CN1307867A - Mizoribine tablet with improved color - Google Patents
Mizoribine tablet with improved color Download PDFInfo
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- CN1307867A CN1307867A CN01102403A CN01102403A CN1307867A CN 1307867 A CN1307867 A CN 1307867A CN 01102403 A CN01102403 A CN 01102403A CN 01102403 A CN01102403 A CN 01102403A CN 1307867 A CN1307867 A CN 1307867A
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- mizoribine
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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Abstract
The present invention relates to a tablet containing mizoribin capable of improving the change of color tone in a non-packaged state and a method of improving the change of color tone. The mizoribin tablet improved with its color tone change in a non-packaged state is constituted by a core material containing the mizoribin as an active ingredient and a pharmaceutically permissible film coating base agent for covering the core material, and has a disintegrating time of less than 30 min. The method of improving the change of color tone of mizoribin tablet in a non-packaged state is that a core material containing the mizoribin as an active ingredient is covered by a pharmaceutically permissible film coating base agent, and has a disintegrating time of less than 30 min.
Description
The present invention relates to not have the improved mizoribine tablet of tone variations under the packed state and improve the method for mizoribine tablet tone.
Mizoribine [chemical name: 4-carbamyl-1-β-D-furan nuclear imidazoles-5-oleate] is the good medicament as the curative of the inhibition immunization that suppresses kidney transplantation exclusion reaction etc., lupus nephritis, chronic arthritis etc.The special fair 6-15556 communique of Japanese Patent Publication 49-12720 communique or Japan discloses the rerum natura and the manufacture method of mizoribine, and mizoribine is sold as tablet for oral use.
Commercially available tablet is the nude film of white, and this nude film has been confirmed secular storage stability in the packaged configuration that imposes PTP aluminum film, do not see special variation.
The objective of the invention is to, provide to meet from now on tablet various requirement, that contain good mizoribine that may propose medical market.
As mentioned above, commercially available tablet is identified secular storage stability, does not have the problem that should note especially in common behaviour in service.
; present inventors are in recent years in a lot of hospital facilities; to save the labour and to improve the flexibility of taking medicine etc. is purpose; when considering to utilize the tablet automatic tablet to divide the probability of subpackage of taking dose chartered plane etc., that implement tablet, capsule; for in mizoribine tablet in the past; whether bring any problem, carried out basic research.
If when dividing chartered plane to carry out a taking dose subpackage with automatic tablet, the PTP packing of considering to remove tablet waits has to place packless state, and then can cause also that according to occasion not allowing to be kept at for a long time automatic tablet divides situation in the chartered plane.About in the past mizoribine tablet, even be suitable for the occasion of such situation, whether research problem does not take place yet at this.
Its result, present inventors newly obtain can making the result of study of tablet variable color under the preservation of so no packed state.That is, obtain following opinion: set automatic tablet divides when preserving 4 time-of-weeks in the chartered plane under no packed state under near the environmental condition of the relative humidity of mizoribine tablet in the past 25 ℃ of temperature, humidity 50%, the tablet variable color.
Deposit about the automatic tablet subpackage organizational security under so no packed state, make the research of the reason of tablet variable color, present inventors are initial to consider that automatic tablet divides the influence of the box of chartered plane with resinous principle, carry out the contact test of resinous principle and mizoribine tablet in the past, but obtain may not influential conclusion.And then with the identical condition of external environment condition that above-mentioned automatic tablet divides chartered plane is set, promptly in the stability test near the constant temperature and humidity machine of the relative humidity temperature 25%, humidity 50%, do not see mizoribine tablet variable color in the past yet.Automatic tablet divides chartered plane, in order to keep the quality of tablet, consider lucifuge and damp proof etc. general rotten reason, although be under the same conditions, in automatic tablet divides chartered plane inside and outside, the former variable color, the non-discoloring result of the latter, therefore, the variable color of inferring the tablet in automatic tablet divides chartered plane has the rotten reason beyond the temperature, humidity, light of common consideration etc.
Repeat repeatedly to test, present inventors have been found that this variable color reason, and nitrogen oxide plays an important role, and is particularly special to mizoribine.
Present inventors are in order to solve such problem, have carried out in automatic tablet divides chartered plane and the experiment of the preservation in the nitrogen oxide atmosphere, have carried out preventing at no packed state the research with keen determination of tablet that should obtain containing mizoribine of variable color.Its result, the base lining nude film in the past of filming by allowing with pharmacy then can prevent variable color, thereby finish the present invention.
That is, the present invention constitutes by containing the base of filming of allowing as the pharmacy of the core body of the mizoribine of effective ingredient and this core body of lining, and disintegration time is to have improved the mizoribine tablet of tone variations under the no packed state in 30 minutes.
