CN104523635B - Mirabegron sustained-release pharmaceutical composition - Google Patents
Mirabegron sustained-release pharmaceutical composition Download PDFInfo
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- CN104523635B CN104523635B CN201410811156.8A CN201410811156A CN104523635B CN 104523635 B CN104523635 B CN 104523635B CN 201410811156 A CN201410811156 A CN 201410811156A CN 104523635 B CN104523635 B CN 104523635B
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- hpmc
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- merariveron
- release tablet
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Abstract
The invention provides a mirabegron sustained-release tablet. The core of the sustained-release tablet is made of hydroxypropyl methyl cellulose serving as a framework material; the mirabegron sustained-release tablet can be continuously released for 8 hours after being orally taken by a human body, and the release amount is not smaller than 90%; and no antioxidants are adopted, so that the pharmacological function and the safety are ensured.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of active medicine meter La Bei for treating overactive bladder
Grand sustained release pharmaceutical composition and preparation method thereof.
Background technology
Mirabegron (mirabegron) tablet was developed by Japanese Astellas (Astellas) drugmaker, in 2011
In Japan's listing, June in 2012,28 food and medicine Surveillance Authority of the Nikkei U.S. (FDA) ratified adult for treating to September on 16th
Human bladder over-activity disease (OAB), trade name Myrbetriq.The molecular formula of Mirabegron is C21H24N4O2S, molecular weight
396, chemical name is (R) -2- (2- amino -1,3-thiazoles -4- bases) -4'- [2- [(2- hydroxyl -2- phenethyls) amino] ethyl]
Phenyl acetamide, its structural formula are as follows：
Mirabegron belongs to fragrant ethanolamines β3Receptor stimulating agent, acts on bladder detrusor smooth muscle β3Adrenoceptor,
Bladder diastole is made, is promoted filling of bladder and is increased urine storage amount, can effectively reduce number of micturitions, improve what bladder hyperactivity caused
Urine, urgent micturition and urinary incontinence etc..Mirabegron is first β for being used to treat overactive bladder3Adrenoceptor is exciting
Agent class medicine, which successfully lists the blank for having filled up beta-2 adrenoceptor agonist in terms for the treatment of overactive bladder.
Mirabegron is in biological agent categorizing system (BCS, biopharmaceutics classification
System belong to the IIIth class of classification in), i.e., highly dissoluble in physiological conditions, hypotonicity medicine.Generation is distributed in vivo
Xie Jun is subject to the appreciable impact of food, and in food, fat can cause C max to decline 45%～75%, AUC declines 17%～51%.
Slow releasing preparation means that in the release medium of regulation lentamente non-constant velocity discharges medicine on request, with corresponding ordinary preparation ratio
Compared with administration frequency at least reduces half than ordinary preparation, or administration frequency has been reduced than ordinary preparation, and can dramatically increase trouble
The preparation of person's compliance or curative effect.Mirabegron is prepared into after slow releasing preparation, by the release speed of effective control active medicine
Rate, then can be prevented effectively from impact of the fat to C max and AUC in food, so as to improve clinical efficacy.
The Merariveron sustained-release tablet for having listed employs hydrophilic gel skeleton slow release means, the framework material for being adopted for
Poly(ethylene oxide) (PEO), the shortcoming using the framework material are that PEO there is substantial amounts of ehter bond on chain due to dividing, therefore are easy to
There is degraded by the attack of oxygen, high temperature, some heavy metal ion, oxidant and ultraviolet can all accelerate its oxidative degradation
Process, it is therefore desirable to add antioxidant BHT (2,6 ditertiary butyl p cresol) in prescription, and poly(ethylene oxide) price is relatively held high
It is expensive, increased medicine manufacturing cost.A kind of Merariveron sustained-release tablet disclosed in Chinese patent CN103655503A, its prescription are constituted
In also using antioxidant, and antioxidant is harmful for human body, it is necessary to do more researchs, and searching is more suitable for human body
The Mirabegron slow releasing preparation taken.
The content of the invention
The invention provides a kind of Merariveron sustained-release tablet, the label of the slow releasing tablet adopts hydroxypropyl methyl cellulose for bone
Frame material, can continue to discharge for 8 hours after human oral, and burst size is not less than 90%, does not use antioxidant, it is ensured that drug effect
And safety.
