CN109662952A - The tablet of mesylate hydrate containing 1- cyclopropyl -8- (difluoro-methoxy) -7- [(1R) -1- methyl -2,3- dihydro -1H- iso-indoles -5- base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid - Google Patents
The tablet of mesylate hydrate containing 1- cyclopropyl -8- (difluoro-methoxy) -7- [(1R) -1- methyl -2,3- dihydro -1H- iso-indoles -5- base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid Download PDFInfo
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- CN109662952A CN109662952A CN201910108608.9A CN201910108608A CN109662952A CN 109662952 A CN109662952 A CN 109662952A CN 201910108608 A CN201910108608 A CN 201910108608A CN 109662952 A CN109662952 A CN 109662952A
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- tablet
- powder
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- plain piece
- mesh
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- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 title claims abstract description 8
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- 238000004090 dissolution Methods 0.000 claims abstract description 27
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 79
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- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000011297 pine tar Substances 0.000 description 1
- 229940068124 pine tar Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095374 tabloid Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 239000008371 vanilla flavor Substances 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
The present invention relates to the tablets of the mesylate hydrate containing 1- cyclopropyl -8- (difluoro-methoxy) -7- [(1R) -1- methyl -2,3- dihydro -1H- iso-indoles -5- base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid.(1) tablet according to the present invention has 1- cyclopropyl -8- (difluoro-methoxy) -7- [(1R) -1- methyl -2 of 80~97.5 mass %, 3- dihydro -1H- iso-indoles -5- base] -4- oxo -1, the containing ratio of 4- dihydroquinoline -3- carboxylic acid mesylate's hydrate, (2) size of the tablet is smaller than commercially available Geninax piece 200mg, (3) therefore, drug compliance can be improved, (4) Dissolution of Tablet is excellent, (5) tablet hardness and wear intensity are excellent, (6) therefore, the present invention is resistant to film coating and transport etc., the tablet of mesylate hydrate as compound A is useful.
Description
The application is Chinese patent application the 201280066321.0th divisional application of denomination of invention of the same name, original bill state
Application No. is PCT/JP2010/070239, international filing date is on November 12nd, 2010 on border.
Technical field
The present invention relates to miniaturization, contain 1- cyclopropyl -8- (difluoro-methoxy) -7- [(1R) -1- methyl -2,3- two
Hydrogen -1H- iso-indoles -5- base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid mesylate hydrate tablet.
Background technique
It is well known that 1- cyclopropyl -8- (difluoro-methoxy) -7- [(1R) -1- methyl -2,3- dihydro -1H- iso-indoles -5-
Base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid (hereinafter referred to as compound A) mesylate hydrate to gram-positive bacteria
With Gram-negative bacteria, particularly to have very strong antibacterial action to MRSA as the therapeutic agent of various infection illness be to have
Compound [patent document 1].
The tablet of mesylate hydrate containing compound A, it is commercially available to have thin membrane coated tablet (Fushan Mountain chemical industry system
Geninax piece 200mg), the compound A containing 200mg in 1, weight: about 357mg, major diameter: about 11.8mm, minor axis: about
7.1mm is thick: about 4.7mm.Containing ratio of the mesylate hydrate of compound A in the tablet is about the 72% of tablet quality
(quality percentage: hereinafter, % used in this specification, unless otherwise noted, it is intended that quality percentage.).The tablet is usual
Oral administration 1 time daily, 2 tablets once.
Above-mentioned biggish tablet can also have medication even for adult patients and resist sense and constriction, for children and
The patient of the dysphagias such as the elderly there is the worry for being not easy to take medicine, drug compliance being caused to reduce.
On the other hand, also have been reported that: the size for being easy the circular tablet of drink-service is 7~8mm of diameter, is easy the ellipse of drink-service
The size of shape tablet is major diameter 9mm [non-patent literature 1].
In order to minimize tablet, need to implement tablet with high-content.
However, when implementing tablet, raw medicine used in tablet can nearly all cause because of the various physical property of raw medicine capping,
The problems such as hardness is insufficient, brittleness (high friability), therefore, only by its own be difficult to realize for example be more than 60% high-content reality
Apply tablet [patent document 2].
Expect tablet more smaller than commercially available Geninax piece 200mg.
[existing technical literature]
[patent document]
No. 99/21849 pamphlet of [patent document 1] International Publication No.
[patent document 2] Japanese Unexamined Patent Publication 2009-35505 bulletin
[non-patent literature]
[non-patent literature 1] clinical pharmacy (Jpn.J.Pharm.Health Care Sci.), volume 32,842~848
Page, 2006
Summary of the invention
Problems to be solved by the invention
The issue of the present invention is to provide more smaller than commercially available Geninax piece 200mg, compound A methanesulfonic acid salt water
Close the tablet of object.
Solution to the problem
In these cases, the inventors of the present invention conduct in-depth research, as a result, it has been found that: the methanesulfonic acid salt water of compound A
The containing ratio for closing object is the tablet of 80~97.5 mass %, is tablet more smaller than commercially available Geninax piece 200mg, has excellent
Different dissolution rate, and hardness and friability are excellent.
Invention effect
Tablet of the invention has following characteristics.
(1) in each preparation, the containing ratio of the mesylate hydrate of compound A is 80~97.5 mass %.
(2) size of tablet is smaller than commercially available Geninax piece 200mg.
(3) its result improves drug compliance.
(4) dissolution rate is excellent.
(5) hardness and friability (abrasion degree) are excellent.
(6) therefore, tolerance film coating and transport etc..
Tablet of the invention is useful as the tablet of the mesylate hydrate of compound A.
Specific embodiment
The present invention is described in detail below.
The mesylate hydrate of compound A used in the present invention, can be according to such as International Publication No. 99/21849
The method recorded in number pamphlet manufactures.
Tablet of the invention contains the mesylate hydrate of compound A.The mesylate hydrate of compound A contains
As long as 80~97.5 mass % of rate plain piece quality, preferably 80~95 mass %.In addition, tablet of the invention can root
According to needing to add disintegrating agent.In turn, addition glidant, lubricant and/or coating agent also be can according to need.
Tablet of the invention can obtain as follows: the prilling powder of mesylate hydrate of the manufacture containing compound A, root
According to needing to be added additive, and compression molding.Furthermore, it is possible to carry out film coating as needed.
Disintegrating agent used in the present invention and other additives may be combined in prilling powder and/or outside prilling powder.
It as disintegrating agent used in the present invention, can enumerate: for example, croscarmellose sodium, carboxymethyl cellulose
The cellulose derivatives such as plain calcium, low-substituted hydroxypropyl cellulose and carboxymethyl cellulose；Primojel and part alphalysed starch
Starch derivatives such as (partially pregelatinized starch)；And the polyvinylpyrrolidones derivative such as Crospovidone.As preferably collapsing
Solve agent, can enumerate: Crospovidone, croscarmellose sodium and calcium carboxymethylcellulose, preferred disintegrating agent can be with
It enumerates: croscarmellose sodium and calcium carboxymethylcellulose.
Above-mentioned disintegrating agent, can be used a kind or two or more is applied in combination.
As long as the 0.5~20% of the containing ratio plain piece quality of disintegrating agent, preferably 1.0~15%, it is more preferable 1.5~
7.5%.
It as glidant used in the present invention, can enumerate: for example, silica.Glidant may be combined in granulation
In powder and/or outside prilling powder.