Mizoribine tablet of the present invention, for example for the tone variations of the core surface of the front and back of this tablet being placed 4 weeks under the atmosphere of the nitrogen oxide of about 20ppb, preferably the Δ E of the mensuration of colour difference meter is in 3.And then for the tone variations of core surface of this tablet being placed 1 hour front and back under the atmosphere of the nitrogen oxide of about 25ppm, preferably the Δ E of the mensuration of colour difference meter is in 3.
In addition, the present invention contains the base of filming that the lining pharmacy is allowed on as the core body of the mizoribine of effective ingredient disintegration time to be made the method for not having the mizoribine tablet tone variations of packed state in 30 minutes with interior improvement.
Below, explain the present invention.
The used mizoribine of the present invention [chemical name: 4-carbamyl-1-β-D-furan nuclear imidazoles-5-oleate] is the good curative of the inhibition immunization, lupus nephritis, chronic arthritis as the rejection that suppresses renal transplantation etc. etc.Its manufacture method is as above-mentioned known, can be monohydrate also as mizoribine, but particularly preferably be anhydride.As anhydride, open at the special fair 6-15556 communique of Japan, known have A type anhydride and a Type B anhydride, but any one can, particularly preferably be the Type B anhydride.In addition, except above-mentioned document, " the outer pharmaceuticals specification 1997 of Pharmacopeia of Japan " elta Force Xtreme has also been put down in writing the anhydride of mizoribine.
The core body that contains mizoribine used in the present invention, as long as contain as the mizoribine of effective ingredient just passable, have no particular limits for its formation, but except the independent occasion of mizoribine, also the carrier modulation that can allow by mizoribine and pharmacy.The carrier of allowing as this pharmacy, only otherwise work mutually with mizoribine at any time, be not particularly limited, for example, as preferred example, Lactis Anhydrous, mannitol, anhydrous calcium phosphate, carboxymethylcellulose calcium, crystalline cellulose, magnesium stearate etc. can be enumerated,, the combination of Lactis Anhydrous, carboxymethylcellulose calcium, crystalline cellulose, magnesium stearate can be enumerated as more preferred example.Usually, can enumerate the carrier that mizoribine and pharmacy are allowed and mix, the common nude film of tabletting or preparation such as tabletting after the surface of the big nuclear of particle diameter is coated with full mizoribine after direct compression or the suitable pelletize.The nuclear that above-mentioned particle diameter is big also can contain the carrier that one or more pharmacy are allowed, for example (for example can enumerate crystalline cellulose, Asahi Chemical Industry Co., Ltd's system, trade name, Sai Erfei), spheroidal particle (for example, Fu Luoyin industry system, trade name, Nuo Paer).As comminution granulation, also can be wet granulation, but preferably use dry pelletizing method usually.Commercially available in the past mizoribine tablet is the typical example of this nude film, utilizes it, and is easy, is ideal.
To different indications, symptom, patient, though can change the mizoribine of the effective ingredient that is present in this core body, normally 1～100mg, 25～50mg preferably.
Shape for core body has no particular limits, but for example can enumerate cylinder, polygon prism or spherical.In the bottom surface of cylinder, preferably has curvature surface.In addition, the thickness of cylinder etc., with less than the diameter of its bottom surface or situation on one side for well.
The size of this core body if consider the convenience take, for example, with the greatest length in the solid of the maximum gauge of bottom surface and thickness or tablet, is preferably done into about 5～11mm.In addition, general, as the maximum gauge of the bottom surface of tablet can enumerate about 5～10mm, the about 1.5～4.5mm of thickness, the about 50～400mg of weight, preferably maximum gauge can be enumerated about 6～8.5mm, the about 2～4mm of thickness, the about 100～250mg of weight.
In addition, the base of filming that the present invention's pharmacy used, the lining core body is allowed, in the exploitation of the pharmaceuticals of wide river bookstore distribution, the 12nd volume, preparation material I, the 2nd chapter, 2.1.5 Liniment item, example is arranged, pharmacy is allowed, refer to polymer substance cellulose-based or synthetic high polymer system, be to be used to be covered tablet or particulate main material, do not comprise the saccharide of white sugar as the employed sugar-coat base of sugar-coat, lactose, mannose etc.As above-mentioned polymer substance, can enumerate molecular weight and be more than 500, preferably more than 1000, particularly preferably be more than 10,000.