The Merariveron sustained-release tablet that the present invention is provided, it is characterised in that mass percent is 8～20% active component rice
La Beilong, 30～55% framework material, 30～50% filler, 3～5% binding agent and 0.5～5% lubricant,
Hydroxypropyl methyl fiber of 2% aqueous solution viscosity range for 70mPaS～550mPaS when the framework material is 20 DEG C
Element.
Hydroxypropyl methyl cellulose (HPMC) is the one kind in the framework material for can be used for matrix type sustained and controlled release medicament preparation,
Model comprising different viscosities is various, for exampleK100M CR (7500mPaS～140000mPaS, 20 DEG C,
2% aqueous solution, LG-DOW),K15MCR (13275mPaS～24780mPaS, 20 DEG C, 2% water
Solution, LG-DOW),K4MCR (2663mPaS～4970mPaS, 20 DEG C, 2% aqueous solution, U.S.'s pottery
Family name),K100LVCR (80mPaS～120mPaS, 20 DEG C, 2% aqueous solution, LG-DOW),E6LV (4.8mPaS～7.2mPaS, 20 DEG C, 2% aqueous solution, LG-DOW),E5LV
(4.0mPaS～6.0mPaS, 20 DEG C, 2% aqueous solution, LG-DOW),SB-4 (about 4mPaS, 20
DEG C, 2% aqueous solution, Japanese SHIN-ETSU HANTOTAI's chemistry),65SH-50 (about 50mPaS, 20 DEG C, 2% aqueous solution, Japan's letter
It is more chemical),90SH-100 (about 100mPaS, 20 DEG C, 2% aqueous solution, Japanese SHIN-ETSU HANTOTAI's chemistry),
90SH-400 (about 400mPaS, 20 DEG C, 2% aqueous solution, Japanese SHIN-ETSU HANTOTAI's chemistry),90SH-4000 is (about
4000mPaS, 20 DEG C, 2% aqueous solution, Japanese SHIN-ETSU HANTOTAI's chemistry),90SH-15000 (about 15000mPaS, 20
DEG C, 2% aqueous solution, Japanese SHIN-ETSU HANTOTAI's chemistry),90SH-30000 (about 30000mPaS, 20 DEG C, 2% aqueous solution,
Japanese SHIN-ETSU HANTOTAI's chemistry), etc..The product of the different brands with similar viscosity can be replaced when sustained-release preparation is studied and be made
With.
Impact of the inventor to the HPMC of different model to the rate of release of Mirabegron is studied.In HPMC percentages
In the case of content identical, release profiles when model is respectively K100M CR, K15MCR, K4MCR, K100LVCR are shown in accompanying drawing 1,
It can be seen that release profiles during with K100LVCR as framework material show that the medicine for being substantially better than other models HPMC tires out
Meter release, therefore the framework material HPMC being considered as is (viscous with other models for K100LVCR or K100LVCR is used alone
Degree) HPMC be used in mixed way, i.e., the framework material in prescription at least will use 20 DEG C when 2% solution viscosity 80mPaS～
The hydroxypropyl methyl cellulose of 120mPaS.And with reference to the accompanying drawings in the prescription shown in 2 K100LVCR different quality percentage ratio pair
The result of study of the impact of drug release finds that the rate of release of active medicine Mirabegron subtracts with increasing for HPMC consumptions
It is little, therefore release of the control of the consumption of HPMC to medicine is extremely important.Find in research no matter individually only with a kind of model or
Be used in mixed way the HPMC of Multiple Type, the viscosity of the framework material HPMC finally used in prescription be 30mPaS～
During 1734mPaS, account for Prescription quality percentage composition for 20～60% when, drug release is more satisfactory.It is preferred that when 20 DEG C 2% water
HPMC of the solution viscosity range for 70mPaS～550mPaS, weight/mass percentage composition is 30～55%, continues to discharge for 8 hours,
And 8 hours cumulative release amounts reach more than 90%.When various different viscosities HPMC are combined use, determining viscous using front
Degree, when being displayed in above-mentioned range of viscosities can use.It is preferred that at least one of K100LVCR and K15MCR, K4MCR are combined and are made
When being used in combination with other models HPMC with, K100LVCR, K100LVCR consumptions account for HPMC gross weights 30%～90%, preferably 80～
90%.The HPMC of above-mentioned model can be substituted by the HPMC of other producer's similar viscosities and be used.