It as silica, can enumerate: for example, Adsolider 101 (Freund industry), (Japan of Aerosil 200
) and the light anhydrous silicic acids such as Sylysia 350 (Wai Kay F) Aerosil；And Adsolider 102 (Freund industry),
The aqueous silicon dioxides such as Carplex#67, #80, #100, #1120 (Shionogi).As preferred silica, Ke Yilie
It lifts: Aerosil 200 and Carplex 80.
The containing ratio of silica is the 0.1~15%, preferably 0.25~7.5% of tablet or prilling powder quality, more excellent
Select 0.5~5%.
By combination silica and disintegrating agent, the containing ratio for the mesylate hydrate for being compound A is 80 matter
The tabloid of % or more is measured, and shows following effect: there is excellent dissolution rate, and hardness and friability are excellent.
It as coating agent used in the present invention, can enumerate: such as hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene
Base alcohol-acryl acid-methyl methacrylate copolymer and polyvinyl alcohol-polyethylene glycol-graft copolymer etc., preferably hydroxypropyl
Methylcellulose and polyvinyl alcohol, more preferable hydroxypropyl methylcellulose.
Above-mentioned coating agent can be used a kind, can also be applied in combination with two or more.
It is preferred that adding lubricant in tablet and prilling powder of the invention.Lubricant may be combined in prilling powder
And/or outside prilling powder.As preferred mixed method, the method mixed outside prilling powder can be enumerated, is more preferably being made
The method mixed in grain powder and outside prilling powder.
It as lubricant, can enumerate: for example, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, talcum
And sucrose fatty ester etc..As preferred lubricant, magnesium stearate and talcum, more preferable magnesium stearate can be enumerated.
The containing ratio of lubricant be tablet or prilling powder quality 0.1~5%, preferably 0.2~4%, more preferable 0.5~
3%.
Excipient can also be further added in tablet and prilling powder of the invention.
The excipient used as required according to the present invention, can enumerate: for example, erythrite, mannitol, xylitol
With the glycitols such as D-sorbite；The carbohydrates such as white sugar, Icing Sugar, lactose and glucose；Alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin,
The cyclodextrins such as hydroxypropylβ-cyclodextrin and sulfobutyl ether beta-cyclodextrin sodium；And cellulose powder and avicel cellulose etc. are fine
Tie up plain class etc..Above-mentioned excipient can be used a kind, can also be applied in combination with two or more.
The additive amount of excipient is not particularly limited, as long as properly mixing aequum according to purpose.
As preferred excipient, avicel cellulose can be enumerated.
Avicel cellulose includes microcrystalline cellulose.
The avicel cellulose of various grades can be used.Be preferably listed average degree of polymerization 100~350, average grain diameter 20~
170 μm, loss on drying 1.0~7.0%, 0.10~0.46g/cm of heap density3Avicel cellulose, more preferably enumerate average polymerization
Spend 100~350,50 μm of average grain diameter, loss on drying 2.0~6.0%, 0.10~0.31g/cm of heap density3Avicel cellulose.
Within the scope of the effect of the invention, usual medicament can be used in tablet and prilling powder of the invention
Used in additive.
It as additive used in usual medicament, can enumerate: corrigent, colorant, aromatic, surface-active
Agent, plasticizer and defoaming agent etc..
It as corrigent, can enumerate: for example, aspartame, saccharin, STEVIA REBAUDIANA, thaumatin and acesulfame potassium
(Acesulfam k) etc..
It as colorant, can enumerate: for example, titanium dioxide, di-iron trioxide, Yellow ferric oxide, black oxidation
Iron, Food Red (edible redness of the skin or complexion) 102, food yellow (edible yellow) No. 4 numbers and food are No. 5 yellow etc..
It as aromatic, can enumerate: for example, the essential oils such as orange oil, lemon oil, peppermint oil and pine tar；Orange flavor and thin
The essence such as lotus essence；The fragrance such as cherry flavor, vanilla flavor and fruit flavor；Apple micro mist, banana micro mist, peach micro mist, strawberry
The powdered flavours such as micro mist and orange micro mist；Vanillic aldehyde；And ethyl vanillin etc..
It as surfactant, can enumerate: for example, NaLS, dioctyl sodium sulfosuccinate, poly- sorbic acid
Ester (salt) class and Crodaret etc..
As plasticizer, can enumerate: for example, triethyl citrate, dibutyl phthalate, glyceryl triacetate and
Propylene glycol etc..
It as defoaming agent, can enumerate: for example, organic silicon defoamer and organic siliconresin emulsion etc..
Above-mentioned additive can be used a kind, can also be applied in combination with two or more, and combined amount is not particularly limited, as long as
According to respective purpose, properly mix so that it shows its effect.
It suitably can select to give the occasion of tablet of the invention according to the age of patient, weight and symptom, to prescription
Method, dosage and administration number of times, usually by the amount that can play drug effect, single administration is administered for several times to being divided into one day,
It for adult, is administered once within usual one day, gives 100~2000mg of drug compound A every time.
It as the manufacturing method of tablet of the invention, can enumerate: manufacture prilling powder, and root using dry pelletizing method
According to needing further to add one or more of excipient, disintegrating agent and lubricant etc., as tabletting mixed-powder, lead to
It crosses tabletting and obtains plain piece, and to the method that it carries out film coating.
It as dry pelletizing method, can enumerate: for example, pressing, pressed disc method and briquetting method etc., preferably pressing.
As pressing, it can enumerate using roll squeezer and manufacture compression molding object, and be crushed and obtain being granulated grain
The method etc. of son.
It is different according to the kinds of machine used as the pressure of roll squeezer, using TF-LABO (Freund industry system)
When, preferably 3~9MPa.
It as the adding method of disintegrating agent, can enumerate: (1) to the mesylate hydrate of compound A and other additions
Disintegrating agent is added in the mixed-powder of agent, the method for manufacturing compression molding object, (2) obtain granulated particles by compression molding object, to
The method for wherein adding other additives and disintegrating agent, and (3) and the method etc. with the method for (1) and (2).
It as the adding method of glidant, can enumerate: (1) to the mesylate hydrate of compound A and disintegrating agent etc.
Mixed-powder in add silica, the method for manufacturing compression molding object, (2) obtain granulated particles by compression molding object, to
The method for wherein adding other additives and silica, and (3) and the method etc. with the method for (1) and (2), can also be by
It is added according to arbitrary method.
As tablet of the invention, circular tablet.The preferred diameter of the size of circular tablet: 7~9mm, thickness: 3~
5mm。
As the hardness of plain piece, preferably 50~200N, more preferable 60~200N.
It is preferably the smaller the better as the friability of plain piece, using Tab attrition testing machine in 25rpm, 750 turns (30 minutes)
Under conditions of, preferably 0~4%, more preferable 0~2%.
Tablet of the invention is dissolved out in the 16th correction Japanese Pharmacopoeia dissolution test method (paddle method) with Japanese Pharmacopoeia
The 1st liquid is tested as experimental liquid, in the dissolution test that revolution is 50 beats/min, 85% dissolution time was at 30 minutes or less
, it is expected that at 15 minutes or less.
The 1st liquid of experimental liquid of Japanese Pharmacopoeia dissolution test method is to be dissolved in sodium chloride 2.0g in hydrochloric acid 7.0mL and water simultaneously
Reach experimental liquid obtained from 1000mL.
