mg is preferred instrument, especially in the case of administration twice about 3. 5 mg preferably about 7mg is preferable instrument 1 day in the case of one dose per day. Also, bone metastasis young properly cancer minodronic acid hydrate is associated with multiple myeloma, when used as a preventive and / or therapeutic agent for bone disease, the dose per day is about 5mg- about 70 mg, more preferably 20-a 60mg, it is preferable to administer this by dividing into, or two 3 times once. As mentioned above, the doses to be used depend upon various conditions, to sometimes sufficient in an amount less than the above dosages, also may be necessary beyond the range.

[0017] For the case minodronic acid hydrate prevention and Z or therapeutic agent for osteoporosis comprising as an active ingredient, illustrating the preferred dosage forms of the present invention are described below. When administered orally to four consecutive days of the month or four weeks, for example, the month, 2, 3 and four consecutive 曰 such 4 days, 1 曰量 force S about 0. 5Mg- about 30mg, preferably ί Maitoshaku lmg Itoshaku 15 mg, more preferably [or about 3. 5Mg- about minodronic acid hydrate 14 mg, 1 or 2 times, particularly preferably administered 1 Kaikei port of 1 month or 4 weeks until the therapeutic effect of the schedule is observed, rather preferably it is repeated about three times a about 150 times. Doses of about 3. 5 mg per one time, if in the case of administered once about 7mg or about 14mg is preferred instrument particularly daily administered twice about the 7mg is preferred instrument 1 day to about 3. 5mg is preferable. Further, the month or the case of oral administration to 4 days of every 7 days out of four weeks, a total of 4 days daily minodronic acid hydrate effective amount every 7 days of a month or four weeks, for example, 1 month orally administered to each week 4 days of the same day of the week out of four weeks in, the 1-month or four weeks of the schedule until the therapeutic effect is observed, preferably from about 3 times a about 150 times, or about three months force is also about 12 years half repeat. At this time, day administered in each week is not particularly limited, for example, a total of 4 days of each week shipping. In addition, the dosing is preferably Yogu especially once carried out once or twice a day.

The present invention, even orally administered according to the schedule of administering 4 days a month or four weeks over a long period of time, also a bone resorption suppressing agent according Packaging bisphosphonates that can be easily managed taking encompasses. Specifically, a blister pack placed several unit dose in the order of use, calendar pack preferably displayed placemarks such date and / or day of the week, there have is that it can be described as required and the like. The calendar one pack has 28 recesses, and molded sheets which can be described landmarks such as date and / or day of the week is displayed, or if necessary, the recesses after accommodating the tablets Each recess opening comprising a sealing sheet for bonding to the molded sheet to seal the. The molded sheet, PVC, PP, PE, PET, single material or a composite material of plastic PS or the like, or a composite material of an aluminum foil is used as the sealing sheet, used aluminum foil, paper, a plastic film or the like be able to. Between the recess of the calendar pack, even if lateral perforation force becomes cutoff line is formed Yogu more cutting of the cutting line, with seven or fourteen recess, two or four separating der Tsutemoyore, which decouple into pieces. Incidentally, the four corners of the calendar packs or separating piece, Yes forms a smooth curve, fear and caught on other products, are to reduce the risk of damaging the skin or the like of the handlers.

1 month or calendar pack packaging the bone absorption inhibitor per schedule for administering the 4 weeks as 1 schedule, for example, shown in Figure 1, Figure 2 or Figure 3. These transverse seven to one sheet-like packaging material, are spaced, which may include a vertical four oral dosage is separately packaged in PTP sheet which can be taken out one by one. Then, the date and / or day of week 1 one 28 near each oral dosage printing in the right direction in this order, marking, can be described by the force ,, or required to be displayed by the seal sticking or the like. 4, or an oral agent comprising bisphosphonate placed one total of four for each seven other 24 oral agent placed comprising a bisphosphonate consecutive among the 28 that are not either, or combination, and Z or replenishers for placebo or inhibiting bone resorption, for example, vitamin D2 or D3 preparations, estrogen preparations, calcitonin preparations, vitamin K2 formulations, be arranged Ivry flavone or calcium preparations and the like, good. Further, in FIG. 1 one 3, indicates that bisphosphonate, a salt thereof or oral agents comprising a containing the hydrate may be arranged one or more in a portion indicated by a black circle, Display portion with a white circle represents that may be arranged that either the oral dosage is not arranged, or combination of Me other placebo or resorptive and / or replenishers. In a schedule of administration and due to this Karen Dapakku, easily can be taken, drug taking misidentification or, it is possible to prevent the drink to forget.

