CN109350605A - A kind of epiphysin slowbreak piece and preparation method thereof - Google Patents
A kind of epiphysin slowbreak piece and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to field of pharmaceutical preparations, it is related to a kind of epiphysin pressed coated slowbreak piece and preparation method thereof.The slowbreak piece is made of the pressed coated of a double-deck core and the performance time-lag action being coated on around label.The double-deck core wherein one layer be pastille slow-release layer, another layer be meet water can occur significantly expand collaboration coating regulation release the drug starting point expanding layer.After said preparation is oral, due to the presence of retardance coating, drug does not release immediately but causes coating to rupture through the significant expansion of the water suction of internal expansion layer after a certain period of time, and medicated layer exposes, the release of sustained-release matrix regulating medicine therein.Advantage of the invention is that providing a kind of epiphysin preparation and preparation method thereof that slowbreak and sustained release can be achieved at the same time.
Description
Technical field
The present invention relates to a kind of epiphysin slowbreak pieces and preparation method thereof, belong to field of pharmaceutical preparations.It is intended to epiphysin
For model drug provide it is a kind of start to release the drug through lagging when 3h, and the preparation of 4~5h slow-release can be played.
Background technique
Sleep is essential content in human lives.Its importance is just like institute in a report of the World Health Organization
Speech, " sleep is the elementary necessaries of human lives as air, food, water ".There is no enough sleeps that can damage the body of people
Body health also brings along some other problems.The survey data of Chinese Medical Association shows that China's sleep disturbance illness rate reaches
42.7%, there are about 300,000,000 a middle-aged persons to suffer from sleep disturbance.Insomnia has a significant impact to individual and society, shows because of insomnia
The expense and treatment expenditure of caused traffic accident increase year by year.It can be seen that insomnia is both medical problem and social concern, draw
Play great attention both domestic and external.
Discovery is investigated to 80 insomniacs of Nanjing Yi Fu hospital Neurology Clinic according to one, wherein 90% insomnia
Disease patient is mostly 55 years old or more the elderly, and insomnia feature shows as falling asleep without difficulty and easily waking up and be difficult in night 2~3 point
It falls asleep again, this insomnia is defined as dysphylaxia disease by we.Such insomnia Producing reason can be from the generation of sleep
Explain with support mechanism: the appearance of sleep is adjusted by two kinds of mechanism interactions, and one is shape constancy support mechanism, separately
One is vivo biodistribution clock mechanism.Both mechanism are a kind of inertia performances of human body, are more by external environment and pressure
It influences, therefore common difficulty falling asleep betides the big young crowd of the fast pressure of rhythm of life.And insomnia of the old people disease shows as more
It falls asleep without difficulty, but difficult maintenance of sleeping, night easily wake up and be difficult to fall asleep again, this is because the reduction of the elderly's melatonin secretion is led
It causes.
Epiphysin (melatonin, molecular formula C13H15N2O2), i.e. N- acetyl -5-MT 5-methoxytryptamine also known as melatonin,
Melatonin is synthesized and is secreted by a body of gland for being called pineal body in brain.Epiphysin is by acting on brain specific region
Cell coordinate the sleep cycle of body, help for sleep.The secretion of epiphysin starts to increase quickly after night arrives, and is insulting
Morning 2-4 point reaches peak, gradually decreases in the second half section at night, it is related with the control of circadian rhythm and light and shade circulation, also with
Hypnotic effect is related with sleep tendency is increased.Due to the decrease with human senility bring body items function, pineal gland
Secreting function weakens, and nocturnal secretion melatonin levels reduce and are not enough to maintain to sleep, and sleep stable state is destroyed, and causes early awakening
Insomnia.