In addition, 85% dissolution time refers to: the compound A of 85 mass % in the compound A for including in tablet dissolves out institute
Use the time.
It is illustrated followed by serviceability of the following tests example to Tablets.
Test example 1
Use the thin membrane coated tablet of Examples 1 to 4,9~10 and reference example 1~2 as sample.
Dissolution test is carried out according to Japanese Pharmacopoeia dissolution test (paddle method).The rotation number of paddle is set as 50rpm.Sample is thrown
Enter in the 1st liquid 900mL of Japanese Pharmacopoeia dissolution test, after 30 minutes, acquires testing liquid, find out compound A according to absorbance method
Dissolution rate (%).It should be noted that the 1st liquid of dissolution test is according to following preparations: sodium chloride 2.0g is dissolved in hydrochloric acid
In (JIS K8180, superfine) 7.0mL and water and reach 1000mL.
The results are shown in Table 1.
[table 1]
Use cornstarch (reference example 1) and hydroxypropul starch (reference example 2) as the thin membrane coated tablet of disintegrating agent, 30 points
Dissolution rate after clock is lower than 85%, shows lower dissolution rate.
On the other hand, using low-substituted hydroxypropyl cellulose (embodiment 1), calcium carboxymethylcellulose (embodiment 2), crosslinking
Sodium carboxymethylcellulose (embodiment 3), sodium starch glycolate (embodiment 4), carboxymethyl cellulose (embodiment 9) and part α
Change the thin membrane coated tablet of starch (embodiment 10) as disintegrating agent, although the mesylate hydrate of compound A is in plain piece
Containing ratio is high-content, and the dissolution rate after up to 85%, 30 minutes is 85% or more, shows excellent dissolution rate.
Test example 2
The thin membrane coated tablet and plain piece for using Examples 1 to 8 are as sample.
The dissolution test of thin membrane coated tablet is carried out similarly with test example 1.
Using tablet hardness tester (tablet hardness tester 8M, Shuroinigeru system), 3 hardness for finding out plain piece are measured.
It is crisp using tablet according to Japanese Pharmacopoeia reference information " the friability test method of tablet " about the friability of plain piece
Broken degree exerciser (PTF1ER PHARMATEST system) finds out 22 pieces under conditions of 25rpm, 750 turns (30 minutes).
The results are shown in Table 2.
[table 2]
The hardness of plain piece (Examples 1 to 4) without light anhydrous silicic acid be 58~86N, in contrast, containing lightweight without
The hardness of the plain piece (embodiment 5~8) of water silicon acid is 88~132N, is greatly improved.In addition, being free of the plain piece of light anhydrous silicic acid
The friability of (Examples 1 to 4) is 1.1~1.7%, in contrast, the plain piece (embodiment 5~8) containing light anhydrous silicic acid
Friability be 0.4~0.7%.The plain piece of Examples 1 to 4 is excellent as the tablet with required hardness and friability, real
The plain piece for applying example 5~8 is excellent as the tablet with the hardness and friability further improved.
Thin membrane coated tablet (Examples 1 to 4) without light anhydrous silicic acid and the film coating containing light anhydrous silicic acid
Piece (embodiment 5~8), the dissolution rate after 30 minutes is 85% or more, shows excellent dissolution rate.
Test example 3
The thin membrane coated tablet and plain piece for using embodiment 11 and embodiment 12 are as sample.
The dissolution test of thin membrane coated tablet is carried out similarly with test example 1.In addition, the hardness of plain piece and the friability of plain piece
It is carried out similarly with test example 2.It should be noted that 10 measurements of the hardness of plain piece are found out.
The results are shown in Table 3.
[table 3]
| Embodiment 11 | Embodiment 12 | |
| The mesylate hydrate (mg) of compound A | 270.0 | 270.0 |
| Calcium carboxymethylcellulose (mg) | 10.85 | 10.85 |
| Light anhydrous silicic acid (mg) | 0.0 | 3.0 |
| Avicel cellulose (mg) | 13.85 | 10.85 |
| Magnesium stearate (mg) | 5.3 | 5.3 |
| Plain piece quality (mg) | 300.0 | 300.0 |
| Dissolution rate (%) | 98.7 | 99.4 |
| Hardness (N) | 76-81 | 134-146 |
| Friability (%) | 1.89 | 0.92 |
Containing ratio of the mesylate hydrate of compound A in plain piece be 90% thin membrane coated tablet (embodiment 11 and
12), the dissolution rate after 30 minutes is 85% or more, shows excellent dissolution rate.In addition, with the element without light anhydrous silicic acid
Piece (embodiment 11) is compared, and the hardness of the plain piece (embodiment 12) containing light anhydrous silicic acid rises to about 2 times, and friability subtracts
As low as about 1/2.
Test example 4
The thin membrane coated tablet and plain piece for using embodiment 6,13 and 14 are as sample.
The dissolution test and test example 1 of thin membrane coated tablet are carried out similarly.In addition, the hardness of plain piece and the friability of plain piece
It is carried out similarly according to test example 2.It should be noted that the hardness of plain piece, measures 3 times, using embodiment using embodiment 6
13 measurements 6 times measure 10 times using embodiment 14 to find out.
The results are shown in Table 4.
[table 4]
| Embodiment 6 | Embodiment 13 | Embodiment 14 | |
| The mesylate hydrate (mg) of compound A | 253.5 | 253.5 | 253.5 |
| Calcium carboxymethylcellulose (mg) | 14.6 | 15.0 | 15.0 |
| Light anhydrous silicic acid (mg) | 2.8 | 9.0 | 0.0 |
| Aqueous titanium dioxide Kui (mg) | 0.0 | 0.0 | 9.0 |
| Avicel cellulose (mg) | 25.6 | 16.5 | 16.5 |
| Magnesium stearate (mg) | 3.5 | 6.0 | 6.0 |
| Plain piece quality (mg) | 300.0 | 300.0 | 300.0 |
| Dissolution rate (%) | 102.2 | 102.4 | 99.5 |
| Hardness (N) | 98-125 | 132-153 | 161-176 |
| Friability (%) | 0.53 | 0.76 | 0.59 |
The containing ratio of light anhydrous silicic acid is 0.9% thin membrane coated tablet (embodiment 6) and 3% film coating in plain piece
Piece (embodiment 13), although the additive amount of light anhydrous silicic acid is different, the dissolution rate after 30 minutes is 85% or more, is shown excellent
Different dissolution rate, the plain piece are excellent as the tablet with required hardness and friability.
Thin membrane coated tablet (embodiment 13) containing light anhydrous silicic acid and the film coating containing aqueous silicon dioxide
Piece (embodiment 14), no matter the type of silica, dissolution rate after 30 minutes is 85% or more, show excellent dissolution rate,
The plain piece is excellent as the tablet with required hardness and friability.
Test example 5
The thin membrane coated tablet and plain piece for using embodiment 15~29 are as sample.
The dissolution test of thin membrane coated tablet is carried out similarly with test example 1.In addition, the hardness of plain piece and the friability of plain piece
It is carried out similarly with test example 2.It should be noted that the Determination of Hardness of plain piece 10 times find out.
The results are shown in Table 5.
[table 5-1]
[table 5-2]
The mesylate hydrate of the compound A thin membrane coated tablet that containing ratio is 95% in plain piece (embodiment 15~
23), the dissolution rate after 30 minutes is 85% or more, shows excellent dissolution rate.In addition, these plain pieces have sufficient hardness.