As this base of filming, for example (for example can enumerate hydroxypropyl emthylcellulose, SHIN-ETSU HANTOTAI's chemistry system, trade name, TC-5 molecular weight: about 13000～68000), methylcellulose (for example, SHIN-ETSU HANTOTAI's chemistry system, trade name, Mo Lezi SM), ethyl cellulose (for example, Dow Chemical system, trade name, ethyl cellulose molecular weight: about 77180), the ethyl cellulose aqueous dispersions (for example, Asahi Chemical Industry's industry system, trade name, the A Ku Aunar), hydroxypropyl cellulose (for example, Japanese Cao Da system, trade name, HPC), the hydroxypropyl emthylcellulose phthalic acid ester, the hydroxypropyl methyl cellulose acetate succinate, carboxymethylethylcellulose, acetic acid phthalic acid cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, aminoalkyl methacrylate co-polymer, methacrylic acid copolymer, CVP Carbopol ETD2050, polyvinyl acetal diethylamine acetas etc., particularly preferably be hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, hydroxypropyl cellulose.Select one or two or more kinds from these bases of filming.
In addition, in order to reach the rerum natura or the purpose of the base of filming that is used for above-mentioned lining, can add other material, for example can suit to select Marko Luo Er 4 as plasticizer, dispersant, coloring agent, 000 (for example, Japan Cao Da system, trade name, day Cao's Polyethylene Glycol #4,000), Marko Luo Er 6,000, the pharmacy of fatty acid glyceride, sucrose fatty acid ester, triethyl citrate, titanium oxide, Talcum, stearic acid, tar colorant, three ferrous oxides etc. the carrier of allowing can use the material that is covered with the above-mentioned base combination of filming.
The base of filming of allowing with pharmacy is overlayed on the method that contains as the core body of the mizoribine of above-mentioned effective ingredient, can enumerate the solution that will disperse, dissolve the base of filming with known method such as sprayings as preferred example and be overlayed on method on the above-mentioned core body.At this moment, the general coating device that has spray pistol, band chassis and pressure fan etc. that preferably uses for example, as preferred example, can be enumerated Pa Laike system coating device (trade name: moral Li Akeda).
According to used solvent or quantity for spray and difference, but the base of filming of preferably in wind pushing temperature is 60～90 ℃ scope pharmacy being allowed is overlayed on the nude film.
Be used to disperse, dissolve the solvent of the base of filming,, can enumerate water, ethanol, acetone, vinyl chloride etc., preferably can enumerate water, ethanol, acetone etc. so long as the solvent that pharmacy is allowed gets final product.Disperse, the solution concentration behind the base of filming of dissolving lining core body, change according to the characteristic of core body or device, but general, the base of filming is 1～20 (w/v%), can enumerate 5～10% as preferred example usually.In addition, contain the method for the core body of mizoribine as the base lining of filming of allowing with pharmacy, also can according to circumstances adopt the base of will filming be coated with full on this core body the method for tabletting.
The base of filming that above-mentioned pharmacy of the present invention is allowed, for the weight that contains as the core body of the mizoribine of effective ingredient, the gross weight of the base of filming of wishing lining is covered 1～20%, in the preferred scope 2～10%.
When lining contains the core body of mizoribine, only be to use the occasion of the carrier that simple pharmacy allows, may not necessarily reach effect of the present invention.
Contain in lining when the core body of mizoribine, under the situation that the carrier that only adopts pharmacy to allow is covered, may not recognize effect of the present invention.
At first, shown in comparative example 2, with dissolving, disperseed the lining aqueous suspension of sucrose, acacia gum, gelatin, deposition calcium carbonate to be overlayed on mizoribine tablet (nude film) to go up and make tablet, when confirming to have or not variable color, see the core body variable color.This result shows that as coating method or lining material sugar-coat is not ideal.
On the other hand, shown in embodiment 2, with coating machine (Pa Laike system, moral Li Akeda DRC-300) hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI chemistry system, bright, the TC-5 of commodity) 8g is dissolved among moisture 50% the ethanol 200ml, disperseed the liquid of titanium oxide 2g to go up lining 5mg therein, be modulated into the lining tablet of 1 215mg at mizoribine tablet (nude film).The lining tablet of the base of filming that this pharmacy is allowed when using the tone variations of estimating no packed state of the present invention, can be seen having on tone variations well and improve.
About the disintegrative of tablet of the present invention, the available slaking test method that corrects Japanese doctor office side ordinary test method for the 13rd time is implemented.That is, water is used for experimental liquid, for nude film, as long as disintegration time just was fit in 30 minutes, for the tablet of suitable Liniment as the agent skin, need only disintegration time at 60 minutes with interior just up to specification.Mizoribine tablet of the present invention, the disintegration time of above-mentioned slaking test method 60 minutes with interior, preferably 30 minutes with interior, particularly preferably be in 15 minutes.