It is clinical at present to use hypnotic sedative agent for the treatment of such dysphylaxia disease more, there is apparent limitation
Property: one, to different insomnia type specific aim not strong, most indications is various insomnias, and side effect is larger；
Two, lack time specific aim, difficulty falling asleep, night awakening and early awakening are different to the time requirement of hypnotic drug, and current
Drug to it is different types of insomnia be all made of the use that is taken at bed time, still have certain blood medicine dense in the stage body for not needing drug
Degree forces hypnosis, along with prolonged side effect；Three, dosage less pertinence treats different insomnia classes with dose
Type is not accomplished to suit the remedy to the case.The important function maintained recently as epiphysin for sleep is found, and because of its half-life period
Short, with the obvious advantage for improving sleep substantially without residual effect from morning, related preparations exploitation is of increasing concern, but current state
The epiphysin preparation of inside and outside listing is mainly ordinary tablet and sustained release tablets, and there are still some problems, as dosage is excessive and aforementioned
Treatment and administration specific aim it is insufficient the problems such as it is still unresolved.Even if it is to trigger a kind of nature that epiphysin, which compares traditional somnifacient,
Sleepy state, without the significant side effect of tradition somnifacient, but since epiphysin also has the endocrine effect of adjusting, abuse
Or long-term improper use also results in endocrine disturbance, serious conditions result even in female acyesis and inhibit male gonad hair
It educates, therefore more and more scholar mechanisms appeal also pay attention to pointedly using in due course for epiphysin.The medical expert of Iceland
It was found that its compatriots has up to 11% population to suffer from winter depression disease, patient shows as burnout without mind, is not related to surrounding desert
The heart, suicide population is more, and this kind of patient's body melatonin content is 2.5 times of normal person.As it can be seen that epiphysin is not no pair
The drug of effect, rationally in due course use should arouse attention.U.S. department of health expert is just once for the unreasonable suitable of epiphysin
When using grave warning is proposed, state-run nutriment association also emphasizes, it is necessary under physician guidance, rationally use in due course, in order to avoid
It causes danger.
The present invention discloses a kind of epiphysin delayed release formulation and preparation method thereof, provide it is a kind of can be achieved through a period of time when
Lag just starts to release the drug and can play the epiphysin preparation of 4~5h slow-release.
Summary of the invention
The purpose of the present invention is to provide it is a kind of through when 3h lag can 4~5h of slow-release epiphysin delayed release formulation and its
Preparation method.
The delayed release formulation is made of the pressed coated of double-deck core and the performance time-lag action being coated on around label.Its
Mechanism of Drug Release are as follows: when preparation is under liquid environment, liquid by the dissolutions of water soluble pore formers (filler) in coating and/or
Duct in coating skeleton enters label, since the effect volume expansion of swelling agent is adjoint after the wetting of label expanding layer contact liq
There is the expansive force expanded outwardly, when the tensile strength of outer layer coating is insufficiently resistant to expansive force of the coating inside from label,
Coating rupture, the exposure of medicated layer label, sustained-release matrix play slow releasing function, and drug release delay time experienced is time lag
(Tlag).Label and coating prescription are adjusted, it can be achieved that target drug release behavior: being accumulated when Accumulation dissolution is no more than 5%, 5h when 3h
Accumulation dissolution is not less than 85% when release is between 50%~70%, 7h.
To achieve the above object, the technical scheme adopted by the invention is as follows:
A kind of epiphysin slowbreak piece, the double-deck core being made of sustained release medicated layer and expanding layer and be coated on double-deck core week
The pressed coated layer composition enclosed, label and coated formula are as follows:
By weight percentage, the pastille slow-release layer of double-deck core is made of following material: 5%~8% epiphysin, 10%
~73% filler, 20%~80% slow-release material, 0%~3% adhesive, 0.3~2% lubricant, each component weight percent
Than the sum of be 100%；
By weight percentage, the expanding layer of double-deck core is made of following material: 75%~96% filler, 3%~
20% swelling agent, 0%~5% adhesive, 0.3%~1.5% lubricant, the sum of weight percentage of each component are 100%；
By weight percentage, coatings are made of following material: 10%~75% filler, 20%~85% retardance
Agent, 0%~5% adhesive, 0.3%~1.5% lubricant, the sum of weight percentage of each component are 100%.