The property of filler is also had a major impact to the release behavior of Mirabegron, and its dissolubility affects the fast of gel formation
Slowly, so to affect medicine rate of release.The filler of the present invention is required as water solublity, optional pregelatinized Starch, Pyrusussuriensiss
Alcohol, maltose alcohol, PEARLITOL 25C, Microcrystalline Cellulose, silicified microcrystalline cellulose, Lactose (include lactose monohydrate and Anhydrous Lactose),
At least one of PVPk30, Polyethylene Glycol (including PEG1500, PEG6000, PEG20000).Inventor is to different filleies pair
Accompanying drawing 3 is shown in the investigation that Mirabegron rate of release affects, when as a result showing that filler is using PEG6000 and Lactose in prescription, work
The rate of release and Cumulative release amount of property medicine best suits requirement.According to the investigation result of filler, the present invention selects PEG6000
Individually or with the combination of Lactose or Microcrystalline Cellulose as filler, it is 30～50% that filler accounts for the mass percent of prescription,
It is preferred that PEG6000 is combined with Lactose as filler, PEG 6000 is 1～2 with the mass ratio of Lactose：1.
The adoptable binding agent of the present invention is selected from hydroxypropyl cellulose (HPC-SL, HPC-SSL, HPC-L, HPC-M, HPC-
H, Tso Tat Co., Ltd., Japan), sodium carboxymethyl cellulose (CMC-Na), Copolyvidone (Kolidon VA64), methylcellulose,
At least one of carboxymethyl cellulose, polyvinyl pyrrolidone.Due to crude drug Mirabegron mobility it is poor, usual wet method
The preparation method of pelletizing press sheet, the preferred hydroxypropyl cellulose of binding agent, the preferred HPC-SL of model, binding agent account for total Prescription quality hundred
Divide than being 2～7%, preferably 3～5%.
Lubricant (including fluidizer) of the present invention is planted selected from magnesium stearate, calcium stearate, Glyceryl Behenate, hydrogenation
At least one of thing oil, Pulvis Talci, micropowder silica gel, at least one in preferred magnesium stearate, micropowder silica gel, lubricant quantity are accounted for
0.5～5%, preferably the 1～2.5% of total recipe quantity mass percent.
The Merariveron sustained-release tablet of the present invention can adopt powder vertical compression, dry granulation tabletting, the technique of wet granule compression tablet
Prepare, but crude drug mobility is poor to be found to crude drug Quality Research, to wet stable, therefore preferably adopt wet granulation
The technique of tabletting, including granulation, granulate, total mixed, preparation process of tabletting, may also include and tablet is coated using coating materials
The step of.
The Merariveron sustained-release tablet that the present invention is provided, label adopt hydroxypropyl methyl cellulose for framework material, and find
Viscosity for 80mPaS～120mPaS (20 DEG C, 2% aqueous solution) hydroxypropyl cellulose as framework material when, activity
The release duration of medicine Mirabegron and Cumulative release amount are optimum, can individually using the viscosity HPMC models or and other
The HPMC models of viscosity are used in mixed way as framework material, and the viscosity for making framework material HPMC total is in 70mPaS～550mPa
Between S, so as to get product release in vitro grinds the Mirabegron slow release that product is consistent, prepares using wet granulation technology with original
Tablet stability is good, it is oral after can continue to discharge for 8 hours, and burst size is not less than 90%, it is ensured that drug effect.Compare the system that original is ground
Agent, employs more cheap framework material, has saved in cost, and prescription without antioxidant, it is ensured that drug safety.
Further below with reference to specific embodiment embodiment and Figure of description the present invention will be further described.
Figure of description
Impacts of accompanying drawing 1 different viscosities (model) HPMC to active agent release rate
Impacts of the 2 different content HPMC K100LVCR of accompanying drawing to active agent release rate
3 different impacts of the filler to active agent release rate of accompanying drawing
Specific embodiment
Embodiment 1
Prescription is constituted
The total HPMC viscosity of prescription middle skeleton material (20 DEG C, 2% aqueous solution) is 120mPaS.
Preparation method：
By 1000g Mirabegron crude drug, 330g HPMCK4MCR、1670g HPMC K100LVAnd 960g PEG6000,
790g Lactose is added in fluidized bed pelletizer, carries out pelletize with 200g 10%HPC-SL aqueous solutions, after granulate, adds 25g hard
Fatty acid magnesium and 25g micropowder silica gels, carry out tabletting with rotary tablet machine, obtain the Merariveron sustained-release tablet of piece weight 250mg.
