CN102895212B - Dry coated tablet containing ftorafur, gimeracil, Oteracil Potassium - Google Patents
Dry coated tablet containing ftorafur, gimeracil, Oteracil Potassium Download PDFInfo
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- CN102895212B CN102895212B CN201210260323.5A CN201210260323A CN102895212B CN 102895212 B CN102895212 B CN 102895212B CN 201210260323 A CN201210260323 A CN 201210260323A CN 102895212 B CN102895212 B CN 102895212B
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Abstract
The invention provides a kind of dry coated tablet, it is made up of kernel and shell, and this kernel contains (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium as effective ingredient.
Description
Technical field
The for oral use dry coated tablet of the present invention's one containing ftorafur (Tegafur), gimeracil (Gimeracil) and Oteracil Potassium (Oteracil potassium).
Background technology
Ftorafur, gimeracil and Oteracil Potassium compounding ingredient are a kind of antitumor agent, it is characterized in that: by coordinating the gimeracil as the decomposing inhibitor of 5-FU and the Oteracil Potassium as phosphorylation inhibitor in the ftorafur of the prodrug as fluorouracil (5-FU), can antitumous effect be improved and alleviate Alimentary toxicity, as tumor chemical therapy medicine that can be oral, extensive use clinically (patent documentation 1).
Now, ftorafur, gimeracil and Oteracil Potassium compounding ingredient, with ftorafur: gimeracil: the mol ratio of Oteracil Potassium is the content of 1:0.4:1, there is capsule so that the title of " TS-1 capsule-containing " is commercially available, and have granule (patent documentation 2) so that the title of " TS-1 coordinates granule " is commercially available.But, capsule or granule sometimes for function of deglutition reduce old people for be difficult to swallow, seeking a kind of Orally disintegrating tablet, even this disintegrating tablet clinically dysphagia person also can easily take, rapid disintegrate in oral cavity.
On the other hand, generally speaking, the active component of many display antitumous effects is more classified as dangerous drug, and then pharmacologically active is higher, and ftorafur is also one of them, gives one's full attention to its action need.The active component of anticarcinogen be the state exposed or because of the breaking of preparation, defect and the state of dispersing time, not only medical personnel but also the patient taken or the care-giver that takes medicine also likely are subject to the impact of drug exposure.Usually, in order to reduce drug exposure.Can to use in the capsule medicament being enclosed and is made up of gelatin etc. or medicament to be made tablet and by coated etc. the method such as sugar, macromolecule.But, because these methods make the disintegrate of preparation postpone, therefore, cannot expect in intraoral rapid disintegrate.
In addition, in order to improve the disintegrative of Orally disintegrating tablet, become the preparation that its corresponding intensity is low more.Now, manufacture cannot be tolerated, the process of circulation maybe cannot tolerate utilization usually makes medicament fall from the height of about 1m and making up a prescription of carrying out its automatic subpackage machine carrying out subpackage, in the formulation produce break, defect, worry to increase the medicament exposure hazard of medical personnel etc.
For the preparation being combined with ftorafur, gimeracil and Oteracil Potassium.Even if such as disclose a kind of also stable and ftorafur, gimeracil and Oteracil Potassium of can be oral coordinate preparation under humidified condition in patent documentation 3.But this cooperation preparation as the stability of preparation as object, does not consider the taking of the patient of dysphagia etc. using raising.In addition, in order to improve the functions such as the disintegrative of tablet, and also use with stable saccharide and add the destabilization that disintegrating agent etc. can cause effective ingredient.In addition, Patent Document 4 discloses the intraoral disintegration tablet being combined with ftorafur, gimeracil and Oteracil Potassium.But, for this patent, although this medicine is highly active anticarcinogen, not for the countermeasure that the pharmacy of medical personnel, care-giver etc. exposes.
Prior art document
Patent documentation
Patent documentation 1: Japan Patent No. 2614164 publications
Patent documentation 2: International Publication 2009/084216 pamphlet
Patent documentation 3: Japanese Unexamined Patent Publication 2010-235539 publication,
Patent documentation 4: the open CN1660105A publication of Chinese patent
Summary of the invention
Invent problem to be solved
As mentioned above, coordinate preparation to ftorafur known up to now, gimeracil and Oteracil Potassium, it is dangerous and having sufficient tablet strength, also can not cause the preparation of drug compliance reduction when taking to it is desirable to obtain a kind of abundant reduction drug exposure.
The object of the present invention is to provide a kind of achieve drug exposure danger reduction, rapidly disintegrative and the dry coated tablet being combined with ftorafur, gimeracil and Oteracil Potassium of tablet strength fully.Specifically, the object of the present invention is to provide a kind of dry coated tablet, it is that formability is good and the combination of the shell that disintegrative is good and the kernel containing effective ingredient, has sufficient mechanical strength, even if reduce the danger of drug exposure and also disintegrate rapidly in oral cavity.
For solving the method for problem
The present inventor in order to solve above-mentioned problem, attempted manufacture various can be oral the tablet being combined with ftorafur, gimeracil and Oteracil Potassium.
Its result, and the dry coated tablet of housing combination that disintegrative good good by the kernel made containing ftorafur, gimeracil and Oteracil Potassium and the formability be made up of specific additive, even if find that there is sufficient mechanical strength, reduce the danger of drug exposure and the preparation of also disintegrate rapidly in oral cavity, thus complete the present invention.
That is, the invention provides following dry coated tablet.
(1) dry coated tablet, it is formed as the kernel of effective ingredient and shell by containing (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium.
(2) dry coated tablet Gen Ju (1), it contains (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium with mol ratio 1:0.4:1.