Arrangement shape of a recess disposed in the calendar packs, such is intended to be limited to those shown in FIGS. 1 to 3 les. Further, Table How to Display and description on the molded sheet of the calendar pack shown in the figures merely examples and not intended to be limited thereto. Further, the present invention is from about per formulation minodronic acid hydrate as an active ingredient 3. 5 mg, about 7 mg or prevention and / or pharmaceutical composition for the treatment of about 14mg comprising at osteoporosis for oral administration, also include to.

Furthermore, the dosage forms, other diseases involving bone resorption, for example, may be applied Pejietsuto disease, etc. hypercalcemia.

The dosage of minodronic acid hydrate, age, body weight, symptom, because different administration schedules, etc., the dosage described above to be used depend upon various conditions, less than the dose les, if the amount is sufficient also to some, also it may be necessary beyond the range.

As forms for oral administration, there are internal take solid, or oral solutions, specifically, the inner dose solid agent such as tablets, pills, capsules (Bruno, Dokapuseru agents, soft capsules), powders, include granules, as the inner liquid preparation for oral administration, for example solutions, suspensions

, Emulsions, syrups Qi J, elixirs.

[0020] in taking solid agent, minodronic acid, as the force \ or excipient and a salt thereof or a hydrate thereof (e.g., Ratatosu, mannitol, Gunorekosu, microcrystalline cellulose, starch emissions (corn starch)), binding Hitoshi lj (e.g., hydroxypropyl cellulose, Poribyuru pyrrolidone, magnesium aluminometasilicate), a disintegrant (e.g., calcium cellulose glycolate), lubricants (e.g., magnesium stearate), stabilizing agents, solubilizing agents ( For example, Gunoretamin acid, mixed with Asuparagin acid), etc., used in each formulation according to a conventional method. Further, the coating agent if necessary (e.g., sucrose, gelatin, hydroxypropyl-flop Honoré loin phthalate, titanium oxide (Norechiru type, anatase type), a plasticizer (e.g., polyethylene Ji glycol, glycerol fatty acid esters, sucrose fatty acid esters, castor oil, Taen triethyl, Toriasechin), stone I be coated with talc or a plurality thereof), also may be coated with two or more layers. Further, the mixed composition containing the active ingredient in the gelatin, cellulose, cellulose derivatives, pullulan, carrageenan, agar, alginic acid, polyvinyl alcohol or the like to the capsule shell as a raw material, a plasticizer, sweet taste, flavoring agents , preservatives, coloring agents, release agents, etc. is appropriately formulated formulated, it may be a capsule.

[0021] the liquid preparation for oral administration is minodronic acid, a salt thereof or a hydrate thereof, commonly used rare Shakuzai (purified water, ethanol, mixture thereof etc.), suspending or emulsifying. Yo les, les, even contain the liquid in is al, wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, fragrances, preservatives, slow 衝剤 like.

In the present invention, preferably a solid preparation for internal use, and more preferably a tablet or capsule Honoré agent, particularly preferably a tablet.

In the present invention, the bisphosphonate, in particular minodronic acid hydrate may be used in combination with other agents as necessary. For example, when used as a preventive and Z or therapeutic agent for osteoporosis, vitamin D2 or D3 preparations, estrogen preparations, calcitonin preparations, vitamin 2 formulations, in combination simultaneously or separately with an agent selected from Ivry flavones, and calcium preparations it can be administered.

[0022] In the present invention, the vitamin D2 or D3 derivative, calcitriol, such as alpha Karushidoru. Examples of the estrogen preparations, estradiol, etc. Esutori ol Examples of the calcitonin preparation, elcatonin, etc. salmon calcitonin and the like. Further, as the vitamin K2 formulations, and the like menatetrenone as the I Purifurabon, etc. Ivry flavone. Examples of calcium preparations, Cal Shitorioru, and the like alfacalcidol is.

[0023] When used as a prophylactic and Z or therapeutic agent for bone lesions in bone metastases or multiple myeloma cancer, can be used in combination with existing anti-cancer agents such as chemotherapeutic agents, these anti Ganzai is orally or parenterally, it can be administered simultaneously with agents of the present invention or separately by using a method of administration suitable therefor.

