CN102895212A - Dry pressed coating tablet containing tegafur, gimeracil and oteracil potassium - Google Patents
Dry pressed coating tablet containing tegafur, gimeracil and oteracil potassium Download PDFInfo
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- CN102895212A CN102895212A CN2012102603235A CN201210260323A CN102895212A CN 102895212 A CN102895212 A CN 102895212A CN 2012102603235 A CN2012102603235 A CN 2012102603235A CN 201210260323 A CN201210260323 A CN 201210260323A CN 102895212 A CN102895212 A CN 102895212A
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Abstract
The invention provides a dry pressed coating tablet which is composed of an inner core and an outer core, and the inner core contains (a)tegafur, (b) gimeracil and (c)oteracil potassium which can be taken as effective components.
Description
Technical field
A kind of dry coated tablet for oral use that contains ftorafur (Tegafur), gimeracil (Gimeracil) and Oteracil Potassium (Oteracil potassium) of the present invention.
Background technology
Ftorafur, gimeracil and Oteracil Potassium compounding ingredient are a kind of antitumor agent, it is characterized in that: by in as the ftorafur of the prodrug of fluorouracil (5-FU), cooperating as the gimeracil of the decomposing inhibitor of 5-FU with as the Oteracil Potassium of phosphorylation inhibitor, can improve antitumous effect and alleviate Alimentary toxicity, as tumor chemical therapy medicine that can be oral, clinically extensive use (patent documentation 1).
Now, ftorafur, gimeracil and Oteracil Potassium compounding ingredient, take ftorafur: gimeracil: the mol ratio of Oteracil Potassium is as the content of 1:0.4:1, so that the title of " TS-1 capsule-containing " is commercially available capsule arranged, and so that the title of " TS-1 cooperates granule " is commercially available granule (patent documentation 2) arranged.But capsule or granule are difficult to swallow sometimes for the old people that function of deglutition reduces, and are seeking a kind of Orally disintegrating tablet, even this disintegrating tablet clinically dysphagia person also can take easily rapidly disintegrate in the oral cavity.
On the other hand, generally speaking, the active component of many demonstration antitumous effects more is classified as dangerous drug, and then pharmacologically active is higher, and ftorafur also is one of them, and its action need is given one's full attention to.Be the state that exposes or during because of the breaking of preparation, the damaged state that disperses, not only medical personnel but also the patient who takes or the care-giver that takes medicine also might be subject to the impact of drug exposure at the active component of anticarcinogen.Usually, in order to reduce drug exposure.Can use and medicament enclosed in the capsule that is made of gelatin etc. or medicament be made tablet and with the method for coatings such as sugar, macromolecule etc.But, because these methods postpone the disintegrate of preparation, therefore, can't expect in intraoral rapid disintegrate.
In addition, in order to improve the disintegrative of Orally disintegrating tablet, become the low preparation of its corresponding intensity more.At this moment, the process that can't tolerate manufacturing, circulation maybe can't tolerate utilization makes the height of medicament from about the 1m fall and to making up a prescription that its automatic subpackage machine that carries out subpackage carries out usually, in preparation, produce break, damaged, worry medical personnel's etc. medicament exposure hazard is increased.
For the preparation that is combined with ftorafur, gimeracil and Oteracil Potassium.Cooperate preparation even for example in patent documentation 3, disclose a kind of ftorafur, gimeracil and Oteracil Potassium of under humidified condition, also stablizing and can be oral.But this cooperates preparation to improve stability as preparation as purpose, does not consider the patient's etc. of dysphagia taking.In addition, in order to improve the functions such as disintegrative of tablet, and with stable saccharide and with and add the destabilization that disintegrating agent etc. can cause effective ingredient.In addition, the intraoral disintegration tablet that is combined with ftorafur, gimeracil and Oteracil Potassium is disclosed in patent documentation 4.But, for this patent, although this medicine is highly active anticarcinogen, do not have the countermeasure for medical personnel, care-giver's etc. pharmacy exposure.
The prior art document
Patent documentation
Patent documentation 1: No. 2614164 communiques of Japan Patent
Patent documentation 2: international 2009/084216 pamphlet that discloses
Patent documentation 3: TOHKEMY 2010-235539 communique,
Patent documentation 4: the open CN1660105A communique of Chinese patent
Summary of the invention
Invent problem to be solved
As mentioned above, known up to now ftorafur, gimeracil and Oteracil Potassium are cooperated preparation, and it is dangerous and have sufficient tablet strength, also can not cause the preparation that drug compliance reduces when taking to wish to obtain a kind of abundant reduction drug exposure.