(3) according to (1) or the dry coated tablet described in (2), wherein, the effective ingredient be made up of (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium accounts for 50 quality % ~ 100 quality % of interior nuclear composition.
(4) according to the dry coated tablet according to any one of (1) ~ (3), wherein, the effective ingredient be made up of (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium accounts for 70 quality % ~ 99 quality % of interior nuclear composition.
(5) according to the dry coated tablet according to any one of (1) ~ (4), wherein, the total content of effective ingredient (a) ~ (c) in dry coated tablet is 10 ~ 60 quality %.
(6) according to the dry coated tablet according to any one of (1) ~ (5), wherein, shell contains a kind, 2 kinds or 3 kinds in lactose, crystalline cellulose, hydroxypropyl cellulose.
(7) dry coated tablet Gen Ju (6), wherein, shell contains a kind or 2 kinds in lactose, crystalline cellulose.
(8) dry coated tablet Gen Ju (7), wherein, shell contains lactose and crystalline cellulose.
(9) according to (6), (7) or the dry coated tablet described in (8), wherein, in shell, also disintegrating agent is contained.
(10) dry coated tablet Gen Ju (9), wherein, disintegrating agent is selected from crospovidone (Crospovidone), carboxymethyl cellulose, corn starch, low degree of substitution hydroxypropyl cellulose, part alphalysed starch.
(11) dry coated tablet Gen Ju (10), wherein, disintegrating agent is crospovidone and/or part alphalysed starch.
(12) according to the dry coated tablet according to any one of (1) ~ (11), wherein, shell contains the lactose of 30 ~ 65 quality %.
(13) according to the dry coated tablet according to any one of (1) ~ (12), wherein, shell contains the crystalline cellulose of 30 ~ 50 quality %.
(14) according to the dry coated tablet according to any one of (1) ~ (13), wherein, shell contains the crospovidone of 2.5 ~ 15 quality %.
(15) according to the dry coated tablet according to any one of (1) ~ (14), wherein, shell contains the part alphalysed starch of 2 ~ 7.5 quality %.
(16) according to the dry coated tablet according to any one of (1) ~ (15), it is characterized in that, the friability with the dry coated tablet when accumulation revolution 100 turns is less than 0.3% and the shell do not cracked in fact in the shatter test from height 1m, and the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 120 seconds.
(17) according to the dry coated tablet according to any one of (1) ~ (16), it is characterized in that, the friability with the dry coated tablet when accumulation revolution 100 turns is less than 0.2%, and the shell do not cracked in fact in the shatter test from height 1m, the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 95 seconds.
(18) according to the dry coated tablet according to any one of (1) ~ (17), wherein, kernel is
the thickness of shell is 0.2 ~ 2mm, and the height of preparation is 1 ~ 10mm.
(19) dry coated tablet Gen Ju (18), wherein, kernel is
the thickness of shell is 0.5 ~ 1.5mm, and the height of preparation is 1.5 ~ 7mm.
(20) according to the dry coated tablet according to any one of (1) ~ (19), wherein, shape is circular or oval.
(21) according to the dry coated tablet according to any one of (1) ~ (20), it is manufactured by compression-molding apparatus, described pressing shaping device in the both up and down of mortar to having pestle, at least go up pestle to be made up of the dual structure of center pestle with the outer pestle of the periphery of this center pestle of encirclement, this center pestle and outer pestle can grind and can carry out squeeze operation.
The effect of invention
According to the present invention, by making dry coated tablet and medicine being enclosed kernel, there is not effective ingredient on the surface of tablet, can greatly reduce the danger that medical personnel etc. is exposed to medicine, tablet strength and the disintegrate rapidly of appropriateness can also be realized.And then, by being divided into kernel and shell, can reduce and the contact promoting the additive that effective ingredient decomposes, therefore, it is possible to suppress to decompose.
Accompanying drawing explanation
Fig. 1 is the schematic diagram involved by section representing dry coated tablet.
Detailed description of the invention
In the present invention, the mol ratio of ftorafur, gimeracil and Oteracil Potassium can suitably be selected, but is preferably respectively the compounding ingredient of 1:0.4:1.Amount as the ftorafur of the effective ingredient in dry coated tablet of the present invention, gimeracil and Oteracil Potassium changes according to dosage form, drug dosage schedule etc., be not particularly limited, suitably to select, but preferably the total content of the effective ingredient of 3 in dry coated tablet is set to about 10 ~ 60 quality %, more preferably be set to 20 ~ 50 quality %, be particularly preferably set to 25 ~ 35 quality %.
The preferred dry coated tablet of the present invention for have friability (accumulation revolution 100 turns) be less than 0.3% shell, more preferably there is the dry coated tablet that friability is the shell of less than 0.1%.Wherein, " friability " is the implication used in the technical field of usual preparation, namely, whether tablet in order to learn through molding can tolerate as the vibration in the coating of subsequent handling, printing, packaging or market-circulation or impact, and to utilize the reduction of the tablet weight using the friability test machine of rotary drum to obtain to carry out the parameter evaluated, be the index of tablet strength.Specifically, the revolution of the drum (internal diameter 287 ± 4mm) with motor is adjusted to such as 1 minute and rotates 24 ~ 26 turns by the reference information " the friability test method of tablet " based on Pharmacopeia of Japan the 15th revised edition, measure certain postrotational tablet weight, calculate its percentage rate of reduction relative to tablet weight when starting, using this value as friability.In this manual, represent friability when accumulation revolution being set to 100 turns, utilize 25rpm, the tablet weight of 4 minutes calculates.It is high that the situation being less than 0.3% by the friability of accumulation revolution 100 turns is defined as tablet strength.On the contrary the situation being greater than 0.3% is defined as tablet strength low.Effective ingredient contained in the present invention, sometimes also referred to as anticarcinogen, compared to general medicament in order to reduce exposure hazard further, also needing to improve tablet strength, therefore, compared with common preparation, more wishing friability to preset lower.
