CN105193803B - A kind of Ilepcimide sustained release preparation and preparation method thereof - Google Patents
A kind of Ilepcimide sustained release preparation and preparation method thereof Download PDFInfo
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- CN105193803B CN105193803B CN201410301465.0A CN201410301465A CN105193803B CN 105193803 B CN105193803 B CN 105193803B CN 201410301465 A CN201410301465 A CN 201410301465A CN 105193803 B CN105193803 B CN 105193803B
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- ilepcimide
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- BLPUOQGPBJPXRL-UHFFFAOYSA-N (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine Natural products C=1C=C2OCOC2=CC=1C=CC(=O)N1CCCCC1 BLPUOQGPBJPXRL-UHFFFAOYSA-N 0.000 title claims abstract description 42
- BLPUOQGPBJPXRL-FNORWQNLSA-N Ilepcimide Chemical compound C=1C=C2OCOC2=CC=1/C=C/C(=O)N1CCCCC1 BLPUOQGPBJPXRL-FNORWQNLSA-N 0.000 title claims abstract description 42
- 229950000956 ilepcimide Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 49
- 239000000853 adhesive Substances 0.000 claims abstract description 14
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- 238000000576 coating method Methods 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
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- -1 aryl pyrimidines Chemical class 0.000 description 4
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- 239000006002 Pepper Substances 0.000 description 3
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- QWMVKSPSWWCSEK-UHFFFAOYSA-N ethene;pyrrolidin-2-one Chemical class C=C.O=C1CCCN1 QWMVKSPSWWCSEK-UHFFFAOYSA-N 0.000 description 2
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- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 2
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 2
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
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- 208000017667 Chronic Disease Diseases 0.000 description 1
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- 108010019160 Pancreatin Proteins 0.000 description 1
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- MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical class C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a kind of Ilepcimide sustained release preparations and preparation method thereof.A kind of Ilepcimide sustained release preparation includes following components by percentage to the quality: Ilepcimide 10-60%, slow-release material 30-85%, adjusting drug release material 0-10%, adhesive 0-3%, filler 5-20%, lubricant 0-2% and coating material 0-5%；Ilepcimide sustained release preparation of the invention can be controlled rate discharge drug, so that preparation is achieved the purpose that Ilepcimide can be discharged in about 24 hours by daily single.The invention further includes the preparation method of Ilepcimide sustained release preparation.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, in particular to a kind of Ilepcimide sustained release preparation and preparation method thereof.
Background technique
Epilepsy is central nervous system chronic disease, needs long-term drug therapy.The antiepileptic clinically used at present
The effective percentage of object only has 70%~80%, and antiepileptic cannot prevent the formation of epileptogenic focus and the progressive of the course of disease, Zhi Nenghuan
Solve symptom.In addition, antiepileptic adverse reaction is more, it is related to multiple systems of human body, common adverse reactions such as fash, head
Dizzy, nausea receives poor, mental act exception, Liver and kidney function exception, endocrine system dysfunction, enlargement of lymph nodes etc..And
Epileptic generally requires Long-term taking medicine or takes several antiepileptics simultaneously, this can aggravate the adverse reaction of drug.Children
Phase is important growth and development stage, therefore the treatment of Patients with Epilepsy in Childhood is different from adult, and application effect is significant, adverse reaction is few
Antiepileptic carry out treatment be very important.Pepper belongs to dialypetalous flower plant, is the evergreen liana of Piperaceae.Using
The folkd therapy of pepper control epileptic attack is spread always in Yunnan Province of China Xishuangbanna to the sixties in last century, by Beijing Medical
The expert of university has found and pays close attention to, and develops effective, wide spectrum, low toxicity pepper bases new type domestic plant by unremitting effort
Class antiepileptic Ilepcimide piece brings Gospel for epileptic, especially child patient.
Ilepcimide is the chemical derivative of piperine, also known as antiepilepsirin, can inhibit sodium electricity by working to sodium channel
Miscarriage life is a kind of antiepileptic of new batrachotoxin to inhibit the effect of the occurrence and development of epilepsy.It is changed
Scientific name is 3- (3 ', 4 ' secondary first dioxy phenyl)-acryloyl acyl piperidines or 3~4 first dioxy aryl pyrimidines, molecular formula are
C15H17NO3.Ilepcimide chemical structure includes two similar benzene ring structures divided by 4 C-C or C-N singly-bounds.This structure with
Traditional antiepileptic carbamazepine is very similar with Lamotrigine, they also have 1 or the segmentation of several C-C or C-N singly-bounds
Two similar benzene ring structures, the two similar benzene ring structures play important function to the antiepileptic action of drug.Due to Karma west
Gentle Lamotrigine can be pushed away by inhibiting sodium channel high-frequency discharge to prevent generalized tonic-clonic breaking-out and epilepsy partial seizures
Comparable curative effect may be had to epilepsy partial seizures by surveying Ilepcimide.