The object of the present invention is to provide a kind of reduction that realizes drug exposure danger, rapidly disintegrative and the sufficient dry coated tablet that is combined with ftorafur, gimeracil and Oteracil Potassium of tablet strength.Particularly, the object of the present invention is to provide a kind of dry coated tablet, it is the shell that formability is good and disintegrative is good and the combination that contains the kernel of effective ingredient, has sufficient mechanical strength, even reduced the dangerous of drug exposure and also rapidly disintegrate in the oral cavity.
Be used for solving the method for problem
The present inventor has attempted making the various tablets that are combined with ftorafur, gimeracil and Oteracil Potassium that can be oral in order to solve above-mentioned problem.
Its result, by making the kernel that contains ftorafur, gimeracil and Oteracil Potassium and the dry coated tablet that is combined by the formability shell good and that disintegrative is good that specific additive consists of, even discovery has sufficient mechanical strength, reduced the dangerous of drug exposure and in the oral cavity the also rapid preparation of disintegrate, thereby finished the present invention.
That is, the invention provides following dry coated tablet.
(1) a kind of dry coated tablet, its by contain (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium consist of as kernel and the shell of effective ingredient.
(2) according to (1) described dry coated tablet, it contains (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium with mol ratio 1:0.4:1.
(3) according to (1) or (2) described dry coated tablet, wherein, by (a) ftorafur, (b) gimeracil and (c) effective ingredient that consists of of Oteracil Potassium account for 50 quality % of interior nuclear composition～100 quality %.
(4) according to each described dry coated tablet in (1)～(3), wherein, by (a) ftorafur, (b) gimeracil and (c) effective ingredient that consists of of Oteracil Potassium account for 70 quality % of interior nuclear composition～99 quality %.
(5) according to each described dry coated tablet in (1)～(4), wherein, the total content of the effective ingredient in the dry coated tablet (a)～(c) is 10～60 quality %.
(6) according to each described dry coated tablet in (1)～(5), wherein, shell contains a kind, 2 kinds or 3 kinds in lactose, crystalline cellulose, the hydroxypropyl cellulose.
(7) according to (6) described dry coated tablet, wherein, shell contains a kind or 2 kinds in lactose, the crystalline cellulose.
(8) according to (7) described dry coated tablet, wherein, shell contains lactose and crystalline cellulose.
(9) according to (6), (7) or (8) described dry coated tablet, wherein, in shell, also contain disintegrating agent.
(10) according to (9) described dry coated tablet, wherein, disintegrating agent is selected from crospovidone (Crospovidone), carboxymethyl cellulose, corn starch, low degree of substitution hydroxypropyl cellulose, part alphalysed starch.
(11) according to (10) described dry coated tablet, wherein, disintegrating agent is crospovidone and/or part alphalysed starch.
(12) according to each described dry coated tablet in (1)～(11), wherein, shell contains the lactose of 30～65 quality %.
(13) according to each described dry coated tablet in (1)～(12), wherein, shell contains the crystalline cellulose of 30～50 quality %.
(14) according to each described dry coated tablet in (1)～(13), wherein, shell contains the crospovidone of 2.5～15 quality %.
(15) according to each described dry coated tablet in (1)～(14), wherein, shell contains the part alphalysed starch of 2～7.5 quality %.
(16) according to each described dry coated tablet in (1)～(15), it is characterized in that, friability with the dry coated tablet when accumulation revolution 100 turns is below 0.3% and at the shell that does not crack in fact from the shatter test of height 1m, and the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 120 seconds.
(17) according to each described dry coated tablet in (1)～(16), it is characterized in that, friability with the dry coated tablet when accumulation revolution 100 turns is below 0.2%, and at the shell that does not crack in fact from the shatter test of height 1m, the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 95 seconds.
(18) according to each described dry coated tablet in (1)～(17), wherein, kernel is
The thickness of shell is 0.2～2mm, and the height of preparation is 1～10mm.
(19) according to (18) described dry coated tablet, wherein, kernel is
The thickness of shell is 0.5～1.5mm, and the height of preparation is 1.5～7mm.
(20) according to each described dry coated tablet in (1)～(19), wherein, be shaped as circle or ellipse.
(21) according to each described dry coated tablet in (1)～(20), it is made by compression-molding apparatus, described pressing shaping device has pestle in up and down two directions of mortar, at least go up pestle and be made of the dual structure of center pestle with the outer pestle of the periphery of surrounding this center pestle, 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 medical personnel and wait the danger that is exposed to medicine, can also realize tablet strength and the rapidly disintegrate of appropriateness.And then, by being divided into kernel and shell, can reducing and promote contacting of additive that effective ingredient decomposes, therefore can suppress to decompose.