The preferred dry coated tablet of the present invention is the dry coated tablet with the shell do not cracked in fact from the shatter test of height 1m, preferably has the dry coated tablet of the shell do not cracked in fact from the shatter test of height 2m.Wherein, " shatter test " be whether can tolerate manufacture to learn-circulation wait or utilize automatic subpackage machine to carry out make up a prescription in vibration or impact, and the test used in the technical field of usual preparation.Specifically, tablet is fallen to corrosion resistant plate naturally from the height of 1m ~ 2m, confirm the crackle of tablet and the rate of mass reduction of test front and back.In addition, in the present invention, " not cracking in fact " refers to when carrying out shatter test to 5 tablets, does not crack completely, and rate of mass reduction in 5 tablets is lower than the degree of 0.1%.
The preferred dry coated tablet of the present invention is the disintegration time of dry coated tablet entirety is within 120 seconds.Specifically, when this dry coated tablet is the slaking test of implementation basis Pharmacopeia of Japan the 15th revised edition ordinary test method slaking test method, its disintegration time is the dry coated tablet within 120 seconds.Within this disintegration time is preferably 95 seconds, more preferably within 80 seconds.When making fast disintegrative dry coated tablet in oral cavity, actual in intraoral dissolving-disintegration time sometimes owing to being applied with intraoral friction, the motion of tongue and identical or faster than it with the disintegration time in above-mentioned slaking test method.In addition, summarize above-mentioned slaking test method simply, as described below.Exerciser is installed on bearing, puts into beaker, be adjusted to 1 minute reciprocal 29 ~ 32 times, amplitude 53 ~ 57mm moves up and down smoothly.Be set to exerciser when dropping to bottom, 25mm at the bottom of the wire side distance beaker of bottom, the amount adding the water of beaker is set to when exerciser drops to bottom, and the upper surface of exerciser is consistent with the surface of liquid.The temperature of liquid is remained on 37 ± 2 DEG C.In the glass tubing of exerciser, put into a slice sample, experimental liquid uses water, puts into bracket panel, moves up and down.Measure the time to the residue of sample unconfirmed in glass tubing, as disintegration time.
In in oral cavity, the disintegrate of tablet depends on the small frictional force of a small amount of moisture, tongue and the maxillary of saliva degree greatly.Therefore, in the various slaking tests (Japanese pharmacy the 14th revised edition ordinary test method slaking test method) that common tablet uses, do not reflect actual in intraoral disintegrate.Therefore, as Orally disintegrating tablet exerciser, develop and sold ODT-101(Fushan Mountain industry system) and field, TRICORPTESTER(ridge Seiko system), by using them, and consider the dependency with the data of the sense evaluation test of people, just can not have individual difference, repeatability is good, and carry out easily measuring (list of references: Narazaki R., Harada T., et al., Chem.Pharm.Bull., 52,704-707(2004)).Utilize disintegration time that the Orally disintegrating tablet exerciser ODT-101 of dry coated tablet of the present invention measures preferably within 20 seconds, more preferably within 16 seconds, particularly preferably within 14 seconds.
The preferred dry coated tablet of the present invention preferably utilizes Pharmacopeia of Japan ordinary test method dissolution test method the 2nd method (50min
-1, experimental liquid water 900mL) and the dissolution rate (CDHP, 15 minutes values) that records is more than 90%, more preferably more than 95%, particularly preferably more than 97%.
Particularly preferred dry coated tablet of the present invention, the friability (accumulation revolution 100 turns) with dry coated tablet is the shell of less than 0.3%, and the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 120 seconds; The dry coated tablet be more preferably, the friability (accumulation revolution 100 turns) with dry coated tablet is the shell of less than 0.2%, and the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 95 seconds;
Preferred dry coated tablet further, the friability (accumulation revolution 100 turns) with dry coated tablet is less than 0.2% and the shell do not cracked in fact in the shatter test from height 1m, and the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 95 seconds; Preferred dry coated tablet further, the friability (accumulation revolution 100 turns) with dry coated tablet is less than 0.2% and the shell do not cracked in fact in the shatter test from height 2m, and the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 95 seconds;
Preferred dry coated tablet further, the friability (accumulation revolution 100 turns) with dry coated tablet is less than 0.2% and the shell do not cracked in fact in the shatter test from height 2m, the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 95 seconds, the disintegration time utilizing Orally disintegrating tablet exerciser ODT-101 to record is within 20 seconds, utilizes Pharmacopeia of Japan ordinary test method dissolution test method the 2nd method (50min
-1, experimental liquid water 900mL) and the dissolution rate (CDHP, 15 minutes values) that records is more than 90%; Particularly preferred dry coated tablet, the friability (accumulation revolution 100 turns) with dry coated tablet is less than 0.2% and the shell do not cracked in fact in the shatter test from height 2m, the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 95 seconds, the disintegration time utilizing Orally disintegrating tablet exerciser ODT-101 to record is within 16 seconds, utilizes Pharmacopeia of Japan ordinary test method dissolution test method the 2nd method (50min
-1, experimental liquid water 900mL) and the dissolution rate (CDHP, 15 minutes values) that records is more than 95%.
In addition, " hardness " is evaluate an index of tablet strength, and the method TABLET BREAKING FORCE that can record based on USP measures.That is, when circular piece, diametrically pressurize with certain speed (below 20N/ second or 3.5mm/ second below) between parallel 2 pressing plates, measure load during tablet fracture.As the hardness of dry coated tablet of the present invention, in view of the balance with disintegrative, be preferably 30N ~ 60N, be more preferably 35N ~ 55N.