In particular, the friability of the plain piece (embodiment 15,17,19~22) containing light anhydrous silicic acid and/or aqueous silicon dioxide is 1
~2%, it is excellent.
In addition, the film coating that containing ratio of the mesylate hydrate of compound A in plain piece is higher 97.5%
Piece (embodiment 24~29), the dissolution rate after 30 minutes is also 85% or more, shows excellent dissolution rate.These plain pieces are as tool
There is the tablet of required hardness and friability, it is excellent.
The present invention is done to illustrate by embodiment and comparative example, but the present invention is not so limited.
If coating agent uses Opadry 00K43069 (hypromellose 2910 66.588%, oxidation without specified otherwise
Titanium 24.847%, glyceryl triacetate 7.951%, di-iron trioxide 0.102%, Yellow ferric oxide 0.512%, Japan
Colorcon system).
It should be noted that the preparation manufactured in following embodiment and reference example are as follows: diameter: about 8.6mm, thickness: about 4.8mm
Circular tablet.
Embodiment 1
By the mesylate hydrate 122.91g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry
System) 13.81g and low-substituted hydroxypropyl cellulose (L-HPC LH-11, SHIN-ETSU HANTOTAI's chemistry system) 7.1g mixing, with 850 μm of sieve of mesh
Sieving 2 times.By magnesium stearate (magnesium stearate, peaceful Chemical Industries system), 1.31g passes through 500 μm of mesh of sieve, and adds upper
It states in mixed-powder, mixes 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, the solid of forming is carried out whole
Grain.500 μm of mesh of sieve will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.3%, and added in obtained whole grain
In powder, mix 30 minutes.Using the double formed punches (ダ Block ル ア ー Le face pestle, double R-surface punch) of disc,
Tabletting is carried out to the mixed-powder with tablet diameter 8.5mm, with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every
The ratio of piece 5.5mg coats coating agent to plain piece, obtains thin membrane coated tablet.It should be noted that coating agent use is to Opadry
It is micro in 00K43069 to be added to substance obtained from organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system).
Embodiment 2
By the mesylate hydrate 122.92g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry
System) 13.81g and calcium carboxymethylcellulose (E.C.G-505, Nichirin chemistry system) 7.1g mixing, with 850 μm of mesh be sieved through
Sieve 2 times.By magnesium stearate (magnesium stearate, peaceful Chemical Industries system), 1.31g passes through 500 μm of mesh of sieve, and adds above-mentioned
In mixed-powder, mix 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, the solid of forming is carried out whole
Grain.500 μm of mesh of sieve will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.3%, and added in obtained whole grain
In powder, mix 30 minutes.Using the double formed punches of disc, the mixed-powder is carried out with tablet diameter 8.5mm, with tableting pressure 10kN
Tabletting obtains the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 5.5mg, obtains thin membrane coated tablet.
It should be noted that coating agent is added to organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI using micro into Opadry 00K43069
Length of schooling) obtained from substance.
Embodiment 3
By the mesylate hydrate 122.92g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry
System) 13.81g and croscarmellose sodium (Purimerosu, DMV system) 7.1g mixing, with 850 μm of mesh of sieved sieve 2
It is secondary.By magnesium stearate (magnesium stearate, peaceful Chemical Industries system), 1.31g passes through 500 μm of mesh of sieve, and adds in above-mentioned mixing
In powder, mix 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, whole grain is carried out to the solid of forming.It will
Pass through 500 μm of mesh of sieve relative to the considerable amount of magnesium stearate of plain piece weight 0.3%, and adds in obtained whole grain powder
In, it mixes 30 minutes.Using the double formed punches of disc, the mixed-powder is pressed with tablet diameter 8.5mm, with tableting pressure 12kN
Piece obtains the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 5.5mg, obtains thin membrane coated tablet.It needs
It is noted that coating agent is added to organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry using micro into Opadry 00K43069
System) obtained from substance.
Embodiment 4
By the mesylate hydrate 122.92g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry
System) 13.81g and primojel (Primojel, DMV system) 7.11g mixing, with sieved sieve 2 times of 850 μm of mesh.It will be hard
1.31g passes through 500 μm of mesh of sieve to fatty acid magnesium (magnesium stearate, peaceful Chemical Industries system), and adds in above-mentioned mixed-powder,
Mixing 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, whole grain is carried out to the solid of forming.It will be relative to element
The considerable amount of magnesium stearate of sheet weight 0.3% passes through 500 μm of mesh of sieve, and adds in obtained whole grain powder, mixing 30
Minute.Using the double formed punches of disc, tabletting is carried out to the mixed-powder with tablet diameter 8.5mm, with tableting pressure 12kN, obtains 1
The round plain piece of 300mg.Coating agent is coated to plain piece with the ratio of every 5.5mg, obtains thin membrane coated tablet.It needs to illustrate
It is that coating agent is added to organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system) and is obtained using micro into Opadry 00K43069
Substance.
Embodiment 5
By the mesylate hydrate 122.9g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
12.4g, light anhydrous silicic acid (Aerosil 200, Japan's Aerosil system) 1.41g and low-substituted hydroxypropyl cellulose (L-HPC
LH-11, SHIN-ETSU HANTOTAI's chemistry system) 7.11g mixing, with sieved sieve 2 times of 850 μm of mesh.By magnesium stearate (magnesium stearate, peaceization
Industry system) 1.3g passes through 500 μm of mesh of sieve, and adds in above-mentioned mixed-powder, it mixes 30 minutes.Use Drygranulatemachine
By the mixed-powder compression molding, whole grain is carried out to the solid of forming.It will be relative to the considerable amount of tristearin of plain piece weight 0.3%
Sour magnesium passes through 500 μm of mesh of sieve, and adds in obtained whole grain powder, mixes 30 minutes.Using the double formed punches of disc, with piece
Agent diameter 8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every
The ratio of 5.7mg coats coating agent to plain piece, obtains thin membrane coated tablet.It should be noted that coating agent use is to Opadry
It is micro in 00K43069 to be added to substance obtained from organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system).
Embodiment 6
By the mesylate hydrate 122.9g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
12.4g, light anhydrous silicic acid (Aerosil 200, Japan's Aerosil system) 1.4g and calcium carboxymethylcellulose (E.C.G-505,
Nichirin chemistry system) 7.1g mixing, with sieved sieve 2 times of 850 μm of mesh.By magnesium stearate, (magnesium stearate, peaceful chemistry are produced
Industry system) 1.3g passes through 500 μm of mesh of sieve, and adds in above-mentioned mixed-powder, it mixes 30 minutes.It should with Drygranulatemachine
Mixed-powder compression molding carries out whole grain to the solid of forming.It will be relative to the considerable amount of magnesium stearate of plain piece weight 0.3%
It by 500 μm of sieve of mesh, and adds in obtained whole grain powder, mixes 30 minutes.Using the double formed punches of disc, with tablet diameter
8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every 5.7mg's
Ratio coats coating agent to plain piece, obtains thin membrane coated tablet.It should be noted that coating agent use is to Opadry 00K43069
In micro be added to substance obtained from organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system).