Description of drawings
Fig. 1 is the related sketch map of section of expression dry coated tablet.
The specific embodiment
In the present invention, the mol ratio of ftorafur, gimeracil and Oteracil Potassium can suitably be selected, but preferably is respectively the compounding ingredient of 1:0.4:1.Amount as ftorafur, gimeracil and the Oteracil Potassium of the effective ingredient in the dry coated tablet of the present invention changes according to dosage form, drug dosage schedule etc., be not particularly limited, suitably select to get final product, but preferably the total content with 3 effective ingredient in the dry coated tablet is made as about 10～60 quality %, more preferably be made as 20～50 quality %, particularly preferably be made as 25～35 quality %.
The preferred dry coated tablet of the present invention for have friability (accumulation revolution 100 turn) be below 0.3% shell, more preferably have a dry coated tablet that friability is the shell below 0.1%.Wherein, " friability " is employed implication in the technical field of common preparation, namely, in order to learn whether tablet through molding can tolerate vibration or the impact in coating, printing, packing or the market-circulation as subsequent handling, and the parameter that the reduction of the tablet weight that obtains with the friability testing machine that utilize to use rotary drum is estimated is the index of tablet strength.Particularly, based on the reference information " the friability test method(s) of tablet " of Pharmacopeia of Japan the 15th revised edition will (revolution of internal diameter 287 ± 4mm) for example is adjusted to, and rotation 24～26 in 1 minute turns with the drum of motor, measure certain postrotational tablet weight, the percentage rate of the reduction of tablet weight is worth as friability with this when calculating it with respect to beginning.In this manual, expression will be accumulated revolution and be made as 100 friabilities when turning, utilize 25rpm, 4 minutes tablet weight to calculate.Be that situation below 0.3% is defined as the tablet strength height with the friability that turns of accumulation revolution 100.It is low to be defined as tablet strength greater than 0.3% situation on the contrary.Effective ingredient contained among the present invention is also referred to as anticarcinogen sometimes, in order further to reduce exposure hazard, also needs to improve tablet strength than general medicament, therefore, compares with common preparation, more wishes to preset friability lower.
The preferred dry coated tablet of the present invention is the dry coated tablet with the shell that does not crack in fact from the shatter test of height 1m, preferably has the dry coated tablet of the shell that does not crack in fact from the shatter test of height 2m.Wherein, " shatter test " be whether can tolerate manufacturing in order to learn-circulation waits or utilizes vibration or impact in the making up a prescription that automatic subpackage machine carries out, and employed test in the technical field of common preparation.Particularly, tablet is fallen on the corrosion resistant plate naturally from the height of 1m～2m, confirm the crackle of tablet and the rate of mass reduction before and after the test.In addition, in the present invention, " not cracking in fact " refers to 5 tablets are being carried out not cracking fully in the situation of shatter test, and the rate of mass reduction in 5 tablets is lower than 0.1% degree.
The preferred dry coated tablet of the present invention is that the disintegration time of dry coated tablet integral body is in 120 seconds.Particularly, 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 be 120 seconds with interior dry coated tablet.This disintegration time was preferably in 95 seconds, more preferably in 80 seconds.In making the oral cavity in the situation of fast disintegrative dry coated tablet, actual sometimes identical or faster than it with disintegration time in the above-mentioned slaking test method owing to applied the motion of intraoral friction, tongue in intraoral dissolving-disintegration time.In addition, summarize simply above-mentioned slaking test method, as described below.Exerciser is installed on bearing, puts into beaker, be adjusted to 1 minute reciprocal 29～32 times, amplitude 53～57mm and move up and down smoothly.When being made as exerciser and dropping to the below, the wire side of bottom apart from beaker at the bottom of 25mm, when the amount that adds the water of beaker was made as below exerciser drops to, the upper surface of exerciser was surperficial consistent with liquid.The temperature of liquid is remained on 37 ± 2 ℃.Put into a slice sample in the glass tubing of exerciser, experimental liquid makes water, puts into bracket panel, moves up and down.Measure the time till the residue of sample unconfirmed in the glass tubing, as disintegration time.