The additive contained in shell as dry coated tablet of the present invention, in order to improve tablet strength, such as can enumerate: crystalline cellulose, lactose, hydroxypropyl cellulose etc., be preferably crystalline cellulose, lactose or their mixture, be more preferably the mixture of crystalline cellulose and lactose.And then, in order to improve disintegrative, stripping property, preferably containing disintegrating agent, such as, containing crospovidone, part alphalysed starch, carboxymethyl cellulose, corn starch, low degree of substitution hydroxypropyl cellulose etc., be more preferably crospovidone and/or part alphalysed starch.
In the present invention, as the amount of the lactose used in jacket ingredients, preferably use 30 ~ 65 quality %, be more preferably 40 ~ 60 quality %, be particularly preferably 45 ~ 55 quality %.When the amount of lactose is less than 30 quality %, there is the trend that disintegrative is deteriorated, when being greater than 65 quality %, having the trend that friability increases.As the amount of crystalline cellulose, preferably use 30 ~ 50 quality %, be more preferably 35 ~ 45 quality %, when the amount of crystalline cellulose is less than 30 quality %, there is the trend that friability increases, when being greater than 50 quality %, having disintegrative to be deteriorated and the trend of taste deterioration.In addition, for the amount ratio of lactose and crystalline cellulose, if consider the hardness of tablet, disintegrative, take the balance of sense, more preferably by quality ratio the amount of lactose and the amount of crystalline cellulose are set to 1:0.5 ~ 1.5, are particularly preferably set to 1:0.8 ~ 1.3.As the amount of crospovidone, preferably use 2.5 ~ 15 quality %, be more preferably 2.5 ~ 7.5 quality %.As the amount of part alphalysed starch, preferably use with 2 ~ 7.5 quality %, more preferably use with 2.5 ~ 5 quality %.
For the kernel of dry coated tablet of the present invention, also can only be made up of the effective ingredient comprising ftorafur, gimeracil and Oteracil Potassium.As the use level of effective ingredient, 50 quality % ~ 100 quality % of interior nuclear composition can be accounted for, preferably account for 70 quality % ~ 99 quality %.And then, in order to provide tablet strength and the disintegrative of appropriateness, pharmaceutically acceptable binding agent and/or the disintegrating agent of appropriate amount also can be added.As this binding agent, as long as the binding agent used in pharmaceutical preparation is just not particularly limited, such as can enumerate: gelatinized corn starch liquid, methylcellulose, hydroxypropyl cellulose (HPC-SSL, HPC-SL, HPC-L etc.), hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose (carmethose), arabic gum, gelatin, agar, Tragacanth, sodium alginate, pulullan polysaccharide, polyvinyl pyrrolidone, polyvinyl alcohol, Polyethylene Glycol etc., they can use one or be used in combination of two or more, and are preferably hydroxypropyl cellulose.The content of binding agent, relative to the total amount of ftorafur, gimeracil and Oteracil Potassium, can add 0.1 ~ 2.0 quality %, more preferably be set to 0.4 ~ 1.0 quality %.In addition, as disintegrating agent, such as can enumerate: carmellose, carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose sodium, crystalline cellulose, low degree of substitution hydroxypropyl cellulose, crospovidone etc., they can use one or be used in combination of two or more, and are preferably crospovidone.The content of disintegrating agent, relative to the total amount of ftorafur, gimeracil and Oteracil Potassium, is preferably 3 ~ 15 quality %.
And then, a small amount of disintegrate auxiliary agent can be added in kernel, as disintegrate auxiliary agent, such as can enumerate: carmellose, carboxymethylcellulose calcium, carmethose, cross-linked carboxymethyl cellulose sodium, low degree of substitution hydroxypropyl cellulose, carboxymethyl starch sodium, corn starch, potato starch, alphalysed starch, part alphalysed starch, hydroxypropyl starch, crospovidone, sodium lauryl sulphate, polysorbate, polyethylene glycol oxide polyoxypropyleneglycol, sorbitan monooleate, propylene glycolmonostearate, mono laurate macrogol ester, they can use one or be used in combination of two or more.
In dry coated tablet of the present invention, except additive as above, in the scope not hindering effect of the present invention, usual used various preparation additives can be contained.As preparation additive, as long as usual used additive is just not particularly limited, such as, lubricant, coloring agent, flavour enhancer and correctives etc. can be enumerated.As lubricant, can enumerate: magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, Talcum and sucrose fatty acid ester etc.As coloring agent, can enumerate: edible Sunset Yellow FCF pigment, edible Amaranth pigment, edible blue No. 2 pigments, edible color lake pigment, Yellow ferric oxide and titanium oxide etc.As flavour enhancer, can enumerate: Fructus Citri tangerinae, the various spice of Fructus Citri Limoniae etc.As correctives, can enumerate: MENTHOL, Camphora, Herba Menthae etc.
