CN109200025A - A kind of asenapine maleate sublingual tablet - Google Patents
A kind of asenapine maleate sublingual tablet Download PDFInfo
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- CN109200025A CN109200025A CN201710531267.7A CN201710531267A CN109200025A CN 109200025 A CN109200025 A CN 109200025A CN 201710531267 A CN201710531267 A CN 201710531267A CN 109200025 A CN109200025 A CN 109200025A
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- sublingual tablet
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- asenapine maleate
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- Molecular Biology (AREA)
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Abstract
The invention belongs to technical field of pharmaceuticals, more particularly to a kind of asenapine maleate sublingual tablet, the asenapine maleate sublingual tablet is by weight percentage comprising following components: asenapine maleate 10-25%, acid-base pair 20-30%, disintegrating agent 50-65%, dispersing agent 1-2%, corrigent 0.1-1% and lubricant 1-2%.Asenapine maleate sublingual tablet prepared by the present invention has many advantages, such as that low production cost, quick release, friability are low, be convenient for carrying, can effectively taste masking, facilitate medication.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of asenapine maleate sublingual tablet.
Background technique
Asenapine maleate (asenapine maleate) be by Organon BioSciences company research and development,
The second generation psychotherapeutic drugs of ScheringPlough company production, on the FDA approval Ou Jianong on the 13rd of August in 2009
City, trade name(asenapine sublingual tablets), specification has 5mg and 10mg (with Arsenal
Flat meter), schizophrenia and adult mania or mixing with or without mental characteristics are recognized for emergency treatment by sublingual administration
The bipolar I type disease of type, and chronic serious and capacity deviation the severe psychiatric diseases for the treatment of.
The embodiment 16 of document 1 (Publication No. CN1861604A patent) discloses the medicine containing asenapine maleate
Compositions, the composition is by the way that the micronization of asenapine maleate to be added in gelatin/mannitol matrix, according to dosage
(250mg) is weighed in pre-formed bag.By passing through freezing channel, matrix is frozen in cover.Then in freeze-dryer
Middle sublimated ice is frozen and dried piece, the complex process, every manufacture 1, i.e., need to weigh primary, repeatedly weighs and causes the process time
Long, Dose accuracy reduces, and freeze drying process, and kinetic energy requires greatly, and sublimation drying is done up to even 48h for 24 hours
It is the easy moisture absorption of dry freezing piece, loose, extra package is needed, and improves preparation cost.The loose performance of height necessarily causes friability
Reduction, transport be easy to appear in carrying process it is broken, it is broken to may cause appearance and reduce compliance.
The embodiment 1 of document 2 (Publication No. CN103893139A patent) discloses a kind of prescription work containing sublimed agent
Skill, after compacting, use (Examples 1 to 3 with 80 DEG C of high temperature the distil 5h) distillation for a long time of 30~100 DEG C of high temperature and formed it is porous,
Loose porous tablet, bad mechanical strength are easy to cause fragment in packaging, transportational process, therefore commercial viability is poor,
And select camphor for sublimed agent in Examples 1 to 3, wherein the fusing point of camphor be 80.5 DEG C, with 80 DEG C it is dry when, lead to camphor
Melt and leads to that tablet collapses and can not produce the unified preparation of slice shape.
The embodiment 9,10 of document 3 (Publication No. CN102952144 A patent) discloses a kind of Malaysia containing asenapine
The sublingual tablet of hydrochlorate specific crystal formation A or B, with the premixing auxiliary material Ludiflash of Basf company (mannitol, crospovidone,
Polyvinyl acetate, povidone and lauryl sodium sulfate etc.) composition, wherein polyvinyl acetate softening point temperature is about 38
DEG C, when carrying out drug influence Factor Experiment (60 DEG C), which softens and disintegration rate is caused to slow down, therefore not can guarantee medicine
The long-term property of object is stablized.
Meanwhile asenapine maleate bitter, conventional use flavoring agent method can not cover its disagreeable taste completely,
To reduce the compliance of mental patient's medication.