The disintegrate of tablet depends on the small frictional force of a small amount of moisture, tongue and the maxillary of saliva degree greatly in the oral cavity.Therefore, in the employed various slaking tests of common tablet (Japanese pharmacy the 14th revised edition ordinary test method slaking test method), reflection is unactual in intraoral disintegrate.Therefore, as the Orally disintegrating tablet exerciser, exploitation and sale have ODT-101(Fushan Mountain industry system) and field, TRICORPTESTER(ridge Seiko system), by using them, and the dependency of the data of consideration and people's sense evaluation test, just can there be the individual difference, repeatability is good, and measure easily (list of references: Narazaki R., Harada T., et al., Chem.Pharm.Bull., 52,704-707(2004)).Utilize in preferred 20 seconds of the disintegration time that the Orally disintegrating tablet exerciser ODT-101 of dry coated tablet of the present invention measures, more preferably in 16 seconds, particularly preferably in 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 below 0.3%, the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 120 seconds; The dry coated tablet that is more preferably, the friability (accumulation revolution 100 turns) with dry coated tablet is the shell below 0.2%, the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 95 seconds;
Further preferred dry coated tablet, friability (accumulation revolution 100 turns) with dry coated tablet is below 0.2% and at the shell that does not crack in fact from the shatter test of height 1m, and the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 95 seconds; Further preferred dry coated tablet, friability (accumulation revolution 100 turns) with dry coated tablet is below 0.2% and at the shell that does not crack in fact from the shatter test of height 2m, and the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 95 seconds;
Further preferred dry coated tablet, friability (accumulation revolution 100 turns) with dry coated tablet is below 0.2% and at the shell that does not crack in fact from the shatter test of height 2m, the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 95 seconds, the disintegration time of utilizing Orally disintegrating tablet exerciser ODT-101 to record is in 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, friability (accumulation revolution 100 turns) with dry coated tablet is below 0.2% and at the shell that does not crack in fact from the shatter test of height 2m, the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 95 seconds, the disintegration time of utilizing Orally disintegrating tablet exerciser ODT-101 to record is in 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 " can be measured based on the method TABLET BREAKING FORCE of USP record for estimating an index of tablet strength.That is, when circular piece, between 2 parallel pressing plates, pressurize the load when measuring the tablet fracture along diametric(al) with certain speed (20N/ below second or 3.5mm/ below second).As the hardness of dry coated tablet of the present invention, in view of with the balance of disintegrative, be preferably 30N～60N, more preferably 35N～55N.
The additive that contains in the shell as dry coated tablet of the present invention, in order to improve tablet strength, such as enumerating: crystalline cellulose, lactose, hydroxypropyl cellulose etc. are preferably crystalline cellulose, lactose or their mixture, more preferably the mixture of crystalline cellulose and lactose.And then, in order to improve disintegrative, stripping property, preferably contain disintegrating agent, such as containing crospovidone, part alphalysed starch, carboxymethyl cellulose, corn starch, low degree of substitution hydroxypropyl cellulose etc., more preferably crospovidone and/or part alphalysed starch.
In the present invention, as the amount of employed lactose in the outer shell component, preferably use 30～65 quality %, more preferably 40～60 quality % are particularly preferably 45～55 quality %.In the situation of amount less than 30 quality % of lactose, the trend of disintegrative variation is arranged, in the situation greater than 65 quality %, the trend that has friability to increase.As the amount of crystalline cellulose, preferably use 30～50 quality %, more preferably 35～45 quality %, in the situation of amount less than 30 quality % of crystalline cellulose, the trend that has friability to increase in the situation greater than 50 quality %, has the trend of disintegrative variation and taste deterioration.In addition, for the amount ratio of lactose and crystalline cellulose, if consider tablet hardness, disintegrative, take the balance of sense, more preferably by quality ratio the amount of lactose and the amount of crystalline cellulose are made as 1:0.5～1.5, particularly preferably be made as 1:0.8～1.3.As the amount of crospovidone, preferably use 2.5～15 quality %, 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 consisted of by the effective ingredient that comprises ftorafur, gimeracil and Oteracil Potassium.As the use level of effective ingredient, can account for 50 quality % of interior nuclear composition～100 quality %, preferably account for 70 quality %～99 quality %.And then, for tablet strength and the disintegrative of appropriateness are provided, also can add pharmaceutically acceptable binding agent and/or the disintegrating agent of appropriate amount.As this binding agent, so long as employed binding agent just is not particularly limited in the pharmaceutical preparation, such as enumerating: 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 a kind of or make up two or more uses, are preferably hydroxypropyl cellulose.The content of binding agent can add 0.1～2.0 quality % with respect to the total amount of ftorafur, gimeracil and Oteracil Potassium, more preferably is made as 0.4～1.0 quality %.In addition, as disintegrating agent, such as enumerating: carmellose, carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose sodium, crystalline cellulose, low degree of substitution hydroxypropyl cellulose, crospovidone etc., they can use a kind of or make up two or more uses, are preferably crospovidone.The content of disintegrating agent is preferably 3～15 quality % with respect to the total amount of ftorafur, gimeracil and Oteracil Potassium.
