CN1993132B - Film coated tablet having plural coats - Google Patents
Film coated tablet having plural coats Download PDFInfo
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- CN1993132B CN1993132B CN2005800256271A CN200580025627A CN1993132B CN 1993132 B CN1993132 B CN 1993132B CN 2005800256271 A CN2005800256271 A CN 2005800256271A CN 200580025627 A CN200580025627 A CN 200580025627A CN 1993132 B CN1993132 B CN 1993132B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
Abstract
The invention aims at providing a film coated tablet containing 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (Compound A) or a physiologically acceptable salt thereof which exhibits excellent storage stability and rapid dissolution. Namely, a film coated tablet which contains Compound A or a physiologically acceptable salt thereof and at least one excipient component (Component B) selected from the group consisting of polyethylene glycol, poloxamers, polyoxyethylene hardened castor oil, polysorbates, and glycerol and which has such a form that Compound A or a physiologically acceptable salt thereof is not in contact with Component B.
Description
Technical field
The present invention relates to film-coated tablet, it contains 4-amino-5-chloro-2-ethyoxyl-N-[[4-(4-luorobenzyl)-2-morpholinyl] methyl] Benzoylamide or the acceptable salt of its physiology.
Background technology
(±)-4-amino-5-chloro-2-ethyoxyl-N-[[4-(4-luorobenzyl)-2-morpholinyl] methyl] Benzoylamide (being sometimes referred to as mosapride (mosapride) hereinafter) is a kind of selective serotonin 4 receptor stimulating agents, and shown that good gastrointestinal activity facilitation is (referring to US patent No.4,870,074).In addition, mosapride and the acceptable salt of its physiology can be used as the medicine of treatment gastroesophageal reflux disease, dumping syndrome and other gastrointestinal symptoms.
As the solid preparation that contains mosapride, the tablet that contains the mosapride citrate is described in US patent No.4, among 870,074 the embodiment 245.Specifically, the solid preparation that contains mosapride citrate, corn starch, lactose, crystalline cellulose, hydroxypropyl cellulose, light anhydrous silicic acid and magnesium stearate is disclosed.
In addition, the mosapride citrate dihydrate in fact has been used to improve the gastrointestinal symptoms relevant with chronic gastritis.In Japan, the tablet (1.72mg or 3.44mg mosapride) that contains 2.5mg or 5mg mosapride citrate (anhydrous) is sold with the trade name of " Gasmotin ".Because mosapride is an amara, this tablet is film-coated tablet.Tablet is the aluminum packing, to prevent producing by-product and variable color during long preservation.
Summary of the invention
The purpose of this invention is to provide rapidly-soluble film-coated tablet superior aspect storage stability, even without the aluminum packing, it contains mosapride or the acceptable salt of its physiology.
The inventor has carried out various researchs, and to attempt to obtain to contain the rapidly-soluble solid preparation of mosapride or the acceptable salt of its physiology, even without the aluminum packing, it also has superiority aspect storage stability.In described process, they have been found that the required specific pharmaceutical excipient of being considered, form film-coated tablet of coatings promotes the decomposition of mosapride.Therefore, they use the coated composition that does not contain specific pharmaceutical excipient to attempt preparation film-coated tablet.As a result, the compositions that forms coatings is used in their latest find, causes the preparation difficulty of preparation.Yet, they have been found that, when not contacting between following two components when preparing the film that contains mosapride and pharmaceutical excipient-coated tablet, can keep quick solubility property, in preparation, can not cause difficulty,, during long preservation, suppress the decomposition of mosapride yet even without the aluminum packing, and variable color that can inhibitory preparation, these cause of the present invention finishing.
Therefore, the invention provides and contain 4-amino-5-chloro-2-ethyoxyl-N-[[4-(4-luorobenzyl)-2-morpholinyl] methyl] the rapidly-soluble film-coated tablet of Benzoylamide (being called " compd A " hereinafter) or the acceptable salt of its physiology, wherein film-coated tablet contains specific pharmaceutical excipient, compd A or the acceptable salt of its physiology do not contact with specific pharmaceutical excipient, specifically, rapidly-soluble film-coated tablet has two or more coatings on the surface of uncoated tablets, the ground floor that wherein forms on uncoated tablets is substantially free of specific pharmaceutical excipient, and the one deck at least in the second layer and the follow-up layer contains specific pharmaceutical excipient.
More particularly, the invention provides following invention.
[1]: a kind of rapidly-soluble film-coated tablet comprises 4-amino-5-chloro-2-ethyoxyl-N-[[4-(4-luorobenzyl)-2-morpholinyl] methyl] Benzoylamide (being called " compd A " hereinafter) or the acceptable salt of its physiology,
Wherein film-coated tablet comprises at least a pharmaceutical excipient (being called " B component " hereinafter), and described excipient is selected from Polyethylene Glycol, poloxamer, polyoxyethylene hydrogenated Oleum Ricini, polysorbate and glycerol, and
Tablet has such structure, and wherein compd A or the acceptable salt of its physiology do not contact with B component.
[2]: the film-coated tablet of [1], it comprises: (a) contain compd A or the acceptable salt of its physiology uncoated tablets and
(b) two or more coatings that on the surface of uncoated tablets, form,
The ground floor that wherein forms on uncoated tablets is substantially free of B component, and
One deck at least in the second layer and the succeeding layer contains B component.
[3]: the film-coated tablet of [2], wherein the one deck at least in the second layer and the succeeding layer comprises about 5 B component to about 98wt% concentration.
[4]: the film-coated tablet of [2] or [3], wherein the outermost coatings comprises B component.
[5]: the film-coated tablet of each of [1] to [4], wherein B component is a Polyethylene Glycol.
[6]: the film-coated tablet of [2], wherein coatings comprises the ground floor and the second layer, wherein the second layer comprises B component.
[7]: the film-coated tablet of [6], wherein ground floor covers about 0.5 to about 10mg/cm
2The uncoated tablets surface.
[8]: the film-coated tablet of [6] or [7], wherein the second layer covers about 0.1 to about 20mg/cm
2The ground floor surface.