The biological intravital dissolving of mizoribine tablet of the present invention after considering to take, when absorbing, the dissolution test method (the 2nd method) that corrects Pharmacopeia of Japan ordinary test method with the 13rd time makes water in experimental liquid, the revolution of blade, when testing with No. 50 revolutions, preferred dissolving eduction rate after 45 minutes is more than 80%, and more preferably 30 minutes dissolving eduction rate is more than 80%.
Like this, under no packed state of the present invention, can be modulated into the mizoribine tablet that improves tone variations.Mizoribine tablet of the present invention is preserved under no packed state in the chartered plane even divide at the automatic tablet of hospital etc., and tone does not also change, and the good preparation of storage stability than in the past nude film can be provided.
For the tone variations of the mizoribine tablet of no packed state of the present invention, whether be fit to the present invention in order to estimate, use following evaluation methodology.In addition, according to circumstances also can measure amount of nitrogen oxides aptly, for example,, estimate the tone variations of the front and back of preserving for 4 weeks as the atmosphere of nitrogen oxide work into about 20ppb.The evaluation of tone variations
In covering the 10ml band plug developmental tube of silica gel plug, at room temperature, make saturated sodium nitrite in aqueous solution 20 μ l and sulphuric acid 100 μ l reaction generate nitrogen oxide.Nitrogen oxide with needle tubing takes 5ml to generate slowly is injected into the 100ml conical flask of putting into mizoribine tablet band silica gel plug in advance, places 1 hour.In the method, usually as the atmosphere of nitrogen oxide work into about 25ppm.
Aberration is to use colour difference meter (CLR-7100F; Shimadzu Seisakusho Ltd.), the L (brightness) by the sample before and after the test of preserving under the above-mentioned preservation condition and a, b's (form and aspect chroma) is poor, obtains aberration (Δ E) with following (formula 1).About the judgement of the tone variations of tablet surface, with the aberration NBS unit of table 1 as a reference, establishing indeclinable standard Δ E is below 3.In addition, the tablet surface in the judgement of tone variations is meant core surface, and lining mizoribine tablet is applicable to the core surface of removing the lining carrier.
(formula 1)
Table 1 aberration NBS (State Standard Bureau) unit
| The fabric item | The performance of sensation | NBS unit (Δ E) |
| Faintly smallly feel obviously greatly very big | The very big aberration of aberration that the tangible aberration of the realizable aberration of the aberration that faint aberration is small is big | 0～0.5 0.5～1.5 1.5～3.0 3.0～6.0 6.0～more than 12.0 12.0 |
Then, enumerate reference example, embodiment, comparative example, experimental example, and then explain the present invention, but the present invention is not subjected to any restriction of these embodiment.
Reference example
To be suspended among the dehydrated alcohol 50ml with the refining mizoribine hydrate crystallization 5.0g that the comparative example 1 of Japan special fair 6-15556 communique is made in the same manner, in the boiling water-bath, refluxed 60 minutes while stirring.Then, cooling is 60 minutes in frozen water, and the crystallization of separating out 40 ℃, one night of vacuum drying, is obtained mizoribine anhydride crystallization 4.61g (water quantities is 0.11%).
Comparative example 1
To mix with mizoribine anhydride 350g, Lactis Anhydrous (DMV system, trade name, Lactis Anhydrous) 882g, crystalline cellulose (Asahi Chemical Industry's industry system, trade name, A Bisaier PH101) 140g, carboxymethylcellulose calcium (five moral medicine systems, trade name, ECG-505) 70g and magnesium stearate (peaceful chemical system, trade name, the magnesium stearate) 14g that reference example is made in the same manner with V-Mixer; use Drygranulatemachine (the Fu Luoyin special product already produces, roll shape compacting TF-MINI); after the dry type pelletize, use the pelletizing machine fragmentation.Add magnesium stearate 14g and mix in this pelletize powder body, the circular pestle tabletting with diameter 8.5mm obtains 1 tablet of tablet (nude film) (thick about 3mm) that contains the 210mg of 50mg mizoribine.The average disintegration time of the tablet that obtains is 5 minutes.In addition, disintegration time corrects Pharmacopeia of Japan ordinary test method with the 13rd time, water is used for experimental liquid implements, with the average disintegration time of 6 samples as average disintegration time.
Embodiment 1
With coating machine (handkerchief is restrained, moral Li Akeda DRC-300) in moisture 50% ethanol 200ml, dissolving hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI's chemistry system, trade name, TC-5) 8g, the dispersion liquid that disperses titanium oxide 2g is more therein overlayed on uses the mizoribine tablet (nude film) of the method preparation identical with comparative example 1 to go up 5mg (for nude film weight, contain 1.9% base of filming), obtain the lining tablet of 1 215mg.The average disintegration time of the tablet that obtains is 6.5 minutes (the about 3mm of thickness).