Embodiment 7
By the mesylate hydrate 122.91g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry
System) 12.4g, light anhydrous silicic acid (Aerosil 200, Japan's Aerosil system) 1.4g and croscarmellose sodium
(Purimerosu, DMV system) 7.1g mixing, with sieved sieve 2 times of 850 μm of mesh.By magnesium stearate (magnesium stearate, peaceization
Industry system) 1.31g passes through 500 μm of mesh of sieve, and adds in above-mentioned mixed-powder, it mixes 30 minutes.It is granulated with dry type
Machine carries out whole grain by the mixed-powder compression molding, to the solid of forming.It will be considerable amount of hard relative to plain piece weight 0.3%
Fatty acid magnesium passes through 500 μm of mesh of sieve, and adds in obtained whole grain powder, mixes 30 minutes.Using the double formed punches of disc, with
Tablet diameter 8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every
The ratio of 6.2mg coats coating agent to plain piece, obtains thin membrane coated tablet.It should be noted that coating agent use is to Opadry
It is micro in 00K43069 to be added to substance obtained from organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system).
Embodiment 8
By the mesylate hydrate 122.91g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry
System) 12.4g, light anhydrous silicic acid (Aerosil200, Japan's Aerosil system) 1.4g and primojel (Primojel,
DMV system) 7.1g mixing, with sieved sieve 2 times of 850 μm of mesh.By magnesium stearate (magnesium stearate, peaceful Chemical Industries system) 1.3g
It by 500 μm of sieve of mesh, and adds in above-mentioned mixed-powder, mixes 30 minutes.With Drygranulatemachine by the mixed-powder
Compression molding carries out whole grain to the solid of forming.Mesh will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.3%
500 μm of sieve, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with
Tableting pressure 12kN carries out tabletting to the mixed-powder, obtains the round plain piece of 1 300mg.With the ratio of every 6.2mg to element
Piece coats coating agent, obtains thin membrane coated tablet.It should be noted that coating agent is added using micro into Opadry 00K43069
Substance obtained from organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system) is added.
Embodiment 9
By the mesylate hydrate 44.07g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
4.44g, light anhydrous silicic acid (Aerosil200, Japan's Aerosil system) 0.5g, carboxymethyl cellulose (NS-300, Nichirin
Chemistry system) 2.54g and passed through 500 μm of mesh sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system) 0.46g it is mixed
It closes, with sieved sieve 2 times of 850 μm of mesh.The mixed-powder is mixed 30 minutes.The mixed-powder is compressed with Drygranulatemachine
Forming carries out whole grain to the solid of forming.500 μ of mesh will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.3%
The sieve of m, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tabletting
Pressure 12kN carries out tabletting to the mixed-powder, obtains the round plain piece of 1 300mg.With the ratio of every 5.3mg to plain piece packet
Coating agent is covered, thin membrane coated tablet is obtained.It should be noted that coating agent is added to using micro into Opadry 00K43069
Substance obtained from organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system).
Embodiment 10
By the mesylate hydrate 44.07g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
4.43g, light anhydrous silicic acid (Aerosil200, Japan's Aerosil system) 0.49g, part alphalysed starch (PCS, Asahi Chemical Industry's chemistry
System) 2.54g and passed through 500 μm of mesh sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system) 0.46g mixing, use
850 μm of mesh of sieved sieve 2 times.The mixed-powder is mixed 30 minutes.With Drygranulatemachine by the mixed-powder compression molding,
Whole grain is carried out to the solid of forming.500 μm of mesh will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.3%
Sieve, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tabletting pressure
Power 12kN carries out tabletting to the mixed-powder, obtains the round plain piece of 1 300mg.It is coated with the ratio of every 5.3mg to plain piece
Coating agent obtains thin membrane coated tablet.It should be noted that coating agent has been added to using micro into Opadry 00K43069
Substance obtained from machine silicon defoaming agent (KM72, SHIN-ETSU HANTOTAI's chemistry system).
Embodiment 11
By the mesylate hydrate 47.32g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
2.43g, calcium carboxymethylcellulose (E.C.G-505, Nichirin chemistry system) 1.89g and passed through 500 μm of mesh sieve it is hard
Fatty acid magnesium (magnesium stearate, peaceful Chemical Industries system) 0.35g mixing, with sieved sieve 2 times of 850 μm of mesh.By the mixed-powder
Mixing 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, whole grain is carried out to the solid of forming.It will be relative to element
The considerable amount of magnesium stearate of sheet weight 1.1% passes through 500 μm of mesh of sieve, and adds in obtained whole grain powder, mixing 30
Minute.Using the double formed punches of disc, tabletting is carried out to the mixed-powder with tablet diameter 8.5mm, with tableting pressure 12kN, obtains 1
The round plain piece of 300mg.Coating agent is coated to plain piece with the ratio of every 5.9mg, obtains thin membrane coated tablet.
Embodiment 12
By the mesylate hydrate 47.31g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
1.91g, light anhydrous silicic acid (Aerosil200, Japan's Aerosil system) 0.52g, calcium carboxymethylcellulose (E.C.G-505,
Nichirin chemistry system) 1.9g and passed through 500 μm of mesh sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system)
0.35g mixing, with sieved sieve 2 times of 850 μm of mesh.The mixed-powder is mixed 30 minutes.With Drygranulatemachine by the mixing
Powder compression molding carries out whole grain to the solid of forming.It will pass through relative to the considerable amount of magnesium stearate of plain piece weight 1.1%
The sieve that 500 μm of mesh, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter
8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every 5.9mg's
Ratio coats coating agent to plain piece, obtains thin membrane coated tablet.
Embodiment 13
By mesylate hydrate 59.83g and light anhydrous silicic acid (Aerosil200, Japan Aerosil of compound A
System) 2.14g mixing, it is sieved using pelletizing machine (Comill, mesh size 1.143mm).Powder after sieving is packed into mixing vessel
In.Then with pelletizing machine (Comill, mesh size 1.143mm), by calcium carboxymethylcellulose, (E.C.G-505, Nichirin are chemical
System) 3.56g and avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system) 3.9g sieving, by after sieving powder be packed into
In mixing vessel.Into the powder after sieving, addition has passed through magnesium stearate (magnesium stearate, peaceization of 500 μm of mesh of sieve
Industry system) 0.65g, it mixes 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, the solid of forming is carried out
Whole grain.500 μm of mesh of sieve will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 1.1%, and added whole what is obtained
In grain powder, mix 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tableting pressure 11kN to the mixed-powder into
Row tabletting obtains the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 5.8mg, obtains film coating
Piece.
Embodiment 14
By the mesylate hydrate 44.42g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
2.89g, aqueous silicon dioxide (CARPLEX#80, DSL Japan system) 1.58g, calcium carboxymethylcellulose (E.C.G-505,
Nichirin chemistry system) 2.63g and passed through 500 μm of mesh sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system)
0.47g mixing, with sieved sieve 2 times of 850 μm of mesh.The mixed-powder is mixed 30 minutes.With Drygranulatemachine by the mixing
Powder compression molding carries out whole grain to the solid of forming.It will pass through relative to the considerable amount of magnesium stearate of plain piece weight 1.1%
The sieve that 500 μm of mesh, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter
8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every 5.9mg's
Ratio coats coating agent to plain piece, obtains thin membrane coated tablet.