Ilepcimide piece is new type domestic plant pepper bases antiepileptic, can be used for the treatment of various epilepsy.Research hair
It is existing, it is being less than half lethal dose TD50Dosage under, Ilepcimide is to MES, MST, strychnine, Picroloxin and intracerebroventricular arrow
Rat caused by poison or glutamic acid and mice convulsion have different degrees of antagonism, and can reduce the death rate of animal.This
Outside, National Institutes of Health (NIH) is by system research it has also been found that Ilepcimide can fight electrofit.Moreover, taking orally her
Carry out western amine easily to absorb rapidly from gastrointestinal tract, 4~6h of blood level peaks, and bioavilability is up to 93.9%.Drug mainly divides
Cloth is eliminated comparatively fast in blood plasma, and is distributed in rapidly in fat, liver, kidney and brain tissue, the ratio in blood plasma and brain tissue
Be worth it is constant, by liver metabolism.
Sustained release preparation grows a lot in recent years, and sustained release preparation is compared with ordinary preparation, drug therapy persistent, and poison is secondary
Act on it is low, times for spraying reduce, blood concentration is steady, can avoid drug blood concentration be more than therapeutic domain, reduce medication
Accumulated dose can reach maximum drug effect with minimum dose.
Commercialized product Ilepcimide piece twice a day, a 50~150mg.It has the disadvantage in that (1) takes not side
Just, patient compliance is poor；(2) Antiepileptic Drugs window is generally relatively narrow, and ordinary tablet blood concentration fluctuation is big, blood concentration mistake
There are larger toxic side effect when high especially patient is children, blood concentration is too low to be not achieved Preferred effects；(3) ordinary tablet medication is total
Dosage is larger, especially big to child patient potential hazard risk.Therefore, there is an urgent need to find a kind of better method to solve this
A problem.
Summary of the invention
The purpose of the present invention is to provide a kind of Ilepcimide sustained release preparations, and drug can be made to enter stomach and intestine with slow rate
Road, rationally, toxic side effect is low, drug safety, drug therapy persistent for said preparation composition, and times for spraying is reduced, blood concentration
Steadily, the blood concentration that can avoid drug is more than therapeutic domain, reduces the accumulated dose of medication, maximum medicine can be reached with minimum dose
Effect.
Another object of the present invention is to provide a kind of preparation method of Ilepcimide sustained release preparation, of the invention she comes
The preparation method of western amine sustained release preparation is easy to produce, and product is easy to store, and can preferably achieve the purpose that control release.
The purpose of the invention is achieved by the following technical solution:
A kind of Ilepcimide sustained release preparation, including following components by percentage to the quality: Ilepcimide 10-60%, delay
It releases material 30-85%, adjust drug release material 0-10%, adhesive 0-3%, filler 5-20%, lubricant 0-2% and coating material
Expect 0-5%；The slow-release material is hydrophilic gel matrix material, selects hydroxypropyl methyl cellulose and polyoxyethylene wherein one
Kind is a variety of；Adjusting drug release material selection carbomer, polyacrylic acid and the sodium carboxymethyl starch one or more of them；Institute
The filler stated selects starch, pregelatinized starch, lactose, mannitol one or more of them；The adhesive select ethyl alcohol,
Water, hydroxypropyl methyl cellulose, cross-linked ethylene pyrrolidones and polyvinylpyrrolidone one or more of them；The lubricant
Select magnesium stearate, talcum powder, calcium stearate, zinc stearate and superfine silica gel powder one or more of them.
Slow-release material of the present invention is that hydrophilic gel matrix material includes hydroxypropyl methyl cellulose and/or polyoxy second
Alkene.In a preferred embodiment of the invention, hydroxypropyl methyl cellulose selects K4M and/or polyoxyethylene to select WSR-205.
Adjusting drug release material selection carbomer, polyacrylic acid and sodium carboxymethyl starch one of which or more of the present invention
Kind.In a preferred embodiment of the invention, preferably Carbomer971 NF.
Filler of the present invention selects starch, pregelatinized starch, lactose, mannitol one or more of them.At this
In the preferred embodiment of invention, preferred lactose.
Adhesive of the present invention selects ethyl alcohol, water, hydroxypropyl methyl cellulose, cross-linked ethylene pyrrolidones and poly- second
Alkene pyrrolidone one or more of them.In a preferred embodiment of the invention, preferably 60% ethyl alcohol.