Preferably, the filler is one of lactose, mannitol, dextrin, starch, microcrystalline cellulose, calcium monohydrogen phosphate
Or a variety of combination；
Preferably, the label slow-release material is acrylic resin, hydroxypropyl methylcellulose, ethyl cellulose, behenic acid
One of ester, sodium alginate, rilanit special, octadecyl alcolol or a variety of combinations；
Preferably, the swelling agent is sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substitution
One of hydroxypropyl methylcellulose or a variety of combinations；
Preferably, the coating retarding agent is hydroxypropyl methylcellulose, ethyl cellulose, behenate, glycerol monostearate
One of ester, beeswax, rilanit special, Brazil wax or a variety of combinations；
Preferably, described adhesive is one of hydroxypropyl methylcellulose, povidone, starch, water, ethyl alcohol or a variety of groups
It closes；
Preferably, the lubricant is one of talcum powder, stearic acid, superfine silica gel powder, magnesium stearate or a variety of groups
It closes.
The preparation of epiphysin pressed coated delayed release formulation of the present invention the following steps are included:
(1) preparation of double-deck core:
A. sustained release medicated layer supplementary material is crossed into 80 meshes respectively, is mixed, adhesive softwood, sieving granulation, drying are added
After whole grain plus lubricant mix after medicated layer particle or supplementary material cross 80 meshes respectively, mix to obtain medicated layer powder；
B. each auxiliary material of expanding layer is crossed into 80 meshes respectively, is mixed, adhesive softwood, sieving granulation, drying whole grain are added
Afterwards plus lubricant mix expanding layer particle or each auxiliary material cross 80 meshes respectively, mix to obtain expanding layer powder；
C. double-deck core is suppressed to obtain；
(2) preparation of coated granule: retarder and remaining auxiliary material are crossed into 60 meshes respectively, mixes, adds adhesive system soft
Material, sieving granulation, after drying whole grain plus lubricant mixes to be cooled to room after coated granule or auxiliary material heating melting after mixing
Temperature is ground, and sieving granulation adds lubricant to mix, spare；
(3) it suppresses slowbreak piece: punch die bottom first is added in the coated granule of half amount, double-deck core is placed in central location,
Add the coated granule of remaining half amount, tabletting to obtain the final product.
The epiphysin slowbreak piece, drug release behavior are that 3h Accumulation dissolution is no more than 5%, show significantly to release the drug and prolong
Late, 5h release is discharged between 50%~70%, 7h up to 85% or more, that is, 4~5h sustained release can be achieved after starting drug release.
The positive beneficial effect of epiphysin pressed coated slowbreak piece of the present invention and preparation method thereof are as follows:
(1) advantage of the invention is that providing a kind of epiphysin preparation that slowbreak and sustained release can be achieved at the same time and its preparation
Method.The preparation is made of the double-deck core containing epiphysin and the pressed coated being coated on around label.Double-deck core its
In one layer for the expanding layer that significantly expands can occur containing swelling agent water suction, another layer is the sustained-release matrix layer containing epiphysin,
It is the repressed resulting retardance coating containing retarder around double-deck core.Due to the presence of retardance coating, medicine after medication
Object does not release immediately but reaches label through moisture after a certain period of time, and volume is significantly swollen after the water suction to a certain extent of internal expansion layer
Swollen that coating is caused to rupture, medicated layer exposure starts to release the drug, and then regulates and controls to realize slow-release by sustained-release matrix.System of the present invention
Agent then regulates and controls can be achieved 4~5h sustained release by sustained-release matrix using 3h as drug release starting point.
(2) the present invention provides a kind of compression coated tablets with double-deck core, said preparation be can reach in certain time not
Drug release then plays the purpose of slow-release, and preparation drug release is not influenced by pH, ensure that the stability of in vivo release.
In addition, said preparation preparation process is simple, production cost is low, the potentiality of great industrialization.