Embodiment 15
By the mesylate hydrate 49.97g of compound A, light anhydrous silicic acid (Aerosil200, Japan Aerosil
System) 0.53g and calcium carboxymethylcellulose (E.C.G-505, Nichirin chemistry system) 1.17g mixing, with 850 μm of mesh be sieved through
Sieve.Into the mixed-powder, addition has passed through the magnesium stearate (magnesium stearate, peaceful Chemical Industries system) of 500 μm of mesh of sieve
0.35g is mixed 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, whole grain is carried out to the solid of forming.By phase
Pass through 500 μm of mesh of sieve for the considerable amount of magnesium stearate of plain piece weight 1.1%, and add in obtained whole grain powder,
Mixing 30 minutes.Using the double formed punches of disc, tabletting is carried out to the mixed-powder with tablet diameter 8.5mm, with tableting pressure 12kN, is obtained
To the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 6.2mg, obtains thin membrane coated tablet.
Embodiment 16
By the mesylate hydrate 49.95g and calcium carboxymethylcellulose (E.C.G-505, Nichirinization of compound A
Length of schooling) 1.69g mixing, with 850 μm of mesh of sieved sieve.Into the mixed-powder, addition has passed through the hard of 500 μm of mesh of sieve
Fatty acid magnesium (magnesium stearate, peaceful Chemical Industries system) 0.35g, mixes 30 minutes.The mixed-powder is compressed with Drygranulatemachine
Forming carries out whole grain to the solid of forming.500 μ of mesh will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 1.1%
The sieve of m, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tabletting
Pressure 12kN carries out tabletting to the mixed-powder, obtains the round plain piece of 1 300mg.With the ratio of every 6.2mg to plain piece packet
Coating agent is covered, thin membrane coated tablet is obtained.
Embodiment 17
By the mesylate hydrate 49.94g of compound A, light anhydrous silicic acid (Aerosil200, Japan Aerosil
System) 0.53g and croscarmellose sodium (Kikkoreto ND-2HS, Asahi Chemical Industry's chemistry system) 1.17g mixing, use mesh
850 μm of sieved sieve.Into the mixed-powder, addition has passed through magnesium stearate (magnesium stearate, peaceization of 500 μm of mesh of sieve
Industry system) 0.35g, it mixes 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, the solid of forming is carried out
Whole grain.500 μm of mesh of sieve will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 1.1%, and added whole what is obtained
In grain powder, mix 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tableting pressure 12kN to the mixed-powder into
Row tabletting obtains the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 6.2mg, obtains film coating
Piece.
Embodiment 18
By the mesylate hydrate 49.99g and croscarmellose sodium of compound A (Kikkoreto ND-2HS,
Asahi Chemical Industry's chemistry system) 1.70g mixing, with 850 μm of mesh of sieved sieve.It is added into the mixed-powder and has passed through 500 μm of mesh
Sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system) 0.35g, mix 30 minutes.With Drygranulatemachine by the mixing
Powder compression molding carries out whole grain to the solid of forming.It will pass through relative to the considerable amount of magnesium stearate of plain piece weight 1.1%
The sieve that 500 μm of mesh, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter
8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every 6.2mg's
Ratio coats coating agent to plain piece, obtains thin membrane coated tablet.
Embodiment 19
By the mesylate hydrate 50.22g of compound A, light anhydrous silicic acid (Aerosil200, Japan Aerosil
System) 0.26g and calcium carboxymethylcellulose (E.C.G-505, Nichirin chemistry system) 1.18g mixing, with 850 μm of mesh be sieved through
Sieve.Into the mixed-powder, addition has passed through the magnesium stearate (magnesium stearate, peaceful Chemical Industries system) of 500 μm of mesh of sieve
0.35g is mixed 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, whole grain is carried out to the solid of forming.By phase
It is considerable amount of for the considerable amount of aqueous silicon dioxide of plain piece weight 0.5% (CARPLEX#80, DSL Japan system) and 1.1%
The magnesium stearate for having passed through 500 μm of mesh of sieve adds in obtained whole grain powder, mixes 30 minutes.Use the double punchings of disc
Head carries out tabletting to the mixed-powder with tablet diameter 8.5mm, with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With
The ratio of every 6.2mg coats coating agent to plain piece, obtains thin membrane coated tablet.
Embodiment 20
By the mesylate hydrate 50.20g of compound A, aqueous silicon dioxide (CARPLEX#80, DSL Japan system)
0.26g and calcium carboxymethylcellulose (E.C.G-505, Nichirin chemistry system) 1.18g mixing, with 850 μm of mesh of sieved sieve.
Into the mixed-powder, addition has passed through the magnesium stearate (magnesium stearate, peaceful Chemical Industries system) of 500 μm of mesh of sieve
0.35g is mixed 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, whole grain is carried out to the solid of forming.By phase
For the considerable amount of light anhydrous silicic acid of plain piece weight 0.5% (Aerosil200, Japan's Aerosil system) and 1.1% a great deal of
The sieve for having passed through 500 μm of mesh magnesium stearate add in obtained whole grain powder, mix 30 minutes.Use the double punchings of disc
Head carries out tabletting to the mixed-powder with tablet diameter 8.5mm, with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With
The ratio of every 6.2mg coats coating agent to plain piece, obtains thin membrane coated tablet.
Embodiment 21
By the mesylate hydrate 50.48g and calcium carboxymethylcellulose (E.C.G-505, Nichirinization of compound A
Length of schooling) 1.19g mixing, with 850 μm of mesh of sieved sieve.Into the mixed-powder, addition has passed through the hard of 500 μm of mesh of sieve
Fatty acid magnesium (magnesium stearate, peaceful Chemical Industries system) 0.35g, mixes 30 minutes.The mixed-powder is compressed with Drygranulatemachine
Forming carries out whole grain to the solid of forming.It will be relative to the considerable amount of aqueous silicon dioxide of plain piece weight 1.0%
The addition of the magnesium stearate of (CARPLEX#80, DSL Japan system) and the 1.1% considerable amount of sieve for having passed through 500 μm of mesh is obtaining
To whole grain powder in, mix 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tableting pressure 12kN to the mixing
Powder carries out tabletting, obtains the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 6.2mg, is obtained thin
Film coating piece.
Embodiment 22
By the mesylate hydrate 49.96g of compound A, light anhydrous silicic acid (Aerosil200, Japan Aerosil
System) 0.53g, calcium carboxymethylcellulose (E.C.G-505, Nichirin chemistry system) 0.60g and Crospovidone (Polyplasdone
XL-10, ISP Japan) 0.60g mixing, with 850 μm of mesh of sieved sieve.It is added into the mixed-powder and has passed through mesh 500
μm sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system) 0.35g, mix 30 minutes.This is mixed with Drygranulatemachine
Powder compression molding is closed, whole grain is carried out to the solid of forming.It will lead to relative to the considerable amount of magnesium stearate of plain piece weight 1.1%
500 μm of mesh of sieve is crossed, and is added in obtained whole grain powder, is mixed 30 minutes.Using the double formed punches of disc, with tablet diameter
8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every 6.2mg's
Ratio coats coating agent to plain piece, obtains thin membrane coated tablet.
Embodiment 23
By the mesylate hydrate 49.96g of compound A, calcium carboxymethylcellulose (E.C.G-505, Nichirin chemistry
System) 0.85g and Crospovidone (Polyplasdone XL-10, ISP Japan) 0.85g mixing, with 850 μm of mesh be sieved through
Sieve.Into the mixed-powder, addition has passed through the magnesium stearate (magnesium stearate, peaceful Chemical Industries system) of 500 μm of mesh of sieve
0.35g is mixed 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, whole grain is carried out to the solid of forming.By phase
Pass through 500 μm of mesh of sieve for the considerable amount of magnesium stearate of plain piece weight 1.1%, and add in obtained whole grain powder,
Mixing 30 minutes.Using the double formed punches of disc, tabletting is carried out to the mixed-powder with tablet diameter 8.5mm, with tableting pressure 12kN, is obtained
To the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 6.2mg, obtains thin membrane coated tablet.