[9]: the film-coated tablet of [2], wherein ground floor comprises one or more film coating reagent.
[10]: the film-coated tablet of each of [1] to [9], wherein compd A or the acceptable salt of its physiology are the citrate dihydrate of compd A.
[11]: the film-coated tablet of each of [1] to [10], wherein uncoated tablets is with about 0.5 to about 70wt% ratio inclusion compound A or the acceptable salt of its physiology based on compd A.
[12]: the film-coated tablet of each of [1] to [11], wherein when tablet being placed in the container and under the unsealing condition, storage is in the time of 6 months under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than about 1%.
[13]: the film-coated tablet of [6], wherein uncoated tablets is with the citrate dihydrate based on about 0.5 to about 50wt% ratio inclusion compound A of compd A,
Ground floor comprises one or more film coating reagent, and covers about 0.7 to 5mg/cm
2The uncoated tablets surface and
The second layer covers about 0.5 to 10mg/cm
2The ground floor surface.
[14]: the film-coated tablet of [13], wherein film coating reagent is selected from hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), ethyl cellulose (EC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and methacrylic acid copolymer.
[15]: the film-coated tablet of [13], wherein B component is a Polyethylene Glycol.
[16]: the film-coated tablet of [6], wherein uncoated tablets is with the citrate dihydrate based on about 0.5 to about 30wt% ratio inclusion compound A of compd A,
Ground floor comprises hydroxypropyl emthylcellulose, and covers about 1.5 to 3mg/cm
2The uncoated tablets surface,
The second layer comprises polyethylene glycol 6000, and covers about 1 to 5mg/cm
2The ground floor surface and
When tablet being placed in the container and under the unsealing condition, storage is in the time of 6 months under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than about 0.6%.
[17]: a kind of commercial package, film-the coated tablet and the written matter relevant with it that comprise [1] have wherein comprised the explanation that film-coated tablet can maybe should be used to promote the gastrointestinal activeness, improve dumping syndrome or prevention or treatment gastroesophageal reflux (GERD) in the written matter on packing material or in packing material.
Because film-coated tablet of the present invention has the above feature, even without protective package aluminum packing etc. for example, compd A and the acceptable salt of its physiology are not easy to decompose, and can store under steady statue.And, during preparation can not cause difficulty.In addition, during administration, do not notice bitterness.
Description of drawings
Fig. 1 is the result's of the citrate of expression The compounds of this invention A-a (racemic modification of compd A) and the test of the incompatibility of each B component a chart.
Fig. 2 is the chart that is illustrated in the result of the stability of formulation test that obtains in embodiment 1 to 5 and the Comparative Examples 1.
Fig. 3 is the chart that is illustrated in the result of the stability of formulation test that obtains in embodiment 1 to 5 and the Comparative Examples 1.
Fig. 4 is the chart that is illustrated in the result of the stability of formulation test that obtains in embodiment 6 to 8 and the Comparative Examples 2.
Fig. 5 is the chart that is illustrated in the result of the stability of formulation test that obtains in embodiment 6 to 8 and the Comparative Examples 2.
The specific embodiment
" fast solubility property " of film-coated tablet of the present invention is meant (37 ℃ of the solubility tests described in Japanese Pharmacopoeia the 14th edition, stirring means, 50rpm, separating medium 900ml water) in, be no less than about 85% dissolving ratio after 30 minutes, preferably be no less than 90%, more preferably be no less than 95%.
Compd A or the acceptable salt of its physiology
Compd A of the present invention, i.e. 4-amino-5-chloro-2-ethyoxyl-N-[[4-(4-luorobenzyl)-2-morpholinyl] methyl] Benzoylamide is the chemical compound that is expressed from the next:
Compd A has good gastrointestinal activity facilitation as selective serotonin 4 receptor stimulating agents.In the present invention, compd A can be a kind of in racemic modification or the optically active form, preferred racemic modification.
In the present invention, compd A can be free state or the acceptable salt of its physiology.For salt, the preferred acid addition salts.Comprise formates with the example of organic acid addition salts, acetate, lactate, adipate, citrate, tartrate, fumarate, mesylate, maleate etc.Comprise hydrochlorate, sulfate, nitrate, phosphate etc. with the example of the addition salts of mineral acid.In the middle of these, optimization citric acid salt especially.Compd A or the acceptable salt of its physiology can be solvate, hydrate or non-hydrate.The hydrate of optimization citric acid salt, especially optimization citric acid monocalcium salt compound.
For example method or the preparation of its similar approach of the above compd A and the acceptable salt of its physiology by describing in the U.S. Patent No. 4870074.
B component
The key component of film-coated tablet of the present invention and the example that does not contact the pharmaceutical excipient (B component) that exists with compd A or the acceptable salt of its physiology comprise Polyethylene Glycol, poloxamer, polysorbate, polyoxyethylene hydrogenated Oleum Ricini and glycerol.Because compd A contacts the decomposition that promotes compd A with B component, so B component does not reach compd A in the present invention.
Think that B component is that preparation film-coated tablet is necessary.For example, do not exist B component can cause film molding problem in membrane component, for example brittle film, sliding capability (comprising flowability) reduce, tarnish etc.When B component does not exist, during commercial production, gather problems such as (picking), cause very difficulty of preparation.Collection is meant during the film coating steps, between the tablet or the layering of the rete of the contact point between tablet and the device.
Polyethylene Glycol is by H (OCH
2CH
2)
nThe chemical compound of OH (n is not less than 4) expression, and have about molecular weight of 200 to 9000.For example, Macrogol 200, PEG400, Macrogol 600, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000 etc. are known.The numeral that " Polyethylene Glycol " indicated afterwards is meant mean molecule quantity.
Poloxamer is the block copolymer of alpha-hydro-omega-hydroxypoly (oxygen ethylene)-poly-(oxypropylene)-poly-(oxygen ethylene), have about molecular weight of 2000 to 20000, and known its is nonionic surfactant.The example of poloxamer comprises poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 etc.Specifically, for example, can use those that sell with the brand name of pluronic (pluronic) etc.