Meanwhile, in order to mitigate the adverse effects on the stomach and intestine, in the present invention, Bisuhosuhone bets, especially minodronic acid hydrate, histamine H2 receptor blockers, proton pump inhibitors, P GI2 receptor agonist and / or PGE2 good record, even when administered in combination with a receptor agonist.

[0024] bisphosphonate, in particular minodronic acid hydrate and histamine H2 receptor blockers, Purotonpo pump inhibitor, combined with PGI2 receptor agonist and / or PGE2 receptor agonists, blending both components in one preparation the morphology of to administered Yogumata separate manufacturing agent also be administered in the form of formulations with connexion may. When administered as separate preparations, it includes administration by simultaneous administration and time lag. In the case of administrations with time difference, bisphosphonate, administering the salt or hydrate thereof earlier, histamine H2 receptor blockers, proton pump inhibitors, after a PGI2 receptor agonist and Z or PGE2 receptor agonists Yo Le be administered, and, histamine H2 receptor blockers, proton pump inhibitors, administered previously for PGI2 receptor agonists and / or PGE2 receptor agonists, bisphosphonate, its salts or hydrates thereof it may be administered after the. More preferably, the method of administering histamine H2 receptor blockers, flop port Tonponpu inhibitor is administered before the PGI2 receptor agonist and Z or PGE2 receptor agonists, bisphosphonate, a salt thereof or a hydrate thereof after it is. In particular, the histamine H2 receptor blockers, proton pump inhibitors, PGI2 receptor agonist and / or PGE2 receptor agonists bisphosphonate, before given projection of a salt or hydrate thereof, about 30 to 12 hours prior to it is preferably administered.

[0025] Histamine H2 receptor blockers in the present invention, a proton pump inhibitor, PGI2 dose of receptor agonists and / or PGE2 receptor agonist, a force used in accordance with the dose of each to disease therapeutic purposes the present invention in the method of administration, that range from small a les, it may also be administered beyond the amount or range that record.

In the present invention, the histamine H2 receptor blocker, famotidine, cimetidine, ranitidine hydrochloride, nizatidine, hydrochloric port hexa cytidine § diacetate or lafutidine can be mentioned et be.

In the present invention, the proton pump inhibitor, Omeburazoru include lansoprazole or label bra tetrazole sodium.

[0026] In the present invention, as the PGI2 receptor agonist, for example, ornoprostil.

In the present invention, the PGE2 receptor agonists, Enpurosuchiru, amino pro stall include sulprostone.

In the present invention, the bisphosphonate, in particular minodronic acid hydrate are PGI2 receptor agonists, more preferably it is preferably combined with Honoré Bruno pro still.

Effect of the invention

[0027] of the present invention, for use in oral administration according to the schedule of administering 4 days a month or four weeks, bone resorption suppressing agent comprising as an active ingredient bisphosphonate, esophagus, the negative impact on the gastric and intestinal Sukunagu and potent bone resorption inhibiting effect, i.e. exhibited a bone mineral density increasing effect. Thus, osteoporosis bone resorption participates, Pejietsuto disease, hypercalcemia, or cancer (e.g., breast, lung, prostate cancer), if e bone lesions (e.g. associated with bone metastasis or multiple myeloma, bone pain, bone melting, fracture, skeletal fracture and / or is effective in the prevention and / or treatment of decreased bone density).

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 is a diagram illustrating a form of a calendar pack displaying the date for oral administration to four consecutive days of the month.

2 is a diagram representing a date calendar pack form that displays for oral administration to 4 days of every 7 days of the month.

3 is a diagram representing the form of a calendar pack displaying the day for oral administration to 4 days of every 7 days out of four weeks.

In [4] rat osteoporosis model is a graph showing the effect of increasing the distal femur bone mineral density of minodronic acid hydrate.

In [5] Rat Osteoporosis model is a graph showing the effect of increasing lumbar bone mineral density of minodronic acid hydrate.

[6] in human myeloma cells ARH- 77 transplanted mice is a graph showing the reduction inhibitory effect of lumbar bone mineral density of minodronic acid hydrate. Each column in the figure shows the mean ± standard error. Numbers in the column indicates the number of cases. * Indicates a significant difference for each control group (* p <0. 05, * * p <0. 01, Dunnett multiple comparison test).

BEST MODE FOR CARRYING OUT THE INVENTION

[0029] Examples illustrating the present invention are shown below, but the present invention is not limited thereto.