This product as sublingual administration drug, such as using common auxiliary material for example microcrystalline cellulose, low-substituted hydroxypropyl cellulose,
The insoluble material such as starch, although disintegration rate is very fast, under oral conditions, saliva amount is few, can not disperse after disintegration, thus
It generates feeling of grittiness and forms swallowing act, it can not effective sublingual mucosal absorption；And use water-soluble good polyethylene glycol, sweet dew
The materials results such as alcohol, sorbierite, sucrose, glucose, sodium chloride, tabletting viscosity is big, be easy to cause sticking and can not continuous tabletting,
Meanwhile the tablet of compacting occurs that disintegration rate is slow, is unable to reach the purpose of fater disintegration dissolution.Such as using conventional effervescent tablet skill
Art, sticking are the problems of effervescent tablet, are needed to environment strict control humidity is prepared, and production difficulty is big, meanwhile, effervescent tablet effervescent agent
Dosage is big (such as document 4: Publication No. CN102058480 A patent), and in a piece of effervescent tablet, acid-base pair reaches 500mg or more, takes
When be added in 100ml water after completely dissolution, then liquid of taking medicine is not suitable for preparing sublingual effervescent tablet.
Summary of the invention
Invention broadly provides a kind of asenapine maleate sublingual tablet, there is low production cost, quick release, crisp
It is broken degree it is low, be convenient for carrying, can effectively taste masking, facilitate the advantages that medication.Its technical solution is as follows:
A kind of asenapine maleate sublingual tablet, by weight percentage comprising following components: asenapine Malaysia
Hydrochlorate 10-25%, acid-base pair 20-30%, disintegrating agent 48-65%, dispersing agent 1-2%, corrigent 0.1-1% and lubricant 1-2%.
Preferably, the acid-base pair is made of sour agent and alkaline agent, it is described acid agent be selected from tartaric acid, citric acid, ascorbic acid,
One of malic acid and maleic acid are a variety of, and the alkaline agent is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, saleratus and carbon
One of sour calcium is a variety of.
Preferably, the sour agent is one or both of tartaric acid and citric acid, and the alkaline agent is sodium bicarbonate and carbon
One or both of potassium hydrogen phthalate.
Preferably, the sour agent accounts for the 10-18% of slice weight, and the alkaline agent accounts for the 10-14% of slice weight.
Preferably, the disintegrating agent is crospovidone, and crospovidone is also referred to as cross-linking polyethylene pyrrolidines, referred to as
PVPP, such as PVPP-xl, PVPP-SF etc..
Preferably, the dispersing agent is colloidal silicon dioxide.
Preferably, the corrigent is Sucralose.
Preferably, the lubricant is magnesium stearate.
Preferably, asenapine maleate, dispersing agent, corrigent, sour agent and partial disintegration agent are as in drug plus portion
Point, use adhesive to pelletize in a manner of normal wet granulation, alkaline agent, remaining disintegrating agent and lubricant as drug Extra Section,
Tabletting after interior plus part is mixed with Extra Section；In wherein plus the quality of partial disintegration agent is the 1- of Extra Section disintegrating agent quality
8 times.
Preferably, described adhesive not alcohol-containing, preferably water.
Using the above scheme, the invention has the following advantages that
The present invention provides a kind of special formula, using being pressed into asenapine maleate after wet granulation
(Asenapine maleate) sublingual tablet, is used simultaneously using acid-base pair and insoluble disintegrating agent, can effectively improve tablet
Disintegration dissolution rate, and there is the absorption rate similar with former triturate, and meet friability requirement.Meanwhile when taking,
After tablet immerses saliva, atmospheric carbon dioxide is released immediately out, benumbs taste bud, to effectively avoid the bitter taste of drug, improves and suffers from
The compliance of person's medication.Using this method produce asenapine maleate sublingual tablet, have withIt is identical molten
Absorption rate out is provided simultaneously with the advantages that production cost is low, and patient takes economy, convenient transportation, carries.
Detailed description of the invention
Embodiment 1 (20130513-1 batches) that Fig. 1 is dissolution medium when being water and embodiment 6 (140401 batches) prepare sublingual
The sublingual tablet of piece and desivac preparationDissolution curve；
Fig. 2 be dissolution medium be pH4.5 buffer when embodiment 1 (20130513-1 batch) and embodiment 6 (140401
Batch) preparation sublingual tablet and desivac preparation sublingual tabletDissolution curve；
Fig. 3 be dissolution medium be pH6.8 buffer when embodiment 1 (20130513-1 batch) and embodiment 6 (140401
Batch) preparation sublingual tablet and desivac preparation sublingual tabletDissolution curve；
It is prepared by embodiment 1 (20130513-1 batches) that Fig. 4 is dissolution medium when being 0.1M hydrochloric acid and embodiment 6 (140401 batches)
Sublingual tablet and desivac preparation sublingual tabletDissolution curve；
Fig. 5 is the sublingual tablet of sublingual tablet prepared by embodiment 8 and desivac preparationSingle sublingual administration is given
Beasle dog mean blood plasma concentration-time plot.