Polysorbate is a polyoxyethylene sorbitol ester, and is nonionic surfactant.For can the commercial chemical compound of buying, polysorbate80 (Tween 80) etc. be known.
Polyoxyethylene hydrogenated Oleum Ricini is prepared as follows: hydrogen is joined in the Oleum Ricini, obtain castor oil hydrogenated, the oxirane with itself and various quantity carries out addition polymerization then.Several products with different polymerization degree can commercially be bought, as NIKKOLHCO-20, and NIKKOL HCO-40, NIKKOL HCO-50, NIKKOLHCO-60 etc.
Glycerol is by CH
2(OH) CH (OH) CH
2The chemical compound that OH represents.
The preferred ingredient B that is used to prepare film-coated tablet of the present invention is a Polyethylene Glycol, more preferably Macrogol 4000 or 6000, especially preferred polyethylene glycol 6000.
Contactless structure
As below with reference to shown in the embodiment, the inventor at first finds, when compd A of the present invention or the acceptable salt of physiology contact with said components B, produces a large amount of catabolites (related substances) of compd A.
For " contactless structure ", for example, can mention such structure, it comprises: uncoated tablets, described uncoated tablets inclusion compound A or the acceptable salt of physiology, ground floor, it is made by the compositions that is substantially free of said components B, it covers uncoated tablets, and the one deck at least in the second layer and the succeeding layer, and it is made by the compositions that comprises B component.This embodiment of specific explanations below.
Uncoated tablets
" uncoated tablets " can comprise compd A or the acceptable salt of its physiology separately, and it further comprises the pharmaceutical excipient of non-said components B usually.
" other pharmaceutical excipient " can be any material, and prerequisite is that it does not cause owing to mixing the inconvenience that causes and being essential.For example, as its example, can enumerate binding agent, diluent, fluidizer, disintegrating agent etc.
In uncoated tablets, based on compd A, ratio inclusion compound A with about 0.01 to about 90wt% or the acceptable salt of its physiology, preferred about 0.5 to about 70wt%, and more preferably from about 0.5 to about 50wt%, is more preferably about 0.5 to about 30wt%.
Binding agent
The object lesson of binding agent comprises Radix Acaciae senegalis, paste, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinyl alcohol, amylopectin, gelatin, ethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrin, polyvinyl pyrrolidone etc.Hydroxypropyl cellulose preferably, hydroxypropyl emthylcellulose, polyvinyl pyrrolidone etc.The content of binding agent can be any amount, as long as it can keep the hardness of tablet and not hinder in gastrointestinal tract decomposing.Usually, in uncoated tablets, with about 0.5 to about 10wt%, preferred about ratio of 1 to about 7wt% comprises binding agent.
Diluent
The object lesson of diluent comprises lactose, starch, mannitol, crystalline cellulose, sucrose, erithritol, trehalose, calcium phosphate dibasic anhydrous, calcium sulfate etc., preferred lactose, starch, mannitol, crystalline cellulose etc.In uncoated tablets, usually with about 5 to about 97wt%, preferably about ratio of 10 to about 80wt% comprises it.
Fluidizer
The object lesson of fluidizer comprises light anhydrous silicic acid, metasilicic acid magnalium etc., preferred light anhydrous silicic acid.In uncoated tablets, usually with about 0.01 to about 10wt%, preferably about ratio of 0.1 to about 5wt% comprises it.
Disintegrating agent
The hydroxypropyl cellulose of low-replacement that examples of disintegrants comprises, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, crospovidone etc.In the middle of these, use hydroxypropyl content common about 5 to about 16wt%, preferred about 7 to about 16wt%, more preferably from about the hydroxypropyl cellulose of 10 to about 16wt% low replacement.In uncoated tablets, usually with about 2 to about 30wt%, preferably about ratio of 5 to about 25wt% comprises disintegrating agent.
In addition, can add pharmaceutical excipient as required, for example lubricant (for example, magnesium stearate, zinc stearate, calcium stearate etc.) etc.
Uncoated tablets can according to conventional method, by above-mentioned pharmaceutical excipient is suitably mixed and compression molding prepare.Preferably select lactose and starch as diluent from above-mentioned excipient, hydroxypropyl cellulose is as binding agent, and light anhydrous silicic acid is as fluidizer, and the hydroxypropyl cellulose of low-replacement is as disintegrating agent, and magnesium stearate is as lubricant.
Coatings
Film-coated tablet of the present invention has at least two coatings.The layer that directly covers uncoated tablets is known as ground floor, and is outside from ground floor, and each layer sequentially is called the second layer, the 3rd layer (if existence) etc.According to the present invention, ground floor is substantially free of B component, and the one deck at least in the second layer and the succeeding layer comprises B component.
Keep quick solubility property on film of the present invention-coated tablet characteristic.Usually, the tablet with two or more film coatings is slow release or enteric-coated tablet.The fast dissolving tablet agent does not have two or more film coatings usually.Therefore, find to exist the inventor of said components B to attempt preparing and have film-coated tablet that one deck does not contain B component.Yet, consider the actual fabrication situation, problems such as collection take place, and this preparation is difficult during commercial production.Therefore, determine that said components B should join in the coatings, and compd A or the acceptable salt of its physiology and said components B should not be in contact with one another.Specifically, the uncoated tablets of inclusion compound A or the acceptable salt of its physiology is with the rete coating that does not contain B component, then further with the rete coating that comprises B component.Tablet with this structure has kept quick solubility property, even shown decomposition and the inhibitory preparation variable color that suppresses compd A under long preservation, and has shown that during commercial production inhibition is gathered.
For example first coatings comprises film coating reagent as follows.The concentration of the film coating reagent of ground floor is about 5 to about 100wt%, and preferred about 30 to about 100wt%, and especially preferably about 50 to about 98wt%.
The coating quantity of control ground floor is to every 1cm
2The surface area of uncoated tablets about 0.5 is to about 10mg, and preferred about 0.7 to about 5mg.For this quantity, list when using when the compositions that comprises B component is further following, compd A or the acceptable salt of its physiology do not contact with B component.More preferably, every 1cm
2The surface area of uncoated tablets, the coating quantity of ground floor is about 1.5 to about 3mg.