Embodiment 2
With coating machine (handkerchief is restrained, moral Li Akeda DRC-300) in moisture 50% ethanol 400ml, dissolving hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI's chemistry system, trade name, TC-5) 16g, the dispersion liquid that disperses titanium oxide 4g is more therein overlayed on uses the method synthetic mizoribine tablet (nude film) identical with comparative example 1 to go up 10mg (for nude film weight, contain 3.8% base of filming), obtain the lining tablet of 1 220mg.The average disintegration time of the tablet that obtains is 15 minutes.
Embodiment 3
With coating machine (handkerchief is restrained, moral Li Akeda DRC-300) in moisture 70% ethanol 400ml, dissolving hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI's chemistry system, trade name, TC-5) 14g/ ethyl cellulose (Dow Chemical system, trade name Etta Sai Er) 2g, the dispersion liquid that disperses titanium oxide 4g is more therein overlayed on uses method synthetic mizoribine tablet (nude film) 5mg identical with comparative example 1 (for nude film weight, contain 1.9% base of filming), obtain the lining tablet of 1 215mg.The average disintegration time of the tablet that obtains is 6.6 minutes.
Embodiment 4
With coating machine (handkerchief is restrained, moral Li Akeda DRC-300) in moisture 10% ethanol 200ml, dissolving hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI's chemistry system, trade name, TC-5) 5.4g and triethyl citrate 0.6g, the dispersion liquid that disperses ethylcellulose dispersion (Asahi Chemical Industry's industry, trade name, A Ku Aunar) 0.8g, Talcum 2.4g, titanium oxide 0.8g is more therein overlayed on uses the method synthetic mizoribine tablet (nude film) identical with comparative example 1 to go up 4mg (for nude film weight, contain 1.1% base of filming), obtain the lining tablet of 1 214mg.The average disintegration time of the tablet that obtains is 5 minutes.
Experimental example 1
Make saturated sodium nitrite in aqueous solution 20 μ l and sulphuric acid 100 μ l, at room temperature reaction generates nitrogen oxide in being stamped the 10ml test tube with ground stopper of silica gel plug.With the nitrogen oxide that needle tubing takes 5ml to generate, slowly be injected into the 100ml conical flask mizoribine tablet, the band silica gel plug of putting into comparative example 1 and embodiment 1～4 in advance, placed 1 hour, carry out discoloration test.The aberration (Δ E) that carries out the discoloration test front and back is to use colour difference meter (CLR-7100F; Shimadzu Seisakusho Ltd.), the difference of the L (brightness) by sample and a, b (form and aspect chroma) is obtained.
Its result is as shown in table 2.
In addition, use inert gas tube (bavin field instruments for scientific research Industrial Co., Ltd system), captured the interior nitrogen oxide of above-mentioned conical flask 1 hour, when measuring nitrous oxides concentration with the graceful method of bundle Wurz, nitrous oxides concentration is about 25ppm.
The operational approach of the graceful method of bundle Wurz of mensuration nitrous oxides concentration is as follows.Water breaks away from the nitrogen oxide that has captured, and its aqueous solution 1ml and water 4ml are mixed, and adds after sulfonamide solution 0.5ml mixes, and places 15 minutes in room temperature.After then adding naphthodiamide solution 0.5ml mixing, after room temperature is placed 30 minutes, with water in contrast, measure the absorbance of 550nm.
Table 2
| ????L | ????a | ????b | ????ΔE | ||
| Comparative example 1 | Before the discoloration test | ??97.29 | ??0.19 | ????1.90 | ????- |
| After the discoloration test | ??92.98 | ??-6.09 | ????33.79 | ????32.8 | |
| Embodiment 1 | Before the discoloration test | ??96.79 | ??0.05 | ????1.70 | ????- |
| After the discoloration test | ??96.08 | ??-0.12 | ????2.25 | ????0.9 | |
| Embodiment 2 | Before the discoloration test | ??96.79 | ??0.03 | ????1.62 | ????- |
| After the discoloration test | ??96.14 | ??-0.06 | ????1.82 | ????0.7 | |
| Embodiment 3 | Before the discoloration test | ??95.98 | ??0.04 | ????1.87 | ????- |
| After the discoloration test | ??95.63 | ??-0.05 | ????2.09 | ????0.4 | |
| Embodiment 4 | Before the discoloration test | ??95.85 | ??-0.04 | ????2.17 | ????- |
| After the discoloration test | ??95.25 | ??-0.05 | ????2.19 | ????0.6 |
Result as table 2 shows, because the significant tone variations of nitrogen oxide display abnormality, the tablet of embodiment 1～4 is 3 almost not see tone variations (variable color) when following at Δ E for the mizoribine tablet in the past of comparative example 1.Thus, the lining tablet of affirmation embodiment 1～4 has the effect that prevents variable color in the nitrogen oxide atmosphere of about 25ppm.