(3) epiphysin preparation of the present invention has the potential for being clinically used for dysphylaxia disease, realizes that specific aim is controlled
It treats, dosage can be reduced to reduce side effect, and maintain complete sleep, adjust sleep quality.
(4) present invention is the clinical treatment of disease of easily breaking out at the disease with chronopharmacology feature, especially night, is mentioned
A kind of new preparation thinking has been supplied, clinical demand is greatly met.
Detailed description of the invention
Fig. 1 is the tablets in vitro curve graph that the embodiment of the present invention 1 measures
Fig. 2 is the tablets in vitro curve graph that the embodiment of the present invention 2 measures
Fig. 3 is the tablets in vitro curve graph that the embodiment of the present invention 3 measures
Fig. 4 is the tablets in vitro curve graph that the embodiment of the present invention 4 measures
Fig. 5 is the tablets in vitro curve graph that the embodiment of the present invention 5 measures
Fig. 6 is the tablets in vitro curve graph that the embodiment of the present invention 6 measures
Specific embodiment
Embodiment 1
Preparation process:
(1) it prepares double-deck core: label medicated layer epiphysin, lactose and the behenate of recipe quantity being taken to cross 80 mesh respectively
Sieve mixes, and adds 10% starch slurry softwood, the granulation of 30 meshes, and dry 2h, 25 mesh sieves at 50 DEG C add superfine silica gel powder mixed
It is even；It takes each auxiliary material of recipe quantity label expanding layer to cross 80 meshes respectively, mixes, add 5%PVPK30 aqueous solution softwood, 30 mesh Shai Zhi
Grain, dry 2h, 25 mesh sieves, stiffened fatty acid magnesium mix at 50 DEG C；It suppresses up to double-deck core；
(2) preparation of coated granule: taking recipe quantity HPMC 100LV and lactose to cross 60 meshes respectively, mixes, adds 95% second
Alcohol is added stearic acid and mixes as adhesive softwood, the granulation of 25 meshes, dry 1h, 20 mesh sieves at 50 DEG C, spare；
(3) compression coated tablets: being first added punch die bottom for the coated granule of half amount, double-deck core be placed in central location,
Add the coated granule of remaining half amount, tabletting to obtain the final product.
Embodiment 2
Preparation process:
(1) it prepares double-deck core: taking label medicated layer epiphysin, EC and the lactose of recipe quantity to cross 80 meshes respectively, mix,
75% ethyl alcohol softwood, the granulation of 30 meshes, dry 1h, 25 mesh sieves, stiffened fatty acid magnesium mix at 50 DEG C；Take recipe quantity piece
Each auxiliary material of core expanding layer crosses 80 meshes respectively, mixes, and adds 10% starch slurry softwood, and 30 meshes are pelletized, the dry 2h at 50 DEG C,
25 mesh sieves, stiffened resin acid mix；It suppresses up to double-deck core；
(2) preparation of coated granule: taking recipe quantity behenate, lactose and calcium monohydrogen phosphate, crosses 60 meshes respectively, mixes,
Add 10%PVPK30 solution as adhesive softwood, the granulation of 25 meshes, talcum is added in dry 2h, 20 mesh sieves at 50 DEG C
Powder mixes, spare；
(3) compression coated tablets: being first added punch die bottom for the coated granule of half amount, double-deck core be placed in central location,
Add the coated granule of remaining half amount, tabletting to obtain the final product.
Embodiment 3
Preparation process:
(1) it prepares double-deck core: each supplementary material of label medicated layer of recipe quantity, each auxiliary material of label expanding layer being taken to cross 80 respectively
Mesh, each layer component mix well, and suppress up to double-deck core；
(2) preparation of coated granule: taking recipe quantity glycerin monostearate, beeswax, mannitol to mix, cold after heating melting
It to room temperature curing, grinds, crosses 30 meshes, talcum powder is added to mix, it is spare；
(3) compression coated tablets: being first added punch die bottom for the coated granule of half amount, double-deck core be placed in central location,
Add the coated granule of remaining half amount, tabletting to obtain the final product.