Form after the above-mentioned ground floor, use the compositions that comprises B component in any stage.For example, the compositions that comprises B component can be used and make the second layer, maybe can use the compositions that do not contain B component forming one to several layers, and can use the compositions that comprises B component at last.In addition, can form two or more layers that comprise B component.
In comprising the layer of B component, with about 5 to about 98wt%, preferred about 7.5 to about 90wt%, especially preferably about ratio of 10 to about 50wt% comprises B component.
The quantity of coatings preferably 2.In this case, with the coating quantity regulating of the second layer to every 1cm
2Ground floor surface area about 0.1 to about 20mg, preferred about 0.5 to about 10mg.For this coating quantity, can be suppressed up hill and dale by decomposition of the caused compd A of said components B etc.More preferably, every 1cm
2The ground floor surface area, the coating quantity of the second layer is about 1 to about 5mg.
Although the weight ratio of the ground floor and the second layer is not particularly limited, the ground floor of per 1 parts by weight, the second layer are for example about 0.1 to about 10 parts by weight, and preferred about 0.5 to about 5 parts by weight.
The composition that is included in each coatings is as follows.
Film coating reagent
The example of film coating reagent comprises for example hydroxypropyl emthylcellulose (HPMC) of cellulose derivative, hydroxypropyl cellulose (HPC), methylcellulose (MC), ethyl cellulose (EC) etc., polyvinyl is polyvinyl alcohol (PVA) for example, and polyvinylpyrrolidone (PVP) etc., acrylic polymer are methacrylic acid copolymer etc. for example, Deng, preferred HPMC.
Except above-mentioned film coating reagent and said components B, the example that can be included in the composition in the coatings comprises coloring agent for example titanium dioxide and iron sesquioxide (quantity in each layer: 0.1 to 50wt%), caking inhibiter is Talcum (quantity in each layer: 0.1 to 50wt%) for example, and polishing material is light anhydrous silicic acid (quantity in each layer: 0.1 to 10wt%) etc. for example.
Ground floor can be prepared as follows: select one or more aforesaid film coating reagent, with film coating agent dissolves or be suspended in water or organic solvent for example in ethanol etc., preferred water obtains fluid composition (coating liquid), and said composition is sprayed on the uncoated tablets.Where necessary, coating liquid can comprise above-mentioned coloring agent, caking inhibiter, polishing material etc.
The layer that comprises B component can be prepared as follows: select B component, it is dissolved or suspended in water or organic solvent for example in the ethanol etc., preferred water obtains fluid composition, and said composition is sprayed.Where necessary, said composition can comprise the above film coating reagent, the above coloring agent, caking inhibiter, polishing material etc.
Other layer that does not contain B component can be by forming to the similar step of step that forms of ground floor.
Film-coated tablet of the present invention is stable, even during long preservation.Therefore, when for example film-coated tablet of the present invention is placed in the container, during in storage 6 months under the unsealing condition, under 40 ℃, 75%RH and the generation quantity (total amount of related substances) by the high effective liquid chromatography for measuring related substances, all the ratio of the area percent of related substanceses is not more than about 1%.Preferably be not more than about 0.6%.
The generation quantity of related substances (total amount of related substances) is the catabolite of compd A, the total amount of the intermediate during the preparation, the impurity etc. during the preparation, and it is meant detectable total amount under the high performance liquid chromatography measuring condition of the following stated.Area percent is the exponential quantity percentage rate, and whole peak areas of the related substances that the high performance liquid chromatography of its expression by the following stated obtains are with respect to the ratio of total peak area.
The measuring condition of above-mentioned high performance liquid chromatography is as described in the embodiment.
Film-coated tablet of the present invention is preferred for promoting the gastrointestinal activeness, improves dumping syndrome or prevention or treatment gastroesophageal reflux disease (GERD).
Embodiment
Explain the present invention hereinafter in more detail by embodiment, described embodiment should not be construed as restrictive.Below among the embodiment, the racemic modification of compd A is defined as compd A-a, the citrate dihydrate of compd A-a is defined as A-b, and employed A-b is Dainippon Pharmaceutical Co.Ltd. preparation (the about 7 μ m of particle mean size).
" polyethylene glycol 6000 " of NOF Corporation preparation is as polyethylene glycol 6000." polyethylene glycol 1500 " of Nacalai Tesque preparation is as polyethylene glycol 1500, " PEG400 " of Maruishi Pharmaceutical Co.Ltd. preparation is as PEG400, " Tween-81 " of Nacalai Tesque preparation is as polysorbate80, " the pluronic PE 6800 " of BASF JAPAN LTD. preparation is as poloxamer 188, and use Wako Pure ChemicalIndustries, the glycerol of Ltd. preparation.
For lactose, use " Pharmatose (trade mark) 200 orders " of DMV preparation.For starch, use Nihon Shoku hin Kako Co., " corn starch " of Ltd. preparation.For light anhydrous silicic acid, use " Aerosil (trade mark) 200 " of NIPPON AEROSIL preparation.For hydroxypropyl cellulose, use NIPPON Soda Co., " the NISSO HPC L " of Ltd. preparation.Hydroxypropyl cellulose for low-replacement uses Shin-EtsuChemical Co., " L-HPC (LH-11) " of Ltd. preparation.For magnesium stearate, use Taihei Chemical Industrial Co., " magnesium stearate " that come from plant of Ltd. preparation.For hydroxypropyl emthylcellulose, use Shin-Etsu Chemical Co., " TC-5RW " of Ltd. preparation.For titanium dioxide, use Ishihara Sangyo Kaisha, " titanium dioxide " of Ltd. preparation.For Talcum, use Nippon Talc Co., it is a kind of that Ltd. prepares.