Lubricant of the present invention selects magnesium stearate, talcum powder, calcium stearate, zinc stearate and superfine silica gel powder wherein one
Kind is a variety of.In a preferred embodiment of the invention, preferred magnesium stearate.
In a preferred embodiment, the present invention provides a kind of Ilepcimide sustained release preparation, Ilepcimide 20-60%, sustained release material
Expect 30-84%, adjust drug release material 1-10%, adhesive 0-10%, filler 5-20%, lubricant 0-2% and coating material
0-5%.
Sustained release preparation of the invention can be the dosage forms such as tablet, capsule, preferred tablet.
The present invention also provides a kind of preparation method of Ilepcimide sustained release preparation, including:
All supplementary materials be crushed into 60-80 mesh
Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
Adhesive softwood is added, pelletizes, it is dry；
After the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
Then it wraps with moisture-proof film-coating, it is dry.The purpose for wrapping moisture-proof clothing film is can to improve the appearance of preparation, is provided simultaneously
Color identifier.The art for coating is well-known technique, and details are not described herein.
Advantages of the present invention: the influence that food absorbs Ilepcimide to it can be reduced, can be taken before or after meals, can be held
The effective blood drug concentration of continuous long-time stable, increases the curative effect of drug, effectively reduces toxic side effect, need to only take medicine within one day primary,
One at a time, convenient to take, increase patient compliance.
Specific embodiment
Following embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by following embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Embodiment 1
Prescription (1000):
Preparation process:
1) all supplementary materials be crushed into 60-80 mesh
2) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
3) adhesive softwood is added, pelletizes, it is dry；
4) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
5) then for packet with moisture-proof film-coating, coating weight gain 2-3% is dry, both.
Embodiment 2
Prescription (1000):
Preparation process:
1) all supplementary materials be crushed into 60-80 mesh
2) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
3) adhesive softwood is added, pelletizes, it is dry；
4) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
5) then for packet with moisture-proof film-coating, coating weight gain 2-3% is dry, both.
Embodiment 3
Prescription (1000):
Preparation process:
1) all supplementary materials be crushed into 60-80 mesh
2) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
3) adhesive softwood is added, pelletizes, it is dry；
4) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
5) then for packet with moisture-proof film-coating, coating weight gain 2-3% is dry, both.
Embodiment 4
Prescription (1000):
Preparation process:
1) all supplementary materials be crushed into 60-80 mesh
2) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
3) adhesive softwood is added, pelletizes, it is dry；
4) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
5) then for packet with moisture-proof film-coating, coating weight gain 2-3% is dry, both.
Embodiment 5
Prescription (1000):
Preparation process:
6) all supplementary materials be crushed into 60-80 mesh
7) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
8) adhesive softwood is added, pelletizes, it is dry；
9) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
10) then for packet with moisture-proof film-coating, coating weight gain 2-3% is dry, both.
Embodiment 6
Prescription (1000):
Preparation process:
1) all supplementary materials be crushed into 60-80 mesh
2) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
3) adhesive softwood is added, pelletizes, it is dry；
4) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
5) then for packet with moisture-proof film-coating, coating weight gain 2-3% is dry, both.
Embodiment 7
Prescription (1000):
Preparation process:
1) all supplementary materials be crushed into 60-80 mesh
2) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
3) adhesive softwood is added, pelletizes, it is dry；
4) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
5) then for packet with moisture-proof film-coating, coating weight gain 2-3% is dry, both.
Embodiment 8
Under the conditions of the dissolution medium of different pH, release test is carried out to tablet of the invention.
The hydrochloric acid solution (pH=1.2) of (1) 0.5% lauryl sodium sulfate；
The Acetic acid-sodium acetate buffer (pH=4.5) of (2) 0.5% lauryl sodium sulfate；
(3) simulated intestinal fluid (pH6.8) without pancreatin simulated.
The aqueous solution of (4) 0.5% lauryl sodium sulfate
Test method: it shines drug release determination method (2010 editions two the first methods of annex X D of Chinese Pharmacopoeia), is surveyed using dissolution rate
The device for determining method (2010 editions two the second methods of annex X C of Chinese Pharmacopoeia) turns respectively using above-mentioned dissolution medium 900ml as solvent
Speed is 75 turns per minute, operates according to methods, took solution 10ml respectively at 4,8,12 and 16 hours, is filtered, and immediately in process container
Middle mutually synthermal, same volume the dissolution medium of supplement；Subsequent filtrate 5ml is taken, is set in 25ml measuring bottle, is diluted to scale with solvent,
It shakes up, according to spectrophotometry (2010 editions two annex IV A of Chinese Pharmacopoeia), measures trap respectively at the wavelength of 326nm；
Ilepcimide reference substance about 10mg separately is taken, it is accurately weighed, it sets in 50ml measuring bottle, adds methanol 20ml, be ultrasonically treated, make to dissolve, use
Methanol dilution shakes up to scale；Precision measures above-mentioned solution 5ml, sets in 50ml measuring bottle, using dissolution medium as solvent, as storage
Standby liquid, by following dilution process, takes a certain amount of stock solution to add suitable solvent respectively using corresponding dissolution medium as solvent, dilute
It is interpreted into certain density Ilepcimide reference substance solution:
Contrast solution 1#, 2#, 3# are taken respectively, and 4#, 5#, 6# are measured in the same method trap, draw standard curve.According to standard song
Line computation goes out the every burst size in different time.It the results are shown in Table 1
1 Ilepcimide dissolution of sustained-release tablets data (n=6) of table
Test result shows that the release of the preparation of method preparation provided by the invention is all met the requirements of the standard.