Embodiment 4
Preparation process:
(1) it prepares double-deck core: label medicated layer epiphysin, EC, HPMC K15M and the lactose of recipe quantity being taken to cross 80 respectively
After mesh, mix；After taking recipe quantity label expanding layer calcium monohydrogen phosphate, low-substituted hydroxypropyl cellulose to cross 80 meshes respectively, mixes, add
Enter 10% starch slurry softwood, the granulation of 30 meshes, 50 DEG C of 2h drying, 25 mesh sieves, the mixing of stiffened fatty acid magnesium；It suppresses up to double
Synusia core；
(2) preparation of coated granule: taking recipe quantity HPMC E50 and lactose to cross 60 meshes respectively, mixes, adds 80% ethyl alcohol
Solution softwood, the granulation of 25 meshes, after 50 DEG C of 1h drying, 20 mesh sieves, stiffened fatty acid magnesium is mixed, spare；
(3) compression coated tablets: being first added punch die bottom for the coated granule of half amount, double-deck core be placed in central location,
Add the coated granule of remaining half amount, tabletting to obtain the final product.
Embodiment 5
Preparation process:
(1) prepare double-deck core: take the label medicated layer epiphysin of recipe quantity, HPMC K4M, starch, microcrystalline cellulose and
Mannitol crosses 80 meshes respectively, mixes, and adds 75% ethyl alcohol softwood, the granulation of 30 meshes, and 25 mesh sieves after 50 DEG C of 1h drying add
Magnesium stearate mixes；Recipe quantity label expanding layer microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose is taken to cross 60 mesh respectively
Sieve mixes, and 10%PVPK30 softwood, the granulation of 30 meshes is added, and 50 DEG C of 2h are dried, and 25 mesh sieves, stiffened fatty acid magnesium mixes；
It suppresses up to double-deck core；
(2) it the preparation of coated granule: takes recipe quantity rilanit special and mannitol to mix, it is solid that room temperature is cooled to after heating melting
Change, grind, 25 meshes granulation, 20 mesh sieves are eventually adding the mixing of recipe quantity magnesium stearate；
(3) compression coated tablets: being first added punch die bottom for the coated granule of half amount, double-deck core be placed in central location,
Add the coated granule of remaining half amount, tabletting to obtain the final product.
Embodiment 6
Preparation process:
(1) it prepares double-deck core: taking label medicated layer epiphysin, rilanit special, lactose and the calcium monohydrogen phosphate of recipe quantity
80 meshes are crossed respectively, are mixed, 10%PVPK30 softwood, the granulation of 30 meshes is added, and 50 DEG C of 2h are dried, and 25 mesh sieves add cunning
Mountain flour mixes；It takes recipe quantity label expanding layer lactose, calcium monohydrogen phosphate, sodium carboxymethyl starch to cross 80 meshes respectively, is added after mixing
10%PVPK30 softwood, the granulation of 30 meshes, 50 DEG C of 2h drying, 25 mesh sieves, stiffened resin acid mix；It suppresses up to double-layer tablets
Core；
(2) it is soft that 10%PVPK30 solution system the preparation of coated granule: is added after taking recipe quantity behenate and lactose to mix
Material, the granulation of 25 meshes, 20 mesh sieves are added recipe quantity magnesium stearate and mix；
(3) compression coated tablets: being first added punch die bottom for the coated granule of half amount, double-deck core be placed in central location,
Add the coated granule of remaining half amount, tabletting to obtain the final product.
Embodiment 7
Extracorporeal releasing test: the dissolution rate I method according to as defined in " Chinese Pharmacopoeia " 2015 editions carries out extracorporeal releasing test, release
Test is at 37 ± 0.5 DEG C, and 900ml medium, revolving speed is to carry out under 100rpm parameter, and 2h is carried out in pH1.2 HCl before discharging,
Later using pH6.8 phosphate buffer as medium, sampled in particular point in time, sample is with 0.45 μm of filtering with microporous membrane, together
When add the medium of same volume.It takes subsequent filtrate HPLC sample introduction measurement drug concentration and calculates Accumulation dissolution.