Reference example
Compd A-b and various " B component " (polyethylene glycol 6000, polyethylene glycol 1500, PEG400, polysorbate80, poloxamer 188, glycerol) are carried out the incompatibility test.Specifically, compd A-b is mixed with each B component weight ratio with 1: 1 in glass container, container is hermetically sealed, and 60 ℃ of storage tests of carrying out one month.When they do not dissolve, they are prepared as suspension or under contact condition, place during mixing.For Comparative Examples, compd A-b is placed on separately in the glass container, container is hermetically sealed, and 60 ℃ of storage tests of carrying out one month with the same manner.After the gas-tight seal one month, measure the generation quantity (total amount of related substances) of related substances.Generation quantity (area percent) by the high effective liquid chromatography for measuring related substances.The total amount of related substances is meant the total amount of the catabolite of compd A-a, the intermediate during the preparation, the impurity during the preparation etc.By with water: methanol (1: 9) joins in the above-mentioned glass container, 20 minutes, centrifugally separating mixture and obtain supernatant and prepare sample stir the mixture.The post that uses is that (Nomura Chemical Co. Ltd.), for mobile phase, uses the mixture of sodium citrate buffer solution (pH value 3.4)/methanol/acetonitrile (24: 9: 7) to Deverosil ODS-7.Measuring wavelength is 274n m.The results are shown among Fig. 1.Understand that when compd A-b mixed with poloxamer, Polyethylene Glycol, polysorbate or glycerol, the quantity of the related substances of generation was bigger during than independent storage compound A-b.
Embodiment 1
(1) preparation uncoated tablets
According to the prescription that is shown in Table 1, prepare the uncoated tablets that each tablet contains 3.43m g compd A-a.(each tablet 130mg, circular tablet, diameter 7.0mm, surface area: 115.5mm
2).
Table 1
| Composition | Uncoated tablets dosage/tablet |
| Compd A-b | 5.29mg |
| Lactose | 61.66mg |
| Starch | 32.5mg |
| The hydroxypropyl cellulose of low-replacement | 26.0mg |
| Hydroxypropyl cellulose | 2.6mg |
| Magnesium stearate | 1.3mg |
| Light anhydrous silicic acid | 0.65mg |
| Uncoated tablets | 130.0mg |
(2) form coatings
Prepare each coating liquid, to form each coatings that each tablet has compositions described in the table 2.That is, titanium dioxide and Talcum joined purify waste water, obtain suspension, previously prepared 10wt% hydroxypropyl emthylcellulose aqueous solution is added wherein, obtain dispersion, dispersion by sieve (No.80), obtained the coating liquid of ground floor.In addition, with polyethylene glycol 6000 and light anhydrous silicic acid join arrive in purifying waste water suspension, this suspension by sieve (No.80), is obtained the coating liquid of the second layer.
Table 2
With the uncoated tablets (400g that obtains in above-mentioned (1), about 3100 tablets) be placed on Hicoater (HC-LABO, Freund Corporation) in, and the coating liquid of ground floor is sprayed on it, so that the coating quantity after dry becomes each tablet 4.25mg.
Subsequently, the coating liquid of the second layer is sprayed on it, so that the coating quantity after dry becomes each tablet 0.75mg.After coating is finished, tablet is dry in Hicoater, obtain target film-coated tablet.
In the coating liquid of Talcum being removed and Talcum is joined the second layer from the coating liquid of ground floor, with the method same with embodiment 1 (2), uncoated tablets (the 400g that will in embodiment 1 (1), obtain, about 3100 tablets) give each tablet coating with two kinds of layers describing in the following table 3, obtain film-coated tablet.
Table 3
Embodiment 3
Give each tablet coating with the uncoated tablets that obtains among the embodiment 1 (1) with two kinds of layers describing in the table 4, obtain film-coated tablet, as follows.
Table 4
Prepare each coating liquid. promptly, titanium dioxide and Talcum joined purify waste water, obtain suspension, previously prepared 10wt% hydroxypropyl emthylcellulose aqueous solution is added wherein, obtain dispersion, dispersion by sieve (No.80), obtained the coating liquid of ground floor.
In addition, polyethylene glycol 6000, titanium dioxide, Talcum and light anhydrous silicic acid joined purify waste water, obtain suspension, 10wt% hydroxypropyl emthylcellulose aqueous solution is added wherein, obtain dispersion, dispersion by sieve (No.80), is obtained the coating liquid of the second layer.
With the uncoated tablets (400g that obtains in the foregoing description 1 (1), about 3100 tablets) be placed on Hicoater (HC-LABO, Freund Corporation) in, and the coating liquid of ground floor is sprayed on it, so that the coating quantity after dry becomes each tablet 3.00mg.
Subsequently, the coating liquid of the second layer is sprayed on it, so that the coating quantity after dry becomes each tablet 2.00mg.After coating finishes, that tablet is dry in Hicoater.
With the method same with embodiment 3, the uncoated tablets that will obtain in embodiment 1 (1) (400g, about 3100 tablets) is given each tablet coating with two kinds of layers describing in the table 5, obtains film-coated tablet.
Table 5
Embodiment 5
In the coating liquid that titanium dioxide is not joined ground floor, with the method same with embodiment 3, give each tablet coating with the uncoated tablets (400g, about 3100 tablets) that obtains among the embodiment 1 (1) with two kinds of layers describing in the following table 6, obtain film-coated tablet.
Table 6
Comparative Examples 1
As follows, preparation film-coated tablet, each tablet coating layer (1 layer) of describing in its invading the exterior 7 are to form on the surface of the uncoated tablets of acquisition among embodiment 1 (1).
Table 7
| Composition | Coatings (1 layer) amount/tablet |
| Hydroxypropyl emthylcellulose | 3.60mg |
| Polyethylene glycol 6000 | 0.70mg |
| Titanium dioxide | 0.50mg |
| Talcum | 0.15mg |
| Light anhydrous silicic acid | 0.05mg |
| Purify waste water | 45.0mg |
| Coating liquid | 50.0mg |
| Coating quantity | 5.00mg |
| Composition | Coatings (1 layer) amount/tablet |
| Per unit area coating quantity | 4.33mg/cm 2 |
Polyethylene glycol 6000, titanium dioxide, Talcum and light anhydrous silicic acid joined purify waste water, obtain suspension, previously prepared 10wt% hydroxypropyl emthylcellulose aqueous solution is added wherein, obtain dispersion, dispersion by sieve (No.80), is obtained coating liquid.