It is made that dry coated tablet of the present invention such as can use tablet machine LIBRA2DC(chrysanthemum water to make), AP-MS-C type has core sheet tablet machine (field ferrum steel made) etc. have core sheet tablet machine, Autograph AG-E50k(Shimadzu Seisakusho Ltd. system can also be used) etc. manufacture.That is, as its general method for making, be roughly made up of four stages, can manufacture as follows: (i) the jacket ingredients of a part is supplied in mortar; (ii) the kernel carrying out tabletting is in advance supplied in mortar; (iii) remaining jacket ingredients is supplied in mortar; (iv) in mortar, up and down, carry out press molding between pestle.In addition, also International Publication 2003-28706 pamphlet, J.Jpn.Soc.Pharm.Mach. & Eng.14(4 can be used), the tablet machine of the method recorded 12-21(2005) etc. and rotary compression molding press (three and chemical research made) manufactures, from the viewpoint of the tablet with the dual structure of kernel and shell easily being carried out molding with high production rate, also preferred this manufacture method.Namely, dry coated tablet of the present invention easily can be manufactured by compression-molding apparatus, described pressing shaping device in the both up and down of mortar to having pestle, at least go up pestle to be made up of the dual structure of center pestle with the outer pestle of the periphery of this center pestle of encirclement, this center pestle and outer pestle all can grind and can carry out squeeze operation.Like this, dry coated tablet of the present invention can manufacture once with 1 tablet machine, therefore need not implement in the past described numerous and diverse technology, operation, can effectively manufacture.Therefore, do not have the position of the core as dry coated tablet in the past to depart from, shell can be obtained very thin.Particularly the thickness of shell can be made below 1mm.The thin layer improvement also contributing to the disintegrative of dry coated tablet of this shell.
As long as the shape of dry coated tablet of the present invention does not have the shape of sense of discomfort when easily taking or take, its shape is just not particularly limited, but preferably makes the preparation of circle or ellipse in the same manner as general pharmaceuticals.In addition, as long as its size can insert port intracavity and chew with difficulty degree.Such as, if circular piece, as long as be then
following degree, is preferably designed for
more preferably be designed to
be more preferably and be designed to
as long as the height of preparation is the degree of below 10mm, can be designed as 1 ~ 10mm, be preferably designed for 1.5 ~ 7mm, be preferably designed for 2 ~ 5mm further.
The shape dependence of kernel in the pestle front end geometry of used pestle, but based on the shape of above-mentioned dry coated tablet.The size of kernel depends on the size of dry coated tablet entirety more, in order to make the molding procedure of kernel successfully carry out, preferably not too small.In addition, in order to improve the disintegrative of dry coated tablet, preferably in the scope molding of shell not being caused to obstruction, increase kernel relative to shell.Therefore, for kernel, if circular piece, as long as be then
following degree, can be designed as
be preferably designed for
more preferably be designed to
in addition, kernel also can be divided into multiple part as required.
The thickness of shell, according to the size of kernel, is set as the thickness that abrasiveness is low, the shape of dry coated tablet can be kept by shell, designs in the scope being suitably in 0.2 ~ 2mm.In order to improve intraoral fast disintegrative, preferably improve the tablet strength of housing parts not too much.Therefore, the thickness of shell, preferably in the scope of problem not having abrasiveness, namely can keep making thin as much as possible in the scope of the shape of dry coated tablet, in reality, be preferably set to 0.5 ~ 1.5mm.
As dry coated tablet of the present invention, preferred kernel is
the thickness of shell is 0.2 ~ 2mm, the height of preparation is the dry coated tablet of 1 ~ 10mm, and more preferably kernel is
the thickness of shell is 0.5 ~ 1.5mm, the height of preparation is the dry coated tablet of 1.5 ~ 7mm, and being more preferably kernel is
the thickness of shell is 0.5 ~ 1.5mm, the height of preparation is the dry coated tablet of 2 ~ 5mm.
[embodiment]
Below, enumerate reference example, embodiment and test example and in further detail the present invention is described, but the present invention is not limited to these examples.It should be noted that, the ftorafur used in this embodiment and gimeracil are roc pharmaceutical industries Inc., and Oteracil Potassium is Sumitomo Chemical Co. Ltd..In addition, hydroxypropyl cellulose (HPC) is Japanese Cao Da Inc., part alphalysed starch and crystalline cellulose are chemical company of Asahi Chemical Industry, magnesium stearate is peaceful chemical company, and crospovidone is BASF AG.
The preparation 1 of nuclear composition in reference example 1()
Use fluidized bed pelletizer Multiplex MP-01(Powrex Inc.); in the mixture of ftorafur 66.1g, gimeracil 19.15g, Oteracil Potassium 64.75g and lactose (Borculo DomoIngredients Inc.) 150g; water 200.0g is sprayed; and carry out pelletize, nuclear composition in preparation.
The preparation 2 of nuclear composition in reference example 2()
By the method same with reference example 1, in the mixture of ftorafur 66.1g, gimeracil 19.15g, Oteracil Potassium 64.75g and lactose (Borculo Domo Ingredients Inc.) 150g, the liquid being dissolved with HPC 1.0g in water 199.0g is sprayed, and carry out pelletize, nuclear composition in preparation.
The preparation 3 of nuclear composition in reference example 3()
By the method same with reference example 1, in the mixture of ftorafur 132.2g, gimeracil 38.3g and Oteracil Potassium 129.5g, water 200g is sprayed, and carries out pelletize, nuclear composition in preparation.
The preparation 4 of nuclear composition in reference example 4()
By the method same with reference example 1, in the mixture of ftorafur 132.2g, gimeracil 38.3g and Oteracil Potassium 129.5g, the liquid being dissolved with HPC 0.3g is sprayed, and carry out pelletize in water 199.7g, nuclear composition in preparation.
The preparation 5 of nuclear composition in reference example 5()
By the method same with reference example 1, in the mixture of ftorafur 132.2g, gimeracil 38.3g and Oteracil Potassium 129.5g, the liquid being dissolved with HPC 1.5g is sprayed, and carry out pelletize in water 198.5g, nuclear composition in preparation.
The preparation 6 of nuclear composition in reference example 6()
By the method same with reference example 1, in the mixture of ftorafur 132.2g, gimeracil 38.3g and Oteracil Potassium 129.5g, the liquid being dissolved with HPC 3.0g is sprayed, and carry out pelletize in water 197.0g, nuclear composition in preparation.
