CN101874783A - Sustained-release preparation containing melatonin and preparation method thereof - Google Patents
Sustained-release preparation containing melatonin and preparation method thereof Download PDFInfo
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- CN101874783A CN101874783A CN2009102346978A CN200910234697A CN101874783A CN 101874783 A CN101874783 A CN 101874783A CN 2009102346978 A CN2009102346978 A CN 2009102346978A CN 200910234697 A CN200910234697 A CN 200910234697A CN 101874783 A CN101874783 A CN 101874783A
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Abstract
The invention discloses a sustained-release preparation containing melatonin and a preparation method thereof. The method comprises the following steps: preparing sustained-release pellets by the melatonin, wherein each sustained-release pellet comprises a celphere, a drug-loaded layer and a coating layer; and then, filling the prepared sustained-release pellets in capsules to prepare sustained-release capsules or pressing the pellets with proper auxiliary materials to form tablets. The preparation can better control sustained release of the medicament. Compared with the sustained-release tablets, the melatonin sustained-release preparation avoids the possible 'burst release' phenomenon of the sustained-release tablets; the pellets are uniformly distributed in a gastrointestinal tract to reduce irritation of the medicament to the gastrointestinal tract; the sustained-release preparation has small impact on food, and is suitable for special people, such as elders and children; and the preparation can be mixed with unit bodies with different releasing velocities to obtain preparations in accordance with different release requirements.
Description
Technical field
The present invention relates to a kind of slow releasing preparation that contains melatonin and preparation method thereof.
Background technology
(melatonin, molecular formula is C to melatonin
13H
16N
2O
2), i.e. N-acetyl group-5-methoxytryptamine belongs to the derivant of 5-hydroxy tryptamine, is a kind of biogenic amine that has indole ring.
Mainly by the pineal gland secretion, it is regulating circadian rhythm, sleep, endocrine, immunity and the anti-ageing multiple important physiological function of waiting for a long time to melatonin in human body.Immunoregulation effect can promote the propagation of T, bone-marrow-derived lymphocyte, suppresses tumor growth.Many studies show that, melatonin can improve sleep effectively, and rapid-action, and toxicity is little, is a kind of novel hypnotic.Melatonin t
Max(peak time) is 30min～50min, t
1/2(eliminating the half-life) is about 1h.The kind dosage form of listing has conventional tablet, capsule and a slow releasing tablet both at home and abroad now.Ordinary tablet and capsule exist rapid-action, but the weak point of holding time; The general slow releasing tablet length of holding time, untoward reaction and ordinary tablet and capsule relatively can reduce, and release phenomenon but still have sometimes to dash forward, and are subjected to food effect bigger, and there is certain zest the part.Make slow-release micro-pill, again the slow-release micro-pill fill is pressed into the above-mentioned shortcoming that tablet can overcome ordinary tablet, capsule and slow releasing tablet effectively in hard capsule or with the adjuvant that suits.
Summary of the invention
The object of the invention is to provide a kind of melatonin slow-releasing agent slow in vivo, stable, that evenly discharge and preparation method thereof, said preparation has that blood drug level is stable, medicine plays a role time is long, not prominent releases advantages such as phenomenon, the influence of unable to take food thing, untoward reaction are light, when improving curative effect, obviously reduce the medication number of times, improve patient's compliance.
Melatonin multi-unit sustained-release preparation of the present invention comprises a plurality of cell cubes that independently have pharmacologically active, these independently cell cube can have different rate of releasing drug, and can make various ways such as micropill, granule, microsphere, microcapsule.Described cell cube is formed by containing celphere, melatonin medicated layer and sustained release coating layer.Again slow-release micro-pill is incapsulated or be pressed into tablet with suitable adjuvant.
One, celphere
As suitable celphere of the present invention, that can mention has sucrose ball core, microcrystalline Cellulose ball core and a starch ball core.
Two, drug-loaded layer
Principal agent and the adjuvant that suits are made into suspension, this suspension is sprayed onto the celphere surface in fluid bed or coating pan, hydrojet limit, limit heat drying promptly.
Three, coatings
The coatings of described cell cube is whole unit body weight gains 0-50%, and wherein the weightening finish of functional coatings material is 0-40%, and the weightening finish of non-functional coating material is 0-10%.
Further, can also contain the plasticizer of 0-60% and the porogen of 0.01%-10% according to percentage by weight in the coatings.
Preferably, contain the plasticizer of 0-20% and the porogen of 1%-6% according to percentage by weight in the coatings.