With the uncoated tablets (400g that obtains in the foregoing description 1 (1), about 3100 tablets) be placed on Hicoater (HC-LABO, Freund Corporation) in, and coating liquid is sprayed on it, so that the coating quantity after dry becomes each tablet 5.00mg.After coating finishes, that tablet is dry in Hicoater.
EXPERIMENTAL EXAMPLE 1: stability test
With the tablet that obtains in embodiment 1 to 5 and the Comparative Examples 1 in (1) vial (gas-tight seal), under 40 ℃, 75%RH condition, preserved 6 months, or in (2) vial (unsealing), under 40 ℃, 75%RH, preserved 6 months, and the generation quantity (total amount of related substances) of check related substances and the variation aspect the tone in given time period.The generation quantity of following mensuration related substances: prepare sample according to the method for describing in the reference example, wherein water (1ml) and methanol (9ml) are joined in two tablets, and sample carried out the high performance liquid chromatography (area percent) described in the reference example, and visually estimate the variation of tone aspect.
The results are shown in Fig. 2 (vial of gas-tight seal) and Fig. 3 (unencapsulated vial) and table 8 (vial of gas-tight seal) and the table 9 (unencapsulated vial).
Table 8
Table 9
As a result, even after storing 6 months, film of the present invention-coated tablet shows: for unsealing and gas-tight seal, the generation quantity of related substances (total amount of related substances) is no more than standard value (1%).In addition, tone is stable less than variation and sample.
Show that as above-mentioned result film-coated tablet of the present invention has superiority under 40 ℃, the condition of 75%RH aspect stable.Therefore, film-coated tablet of the present invention also can carry out the storage to determined number, and need not pack (for example PTP packing etc.) respectively, and is promptly so-called in bulk.Therefore, can prescribing give the patient film-coated tablet of the present invention with simple packaged form (for example using cellophane, medico paper etc. to pack), or concentrate unit dose package for each administration.
EXPERIMENTAL EXAMPLE 2: bitterness shielding test
The tablet that obtains in the foregoing description 1 to 5 is carried out the bitterness shielding test.That is, check the screen effect of the unhappy taste of making us of comparing with compd A-b by 3 members of panel of expert.As a result, all tablets have shown screen effect significantly, and it has stoped the taste that makes us unhappy fully.
According to the prescription that is shown in Table 10, prepare uncoated tablets (each tablet 80mg, circular tablet, diameter 6.5mm, surface area: 83.6mm that each tablet contains 1.72mg compd A-a
2), and with and the same method of embodiment 1 to 5, the prescription according to being shown in Table 11 forms coatings on the uncoated tablets that is obtained, obtain film-coated tablet.
Table 10
| Composition | Uncoated tablets dosage/tablet |
| Compd A-b | 2.65mg |
| Lactose | 38.55mg |
| Starch | 20.0mg |
| The hydroxypropyl cellulose of low-replacement | 16.0mg |
| Hydroxypropyl cellulose | 1.6mg |
| Composition | Uncoated tablets dosage/tablet |
| Magnesium stearate | 0.80mg |
| Light anhydrous silicic acid | 0.40mg |
| Uncoated tablets | 80.0mg |
Comparative Examples 2
As follows, preparation film-coated tablet, the coatings (1 layer) of each tablet of describing in its invading the exterior 12 is to form on the surface of the uncoated tablets that obtains in embodiment 6.
Table 12
| Composition | Coatings (1 layer) amount/tablet |
| Hydroxypropyl emthylcellulose | 2.16mg |
| Polyethylene glycol 6000 | 0.42mg |
| Titanium dioxide | 0.30mg |
| Talcum | 0.09mg |
| Light anhydrous silicic acid | 0.03mg |
| Purify waste water | 27.0mg |
| Coating liquid | 30.0mg |
| Coating quantity | 3.00mg |
| Per unit area coating quantity | 3.59mg/cm 2 |
Polyethylene glycol 6000, titanium dioxide, Talcum and light anhydrous silicic acid joined purify waste water, obtain suspension, previously prepared 10wt% hydroxypropyl emthylcellulose aqueous solution is added wherein, obtain dispersion, dispersion by sieve (No.80), is obtained coating liquid.
The uncoated tablets (400g, about 5000 tablets) that obtains among the embodiment 6 is placed among the Hicoater (HC-LABO, Freund Corporation), and coating liquid is sprayed on it, so that the coating quantity after dry becomes each tablet 3.00mg.After coating finishes, that tablet is dry in Hicoater.
EXPERIMENTAL EXAMPLE 3: stability test
With the tablet that obtains in embodiment 6 to 8 and the Comparative Examples 2 in (1) vial (gas-tight seal), under 40 ℃, 75%RH condition, preserved 6 months, or in (2) vial (unsealing), under 40 ℃, 75%RH, preserved 6 months, and the generation quantity (total amount of related substances) of check related substances and the variation aspect the tone in given time period.With with the same method of EXPERIMENTAL EXAMPLE 1, generation quantity (area percent) by the high effective liquid chromatography for measuring related substances, and visually estimate the variation of tone aspect.
The results are shown in Fig. 4 (vial of gas-tight seal) and Fig. 5 (unencapsulated vial) and table 13 (vial of gas-tight seal) and the table 14 (unencapsulated vial).
The result, even after storing 6 months, film of the present invention-coated tablet shows: the generation quantity of related substances (total amount of related substances) is no more than standard value (1%) for unsealing and gas-tight seal. and in addition, tone does not change and sample is stable.
Table 13
Table 14
Embodiment 9
As follows, preparation film-coated tablet, two kinds of coatings of each tablet of describing in its invading the exterior 15 are to form on the surface of the uncoated tablets of acquisition among embodiment 1 (1).
Table 15
Prepare each coating liquid.That is, titanium dioxide and Talcum joined purify waste water, obtain suspension, previously prepared 10wt% hydroxypropyl emthylcellulose aqueous solution is added wherein, obtain dispersion, dispersion by sieve (No.80), obtained the coating liquid of ground floor.