Experimental example 2
The mizoribine tablet that comparative example 1 and embodiment 1～4 obtain was preserved for 4 weeks in the thermostat of 30 ℃ of temperature, humidity 75% relative humidity.Use colour difference meter (CLR-7100F; Shimadzu Seisakusho Ltd.), obtain the aberration (Δ E) of preserving front and back by the L (brightness) of sample and the difference of a, b (form and aspect chroma).
Its result is as shown in table 3.
Table 3
| ????L | ????a | ????b | ????ΔE | ||
| Comparative example 1 | Before the discoloration test | ??96.55 | ????0.08 | ????2.20 | ??- |
| After the discoloration test | ??95.81 | ????-3.66 | ????14.34 | ??12.73 | |
| Embodiment 1 | Before the discoloration test | ??96.23 | ????0.32 | ????2.45 | ??- |
| After the discoloration test | ??96.13 | ????0.16 | ????2.66 | ??0.3 | |
| Embodiment 2 | Before the discoloration test | ??96.09 | ????0.18 | ????2.40 | ??- |
| After the discoloration test | ??96.94 | ????0.01 | ????2.50 | ??0.2 | |
| Embodiment 3 | Before the discoloration test | ??96.55 | ????-0.08 | ????2.69 | ??- |
| After the discoloration test | ??96.39 | ????-0.17 | ????2.69 | ??0.2 | |
| Embodiment 4 | Before the discoloration test | ??96.31 | ????0.06 | ????2.29 | ??- |
| After the discoloration test | ??96.13 | ????-0.24 | ????2.92 | ??0.7 |
From then on the result shows, for the mizoribine tablet in the past of comparative example 1, under the stringent condition of 30 ℃ of temperature, humidity 75% relative humidity, preserved for 4 weeks, having shown tone variations, and the tablet of embodiment 1～4, is 3 almost not see tone variations (variable color) when following at Δ E.Thus, confirm the mizoribine tablet of the present invention of the lining of embodiment 1～4,, also confirm to have the effect of the variable color of preventing even under the condition of the variable color of nude film in the past in 4 weeks of preservation of 30 ℃ of temperature, humidity 75% relative humidity.
Experimental example 3
The tablet of comparative example 1 and embodiment 1 was preserved for 4 weeks in the Constant Temperature and Humidity Chambers of 25 ℃ of temperature, humidity 50% relative humidity.Use colour difference meter (CLR-7100F; Shimadzu Seisakusho Ltd.), obtain the aberration (Δ E) of preserving front and back by the L (lightness) of sample and the difference of a, b (form and aspect chroma).
Its result is as shown in table 4.
Table 4
| ????L | ????a | ????b | ???ΔE | ||
| Comparative example 1 | Before the discoloration test | ??96.53 | ??0.09 | ????2.05 | ???- |
| After the discoloration test | ??96.31 | ??0.03 | ????2.08 | ???0.28 | |
| Embodiment 1 | Before the discoloration test | ??96.48 | ??-0.21 | ????3.03 | ???- |
| After the discoloration test | ??96.36 | ??-0.17 | ????3.05 | ???0.13 |
When the lining mizoribine tablet of the mizoribine tablet in the past of comparative example 1 and embodiment 1 was preserved for 4 weeks in the Constant Temperature and Humidity Chambers of 25 ℃ of temperature, humidity 50% relative humidity, do not see tone variations.
Experimental example 4
The automatic tablet of tablet under the environmental condition of the relative humidity that places 25 ℃ of temperature, humidity about 50% of comparative example 1 and embodiment 1 divided under the state of rotating device in the chartered plane and preserved for 4 weeks.Use colour difference meter (CLR-7100F; Shimadzu Seisakusho Ltd.), obtain the aberration (Δ E) of preserving front and back by the L (brightness) of sample and the difference of a, b (form and aspect chroma).
Its result is as shown in table 5.
In addition, automatic tablet at this moment divides in the chartered plane and each outside 2 place are provided with inert gas tube, and trapping nitrogen oxides 24 hours is measured nitrous oxides concentration with pricking the graceful method of Wurz.This result is illustrated in the table 6.