The present invention has also been made the release curve that pharmaceutical specifications are 100mg and 150mg sample and simultaneously in different pH value item
Release curve under part.The release curve of sustained release tablets of the invention under different ph values illustrate product of the invention its
It is not influenced by pH value in the intracorporal absorption of people, effect stability.
Claims (3)
1. a kind of Ilepcimide sustained release preparation, is made of the following components:
Ilepcimide 150g
Hydroxypropyl methyl cellulose (K4M) 70g
Carbomer (971PNF) 12g
Lactose 20g
Magnesium stearate 1.0g
60% ethyl alcohol 150ml
Opadry 50g
Water 3000ml.
2. a kind of Ilepcimide sustained release preparation, is made of the following components:
Ilepcimide 150g
Hydroxypropyl methyl cellulose (K4M) 120g
Carbomer (971PNF) 30g
Lactose 35g
Magnesium stearate 2.0g
60% ethyl alcohol 200ml
Opadry 50g
Water 2000ml.
3. a kind of preparation method of Ilepcimide sustained release preparation of any of claims 1 or 2, the preparation method include:
1) all supplementary materials be crushed into 60-80 mesh；
2) Ilepcimide and slow-release material, adjusting releasable material, packing material are uniformly mixed；
3) adhesive softwood is added, pelletizes, it is dry；
4) by after the particle whole grain after drying, lubricant is preferably added, is mixed, tabletting；
5) then packet is with moisture-proof film-coating, coating weight gain 2-3%, it is dry to get.
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| CN105943537B (en) * | 2016-06-28 | 2019-03-19 | 顾万清 | Compouneded anisodamine neostigmine sustained release tablets and preparation method thereof |
| CN113521022B (en) * | 2021-06-24 | 2023-02-10 | 北京斯利安健康科技有限公司 | Sustained-release tablet containing alexidine and preparation method thereof |
| CN113577037B (en) * | 2021-06-24 | 2023-03-21 | 北京斯利安健康科技有限公司 | Controlled release tablet containing alexidine and preparation method and application thereof |
| CN115590830A (en) * | 2021-07-08 | 2023-01-13 | 武汉熙瑞医药科技有限公司（Cn） | Broglitazone sustained-release preparation and preparation method thereof |
| CN114796127A (en) * | 2022-05-16 | 2022-07-29 | 北京斯利安药业有限公司 | Iloxamine sustained-release dry suspension and preparation method thereof |
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| CN101015532A (en) * | 2005-09-26 | 2007-08-15 | 刘凤鸣 | Sustained release preparation of phenytoin sodiumslow release |
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| CN101647784A (en) * | 2008-08-15 | 2010-02-17 | 北京科信必成医药科技发展有限公司 | Carbamazepine sustained-release tablet and preparation method thereof |
| CN102697779A (en) * | 2012-06-01 | 2012-10-03 | 康阳润和（北京）医药科技有限公司 | High-dissolving-rate ilepcimide drug composition and preparation method thereof |
| CN103083272A (en) * | 2013-01-22 | 2013-05-08 | 上海应用技术学院 | Levetiracetam bioadhesive sustained-release tablet and preparation method thereof |
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| CN101229169A (en) * | 2002-07-29 | 2008-07-30 | 葛兰素集团有限公司 | Sustained release formulations comprising lamotrigine |
| CN101015532A (en) * | 2005-09-26 | 2007-08-15 | 刘凤鸣 | Sustained release preparation of phenytoin sodiumslow release |
| CN101647784A (en) * | 2008-08-15 | 2010-02-17 | 北京科信必成医药科技发展有限公司 | Carbamazepine sustained-release tablet and preparation method thereof |
| CN102697779A (en) * | 2012-06-01 | 2012-10-03 | 康阳润和（北京）医药科技有限公司 | High-dissolving-rate ilepcimide drug composition and preparation method thereof |
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