In addition, poloxamer 188, titanium dioxide, Talcum and light anhydrous silicic acid joined purify waste water, obtain suspension, 10wt% is contained the hydroxypropyl emthylcellulose aqueous solution to add wherein, obtain dispersion, suspension by sieve (No.80), is obtained the coating liquid of the second layer.
With the uncoated tablets (400g that obtains in the foregoing description 1 (1), about 3100 tablets) be placed on Hicoater (HC-LABO, Freund Corporation) in, and the coating liquid of ground floor is sprayed on it, so that the coating quantity after dry becomes each tablet 3.00mg.
Subsequently, the coating liquid of the second layer is sprayed on it, so that the coating quantity after dry becomes each tablet 2.00mg.After coating finishes, that tablet is dry in Hicoater.
EXPERIMENTAL EXAMPLE 4: stability test
With the tablet that obtains among the embodiment 9 in (1) vial (unsealing), under 40 ℃, 75%RH, preserved 1 month, and with and the generation quantity (total amount of related substances) of the same method mensuration related substances of EXPERIMENTAL EXAMPLE 1.As a result, all tablets are stable.
EXPERIMENTAL EXAMPLE 5: solubility test
Use the tablet of embodiment 4, the solubility test (37 ℃, stirring means, 50rpm, separating medium 900ml water) according to the 14th edition description of Japanese Pharmacopoeia carries out solubility test.As a result, the dissolving ratio after 30 minutes is 102.7%.
Industrial applicibility
According to film-coated tablet of the present invention, compd A and the acceptable salt of its physiology are not easy to decompose, and can preserve with stable state, even without protective package such as aluminium packing etc. In addition, during preparation can not cause difficulty. In addition, during administration, do not notice bitter taste.
The application is incorporated herein its full content as reference based on the patent application No.2004-220863 that submits in Japan
Claims (30)
1. a rapidly-soluble film-coated tablet comprises 4-amino-5-chloro-2-ethyoxyl-N-[[4-(4-luorobenzyl)-2-morpholinyl] methyl] Benzoylamide is compd A or the acceptable salt of its physiology,
It is B component that wherein said film-coated tablet comprises at least a pharmaceutical excipient, and described excipient is selected from Polyethylene Glycol, poloxamer, polyoxyethylene hydrogenated Oleum Ricini, polysorbate and glycerol, and
Described tablet has such structure, and wherein compd A or the acceptable salt of its physiology do not contact with B component.
2. film-the coated tablet of claim 1 comprises:
(a) contain compd A or the acceptable salt of its physiology uncoated tablets and
(b) two or more coatings that on the surface of uncoated tablets, form,
The ground floor that wherein forms on uncoated tablets is substantially free of B component, and
One deck at least in the second layer and the succeeding layer contains B component.
3. film-the coated tablet of claim 2, wherein the one deck at least in the second layer and the succeeding layer comprises the B component of 5～98wt% concentration.
4. film-the coated tablet of claim 2, wherein the outermost coatings comprises B component.
5. film-the coated tablet of claim 3, wherein the outermost coatings comprises B component.
6. each film-coated tablet of claim 1～5, wherein B component is a Polyethylene Glycol.
7. film-the coated tablet of claim 2, wherein coatings comprises the ground floor and the second layer, wherein the second layer comprises B component.
8. film-the coated tablet of claim 7, wherein ground floor covers 0.5～10mg/cm
2The surface of uncoated tablets.
9. film-the coated tablet of claim 7, wherein the second layer covers 0.1～20mg/cm
2The surface of ground floor.
10. film-the coated tablet of claim 8, wherein the second layer covers 0.1～20mg/cm
2The surface of ground floor.
11. the film-coated tablet of claim 2, wherein ground floor comprises one or more film coating reagent.
12. claim 1～5 and 7～11 each film-coated tablets, wherein compd A or the acceptable salt of its physiology are the citrate dihydrate of compd A.
13. the film-coated tablet of claim 6, wherein compd A or the acceptable salt of its physiology are the citrate dihydrate of compd A.
14. claim 1～5 and 7～11 each film-coated tablets, wherein uncoated tablets is with ratio inclusion compound A or the acceptable salt of its physiology based on 0.5～70wt% of compd A.
15. the film-coated tablet of claim 6, wherein uncoated tablets is with ratio inclusion compound A or the acceptable salt of its physiology based on 0.5～70wt% of compd A.
16. the film-coated tablet of claim 12, wherein uncoated tablets is with ratio inclusion compound A or the acceptable salt of its physiology based on 0.5～70wt% of compd A.
17. the film-coated tablet of claim 13, wherein uncoated tablets is with ratio inclusion compound A or the acceptable salt of its physiology based on 0.5～70wt% of compd A.
18. claim 1～5 and 7～11 each film-coated tablets are wherein when tablet being placed in the container and under the unsealing condition, storage is in the time of 6 months under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
19. the film-coated tablet of claim 6, wherein when tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
20. the film-coated tablet of claim 12, wherein when tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
21. the film-coated tablet of claim 13, wherein when tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
22. the film-coated tablet of claim 14, wherein when tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
23. the film-coated tablet of claim 15, wherein when tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
24. the film-coated tablet of claim 16, wherein when tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
25. the film-coated tablet of claim 17, wherein when tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 1%.
26. the film-coated tablet of claim 7, wherein uncoated tablets is with the citrate dihydrate based on the ratio inclusion compound A of 0.5～50wt% of compd A,
Ground floor comprises one or more film coating reagent, and covers 0.7～5mg/cm
2Uncoated tablets the surface and
The second layer covers 0.5～10mg/cm
2The surface of ground floor.
27. the film-coated tablet of claim 26, wherein film coating reagent is selected from: hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), ethyl cellulose (EC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and methacrylic acid copolymer.
28. the film-coated tablet of claim 26, wherein B component is a Polyethylene Glycol.
29. the film-coated tablet of claim 7, wherein uncoated tablets is with the citrate dihydrate based on the ratio inclusion compound A of 0.5～30wt% of compd A,
Ground floor comprises hydroxypropyl emthylcellulose, and covers 1.5～3mg/cm
2The surface of uncoated tablets,
The second layer comprises polyethylene glycol 6000, and covers 1～5mg/cm
2The surface of ground floor, and
When tablet being placed in the container and storage is in the time of 6 months under the unsealing condition, under 40 ℃, 75%RH, the related substances ratio of the compd A of generation is not more than 0.6%.