Table 5
| ????L | ????a | ????b | ????ΔE | ||
| Comparative example 1 | Before the discoloration test | ??97.12 | ??0.15 | ????1.73 | ??- |
| After the discoloration test | ??96.19 | ??-4.22 | ????14.89 | ??13.90 | |
| Embodiment 1 | Before the discoloration test | ??96.48 | ??-0.21 | ????3.03 | ??- |
| After the discoloration test | ??96.36 | ??-0.17 | ????3.05 | ??0.13 |
Table 6
| The place is set | Sequence number | Nitrous oxides concentration (ppb) |
| Automatic tablet dividing and packaging machine inside | ????1 | ????19.7 |
| ????2 | ????12.8 | |
| The automatic tablet dividing and packaging machine outside | ????1 | ????2.9 |
| ????2 | ????3.3 |
When the mizoribine tablet in the past of experimental example 3 was preserved for 4 weeks in 25 ℃ of temperature, humidity 50%, do not see tone variations.In contrast, in experimental example 4, automatic tablet under the relative humidity that places 25 ℃ of temperature as identical condition, humidity about 50% divides when preserving for 4 weeks in the chartered plane, seen the tone variations of the mizoribine tablet in the past of comparative example 1, but, do not see tone variations for the mizoribine tablet of embodiments of the invention 1.This can think and shows as table 6 result, owing to the nitrous oxides concentration height of any reason in the inside of device, thus, thinks for the mizoribine tablet of preserving in automatic tablet divides chartered plane in the past, has caused tone variations.
From experimental example 3,4 and table 6,, do not see the tone variations of mizoribine tablet of the present invention even under the atmosphere of the nitrogen oxide of about 20ppb, preserved for 4 weeks yet.
Comparative example 2
With sugar-coat dish (chrysanthemum water make made, NO160-S) with sucrose 850g, gelatin 5g, acacia gum 20g, deposition calcium carbonate 1000g, heat, disperse, be dissolved in the solution 180mg in the Purified Water of 450g, overlayed on and used on the synthetic mizoribine tablet of method (nude film) identical, obtained the tablet that is covered with comparative example 1.
After modulating above-mentioned lining tablet, when preserving for 4 weeks under the condition of 25 ℃ of temperature, humidity 50%, showing the tone of the core surface of the tablet that is covered, before and after lining, can see big tone variations, is not ideal as the coating method sugar-coat.This result is as shown in table 7.
Table 7
Experimental example 5
| ????L | ????a | ????b | ????ΔE | ||
| Comparative example 2 | Before the lining | ??96.53 | ????0.09 | ????2.05 | ????- |
| After the lining | ??96.48 | ????-2.38 | ????8.80 | ????7.19 |
The tablet that will be obtained by comparative example 1 and embodiment 2 is with the dissolution test method (the 2nd method) that corrects Pharmacopeia of Japan ordinary test method for the 13rd time, in experimental liquid, make water, the revolution of blade: change to dissolve with 50 and separate out test (the dissolving eduction rate is 6 a meansigma methods).
Its result, the dissolving eduction rate of the tablet of comparative example 1 was to be to be 98% after 93%, 45 minute after 62%, 30 minute after 15 minutes, the dissolving eduction rate of the tablet of embodiment 2 was to be to be 98% after 94%, 45 minute after 66%, 30 minute after 15 minutes.
The tablet of comparative example 1 and embodiment 2 has shown that identical dissolving separates out distribution, shows the dissolving eduction rate of about 90% (being more than 80% at least) after 30 minutes, is rapidly-soluble tablet.
Utilizability on the industry
According to the present invention, can provide without the mizoribine tablet that has significantly improved tone variations under the packed state.
Claims (10)
1. mizoribine tablet that tone variations has improved under no packed state, it is characterized in that, by containing core body that mizoribine as effective ingredient is 4-carbamyl-1-β-D-furan nuclear imidazoles-5-oleate and, disintegration time that base constitutes in 30 minutes filming of allowing of the pharmacy of this core body lining.
2. the described tablet of claim 1, wherein, as the tone variations of this tablet being placed the core surface before and after 4 weeks under the atmosphere of the nitrogen oxide of about 20ppb, the Δ E that measures with colour difference meter is in 3.
3. claim 1 or 2 described tablets wherein, are placed the tone variations of the core surface before and after 1 hour as this tablet under the atmosphere of the nitrogen oxide of about 25ppm, be in 3 with the Δ E of the mensuration of colour difference meter.
4. any 1 described tablet in the claim 1～3, wherein, the pharmacy base of filming of allowing of lining core body is from hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, the ethyl cellulose aqueous dispersions, hydroxypropyl cellulose, the hydroxypropyl emthylcellulose phthalic acid ester, hydroxypropyl methyl cellulose acetate, carboxymethylethylcellulose, acetic acid phthalic acid cellulose, hydroxyethyl-cellulose, methyl hydroxyl ethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, the aminoalkyl methacrylate copolymer, methacrylic acid copolymer, select more than a kind or 2 kinds among the group that carboxy vinyl copolymer and polyvinyl acetal lignocaine acetas are formed.