And then, can in kernel, add a small amount of disintegrate auxiliary agent, as the disintegrate auxiliary agent, for example 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, the part alphalysed starch, hydroxypropyl starch, crospovidone, sodium lauryl sulphate, polysorbate, the polyethylene glycol oxide polyoxypropyleneglycol, sorbitan monooleate, propylene glycolmonostearate, the mono laurate macrogol ester, they can use a kind of or make up two or more uses.
In dry coated tablet of the present invention, except aforesaid additive, in the scope that does not hinder effect of the present invention, can contain usually employed various preparation additives.As the preparation additive, so long as common employed additive just is not particularly limited, such as enumerating lubricant, coloring agent, flavour enhancer and correctives etc.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 iron sesquioxide 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.
Dry coated tablet of the present invention is made such as using tablet machine LIBRA2DC(chrysanthemum water to make), the AP-MS-C type has the nuclear sheet tablet machine (field ferrum steel made) etc. nuclear sheet tablet machine is arranged, can also use Autograph AG-E50k(Shimadzu Seisakusho Ltd. system) etc. make.That is, as its general method for making, roughly be made of the quadravalence section, can make as follows: (i) the outer shell component with a part is supplied in the mortar; The kernel that (ii) will carry out in advance tabletting is supplied in mortar; (iii) remaining outer shell component is supplied in mortar; (iv) in mortar, carry out press molding between pestle up and down.In addition, also can use international open 2003-28706 pamphlet, J.Jpn.Soc.Pharm.Mach.﹠Eng.14(4), the tablet machine of the method for record and rotary compression molding press 12-21(2005) etc. (three and chemical research made) is made, from the tablet with dual structure of kernel and shell can being considered with high production rate and the aspect of easily carrying out molding, also preferred this manufacture method.Namely, dry coated tablet of the present invention can easily be made by compression-molding apparatus, described pressing shaping device has pestle in up and down two directions of mortar, at least go up pestle and be made of the dual structure of center pestle with the outer pestle of the periphery of surrounding this center pestle, 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 be made by enough 1 tablet machine once, therefore need not implement in the past described numerous and diverse technology, operation, can effectively make.Therefore, do not have the position deviation of the nuclear as dry coated tablet in the past, shell can be made as thin as a wafer.Particularly the thickness of shell can be made below the 1mm.The thin layerization of this shell also helps the improvement of the disintegrative of dry coated tablet.
The shape of dry coated tablet of the present invention is so long as take easily or do not have the shape of sense of discomfort when taking, and its shape just is not particularly limited, but preferred and general pharmaceuticals are similarly made circular or oval-shaped preparation.In addition, but its size so long as insert port intracavity and chewing does not follow the degree of difficulty to get final product.For example, if circular piece, as long as then be
Following degree gets final product, and is preferably designed for
More preferably be designed to
Be more preferably and be designed to
The height of preparation is preferably designed for 1.5～7mm as long as for the following degree of 10mm, can be designed as 1～10mm, further is preferably designed for 2～5mm.
The shape of kernel depends on the pestle front end shape of employed pestle, but based on the shape of above-mentioned dry coated tablet.The size of kernel depends on the size of dry coated tablet integral body more, and is for the molding procedure that makes kernel is successfully carried out, preferably not too small.In addition, in order to improve the disintegrative of dry coated tablet, preferably in the scope that molding of shell is not caused obstruction, increase kernel with respect to shell.Therefore, for kernel, if circular piece, as long as then be
Following degree gets final product, and can be designed as
Be preferably designed for
More preferably be designed to
In addition, kernel also can be divided into a plurality of parts as required.
The thickness of shell is according to the size of kernel, is set as that abrasiveness is low, the shape of dry coated tablet can get final product by the thickness that shell keeps, and is suitably in the scope of 0.2～2mm to design.In order to improve intraoral fast disintegrative, the tablet strength of preferred raising housing parts within reason.Therefore, the thickness of shell namely can keep making as much as possible thinly in the scope of shape of dry coated tablet preferably in the scope of the problem that does not have abrasiveness, is preferably set to 0.5～1.5mm in reality.
As dry coated tablet of the present invention, preferred kernel is
The thickness of shell is that the height of 0.2～2mm, preparation is the dry coated tablet of 1～10mm, and more preferably kernel is
The thickness of shell is that the height of 0.5～1.5mm, preparation is the dry coated tablet of 1.5～7mm, is more preferably kernel and is
The thickness of shell is that the height of 0.5～1.5mm, preparation is the dry coated tablet of 2～5mm.