Specific embodiment
Embodiment 1-8
Material and proportion are shown in Table shown in 1-2 in each embodiment.
1 embodiment 1-5 prescription of table
2 embodiment 6-8 prescription of table
Above each prescription preparation process is equal are as follows: sieves with 100 mesh sieve each material, weighs according to recipe quantity, by asenapine horse
Carry out hydrochlorate to be uniformly mixed with each interior plus material, adhesive is added, is pelletized using conventional method, dry, whole grain is added alkaline agent and mixes
Afterwards, lubricant, disintegrating agent are added, is mixed, tabletting.
Embodiment 9
The measurement of dissolution rate:
Sublingual tablet made of difference Example 1 (20130513-1 batches) and embodiment 6 (140401 batches) and freeze-drying legal system
Standby sublingual tablet(5mg, Schering-Plough) each 6, according to dissolution method [Chinese Pharmacopoeia version in 2015
Two annex X C (the second method)] it measures respectively, with water, pH4.5 acetate buffer solution, pH6.8 phosphate buffer and 0.1N hydrochloric acid
500ml is solvent, and revolving speed 50rpm is operated according to methods.It is sampled respectively at different time, using ultraviolet spectrophotometry at 270nm
Measure the amount of dissolution.
As a result as shown in Figs 1-4.By Fig. 1-4 it is found that embodiment 1 and embodiment 6 make sublingual tablet by oneself in 4 kinds of dissolution medium items
Under part, dissolution curve withIt is similar, the amount of dissolution > 80% in 2min.
Embodiment 10
The sublingual tablet that embodiment 8 is developed using Beagle dog withCarry out Internal pharmacokinetics evaluation, beasle dogWeight 8.45-11.20kg, the experimental animal age: -2 years 6 months, it is dynamic that Guangzhou medical industry studies total institute's experiment
Object research and development centre (production licence number: SCXK (Guangdong) 2008-0007, quality certification number: 44006900000003).
Experimental result is as shown in table 3:
3 Beagle dog Internal pharmacokinetics evaluation result of table
Experimental result is shown: self-control sublingual tablet and reference preparationWith similar pharmacokinetics behavior, phase
To bioavilability F to make in terms of sublingual tablet (115.1 ± 13.0) % (n=6) by oneself.
It will be apparent to those skilled in the art that can make various other according to the above description of the technical scheme and ideas
Corresponding change and deformation, and all these changes and deformation all should belong to the protection scope of the claims in the present invention
Within.
Claims (10)
1. a kind of asenapine maleate sublingual tablet, by weight percentage comprising following components: asenapine maleic acid
Salt 10-25%, acid-base pair 20-30%, disintegrating agent 48-65%, dispersing agent 1-2%, corrigent 0.1-1% and lubricant 1-2%.
2. asenapine maleate sublingual tablet according to claim 1, it is characterised in that: the acid-base pair by sour agent and
Alkaline agent composition, the acid agent is selected from one of tartaric acid, citric acid, ascorbic acid, malic acid and maleic acid or a variety of, described
Alkaline agent is selected from one of sodium bicarbonate, sodium carbonate, potassium carbonate, saleratus and calcium carbonate or a variety of.
3. asenapine maleate sublingual tablet according to claim 2, it is characterised in that: it is described acid agent be tartaric acid and
One or both of citric acid, the alkaline agent are one or both of sodium bicarbonate and saleratus.
4. asenapine maleate sublingual tablet according to claim 2, it is characterised in that: the acid agent accounts for slice weight
10-18%, the alkaline agent account for the 10-14% of slice weight.
5. asenapine maleate sublingual tablet according to claim 1, it is characterised in that: the disintegrating agent is that crosslinking is poly-
Tie up ketone.