Embodiment 24
By the mesylate hydrate 48.99g of compound A, light anhydrous silicic acid (Aerosil200, Japan Aerosil
System) 0.25g and croscarmellose sodium (Kikkoreto ND-2HS, Asahi Chemical Industry's chemistry system) 0.75g mixing, use mesh
850 μm of sieved sieve.The mixed-powder is mixed 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, to forming
Solid carry out whole grain.500 μm of mesh of sieve will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.5%, and added
In the whole grain powder being added in, mix 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with 12kN pairs of tableting pressure
The mixed-powder carries out tabletting, obtains the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 6.6mg,
Obtain thin membrane coated tablet.
Embodiment 25
By the mesylate hydrate 48.99g of compound A, aqueous titanium dioxide (CARPLEX#80, DSL Japan system)
0.25g and croscarmellose sodium (Kikkoreto ND-2HS, Asahi Chemical Industry's chemistry system) 0.75g mixing, with 850 μm of mesh
Sieved sieve.The mixed-powder is mixed 30 minutes.With Drygranulatemachine by the mixed-powder compression molding, to the solid-state of forming
Object carries out whole grain.500 μm of mesh of sieve will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.5%, and add and obtaining
To whole grain powder in, mix 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tableting pressure 12kN to the mixing
Powder carries out tabletting, obtains the round plain piece of 1 300mg.Coating agent is coated to plain piece with the ratio of every 6.6mg, is obtained thin
Film coating piece.
Embodiment 26
By the mesylate hydrate 49.24g and croscarmellose sodium of compound A (Kikkoreto ND-2HS,
Asahi Chemical Industry's chemistry system) 0.76g mixing, with 850 μm of mesh of sieved sieve.The mixed-powder is mixed 30 minutes.It is granulated with dry type
Machine carries out whole grain by the mixed-powder compression molding, to the solid of forming.It will be considerable amount of light relative to plain piece weight 0.5%
Matter silicic acid anhydride (Aerosil200, Japan's Aerosil system) and it is considerable amount of relative to plain piece weight 0.5%, passed through 500 μm
Sieve magnesium stearate add in obtained whole grain powder, mix 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm,
Tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With the ratio of every 6.6mg to
Plain piece coats coating agent, obtains thin membrane coated tablet.
Embodiment 27
By the mesylate hydrate 49.24g and croscarmellose sodium of compound A (Kikkoreto ND-2HS,
Asahi Chemical Industry's chemistry system) 0.76g mixing, with 850 μm of mesh of sieved sieve.The mixed-powder is mixed 30 minutes.It is granulated with dry type
Machine carries out whole grain by the mixed-powder compression molding, to the solid of forming.It will contain relative to plain piece weight 0.5% is considerable amount of
Water silica (CARPLEX#80, DSL Japan system) and it is considerable amount of relative to plain piece weight 0.5%, passed through 500 μm
The magnesium stearate of sieve adds in obtained whole grain powder, mixes 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with
Tableting pressure 12kN carries out tabletting to the mixed-powder, obtains the round plain piece of 1 300mg.With the ratio of every 6.6mg to element
Piece coats coating agent, obtains thin membrane coated tablet.
Embodiment 28
By the mesylate hydrate 48.99g and calcium carboxymethylcellulose (E.C.G-505, Nichirinization of compound A
Length of schooling) 1.01g mixing, with 850 μm of mesh of sieved sieve.The mixed-powder is mixed 30 minutes.This is mixed with Drygranulatemachine
Powder compression molding is closed, whole grain is carried out to the solid of forming.It will lead to relative to the considerable amount of magnesium stearate of plain piece weight 0.5%
500 μm of sieve is crossed, and is added in obtained whole grain powder, is mixed 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm,
Tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With the ratio of every 6.6mg to
Plain piece coats coating agent, obtains thin membrane coated tablet.
Embodiment 29
By the mesylate hydrate 48.99g and croscarmellose sodium of compound A (Kikkoreto ND-2HS,
Asahi Chemical Industry's chemistry system) 1.01g mixing, with 850 μm of mesh of sieved sieve.The mixed-powder is mixed 30 minutes.It is granulated with dry type
Machine carries out whole grain by the mixed-powder compression molding, to the solid of forming.It will be considerable amount of hard relative to plain piece weight 0.5%
Fatty acid magnesium passes through 500 μm of sieve, and adds in obtained whole grain powder, mixes 30 minutes.Using the double formed punches of disc, with tablet
Diameter 8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every 6.6mg
Ratio to plain piece coat coating agent, obtain thin membrane coated tablet.
Reference example 1
By the mesylate hydrate 44.05g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
4.43g, light anhydrous silicic acid (Aerosil200, Japan's Aerosil system) 0.49g, cornstarch (solar eclipse CornstarchW, day
This food chemistry system) 2.53g and passed through 500 μm of mesh sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system)
0.46g mixing, twice with 850 μm of mesh of sieved sieves.The mixed-powder is mixed 30 minutes.With Drygranulatemachine by the mixing
Powder compression molding carries out whole grain to the solid of forming.It will pass through relative to the considerable amount of magnesium stearate of plain piece weight 0.3%
The sieve that 500 μm of mesh, and add in obtained whole grain powder, it mixes 30 minutes.Using the double formed punches of disc, with tablet diameter
8.5mm, tabletting is carried out to the mixed-powder with tableting pressure 12kN, obtains the round plain piece of 1 300mg.With every 5.3mg's
Ratio coats coating agent to plain piece, obtains thin membrane coated tablet.It should be noted that as coating agent, using in Opadry
Substance obtained from micro addition organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system) in 00K43069.
Reference example 2
By the mesylate hydrate 44.07g of compound A, avicel cellulose (CEOLUS PH101, Asahi Chemical Industry's chemistry system)
(HPS101, day form sediment chemical for 4.45g, light anhydrous silicic acid (Aerosil200, Japan's Aerosil system) 0.49g, hydroxypropul starch
System) 2.53g and passed through 500 μm of mesh sieve magnesium stearate (magnesium stearate, peaceful Chemical Industries system) 0.46g mixing, use
850 μm of mesh of sieved sieve is twice.The mixed-powder is mixed 30 minutes.The mixed-powder is compressed into Drygranulatemachine
Shape carries out whole grain to the solid of forming.500 μm of mesh will be passed through relative to the considerable amount of magnesium stearate of plain piece weight 0.3%
Sieve, and add in obtained whole grain powder, mix 30 minutes.Using the double formed punches of disc, with tablet diameter 8.5mm, with tabletting
Pressure 12kN carries out tabletting to the mixed-powder, obtains the round plain piece of 1 300mg.With the ratio of every 5.3mg to plain piece packet
Coating agent is covered, thin membrane coated tablet is obtained.It should be noted that being added as coating agent using micro in Opadry 00K43069
Add substance obtained from organic silicon defoamer (KM72, SHIN-ETSU HANTOTAI's chemistry system).