Example

[0030] Example 1: osteoporosis model

Perform extirpation of both sides ovaries of the rat (12 cases in each group) were generated osteoporosis model. The ovarian excised date and day 0, group 1 (the group administered once daily 4 days every 7 days of the month) is 1, 8, 15, 22, 29, 36, 43, 50, 57 , 64, 71 and 78 曰目, I or 1 (the group administered one 曰 once four consecutive 曰 of the month) group 2, 2, 3, 4, 29, 30, 31, 32, 57 , 58, 59 Contact and day 60, 1, 5% methylcellulose solution test drug orally administered respectively (0 · 21 mg / kg / day, or 1-05MG / kg / day) was. Both groups were necropsied on day 85, were taken femoral you and the lumbar spine. Dual energy X-ray absorptiometry apparatus (DCS-600, Aroka Co., Ltd.) was used to measure the bone mineral content of the femur and lumbar spine.

In order to accurately experiments based on chemical grounds determination, one month in the test drug which was set at 28 days, Bok-hydroxy-2_ (imidazo [1, 2_a] pyridine one 3-I le) Echiridenbisu phosphonic acid 1 hydrate (minodronic acid hydrate) was used.

The results are shown in FIGS. The "operation" shown in both figures, shows a group oophorectomy has been performed, the "sham-operated" refers to the group has been subjected only surgical procedure without ovariectomized.

[0031] Example 2: esophagus, irritation to the stomach or intestine

Or esophagus of bisphosphonates, irritation to the stomach or intestines, for example, experimental animal (rat, I j, etc.) a bisphosphonate, to one month oral administration of 5 consecutive days daily a salt or hydrate thereof , or by 4 days orally administering to a month or four weeks, it can be evaluated by looking at their relative irritation.

[0032] Example 3: myeloma model

C. B17 / Icr_scid mice (male, 5 weeks old, 15. 7-23. 4g, CLEA Japan) after were anesthetized with Pentoba Rubitaru, human myeloma cells ARH-77 (10 6 cells in a room under left heart closed-chest / a 0. LML / body) was injected using a 27G needle with syringe. To enhance the engraftment of cells, anti Ashiaro GM1 antibody (Wako Pure Chemical) were given tail vein projecting to 6 days after the day before tumor implantation and transplantation (0. 5mg / 0. 2mL / body). The sham operation group was injected with phosphate buffered saline not containing tumor cells (PBS) (0. lmL / body). Minodronic acid hydrate was a test drug is adjusted with distilled water to each concentration was forcibly administered orally using an oral sonde in the amount of liquid 10 mL / kg.

[0033] Tumor implantation mice were grouped randomly into 2 weeks after tumor implantation, the present invention administered group minodronic acid hydrate 1 per (0, 21, 2.1 or 21 mg / kg / day) for 7 days once was a total of two times orally administered on Sukejiyu Le of the day. In the control group sham operation group was administered distilled water 10 mLZkg in the same dosage schedule. Comparison group, minodronic acid hydrate (0.03, 0.3 or 3MgZkg / day) once daily for 14 days (14 times) consecutively administered orally, as well to the control group and sham operation group It was administered distilled water lOmLZkg. Were dissected on day 15 from the administration, the vertebrae comprising a lumbar collected, the bone density of the first one 6 lumbar bone dual energy X-ray absorptiometry apparatus (DCS_600, Aroka Co.) was used for the measurement.

Figure 6 shows the [0034] results. Lumbar bone mineral density of the control group was significantly decreased compared to the sham operation group. In contrast, the present invention projecting Azukagun was administered in daily schedule minodronic acid hydrate every 7 days showed a dose-dependent bone density reduction inhibitory effect, almost at a dose of 2. lmg / kg Kan It inhibited the decrease in lumbar bone density in all. This was substantially the same excellent effect as in Comparative Example was orally minodronic acid hydrate in the same dosage schedule of daily administration.

These results, which minodronic acid hydrate of the present invention as an active ingredient for oral administration bone resorption suppressing agent according to the schedule of administering 4 days a month or four weeks, while having the same effect and administered daily , can reduce the frequency of administration to 1Z7, was shown to be excellent agents for achieving a risk reduction of injury to the esophagus upon administration to the convenience improving parallel beauty of the patient.

Example 4: Formulation Example 1

After obtaining compressed into tablets after mixing by a conventional method the following components, was coated by co one coating agent containing titanium oxide, a Kotin grayed Tablets containing the active ingredient 7mg in one tablet 1 ten thousand tablets obtained.