Described functional coatings material is selected from but is not limited to the aqueous dispersion of acrylic resin, ethyl cellulose, acetyl cellulose, polyvinyl acetate, polyvinyl alcohol, methacrylic resin and powder etc., and commercial obtainable slow controlled release filmogen
NE30D,
RS30D, Eudragit RS PO,
RL 30D,
SR 30D,
ETHOCEL etc. can be above-mentioned one or more combination.The functional coatings material has the prolong drug effect of release time, has also prolonged the action time of medicine, has improved therapeutic index.
Described non-functional coating material is selected from but is not limited to commercial obtainable
Deng thin film coating material and premix powder thereof, or the coating solution of preparing voluntarily with hyprolose, Polyethylene Glycol, titanium dioxide etc. can be above-mentioned one or more combination.
Described plasticizer is selected from but is not limited to one or more combination of triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, Dibutyl phthalate, glycerol, triacetin, monoacetin, cochin oil, Polyethylene Glycol, propylene glycol, diethyl phthalate, Tween-80, Semen Ricini wet goods.
Described porogen is selected from but is not limited to one or more combination of sodium lauryl sulphate, Polyethylene Glycol, hydroxypropyl methylcellulose, polyvidone etc.
Again further, in order to adjust the viscosity of coating solution, can also be to wherein adding antiplastering aid, be selected from but be not limited in Pulvis Talci, glyceryl monostearate, micropowder silica gel, high mountain range scholar, magnesium trisilicate, the magnesium stearate one or more, wherein the preferably talc powder.
Melatonin slow-releasing agent of the present invention and preparation method thereof comprises following four steps:
(1) celphere preparation or selection: with extruding spheronization and other suitable method, the method suitable with microcrystalline Cellulose, starch, sucrose etc. prepares celphere.Also can select commercial obtainable blank micropill, as blank sugar pill etc.
(2) preparation medicine carrying micropill: purified water such as melatonin, low viscous hydroxypropyl emthylcellulose, Polyethylene Glycol are made suspension; With celphere fluidisation or in equipment such as coating pan, roll in equipment such as fluid bed, limit fluidisation or rolling limit spray coating solution, reheat, the medicine carrying micropill.
(3) preparation slow-release micro-pill: the medicine carrying micropill that step (2) is obtained places in fluid bed or other coating equipment, limit spray coating solution, and the limit blowing hot-air promptly obtains slow-release micro-pill;
(4) slow-release micro-pill of above-mentioned (3) gained is incapsulated in or promptly make the slow releasing preparation of melatonin of the present invention with suitable adjuvant tabletting.
Preferably, above-mentioned steps (2) (3) can adopt coating pan method, fluidization process, wherein preferred fluidized bed coating, and the cell cube that makes is the entity micropill of outward appearance globulate or almost spherical.
The dissolubility of melatonin in water is to dissolve 800mg in 1 premium on currency, belongs to slightly soluble.As with breaking method the principal agent melatonin is pulverized with extruding to roll out that spheronization is made the pastille micropill or add medicine on celphere made the medicine carrying micropill and wrap extended release coatings the more incomplete phenomenon of terminal point release is all arranged.The principal agent melatonin is crushed to below the 21um by micronization, makes slow-release micro-pill and the incomplete phenomenon of terminal point release also can occur by extruding spheronization with slow-release auxiliary material.Add medicine on celphere by micronized melatonin, wrap extended release coatings again, release has obtained better controlled, and the release of terminal point is more complete, has obtained beat all effect.
The present invention reaches the purpose of slow release again by adding medicine to by the bag extended release coatings on celphere, delayed the release of medicine, has prolonged the action time of medicine, has reduced the peak blood drug level of medicine.Simultaneously, no matter be during slow-release micro-pill is incapsulated or slow-release micro-pill and suitable adjuvant are pressed into the multiple-unit pellet tablet, owing to be multiple unit system, so also have following advantage: (1) even the effect that medicine " prominent release " in the individual elements body also can obviously not influence medicine integral body occurs, " all or none " phenomenon that has often occurred when having avoided a unit administration; (2) medicine can be evenly dispersed in and make drug absorption complete in the gastrointestinal tract, has avoided the influence of food to medicine effectively, thereby the difference that discharges in Different Individual, absorbs is very little, and it is wide to be suitable for the crowd; (3) belong to the decentralized preparation, be distributed in gastrointestinal tract, avoided, reduce untoward reaction the gastrointestinal stimulation; (4) can contain the cell cube of different rate of releasing drug in the medicine, combine to take and to reach effective treatment concentration fast and can keep this concentration for a long time again.In addition, preparation method technology of the present invention is simple, easy operating and control.