The preparation 7 of nuclear composition in reference example 7()
By the method same with reference example 1, in the mixture of ftorafur 132.2g, gimeracil 38.3g and Oteracil Potassium 129.5g, the liquid being dissolved with HPC 4.5g is sprayed, and carry out pelletize in water 195.5g, nuclear composition in preparation.
The preparation 8 of nuclear composition in reference example 8()
By the method same with reference example 1, in the mixture of ftorafur 132.2g, gimeracil 38.3g and Oteracil Potassium 129.5g, the liquid being dissolved with HPC 6.0g is sprayed, and carry out pelletize in water 194.0g, nuclear composition in preparation.
The preparation 9 of nuclear composition in reference example 9()
By the method same with reference example 1, in the mixture of ftorafur 200g, gimeracil 58g and Oteracil Potassium 196g and part alphalysed starch (chemical company of Asahi Chemical Industry system) 14g, the liquid being dissolved with HPC 4g in water 396g is sprayed, and carries out pelletize, nuclear composition in preparation.
Preparation 10 > of nuclear composition in reference example 10(
By the method same with reference example 1, in the mixture of ftorafur 200g, gimeracil 58g and Oteracil Potassium 196g, the liquid being dissolved with HPC 4g is sprayed, and carry out pelletize in water 396g, nuclear composition in preparation.
Embodiment 1
Use Autograph AG-E50k(Shimadzu Seisakusho Ltd. system), lactose (MEGGLEExcipients & Technology Inc.) 59.88mg will be mixed, the mixture of crystalline cellulose 60mg and magnesium stearate 0.12mg is as shell, be 25mg using the granules 57mg(ftorafur at reference example 5) in the mixture of adding portion alphalysed starch 2.84mg and magnesium stearate 0.28mg as kernel, according to shell ground floor 30mg, kernel 60.12mg, and then the order of shell second layer 60mg is filled, the dry coated tablet of tablet external diameter 8mm is prepared with tableting pressure 5kN.Schematic diagram involved by the section of the dry coated tablet obtained is shown in Fig. 1.The interior nuclear diameter of the dry coated tablet obtained is 6mm, and the thickness (a) of shell is 1mm.
Embodiment 2
Use Autograph AG-E50k(Shimadzu Seisakusho Ltd. system), similarly to Example 1 will with lactose 53.76mg(MEGGLE Excipients & Technology Inc.), crystalline cellulose 60mg, the mixture that the ratio of crospovidone 6mg and magnesium stearate 0.24mg mixes is as shell, be 25mg using the granules 57mg(ftorafur at reference example 5) in the mixture of adding portion alphalysed starch 2.84mg and magnesium stearate 0.28mg as kernel, at shell 120mg, kernel 60.12mg, the dry coated tablet of preparation containing ftorafur 25mg under the condition of tableting pressure 5kN.The external diameter of the dry coated tablet obtained is 8mm, and interior nuclear diameter is 6mm, and the thickness of shell is 1mm.
Embodiment 3
Use Autograph AG-E50k(Shimadzu Seisakusho Ltd. system), use the interior nuclear composition of reference example 1 ~ 4 and 6 ~ 10, in addition, by the dry coated tablet desired by preparation method preparation similarly to Example 1.
Embodiment 4
Use the rotary compression molding press (three and chemical research made) recorded in International Publication 2003-28706 pamphlet, by the mixture that mixes using the ratio shown in table 1 as shell, be 25mg by the granules 57.25mg(ftorafur amount at reference example 10) in add crospovidone 1.5mg, part alphalysed starch 1.5mg, correctives 1.5mg, the mixture of magnesium stearate 0.25mg is as interior nuclear composition, according to shell ground floor, kernel 62mg, and then the order of the shell second layer carries out filling (amount of shell ground floor: the amount=35:85 of the shell second layer), the dry coated tablet 1 ~ 4 of tablet external diameter 8mm is prepared with tableting pressure 4kN.
Test example 1
For the dry coated tablet 1 ~ 4 obtained in embodiment 4, implement hardness, friability, intraoral disintegration test and dissolution test.Show the result in table 1.Result, from the viewpoint of hardness, friability, intraoral disintegration and stripping property, for jacket ingredients, confirming when direct compression lactose 34 ~ 64 quality %, crystalline cellulose 30 ~ 50 quality % and crospovidone 5 ~ 15 quality %, is the dry coated tablet of excellence.
(experimental condition)
Hardness tablet hardness tester TABLET TESTER 8M, Shleuniger system
Friability tablet friability exerciser 100 turns (25rpm, 4 minutes)
Slaking test Pharmacopeia of Japan ordinary test method slaking test method experimental liquid water
Intraoral disintegration test intraoral disintegration exerciser ODT-101, Fushan Mountain chemistry counterweight processed
rotating speed 75rpm, experimental liquid water
Dissolution test Pharmacopeia of Japan ordinary test method dissolution test method the 2nd method (50min
-1), experimental liquid water 900mL
[table 1]
Embodiment 5
Use rotary compression molding press similarly to Example 4 (three and chemical research made), by the mixture that mixes using the ratio shown in table 2 as shell, by nuclear composition in preparation method preparation similarly to Example 4, carry out filling (amount of shell ground floor: the amount=35:85 of the shell second layer) according to the order of shell ground floor, kernel 60mg and then the shell second layer, prepare the dry coated tablet 5 ~ 8 of tablet external diameter 8mm with tableting pressure 4kN.