[embodiment]
Below, enumerate reference example, embodiment and test example the present invention is described in further detail, but the present invention is not limited to these examples.Need to prove that employed ftorafur and gimeracil are roc pharmaceutical industries company system among this embodiment, Oteracil Potassium is Sumitomo Chemical Co. Ltd.'s system.In addition, hydroxypropyl cellulose (HPC) is Japanese Cao Da company system, part alphalysed starch and crystalline cellulose are chemical company of Asahi Chemical Industry system, magnesium stearate is peaceful chemical company system, and crospovidone is BASF AG's system.
The preparation 1 of nuclear composition in the reference example 1()
Use fluidized bed pelletizer Multiplex MP-01(Powrex company system); in the mixture of ftorafur 66.1g, gimeracil 19.15g, Oteracil Potassium 64.75g and lactose (Borculo Domo Ingredients company system) 150g; water 200.0g is sprayed; and carry out pelletize, nuclear composition in preparing.
The preparation 2 of nuclear composition in the 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 company system) 150g, to be dissolved with the liquid that HPC 1.0g forms in water 199.0g sprays, and carry out pelletize, nuclear composition in preparing.
The preparation 3 of nuclear composition in the 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 carry out pelletize, nuclear composition in the preparation.
The preparation 4 of nuclear composition in the 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, will in water 199.7g, be dissolved with the liquid that HPC 0.3g forms and spray, and carry out pelletize, nuclear composition in the preparation.
The preparation 5 of nuclear composition in the 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, will in water 198.5g, be dissolved with the liquid that HPC 1.5g forms and spray, and carry out pelletize, nuclear composition in the preparation.
The preparation 6 of nuclear composition in the 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, will in water 197.0g, be dissolved with the liquid that HPC 3.0g forms and spray, and carry out pelletize, nuclear composition in the preparation.
The preparation 7 of nuclear composition in the 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, will in water 195.5g, be dissolved with the liquid that HPC 4.5g forms and spray, and carry out pelletize, nuclear composition in the preparation.
The preparation 8 of nuclear composition in the 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, will in water 194.0g, be dissolved with the liquid that HPC 6.0g forms and spray, and carry out pelletize, nuclear composition in the preparation.
The preparation 9 of nuclear composition in the 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, to in water 396g, be dissolved with the liquid that HPC 4g forms and spray, and carry out pelletize, nuclear composition in the preparation.
The preparation 10 of nuclear composition in the reference example 10(＞
By the method same with reference example 1, in the mixture of ftorafur 200g, gimeracil 58g and Oteracil Potassium 196g, will in water 396g, be dissolved with the liquid that HPC 4g forms and spray, and carry out pelletize, nuclear composition in the preparation.
Embodiment 1
Use Autograph AG-E50k(Shimadzu Seisakusho Ltd. system), to mix lactose (MEGGLE Excipients﹠Technology company system) 59.88mg, the mixture that crystalline cellulose 60mg and magnesium stearate 0.12mg form is as shell, to be 25mg at the granules 57mg(of reference example 5 ftorafur) in add mixture that part alphalysed starch 2.84mg and magnesium stearate 0.28mg form as kernel, according to shell ground floor 30mg, kernel 60.12mg, and then the order of shell second layer 60mg fills, and prepares the dry coated tablet of tablet external diameter 8mm with tabletting pressure 5kN.Related the illustrating in Fig. 1 of section with the dry coated tablet that obtains.The interior nuclear diameter of the dry coated tablet that obtains is 6mm, and the thickness of shell (a) is 1mm.
Embodiment 2
Use Autograph AG-E50k(Shimadzu Seisakusho Ltd. system), similarly to Example 1 will be with lactose 53.76mg(MEGGLE Excipients﹠Technology company system), crystalline cellulose 60mg, the mixture that the ratio of crospovidone 6mg and magnesium stearate 0.24mg mixes is as shell, to be 25mg at the granules 57mg(of reference example 5 ftorafur) in add mixture that part alphalysed starch 2.84mg and magnesium stearate 0.28mg form as kernel, at shell 120mg, kernel 60.12mg, preparation contains the dry coated tablet of ftorafur 25mg under the condition of tabletting pressure 5kN.The external diameter of the dry coated tablet that obtains 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, the preparation method by similarly to Example 1 prepares desired dry coated tablet.