5. any 1 described tablet in the claim 1～5, wherein, in the core body as the mizoribine that contains effective ingredient, its greatest length is 5～11mm, for the weight of core body, the gross weight of the pharmacy base of filming of allowing of lining is 1～20%, and the dissolving eduction rate behind 45 minutes of the tablet of lining is more than 80%.
6. the method for the tone variations of improving the mizoribine tablet under no packed state, it is characterized in that, the base lining of filming of allowing with pharmacy is as the core body that contains the mizoribine of effective ingredient, makes disintegration time and be 30 minutes with interior mizoribine tablet.
7. the described method of improving tone variations of claim 6, wherein, as the tone variations of the mizoribine tablet being placed the core surface before and after 4 weeks under the atmosphere of the nitrogen oxide of about 20ppb, the aberration Δ E that measures with colour difference meter is below 3.
8. the described method of improving tone variations of claim 7, wherein, as the tone variations of the mizoribine tablet being placed the core surface before and after 1 hour under the atmosphere of the nitrogen oxide of about 25ppm, the aberration Δ E that measures with colour difference meter is below 3.
9. any 1 described method of improving tone variations in the claim 6～8, wherein, the base of filming of allowing as the pharmacy of lining core body is from hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, the ethyl cellulose aqueous dispersions, hydroxypropyl cellulose, the hydroxypropyl emthylcellulose phthalic acid ester, hydroxypropyl methyl cellulose acetate, carboxymethylethylcellulose, acetic acid phthalic acid cellulose, hydroxyethyl-cellulose, methyl hydroxyl ethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, the aminoalkyl methacrylate copolymer, methacrylic acid copolymer, select more than a kind or 2 kinds among the group that carboxy vinyl copolymer and polyvinyl acetal lignocaine acetas are formed.
10. any 1 described method of improving tone variations in the claim 6～9, wherein, contain in the core body as the mizoribine of effective ingredient, its greatest length is 5～11mm, for the weight of core body, the gross weight of the pharmacy base of filming of allowing of lining is 1～20%, and the dissolving eduction rate behind 45 minutes of the tablet of lining is more than 80%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP016527/2000 | 2000-01-26 | ||
| JP2000016527 | 2000-01-26 |
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| Publication Number | Publication Date |
|---|---|
| CN1307867A true CN1307867A (en) | 2001-08-15 |
| CN1178652C CN1178652C (en) | 2004-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011024038A Expired - Fee Related CN1178652C (en) | 2000-01-26 | 2001-01-22 | Mizoribine tablet with improved color |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP5350436B2 (en) |
| KR (1) | KR100446079B1 (en) |
| CN (1) | CN1178652C (en) |
| HK (1) | HK1038877A1 (en) |
| TW (1) | TWI275394B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101320016B1 (en) * | 2005-12-14 | 2013-10-29 | 주식회사 대웅 | Combination containing stabilized coenzyme q10, multivitamins and minerals |
| CN100414293C (en) * | 2006-01-16 | 2008-08-27 | 复旦大学附属华山医院 | Method for determining blood drug level of mizoribine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57156418A (en) * | 1981-03-19 | 1982-09-27 | Sumitomo Chem Co Ltd | Carcinostatic |
| JPH0615556B2 (en) * | 1989-11-10 | 1994-03-02 | 旭化成工業株式会社 | 4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate anhydrous crystal |
| ID21762A (en) * | 1996-09-24 | 1999-07-22 | Lilly Co Eli | FORMULATED PARTICLE FORMULATION |
| JP4046475B2 (en) * | 2000-01-26 | 2008-02-13 | 旭化成ファーマ株式会社 | Mizoribine tablets with improved color change |
| JP4818994B2 (en) * | 2000-01-26 | 2011-11-16 | 旭化成ファーマ株式会社 | Mizoribine tablets with improved color change |
-
2001
- 2001-01-20 TW TW090101525A patent/TWI275394B/en not_active IP Right Cessation
- 2001-01-22 KR KR10-2001-0003543A patent/KR100446079B1/en active IP Right Grant
- 2001-01-22 CN CNB011024038A patent/CN1178652C/en not_active Expired - Fee Related
- 2001-12-15 HK HK01108821A patent/HK1038877A1/en not_active IP Right Cessation
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| Publication number | Publication date |
|---|---|
| JP5350436B2 (en) | 2013-11-27 |
| JP2011190282A (en) | 2011-09-29 |
| TWI275394B (en) | 2007-03-11 |
| KR100446079B1 (en) | 2004-08-30 |
| KR20010078049A (en) | 2001-08-20 |
| CN1178652C (en) | 2004-12-08 |
| HK1038877A1 (en) | 2002-04-04 |
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