Test example 2
For the dry coated tablet 5 ~ 8 obtained in embodiment 5, implement hardness, friability, intraoral disintegration test and dissolution test.Show the result in table 2.Result, from the viewpoint of hardness, friability, intraoral disintegration and stripping property, confirm direct compression lactose 39 ~ 59 quality %, crystalline cellulose 30 ~ 50 quality %, crospovidone 2.5 ~ 7.5 quality % and part alphalysed starch 2.5 ~ 7.5 quality % time, be the dry coated tablet of excellence.
(experimental condition)
Hardness tablet hardness tester TABLET TESTER 8M, Schleuniger system
Friability tablet friability exerciser PTF30ERA, PharmaTest Apparatebau system 100 turns (25rpm, 4 minutes)
Slaking test Pharmacopeia of Japan ordinary test method slaking test method experimental liquid water
Intraoral disintegration test intraoral disintegration exerciser ODT-101, Fushan Mountain chemistry counterweight processed
rotating speed 75rpm, experimental liquid water
Dissolution test Pharmacopeia of Japan ordinary test method dissolution test method the 2nd method (50min
-1), experimental liquid water 900mL
[table 2]
Embodiment 6
Use rotary compression molding press similarly to Example 4 (three and chemical research made), by the mixture that mixes using the ratio shown in table 3 as shell, be 20mg by the granules 45.8mg(ftorafur amount at reference example 10) in add crospovidone 2mg, part alphalysed starch 0.4mg, correctives 1.2mg, the mixture of magnesium stearate 0.2mg is as interior nuclear composition, according to shell ground floor, kernel 49.6mg, and then the order of the shell second layer carries out filling (amount of shell ground floor: the amount=30:66 of the shell second layer), the dry coated tablet 9 ~ 12 of tablet external diameter 8mm is prepared with tableting pressure 4kN.
Test example 3
For the dry coated tablet 9 ~ 12 obtained in embodiment 6, implement hardness, friability, intraoral disintegration test and dissolution test.Show the result in table 3.Result, from the viewpoint of hardness, friability, intraoral disintegration and stripping property, confirm direct compression lactose 39 ~ 59 quality %, crystalline cellulose 30 ~ 50 quality %, crospovidone 2.5 ~ 7.5 quality % and part alphalysed starch 2.5 ~ 7.5 quality % time, be the dry coated tablet of excellence.
[table 3]
Test example 4
For the dry coated tablet 6 ~ 8 obtained in embodiment 5 and commercially available Orally disintegrating tablet (A company, B company, C company, D company, E company), implement to make its height from 1m naturally fall tablet shatter test on stainless steel.Show the result in table 4 and table 5.As a result, confirming dry coated tablet 5 ~ 8 compared with commercially available Orally disintegrating tablet, is crackle and the equal excellent dry coated tablet of rate of mass reduction.
(experimental condition)
Tablet shatter test corrosion resistant plate, height 1m(5)
[table 4]
[table 5]
Comparative example
Claims (17)
1. an Orally disintegrating tablet, is characterized in that:
It is made up of kernel and shell, and described kernel contains (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium as effective ingredient,
Wherein, the effective ingredient be made up of (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium accounts for 70 quality % ~ 99 quality % of interior nuclear composition,
Shell contains the crystalline cellulose of 30 ~ 50 quality %.
2. Orally disintegrating tablet as claimed in claim 1, is characterized in that:
It contains (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium with mol ratio 1:0.4:1.
3. Orally disintegrating tablet as claimed in claim 1 or 2, is characterized in that:
The total content of effective ingredient (a) ~ (c) in Orally disintegrating tablet is 10 ~ 60 quality %.
4. Orally disintegrating tablet as claimed in claim 1, is characterized in that:
Shell is also containing a kind or 2 kinds in lactose and hydroxypropyl cellulose.
5. Orally disintegrating tablet as claimed in claim 4, is characterized in that:
Shell is also containing lactose.
6. the Orally disintegrating tablet as described in claim 4 or 5, is characterized in that:
Also containing the disintegrating agent beyond crystalline cellulose in shell.
7. Orally disintegrating tablet as claimed in claim 6, is characterized in that:
Disintegrating agent is selected from crospovidone, carboxymethyl cellulose, corn starch, low degree of substitution hydroxypropyl cellulose, part alphalysed starch.
8. Orally disintegrating tablet as claimed in claim 7, is characterized in that:
Disintegrating agent is crospovidone and/or part alphalysed starch.
9. the Orally disintegrating tablet as described in claim 4 or 5, is characterized in that:
Shell contains the lactose of 30 ~ 65 quality %.
10. Orally disintegrating tablet as claimed in claim 7, is characterized in that:
Shell contains the crospovidone of 2.5 ~ 15 quality %.
11. Orally disintegrating tablets as claimed in claim 7, is characterized in that:
Shell contains the part alphalysed starch of 2 ~ 7.5 quality %.
12. Orally disintegrating tablets according to any one of claim 1 ~ 11, is characterized in that:
The friability with the Orally disintegrating tablet when accumulation revolution 100 turns is the shell of less than 0.3%, and the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 120 seconds.
13. Orally disintegrating tablets according to any one of claim 1 ~ 11, is characterized in that:
The friability with the Orally disintegrating tablet when accumulation revolution 100 turns is less than 0.2% and the shell do not cracked in fact in the shatter test from height 1m, the disintegration time utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is less than 95 seconds, wherein, " do not crack in fact " and refer to when carrying out shatter test to 5 tablets, do not crack completely, and rate of mass reduction in 5 tablets is lower than the degree of 0.1%.
14. Orally disintegrating tablets according to any one of claim 1 ~ 11, is characterized in that:
Kernel is φ 3 ~ 24mm, and the thickness of shell is 0.2 ~ 2mm, and the height of preparation is 1 ~ 10mm.