Embodiment 4
Use the rotary compression molding press put down in writing in the international open 2003-28706 pamphlet (three and chemical research made), the mixture that will mix with the ratio shown in the table 1 is as shell, to be 25mg in the granules 57.25mg(of reference example 10 ftorafur amount) in add crospovidone 1.5mg, part alphalysed starch 1.5mg, correctives 1.5mg, the mixture that magnesium stearate 0.25mg forms is as interior nuclear composition, according to the shell ground floor, kernel 62mg, and then the order of the shell second layer is filled the (amount of shell ground floor: the amount of the shell second layer=35:85), prepare the dry coated tablet 1～4 of tablet external diameter 8mm with tabletting pressure 4kN.
Test example 1
For the dry coated tablet 1～4 that obtains among the embodiment 4, implement hardness, friability, intraoral disintegration test and dissolution test.Show the result in table 1.The result, consider from the viewpoint of hardness, friability, intraoral disintegration and stripping property, for outer shell component, confirmed when direct compression lactose 34～64 quality %, crystalline cellulose 30～50 quality % and crospovidone 5～15 quality %, to be the dry coated tablet of excellence.
(experimental condition)
Hardness tablet hardness tester TABLET TESTER 8M, the 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 similarly to Example 4 rotary compression molding press (three and chemical research made), the mixture that will mix with the ratio shown in the table 2 is as shell, by nuclear composition in the preparation method preparation similarly to Example 4, order according to shell ground floor, kernel 60mg and then the shell second layer is filled the (amount of shell ground floor: the amount of the shell second layer=35:85), prepare the dry coated tablet 5～8 of tablet external diameter 8mm with tabletting pressure 4kN.
Test example 2
For the dry coated tablet 5～8 that obtains among the embodiment 5, implement hardness, friability, intraoral disintegration test and dissolution test.Show the result in table 2.The result, consider from the viewpoint of hardness, friability, intraoral disintegration and stripping property, confirmed when 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 %, to be the dry coated tablet of excellence.
(experimental condition)
Hardness tablet hardness tester TABLET TESTER 8M, the 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 similarly to Example 4 rotary compression molding press (three and chemical research made), the mixture that will mix with the ratio shown in the table 3 is as shell, to be 20mg in the granules 45.8mg(of reference example 10 ftorafur amount) in add crospovidone 2mg, part alphalysed starch 0.4mg, correctives 1.2mg, the mixture that magnesium stearate 0.2mg forms is as interior nuclear composition, according to the shell ground floor, kernel 49.6mg, and then the order of the shell second layer is filled the (amount of shell ground floor: the amount of the shell second layer=30:66), prepare the dry coated tablet 9～12 of tablet external diameter 8mm with tabletting pressure 4kN.
Test example 3
For the dry coated tablet 9～12 that obtains among the embodiment 6, implement hardness, friability, intraoral disintegration test and dissolution test.Show the result in table 3.The result, consider from the viewpoint of hardness, friability, intraoral disintegration and stripping property, confirmed when 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 %, to be the dry coated tablet of excellence.
[table 3]
Test example 4
For the dry coated tablet 6～8 that obtains among the 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 to fall tablet shatter test on corrosion resistant plate.Show the result in table 4 and table 5.As a result, having confirmed that dry coated tablet 5～8 compares with commercially available Orally disintegrating tablet, is all excellent dry coated tablets of crackle and rate of mass reduction.
(experimental condition)
Tablet shatter test corrosion resistant plate, 1m(5 of height)
[table 4]
[table 5]
Comparative example
Claims (21)
1. dry coated tablet is characterized in that:
It is made of kernel and shell, described kernel contain (a) ftorafur, (b) gimeracil and (c) Oteracil Potassium as effective ingredient.
2. dry coated 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. dry coated tablet as claimed in claim 1 or 2 is characterized in that:
By (a) ftorafur, (b) gimeracil and (c) effective ingredient that consists of of Oteracil Potassium account for 50 quality % of interior nuclear composition～100 quality %.
4. such as each described dry coated tablet in the claim 1～3, it is characterized in that:
By (a) ftorafur, (b) gimeracil and (c) effective ingredient that consists of of Oteracil Potassium account for 70 quality % of interior nuclear composition～99 quality %.
5. such as each described dry coated tablet in the claim 1～4, it is characterized in that:
The total content of the effective ingredient in the dry coated tablet (a)～(c) is 10～60 quality %.
6. such as each described dry coated tablet in the claim 1～5, it is characterized in that:
Shell contains a kind, 2 kinds or 3 kinds in lactose, crystalline cellulose, the hydroxypropyl cellulose.
7. dry coated tablet as claimed in claim 6 is characterized in that:
Shell contains a kind or 2 kinds in lactose, the crystalline cellulose.
8. dry coated tablet as claimed in claim 7 is characterized in that:
Shell contains lactose and crystalline cellulose.