Fig. 1 embodiment 1 melatonin was accumulated the drug release percentage amounts in 10 hours
Fig. 2 embodiment 2 melatonin were accumulated the drug release percentage amounts in 10 hours
Fig. 3 embodiment 3 melatonin were accumulated the drug release percentage amounts in 10 hours
Fig. 4 embodiment 4 melatonin were accumulated the drug release percentage amounts in 10 hours
The specific embodiment
By following examples the present invention is done further to specify, but be not limited to following example.
Embodiment 1:
The medicine carrying coating solution:
Sustained release coating liquid:
Preparation technology:
Get 150g microcrystalline Cellulose celphere, take by weighing respectively that supplementary material is scattered in respectively in the purified water in the prescription, be made into melatonin medicine carrying coating solution and sustained release coating liquid.Blank core is in fluidized state in fluid bed, sprays into melatonin medicine carrying coating solution and sustained release coating liquid successively.The coating temperature is controlled at 60 ℃ during the drug-loaded layer coating, and sustained release coating layer coating temperature is controlled at and is no more than 40 ℃, after coating finishes dry 5 minutes again.The melatonin slow-releasing capsule that to make 1000 specifications in 1000 capsules of at last slow-release micro-pill being packed into be 3mg.
Embodiment 2:
The medicine carrying coating solution:
Sustained release coating liquid:
Preparation technology:
Get 100g sucrose celphere, take by weighing respectively that supplementary material is scattered in respectively in the purified water in the prescription, be made into melatonin medicine carrying coating solution and sustained release coating liquid.Blank core is in fluidized state in fluid bed, sprays into melatonin medicine carrying coating solution and sustained release coating liquid successively.The coating temperature is controlled at 60 ℃ during the drug-loaded layer coating, and sustained release coating layer coating temperature is controlled at and is no more than 40 ℃, and the micropill that coating makes wore out 12 hours in the baking oven in 40 ℃.The melatonin slow-releasing capsule that to make 1000 specifications in 1000 capsules of at last slow-release micro-pill being packed into be 2mg.
Embodiment 3:
The medicine carrying coating solution:
Sustained release coating liquid:
The film coating layer:
Preparation technology:
Get 100g sucrose starch celphere, take by weighing respectively that supplementary material is scattered in respectively in the purified water in the prescription, be made into melatonin medicine carrying coating solution and sustained release coating liquid.Blank core is in fluidized state in fluid bed, sprays into melatonin medicine carrying coating solution, sustained release coating liquid and film coating layer successively.The coating temperature is controlled at 60 ℃ during the drug-loaded layer coating, and sustained release coating layer coating temperature is controlled at and is no more than 40 ℃, and the micropill that coating makes wore out 12 hours in the baking oven in 40 ℃.The melatonin slow-releasing micropill that will wrap extended release coatings again wraps film-coat in fluid bed, the melatonin slow-releasing capsule that to make 1000 specifications in 1000 capsules of at last slow-release micro-pill being packed into be 2mg.
Embodiment 4:
The medicine carrying coating solution:
Sustained release coating liquid:
The multiple-unit pellet tablet:
Preparation technology:
Get 100g sucrose celphere, take by weighing respectively that supplementary material is scattered in respectively in the purified water in the prescription, be made into melatonin medicine carrying coating solution and sustained release coating liquid.Blank core is in fluidized state in fluid bed, sprays into melatonin medicine carrying coating solution and sustained release coating liquid successively.The coating temperature is controlled at 60 ℃ during the drug-loaded layer coating, and sustained release coating layer coating temperature is controlled at and is no more than 40 ℃, and the micropill that coating makes wore out 12 hours in the baking oven in 40 ℃.With slow-release micro-pill and microcrystalline Cellulose and the compacting of lubricant sodium stearyl fumarate in flakes, promptly get melatonin multiple-unit micropill slow releasing tablet at last.
Claims (9)
1. a slow-release micro-pill that contains melatonin comprises celphere, drug-loaded layer and sustained release coating layer.
2. slow-release micro-pill according to claim 1 is characterized in that described celphere is sucrose ball core, microcrystalline Cellulose ball core or starch ball core.
3. drug-loaded layer according to claim 1 is characterized in that described pastille coatings comprises active component melatonin, hydroxypropyl cellulose and plasticizer and forms.
4. slow-release micro-pill according to claim 1 also is surrounded by a layer sustained-release coating layer outside drug-loaded layer.