Dissolution experiments：
Dissolution test is carried out to obtained Merariveron sustained-release tablet according to USP dissolution test methods (basket method).Release medium is used
The phosphate buffer of the pH6.8 of 900mL, determines 2h using UV, and 4h, 8h Accumulation dissolution is as a result as follows：
| Time | 2h | 4h | 8h |
| Accumulative releasing degree | (20.25 ± 0.74) % | (49.54 ± 1.73) % | (101.34 ± 0.55) % |
As a result show that rate of release is steady in this product 8 hours, and discharge be close to it is complete.
Stability test：
By the sealing placement 3 in medicinal high-density polyethylene bottle and aluminum/aluminum blister package respectively of obtained Mirabegron piece
Individual month (40 DEG C, 75%RH), and place 15 days under the conditions of illumination (4500 ± 50) lx, product under the conditions of investigation is above-mentioned 3 kinds
Stability.According to above-mentioned dissolution laboratory method, determine product after placing in 2h, 4h, 8h Accumulation dissolution is as a result as follows:
As a result after showing to place, dissolution rate is front with placement without substantially change, and product stability is good.
Product is investigated simultaneously to be sealed in medicinal high-density polyethylene bottle, under conditions of 40 DEG C, 75%RH places 3
Month, 0, relevant material situation of change when 1,2,3 month determines relevant content of material using HPLC.As a result it is as follows：
As a result show that relevant material has no significantly raised.
Embodiment 2
Prescription table
The total HPMC viscosity of prescription middle skeleton material (20 DEG C, 2% aqueous solution) is 115mPaS.
Preparation method：
By 1000g Mirabegron crude drug, 330g HPMCK4MCR、HPMC K100LV1670th, 960g Polyethylene Glycol, 790g are newborn
Sugar is added in fluidized bed pelletizer, carries out pelletize with 200g 10%HPC-SL aqueous solutions, after granulate, adds 25g magnesium stearate
And 25g micropowder silica gels, tabletting is carried out with rotary tablet machine, high-efficiency coating machine, spray coating thin film bag are adopted to obtained tablet
The aqueous dispersions of clothing agent (OPADRY 03F22733), obtain the Merariveron sustained-release tablet of piece weight 257.5mg.
Embodiment 3
Prescription table
The total HPMC viscosity of prescription middle skeleton material (20 DEG C, 2% aqueous solution) is 85mPaS.
Preparation method：
By 100g Mirabegron crude drug, HPMCK4MCR 38g、HPMC K100LV187g, PEG6000155g, are placed in mixing
It is uniformly dispersed in granulator, adds 10% hydroxypropyl cellulose aqueous solutions of 15g to carry out pelletize, after granulate, adds magnesium stearate 5g
Be sufficiently mixed, tabletting carried out using rotary tablet machine, obtain the Merariveron sustained-release tablet of piece weight 250mg.
Embodiment 4
Prescription table
The total HPMC viscosity of prescription middle skeleton material (20 DEG C, 2% aqueous solution) is 345mPaS.
Preparation method：
By 100g Mirabegron crude drug, 290g HPMCK4MCR、HPMC K100LV164 and 195g Polyethylene Glycol, use 85g
10%HPC-SL aqueous solutions carry out pelletize, obtain the sustained release pharmaceutical composition granule of the present invention.By the slow releasing pharmaceutical group of the present invention
After compound carries out granulate, 25g magnesium stearate and 25g micropowder silica gels are added, tabletting is carried out with rotary tablet machine, is obtained piece weight
The Merariveron sustained-release tablet of 250mg.
Embodiment 5
Prescription table
The total HPMC viscosity of prescription middle skeleton material (20 DEG C, 2% aqueous solution) is 548mPaS.
Preparation method：
By 1000g Mirabegron crude drug, 135g HPMK15MCR、240g HPMC K4MCR、1875g HPMC K100LV、
1200g PEG6000,550g Lactose is added in fluidized bed pelletizer, is carried out pelletize with 200g 10%HPC-SL aqueous solutions, is obtained
To the sustained release pharmaceutical composition granule of the present invention.The sustained release pharmaceutical composition of the present invention is carried out after granulate, 50g stearic acid is added
Magnesium, carries out tabletting with rotary tablet machine, obtains the Merariveron sustained-release tablet of piece weight 250mg.
Embodiment 6
Prescription table
The total HPMC viscosity of prescription middle skeleton material (20 DEG C, 2% aqueous solution) is 208mPaS.