Industrial applicibility
About tablet of the invention, the containing ratio of the mesylate hydrate of (1) compound A is 80~97.5 mass %,
(2) size of tablet is smaller than commercially available Geninax piece 200mg, and (3) therefore, can improve drug compliance, (4) dissolution rate
Excellent, (5) hardness and friability are excellent, and (6) therefore, can be resistant to film coating and transport etc., the methanesulfonic acid as compound A
The tablet of salt hydrate is useful.
Claims (8)
1. a kind of tablet, wherein 1- cyclopropyl -8- (difluoro-methoxy) -7- [different Yin of (1R) -1- methyl -2,3- dihydro -1H-
Diindyl -5- base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid mesylate hydrate containing ratio be 80~97.5 mass %.
2. tablet according to claim 1, wherein containing ratio is 80~95 mass %.
3. tablet according to claim 1 or 2, wherein using the 1st liquid of Japanese Pharmacopoeia dissolution test as experimental liquid, general
Rotation number is set as in the 2nd method (paddle method) of Japanese Pharmacopoeia dissolution test method of 50rpm, 1- cyclopropyl -8- (difluoro-methoxy) -7-
The methanesulfonic acid salt water of [(1R) -1- methyl -2,3- dihydro -1H- iso-indoles -5- base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid
85% dissolution time for closing object is within 30 points.
4. tablet described in any one of claim 1 to 3, also contains disintegrating agent.
5. tablet according to claim 4, wherein disintegrating agent is selected from cellulose derivative, starch derivatives and poly- second
One or more of vinyl pyrrolidone derivative.
6. tablet according to claim 5, wherein
Cellulose derivative is croscarmellose sodium, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose and carboxylic first
Base cellulose,
Starch derivatives be primojel and part alphalysed starch,
Polyvinylpyrrolidone derivative is Crospovidone.
7. tablet described according to claim 1~any one of 6, also contains glidant.
8. tablet according to claim 7, wherein glidant is silica.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011261727 | 2011-11-30 | ||
| JP2011-261727 | 2011-11-30 | ||
| CN201280066321.0A CN104039322A (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201280066321.0A Division CN104039322A (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109662952A true CN109662952A (en) | 2019-04-23 |
Family
ID=48535494
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201280066321.0A Pending CN104039322A (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate |
| CN201910108608.9A Pending CN109662952A (en) | 2011-11-30 | 2012-11-29 | The tablet of mesylate hydrate containing 1- cyclopropyl -8- (difluoro-methoxy) -7- [(1R) -1- methyl -2,3- dihydro -1H- iso-indoles -5- base] -4- oxo -1,4- dihydroquinoline -3- carboxylic acid |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201280066321.0A Pending CN104039322A (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JP6117112B2 (en) |
| CN (2) | CN104039322A (en) |
| BR (1) | BR112014012994A2 (en) |
| MX (1) | MX350659B (en) |
| MY (1) | MY169750A (en) |
| PH (1) | PH12014501224A1 (en) |
| RU (1) | RU2633477C2 (en) |
| SG (1) | SG11201402597WA (en) |
| WO (1) | WO2013081044A1 (en) |
| ZA (1) | ZA201403942B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017073738A1 (en) * | 2015-10-29 | 2017-05-04 | 日本臓器製薬株式会社 | Tablet having fexofenadine as effective component thereof |
| TWI727036B (en) * | 2016-04-27 | 2021-05-11 | 日商富山化學工業股份有限公司 | Tablet comprising tosufloxacin tosilate, disintegrant and acidic amino acid |
| JP7058104B2 (en) * | 2017-10-19 | 2022-04-21 | 日本化薬株式会社 | Pharmaceutical tablets containing aprepitant as an active ingredient |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070249577A1 (en) * | 2005-05-10 | 2007-10-25 | Hopkins Scott J | Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4639458A (en) * | 1985-01-22 | 1987-01-27 | Merck & Co., Inc. | Tablet and formulation |
| EE04418B1 (en) * | 1998-11-10 | 2005-02-15 | Bayer Aktiengesellschaft | Pharmaceutical preparation of moxifloxacin |
| JP4370050B2 (en) * | 2000-12-04 | 2009-11-25 | 大正製薬株式会社 | Clarithromycin tablets and method for producing the same |
| ATE382338T1 (en) * | 2003-03-19 | 2008-01-15 | Jordanian Pharmaceutical Mfg | NON-HYGROSCOPIC PHARMACEUTICAL COMPOSITIONS CONTAINING NON-HYDRATED QUINOLONE CARBONIC ACID |
| JP4702763B2 (en) * | 2003-07-30 | 2011-06-15 | 塩野義製薬株式会社 | Stable tablets containing crystalline cellulose |
| CA2576589C (en) * | 2004-08-13 | 2013-11-12 | Schering-Plough Ltd. | Pharmaceutical formulation comprising an antibiotic, a triazole and a corticosteroid |
| FI20080352A0 (en) * | 2008-05-09 | 2008-05-09 | Atacama Labs Oy | Process for preparing a tablet with high drug content |
| FI20080353A0 (en) * | 2008-05-09 | 2008-05-09 | Atacama Labs Oy | Process for preparing a tablet with extra high drug content |
| JP2011068647A (en) * | 2009-08-31 | 2011-04-07 | Kowa Co | Solid formulation containing aspartic acid or salt thereof |
| WO2011059075A1 (en) * | 2009-11-13 | 2011-05-19 | 味の素株式会社 | Glutamic acid-rich and arginine-rich preparation |
-
2012
- 2012-11-29 MX MX2014006378A patent/MX350659B/en active IP Right Grant
- 2012-11-29 WO PCT/JP2012/080887 patent/WO2013081044A1/en active Application Filing
- 2012-11-29 JP JP2013547208A patent/JP6117112B2/en active Active
- 2012-11-29 MY MYPI2014701375A patent/MY169750A/en unknown
- 2012-11-29 BR BR112014012994A patent/BR112014012994A2/en not_active Application Discontinuation
- 2012-11-29 CN CN201280066321.0A patent/CN104039322A/en active Pending
- 2012-11-29 CN CN201910108608.9A patent/CN109662952A/en active Pending
- 2012-11-29 RU RU2014126094A patent/RU2633477C2/en active
- 2012-11-29 SG SG11201402597WA patent/SG11201402597WA/en unknown
-
2014
- 2014-05-29 ZA ZA2014/03942A patent/ZA201403942B/en unknown
- 2014-05-30 PH PH12014501224A patent/PH12014501224A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070249577A1 (en) * | 2005-05-10 | 2007-10-25 | Hopkins Scott J | Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures |
Non-Patent Citations (1)
| Title |
|---|
| 古一雯: "微粉硅胶在制剂工艺中的应用", 《安徽医药》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA201403942B (en) | 2015-08-26 |
| MY169750A (en) | 2019-05-15 |
| CN104039322A (en) | 2014-09-10 |
| WO2013081044A1 (en) | 2013-06-06 |
| SG11201402597WA (en) | 2014-09-26 |
| BR112014012994A2 (en) | 2017-06-13 |
| MX2014006378A (en) | 2014-10-13 |
| PH12014501224B1 (en) | 2014-09-08 |
| RU2014126094A (en) | 2016-01-27 |
| PH12014501224A1 (en) | 2014-09-08 |
| MX350659B (en) | 2017-09-13 |
| JPWO2013081044A1 (en) | 2015-04-27 |
| RU2633477C2 (en) | 2017-10-12 |
| JP6117112B2 (en) | 2017-04-19 |
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Application publication date: 20190423 |