5. according to right 4 described sustained-release coating layers, it is characterized in that described functional coatings material is selected from the aqueous dispersion of acrylic resin, ethyl cellulose, acetyl cellulose, polyvinyl acetate, polyvinyl alcohol, methacrylic resin etc. and powder etc., and commercial obtainable slow controlled release filmogen
NE 30D,
RS 30D, Eudragit RS PO,
RL30D,
SR 30D,
ETHOCEL etc. can be above-mentioned one or more combination.
6. slow-release micro-pill according to claim 4, its special sheet are that described antiplastering aid is a Pulvis Talci.
7. according to right 4 described slow-release micro-pill, it is characterized in that described porogen is the mixing of one or more in methylcellulose, the polyvidone in Polyethylene Glycol, the hydroxyl.
8. slow-release micro-pill that contains melatonin is characterized in that may further comprise the steps:
(1) selects celphere of uniform size;
(2) with melatonin by comminution by gas stream to particle diameter less than 21um;
(3) hydroxypropyl emthylcellulose and micronized melatonin are made suspension through stirring;
(4) solution that will contain melatonin is coated on and makes the medicine carrying micropill on the celphere;
(5) insoluble polymer, porogen and antiplastering aid are made suspension through stirring;
(6) this suspension is coated on the medicine carrying micropill forms slow-release micro-pill.
(7) above-mentioned multiple-unit micropill is incapsulated or form the multiple-unit pellet preparations of melatonin with suitable adjuvant tabletting.
9. the preparation method of melatonin multi-unit sustained-release preparation according to claim 8, it is characterized in that described step (4) step (6) adopts coating pan method, fluidized bed process, preferred fluidized bed coating, the cell cube that makes is the entity micropill of outward appearance globulate or almost spherical.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009102346978A CN101874783A (en) | 2009-11-27 | 2009-11-27 | Sustained-release preparation containing melatonin and preparation method thereof |
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|---|---|---|---|
| CN2009102346978A CN101874783A (en) | 2009-11-27 | 2009-11-27 | Sustained-release preparation containing melatonin and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102133195A (en) * | 2011-03-17 | 2011-07-27 | 王国栋 | Trimetazidine dihydrochloride sustained control release pellet and preparation method thereof |
| CN104546777A (en) * | 2014-12-16 | 2015-04-29 | 深圳翰宇药业股份有限公司 | Preparation method of melatonin controlled-release composition and preparation method of melatonin controlled-release tablet |
| WO2019038586A1 (en) | 2017-08-19 | 2019-02-28 | Ftf Pharma Private Limited | Pharmaceutical composition of melatonin |
| CN112136816A (en) * | 2020-09-27 | 2020-12-29 | 甘肃省科学院生物研究所 | Compound preparation for preventing and treating early bolting of angelica sinensis as well as use method and application thereof |
| CN114555057A (en) * | 2019-12-10 | 2022-05-27 | 耐贝医药株式会社 | Granules containing melatonin |
| WO2022180398A1 (en) * | 2021-02-24 | 2022-09-01 | Closed Loop Medicine Ltd | Formulation of a multi layered pellet comprising melatonin |
-
2009
- 2009-11-27 CN CN2009102346978A patent/CN101874783A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102133195A (en) * | 2011-03-17 | 2011-07-27 | 王国栋 | Trimetazidine dihydrochloride sustained control release pellet and preparation method thereof |
| CN104546777A (en) * | 2014-12-16 | 2015-04-29 | 深圳翰宇药业股份有限公司 | Preparation method of melatonin controlled-release composition and preparation method of melatonin controlled-release tablet |
| WO2019038586A1 (en) | 2017-08-19 | 2019-02-28 | Ftf Pharma Private Limited | Pharmaceutical composition of melatonin |
| CN114555057A (en) * | 2019-12-10 | 2022-05-27 | 耐贝医药株式会社 | Granules containing melatonin |
| CN112136816A (en) * | 2020-09-27 | 2020-12-29 | 甘肃省科学院生物研究所 | Compound preparation for preventing and treating early bolting of angelica sinensis as well as use method and application thereof |
| WO2022180398A1 (en) * | 2021-02-24 | 2022-09-01 | Closed Loop Medicine Ltd | Formulation of a multi layered pellet comprising melatonin |
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Addressee: Wuxi Ding Fu Pharmaceutical Co., Ltd. Chu Haiyan Document name: Notification of an Office Action |
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Address after: 214191 10 Furong Road five, Xishan Economic Development Zone, Wuxi, Jiangsu Applicant after: Wuxi Dingfu Pharmaceutical Co., Ltd. Address before: 214174 No. 1608, Huishan Avenue, Huishan District, Jiangsu, Wuxi Applicant before: Wuxi Dingfu Pharmaceutical Co., Ltd. |
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Application publication date: 20101103 |