[table 1]

• 1-hydroxy-2- (imidazo [1, 2 - a] pyridine one 3-I le) E dust Den bisphosphonic acid monohydrate

•lactose

• cornstarch

•Magnesium stearate

• availability of on hydroxypropyl cellulose industry

By the oral administration child according to the schedule of administering 4 days bisphosphonate month or four weeks, it is convenient dosing the patient, esophagus, adversely small instrument and bone resorption inhibition of the stomach and intestines, i.e. bone mineral content increasing effect for achieving the, osteoporosis, Pejietsuto disease, it is effective in the prevention and / or treatment of bone lesions with the hypercalcemia or bone metastases or multiple myeloma cancer.

Claims

The scope of the claims
[I] bisphosphonate as an active ingredient, a bone resorption inhibitor, wherein the orally administered on a schedule of administering 4 days a month or four weeks.
[2] agent according to range 囲第 preceding claims which is scheduled to be administered four consecutive days schedule force month or 4 weeks.
[3] agent according to range 囲第 preceding claims which is scheduled to be administered four days of scheduled power month or every 7 days 4 weeks.
[4] Claim 2 month or 4 weeks in which the schedule of administering 4 days repeated about 3 150 times or agent according to paragraph 3.
[5] agent according to claim 4, characterized in that it is packaged in dosage component force calendar pack according one schedule.
[6] agent according to paragraphs 1 through claim 3, which is a prophylactic and / or therapeutic agent for osteoporosis.
[7] involved in the bone metastasis or multiple myeloma cancer, agent according to paragraphs 1 through claim 3, which is a prophylactic and / or therapeutic agent for bone disease.
[8] bisphosphonates, minodronic acid, alendronate, Inca alendronate, clodronate
, Chinoredoroneto, Echidoroneto, Ibando port sulfonates, risedronate, piridronate, Pa Midoroneto, zoledronate, olpadronate, or neridronate, agent according to claim 2 which is a salt thereof, or is a hydrate thereof.
[9] bisphosphonate, agents placing serial paragraph 2 or claim 3 which is minodronic acid hydrate.
[10] The daily dosage of minodronic acid hydrate, agent according to claim 6 which is about 0. 5 mg 30 mg.
[II] 1 daily dosage of minodronic acid hydrate, agents according to the mounting serial to claim 7 is about 5mg- 70mg.
[12] agent according to one or two paragraphs 1 through claim 3 orally administered daily.
[13] approximately 3 · 5 mg per about 7 mg, and the amount of minodronic acid hydrate was selected from about 14 mg, once or scope of the two claimed orally is for administration Section 10 day agent described.
[14] bisphosphonate, histamine H2 receptor blockers, proton pump inhibitors, PGI2 receptor agonist, and PGE2 1 or more kinds and combination allowed comprising medicament selected from receptor agonist.
[15] about per formulation minodronic acid hydrate as an active ingredient 3. 5 mg, about 7mg or prevention and Z or a pharmaceutical composition for the treatment of about 14 mg comprising at osteoporosis for oral administration.
[16] The oral dosage comprising the bisphosphonate are arranged in four consecutive, or every seven to
A total of one to four placed month or calendar pack of 4-week units.
[17] Vertical consists of 4 columns and recesses composed of 7 horizontal rows, calendar packs described in the scope paragraph 16 according to which the vertical disposed four consecutive in the first column.
[18] bisphosphonate according to paragraph 16 claims is minodronic acid hydrate Calendar
- Ha, Seok.
[19] an effective amount of a bisphosphonate to a mammal, inhibiting bone resorption wherein the oral administration according to the schedule of administering 4 days a month or four weeks.
[20] use of a bisphosphonate for the manufacture of a bone resorption inhibitor for use in the oral administration according to the schedule of administering 4 days a month or four weeks.
PCT/JP2005/001252 2004-02-02 2005-01-28 Bone resorption inhibitors WO2005072747A1 (en)

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US9943531B2 (en) 2014-08-08 2018-04-17 Antecip Bioventures Ii Llc Osteoclast inhibitors such as zoledronic acid for low back pain treatment
CN104434854A (en) * 2014-12-10 2015-03-25 哈药集团技术中心 Minodronic acid tablet and preparation process thereof
US10265384B2 (en) 2015-01-29 2019-04-23 Novo Nordisk A/S Tablets comprising GLP-1 agonist and enteric coating

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