30. commercial package, film-the coated tablet and the written matter relevant with it that comprise claim 1 have wherein comprised the explanation that described film-coated tablet can maybe should be used to promote the gastrointestinal activeness, improve dumping syndrome or prevention or treatment gastroesophageal reflux (GERD) in the written matter on packing material or in packing material.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP220863/2004 | 2004-07-28 | ||
| JP2004220863 | 2004-07-28 | ||
| PCT/JP2005/014150 WO2006011638A1 (en) | 2004-07-28 | 2005-07-27 | Film coated tablet having plural coats |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1993132A CN1993132A (en) | 2007-07-04 |
| CN1993132B true CN1993132B (en) | 2010-05-05 |
Family
ID=35786373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800256271A Expired - Fee Related CN1993132B (en) | 2004-07-28 | 2005-07-27 | Film coated tablet having plural coats |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP4795955B2 (en) |
| KR (1) | KR101038403B1 (en) |
| CN (1) | CN1993132B (en) |
| HK (1) | HK1107257A1 (en) |
| TW (1) | TW200609005A (en) |
| WO (1) | WO2006011638A1 (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2077132A1 (en) | 2008-01-02 | 2009-07-08 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispensing device, storage device and method for dispensing a formulation |
| EA201001453A1 (en) | 2008-03-17 | 2011-04-29 | Бёрингер Ингельхайм Интернациональ Гмбх | TANK AND SPRAYER |
| EP2414560B1 (en) | 2009-03-31 | 2013-10-23 | Boehringer Ingelheim International GmbH | Method for coating a surface of a component |
| JP5763053B2 (en) | 2009-05-18 | 2015-08-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Adapter, inhaler and atomizer |
| EP2504051B1 (en) | 2009-11-25 | 2019-09-04 | Boehringer Ingelheim International GmbH | Nebulizer |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| EA026241B1 (en) | 2009-11-25 | 2017-03-31 | Бёрингер Ингельхайм Интернациональ Гмбх | Nebulizer |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| WO2012130757A1 (en) | 2011-04-01 | 2012-10-04 | Boehringer Ingelheim International Gmbh | Medical device comprising a container |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| WO2013152894A1 (en) | 2012-04-13 | 2013-10-17 | Boehringer Ingelheim International Gmbh | Atomiser with coding means |
| CN103316056B (en) * | 2013-06-24 | 2015-07-08 | 江苏鹏鹞药业有限公司 | Radix isatidis coating dispersible tablet and preparation method thereof |
| EP3030298B1 (en) | 2013-08-09 | 2017-10-11 | Boehringer Ingelheim International GmbH | Nebulizer |
| ES2836977T3 (en) | 2013-08-09 | 2021-06-28 | Boehringer Ingelheim Int | Nebulizer |
| MX2016014403A (en) | 2014-05-07 | 2017-01-20 | Boehringer Ingelheim Int | Container, indicator device, and nebulizer. |
| PL3139979T3 (en) | 2014-05-07 | 2023-12-27 | Boehringer Ingelheim International Gmbh | Unit, nebulizer and method |
| WO2015169430A1 (en) | 2014-05-07 | 2015-11-12 | Boehringer Ingelheim International Gmbh | Nebulizer |
| JP2021518423A (en) * | 2018-04-13 | 2021-08-02 | サムヤン バイオファーマシューティカルズ コーポレイションＳａｍｙａｎｇ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏｒｐｏｒａｔｉｏｎ | Oral coating tablet composition of lenalidomide |
| CN111529492A (en) * | 2020-05-25 | 2020-08-14 | 重庆方通动物药业有限公司 | Compound mosapride soluble powder and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1359680A (en) * | 2001-12-26 | 2002-07-24 | 成都康弘制药有限公司 | Prescription of preparing moxapride citrate |
| EP0814840B1 (en) * | 1996-01-08 | 2002-11-20 | AstraZeneca AB | Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a prokinetic agent |
| US20030007962A1 (en) * | 2001-05-23 | 2003-01-09 | Vergez Juan A. | Pharmaceutical composition containing mosapride and pancreatin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU571312B2 (en) * | 1984-02-10 | 1988-04-14 | Nycomed Danmark A/S | Diffusion coated multiple-units dosage form |
| JPS63264467A (en) * | 1986-04-30 | 1988-11-01 | Dainippon Pharmaceut Co Ltd | Benzamide derivative |
-
2005
- 2005-07-27 WO PCT/JP2005/014150 patent/WO2006011638A1/en active Application Filing
- 2005-07-27 CN CN2005800256271A patent/CN1993132B/en not_active Expired - Fee Related
- 2005-07-27 JP JP2006527890A patent/JP4795955B2/en not_active Expired - Fee Related
- 2005-07-27 TW TW094125372A patent/TW200609005A/en unknown
- 2005-07-27 KR KR1020077002409A patent/KR101038403B1/en not_active IP Right Cessation
-
2007
- 2007-11-26 HK HK07112895.4A patent/HK1107257A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0814840B1 (en) * | 1996-01-08 | 2002-11-20 | AstraZeneca AB | Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a prokinetic agent |
| US20030007962A1 (en) * | 2001-05-23 | 2003-01-09 | Vergez Juan A. | Pharmaceutical composition containing mosapride and pancreatin |
| CN1359680A (en) * | 2001-12-26 | 2002-07-24 | 成都康弘制药有限公司 | Prescription of preparing moxapride citrate |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4795955B2 (en) | 2011-10-19 |
| HK1107257A1 (en) | 2008-04-03 |
| KR101038403B1 (en) | 2011-06-01 |
| TW200609005A (en) | 2006-03-16 |
| CN1993132A (en) | 2007-07-04 |
| WO2006011638A1 (en) | 2006-02-02 |
| JPWO2006011638A1 (en) | 2008-05-01 |
| KR20070042993A (en) | 2007-04-24 |
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