6. asenapine maleate sublingual tablet according to claim 1, it is characterised in that: the dispersing agent is colloidal state two
Silica.
7. asenapine maleate sublingual tablet according to claim 1, it is characterised in that: the corrigent is trichlorine sugarcane
Sugar.
8. asenapine maleate sublingual tablet according to claim 1, it is characterised in that: the lubricant is stearic acid
Magnesium.
9. asenapine maleate sublingual tablet according to claim 2, it is characterised in that: asenapine maleate,
Dispersing agent, corrigent, sour agent and partial disintegration agent use adhesive system in a manner of normal wet granulation as in drug plus part
Grain, alkaline agent, remaining disintegrating agent and lubricant are as drug Extra Section, tabletting after interior plus part is mixed with Extra Section；Wherein
Interior plus partial disintegration agent quality is 1-8 times of Extra Section disintegrating agent quality.
10. asenapine maleate sublingual tablet according to claim 9, it is characterised in that: described adhesive is water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710531267.7A CN109200025A (en) | 2017-06-29 | 2017-06-29 | A kind of asenapine maleate sublingual tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710531267.7A CN109200025A (en) | 2017-06-29 | 2017-06-29 | A kind of asenapine maleate sublingual tablet |
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| Publication Number | Publication Date |
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| CN109200025A true CN109200025A (en) | 2019-01-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710531267.7A Pending CN109200025A (en) | 2017-06-29 | 2017-06-29 | A kind of asenapine maleate sublingual tablet |
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|---|---|---|---|---|
| CN1861604A (en) * | 2005-04-07 | 2006-11-15 | 奥格诺爱尔兰有限公司 | Crystal form of asenapine maleate |
| CN1901891A (en) * | 2003-12-31 | 2007-01-24 | 奇马实验室公司 | Effervescent oral opiate dosage form |
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| CN101181267A (en) * | 2007-11-30 | 2008-05-21 | 重庆医科大学医药研究所 | Zolmitriptan tongue tablet |
| CN102952144A (en) * | 2011-08-29 | 2013-03-06 | 上海华拓医药科技发展股份有限公司 | Crystal forms of asenapine maleate, and preparation method and medical composition thereof |
| WO2013114400A2 (en) * | 2012-01-20 | 2013-08-08 | Rubicon Research Private Limited | Compressed pharmaceutical compositions of atypical antipsychotics |
| CN103893139A (en) * | 2012-12-28 | 2014-07-02 | 石药集团中奇制药技术（石家庄）有限公司 | Asenapine composition and preparation method thereof |
| WO2014127786A1 (en) * | 2013-02-22 | 2014-08-28 | Zentiva, K.S. | Orally disintegrating pharmaceutical composition comprising asenapine |
| CN106580902A (en) * | 2017-02-24 | 2017-04-26 | 佛山市弘泰药物研发有限公司 | Brexpiprazole oral disintegrating tablet and preparation method thereof |
| CN106667929A (en) * | 2015-11-10 | 2017-05-17 | 天津汉瑞药业有限公司 | Asenapine tablets and preparation method thereof |
| CN106667931A (en) * | 2015-11-10 | 2017-05-17 | 天津汉瑞药业有限公司 | Tablet containing asenapine and preparation method thereof |
-
2017
- 2017-06-29 CN CN201710531267.7A patent/CN109200025A/en active Pending
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| CN1901891A (en) * | 2003-12-31 | 2007-01-24 | 奇马实验室公司 | Effervescent oral opiate dosage form |
| CN1861604A (en) * | 2005-04-07 | 2006-11-15 | 奥格诺爱尔兰有限公司 | Crystal form of asenapine maleate |
| CN1970085A (en) * | 2005-11-25 | 2007-05-30 | 上海秀新臣邦医药科技有限公司 | Orally disintegrating tablet of ubenimex and preparation method thereof |
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| CN106667931A (en) * | 2015-11-10 | 2017-05-17 | 天津汉瑞药业有限公司 | Tablet containing asenapine and preparation method thereof |
| CN106580902A (en) * | 2017-02-24 | 2017-04-26 | 佛山市弘泰药物研发有限公司 | Brexpiprazole oral disintegrating tablet and preparation method thereof |
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| Title |
|---|
| 田燕: "《中药学专业知识（一）》", 30 May 2007 * |
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