Preparation method：
By 1000g Mirabegron crude drug, 20g HPMK15MCR、1800g HPMC K100LV、960g PEG6000、
8400gMCC is added in fluidized bed pelletizer, carries out pelletize with 150g 10%HPC-SL aqueous solutions, after granulate, adds 50g hard
Fatty acid magnesium, carries out tabletting with rotary tablet machine, obtains the Merariveron sustained-release tablet of piece weight 250mg.
7 embodiment 1-6 product of embodiment grinds the contrast of product (RLD) release in vitro situation with original
Using non-pattern fitting method, by f2Similar factors and f1The calculating of difference factor, comparative example's prescription and original
Whether the release behavior for grinding product is consistent.As a result see the table below：
Embodiment grinds product accumulation burst size with original
Non- models fitting f2With f1As a result table
Work as f2>50, it is believed that the two release behavior is consistent, f1<15 think that the two release behavior is consistent, therefore result shows this
It is consistent that Merariveron sustained-release tablet prepared by invention grinds product release in vitro with original.
Claims (5)
1. a kind of Merariveron sustained-release tablet, it is characterised in that by the active component Mirabegron that mass percent is 8～20%,
30～55% framework material, 30～50% filler, 3～5% binding agent and 0.5～5% lubricant composition, it is described
Hydroxypropyl methyl cellulose of 2% aqueous solution viscosity range for 70mPaS～550mPaS, institute when framework material is 20 DEG C
Stating hydroxypropyl methyl cellulose and being combined with least one of HPMC K15MCR, HPMC K4MCR for model HPMC K100LVCR is made
With wherein HPMC K100LVCR account for the 30～90% of HPMC total amounts, and the filler is selected from PEG6000 or PEG6000 and Lactose
Or the combination of Microcrystalline Cellulose, described adhesive is hydroxypropyl cellulose HPC-SL, and the lubricant is selected from magnesium stearate, micropowder
At least one in silica gel.
2. Merariveron sustained-release tablet according to claim 1, it is characterised in that the hydroxypropyl methyl cellulose is model
HPMC K100LVCR and HPMC K4MCR are applied in combination.
3. Merariveron sustained-release tablet according to claim 1, it is characterised in that the filler is selected from PEG6000 and breast
The combination of sugar, PEG 6000 are 1～2 with the mass ratio of Lactose：1.
4. Merariveron sustained-release tablet according to claim 1, it is characterised in that its preparation method is wet granule compression tablet work
Skill, comprising granulation, granulate, total mixed, tabletting preparation process.
5. Merariveron sustained-release tablet according to claim 1, it is characterised in that its preparation method is also comprising using coating materials
The step of tablet is coated.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3777853A1 (en) * | 2019-08-14 | 2021-02-17 | Biohorm, S.L. | Mirabegron composition and uses thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106361715A (en) * | 2016-09-02 | 2017-02-01 | 迪沙药业集团有限公司 | Mirabegron composition |
| EP3335700A1 (en) * | 2016-12-13 | 2018-06-20 | Stada Arzneimittel Ag | Solid pharmaceutical oral dosage form comprising an extended release of the active ingredient comprising mirabegron |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102170878A (en) * | 2008-09-30 | 2011-08-31 | 安斯泰来制药株式会社 | Controlled release pharmaceutical composition |
| EP2554168A1 (en) * | 2010-03-29 | 2013-02-06 | Astellas Pharma Inc. | Controlled release pharmaceutical composition |
| CN103655503A (en) * | 2013-11-25 | 2014-03-26 | 北京润德康医药技术有限公司 | Merariveron sustained-release tablet and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102170878A (en) * | 2008-09-30 | 2011-08-31 | 安斯泰来制药株式会社 | Controlled release pharmaceutical composition |
| EP2554168A1 (en) * | 2010-03-29 | 2013-02-06 | Astellas Pharma Inc. | Controlled release pharmaceutical composition |
| CN103655503A (en) * | 2013-11-25 | 2014-03-26 | 北京润德康医药技术有限公司 | Merariveron sustained-release tablet and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3777853A1 (en) * | 2019-08-14 | 2021-02-17 | Biohorm, S.L. | Mirabegron composition and uses thereof |
| WO2021028538A1 (en) * | 2019-08-14 | 2021-02-18 | Biohorm S.L. | Mirabegron composition and uses thereof |
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