15. Orally disintegrating tablets as claimed in claim 14, is characterized in that:
Kernel is φ 5 ~ 15mm, and the thickness of shell is 0.5 ~ 1.5mm, and the height of preparation is 1.5 ~ 7mm.
16. Orally disintegrating tablets according to any one of claim 1 ~ 11, is characterized in that:
Shape is circular or oval.
17. Orally disintegrating tablets according to any one of claim 1 ~ 11, is characterized in that:
It is obtained by compression-molding apparatus manufacture, described compression-molding apparatus has pestle in the both direction up and down of mortar, at least go up pestle to be made up of the dual structure of center pestle with the outer pestle of the periphery of this center pestle of encirclement, this center pestle and outer pestle all can grind and can carry out squeeze operation.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210260323.5A CN102895212B (en) | 2011-07-25 | 2012-07-25 | Dry coated tablet containing ftorafur, gimeracil, Oteracil Potassium |
| CN201510178161.4A CN104873517A (en) | 2011-07-25 | 2012-07-25 | Dry-pressed coated tablet containing tegafur, gimeracil and oteracil potassium |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110208402 | 2011-07-25 | ||
| CN201110208402.7 | 2011-07-25 | ||
| CN2011102084027 | 2011-07-25 | ||
| CN201210260323.5A CN102895212B (en) | 2011-07-25 | 2012-07-25 | Dry coated tablet containing ftorafur, gimeracil, Oteracil Potassium |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510178161.4A Division CN104873517A (en) | 2011-07-25 | 2012-07-25 | Dry-pressed coated tablet containing tegafur, gimeracil and oteracil potassium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102895212A CN102895212A (en) | 2013-01-30 |
| CN102895212B true CN102895212B (en) | 2015-09-30 |
Family
ID=47567900
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201220364549 Expired - Fee Related CN203227048U (en) | 2011-07-25 | 2012-07-25 | Dry-coated tablet as anti-tumor agent |
| CN201210260323.5A Expired - Fee Related CN102895212B (en) | 2011-07-25 | 2012-07-25 | Dry coated tablet containing ftorafur, gimeracil, Oteracil Potassium |
| CN201510178161.4A Pending CN104873517A (en) | 2011-07-25 | 2012-07-25 | Dry-pressed coated tablet containing tegafur, gimeracil and oteracil potassium |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201220364549 Expired - Fee Related CN203227048U (en) | 2011-07-25 | 2012-07-25 | Dry-coated tablet as anti-tumor agent |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510178161.4A Pending CN104873517A (en) | 2011-07-25 | 2012-07-25 | Dry-pressed coated tablet containing tegafur, gimeracil and oteracil potassium |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN203227048U (en) |
| HK (2) | HK1180584A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104840464A (en) * | 2014-08-22 | 2015-08-19 | 山东新时代药业有限公司 | Oral disintegrating preparation containing tegafur, gimeracil and potassium oxonate |
| CN106581001B (en) * | 2016-11-03 | 2018-12-21 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of tegafur, gimeracil and oteracil potassium composition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1558753A (en) * | 2001-09-28 | 2004-12-29 | ��ʽ�������ͻ�ѧ�о��� | Cored molded article undergoing quick disintegration |
| CN1660105A (en) * | 2004-12-23 | 2005-08-31 | 鲁南制药股份有限公司 | Disintegration piece taken through oral cavity containing Gimeracil and Oteracil Potassium with fluorine being added |
| CN101380327A (en) * | 2008-10-09 | 2009-03-11 | 北京恒瑞康达医药科技发展有限公司 | Anti-cancer composite sustained-release composition and preparation method thereof |
| CN101711765A (en) * | 2009-10-31 | 2010-05-26 | 山东新时代药业有限公司 | Dispersing tablet containing tegafur, gimeracil and oteracil potassium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102458475B (en) * | 2009-05-20 | 2016-03-30 | 大日本住友制药株式会社 | The oral cavity disintegration tablet of pressed coated |
-
2012
- 2012-07-25 CN CN 201220364549 patent/CN203227048U/en not_active Expired - Fee Related
- 2012-07-25 CN CN201210260323.5A patent/CN102895212B/en not_active Expired - Fee Related
- 2012-07-25 CN CN201510178161.4A patent/CN104873517A/en active Pending
-
2013
- 2013-07-03 HK HK13107789.5A patent/HK1180584A1/en not_active IP Right Cessation
-
2015
- 2015-12-15 HK HK15112304.9A patent/HK1211481A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1558753A (en) * | 2001-09-28 | 2004-12-29 | ��ʽ�������ͻ�ѧ�о��� | Cored molded article undergoing quick disintegration |
| CN1660105A (en) * | 2004-12-23 | 2005-08-31 | 鲁南制药股份有限公司 | Disintegration piece taken through oral cavity containing Gimeracil and Oteracil Potassium with fluorine being added |
| CN101380327A (en) * | 2008-10-09 | 2009-03-11 | 北京恒瑞康达医药科技发展有限公司 | Anti-cancer composite sustained-release composition and preparation method thereof |
| CN101711765A (en) * | 2009-10-31 | 2010-05-26 | 山东新时代药业有限公司 | Dispersing tablet containing tegafur, gimeracil and oteracil potassium |
Also Published As
| Publication number | Publication date |
|---|---|
| HK1180584A1 (en) | 2013-10-25 |
| CN104873517A (en) | 2015-09-02 |
| CN203227048U (en) | 2013-10-09 |
| HK1211481A1 (en) | 2016-05-27 |
| CN102895212A (en) | 2013-01-30 |
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