9. such as claim 6,7 or 8 described dry coated tablets, it is characterized in that:
In shell, also contain disintegrating agent.
10. dry coated tablet as claimed in claim 9 is characterized in that:
Disintegrating agent is selected from crospovidone, carboxymethyl cellulose, corn starch, low degree of substitution hydroxypropyl cellulose, part alphalysed starch.
11. dry coated tablet as claimed in claim 10 is characterized in that:
Disintegrating agent is crospovidone and/or part alphalysed starch.
12. such as each described dry coated tablet in the claim 1～11, it is characterized in that:
Shell contains the lactose of 30～65 quality %.
13. such as each described dry coated tablet in the claim 1～12, it is characterized in that:
Shell contains the crystalline cellulose of 30～50 quality %.
14. such as each described dry coated tablet in the claim 1～13, it is characterized in that:
Shell contains the crospovidone of 2.5～15 quality %.
15. such as each described dry coated tablet in the claim 1～14, it is characterized in that:
Shell contains the part alphalysed starch of 2～7.5 quality %.
16. such as each described dry coated tablet in the claim 1～15, it is characterized in that:
Friability with the dry coated tablet when accumulation revolution 100 turns is the shell below 0.3%, and the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 120 seconds.
17. such as each described dry coated tablet in the claim 1～16, it is characterized in that:
Friability with the dry coated tablet when accumulation revolution 100 turns is below 0.2% and at the shell that does not crack in fact from the shatter test of height 1m, and the disintegration time of utilizing Pharmacopeia of Japan ordinary test method slaking test method to obtain is below 95 seconds.
18. such as each described dry coated tablet in the claim 1～17, it is characterized in that:
Kernel is
The thickness of shell is 0.2～2mm, and the height of preparation is 1～10mm.
19. dry coated tablet as claimed in claim 18 is characterized in that:
Kernel is
The thickness of shell is 0.5～1.5mm, and the height of preparation is 1.5～7mm.
20. such as each described dry coated tablet in the claim 1～19, it is characterized in that:
Be shaped as circle or ellipse.
21. such as each described dry coated tablet in the claim 1～20, it is characterized in that:
It obtains by the compression-molding apparatus manufacturing, described compression-molding apparatus has pestle at the up and down both direction of mortar, at least go up pestle and be made of the dual structure of center pestle with the outer pestle of the periphery of surrounding this center pestle, 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 |
|---|---|---|---|
| CN2011102084027 | 2011-07-25 | ||
| CN201110208402.7 | 2011-07-25 | ||
| CN201110208402 | 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 true CN102895212A (en) | 2013-01-30 |
| CN102895212B CN102895212B (en) | 2015-09-30 |
Family
ID=47567900
Family Applications (3)
| 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 |
| CN201210260323.5A Expired - Fee Related CN102895212B (en) | 2011-07-25 | 2012-07-25 | Dry coated tablet containing ftorafur, gimeracil, Oteracil Potassium |
| CN 201220364549 Expired - Fee Related CN203227048U (en) | 2011-07-25 | 2012-07-25 | Dry-coated tablet as anti-tumor agent |
Family Applications Before (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 |
Family Applications After (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 |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN104873517A (en) |
| HK (2) | HK1180584A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104147012A (en) * | 2014-08-22 | 2014-11-19 | 山东新时代药业有限公司 | Oral disintegrating preparation containing tegafur, gimeracil and oteracil potassium |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|---|---|---|---|
| JP5458096B2 (en) * | 2009-05-20 | 2014-04-02 | 大日本住友製薬株式会社 | Nucleated orally disintegrating tablets |
-
2012
- 2012-07-25 CN CN201510178161.4A patent/CN104873517A/en active Pending
- 2012-07-25 CN CN201210260323.5A patent/CN102895212B/en not_active Expired - Fee Related
- 2012-07-25 CN CN 201220364549 patent/CN203227048U/en not_active Expired - Fee Related
-
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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104147012A (en) * | 2014-08-22 | 2014-11-19 | 山东新时代药业有限公司 | Oral disintegrating preparation containing tegafur, gimeracil and oteracil potassium |
| 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 |
| CN104147012B (en) * | 2014-08-22 | 2016-08-24 | 山东新时代药业有限公司 | A kind of oral disintegrated preparation containing ftorafur, Gimeracil and oteracil potassium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN203227048U (en) | 2013-10-09 |
| HK1211481A1 (en) | 2016-05-27 |
| HK1180584A1 (en) | 2013-10-25 |
| CN102895212B (en) | 2015-09-30 |
| CN104873517A (en) | 2015-09-02 |
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