The present invention is intended to provide a kind of novel epiphysin pressed coated slowbreak piece and preparation method thereof, release behavior meets
3h release discharges 50%~70%, 7h release up to 85% or more lower than 5%, 5h.The release at above-described embodiment 1-6 corresponding time point
Degree measurement result is summarized as follows table:
Release profiles are shown in attached drawing 1~6.
It should be understood that described above is only concrete example explanation made by the present invention to clearly illustrate,
It is not intended to restrict the invention, all within the spirits and principles of the present invention, any modification and improvement made should be included in
Within protection scope of the present invention.
Claims (5)
1. a kind of epiphysin pressed coated slowbreak piece, the preparation include the double-deck core being made of sustained release medicated layer and expanding layer
And it is coated on the pressed coated layer composition around double-deck core.
2. slowbreak piece according to claim 1, it is characterised in that:
The double-deck core medicated layer prescription, by weight percentage, including following components: 5%~8% epiphysin, 10%~
73% filler, 20%~80% slow-release material, 0%~3% adhesive, 0.3~2% lubricant, weight percentage of each component
The sum of be 100%；
The double-deck core expanding layer prescription, by weight percentage, including following components: 75%~96% filler, 3%~
20% swelling agent, 0%~5% adhesive, 0.3%~1.5% lubricant, the sum of weight percentage of each component are 100%；
The coatings prescription, by weight percentage, including following components: 10%~75% filler, 20%~85% resistance
Stagnant dose, 0%~5% adhesive, 0.3%~1.5% lubricant, the sum of weight percentage of each component are 100%.
3. -2 epiphysin pressed coated slowbreak piece according to claim 1, it is characterised in that:
The filler is one of lactose, mannitol, dextrin, starch, microcrystalline cellulose, calcium monohydrogen phosphate or a variety of groups
It closes；
The label slow-release material is acrylic resin, hydroxypropyl methylcellulose, ethyl cellulose, behenate, sodium alginate, hydrogen
Change one of castor oil, octadecyl alcolol or a variety of combinations；
The swelling agent is sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl methylcellulose
One of or a variety of combinations；
The coating retarding agent is hydroxypropyl methylcellulose, ethyl cellulose, behenate, glycerin monostearate, beeswax, hydrogenation
One of castor oil, Brazil wax or a variety of combinations；
Described adhesive is one of hydroxypropyl methylcellulose, povidone, starch, water, ethyl alcohol or a variety of combinations；
The lubricant is one of talcum powder, stearic acid, superfine silica gel powder, magnesium stearate or a variety of combinations.
4. pressed coated slowbreak piece according to claim 1, which is characterized in that the preparation of the preparation the following steps are included:
(1) preparation of double-deck core:
A. sustained release medicated layer supplementary material is crossed into 80 meshes respectively, is mixed, adhesive softwood, sieving granulation, drying whole grain are added
Afterwards plus lubricant mix after medicated layer particle or supplementary material cross 80 meshes respectively, mix to obtain medicated layer powder；
B. each auxiliary material of expanding layer is crossed into 80 meshes respectively, is mixed, adhesive softwood is added, sieving is pelletized, and is added after drying whole grain
Lubricant mix expanding layer particle or each auxiliary material cross 80 meshes respectively, mix to obtain expanding layer powder；
C. double-deck core is suppressed to obtain；
(2) preparation of coated granule: retarder and remaining auxiliary material are crossed into 60 meshes respectively, mixes, adds adhesive softwood, mistake
Sieve granulation, after drying whole grain plus lubricant mixes to be cooled to room temperature after coated granule or auxiliary material heating melting after mixing, grinds
It is milled broken, sieving granulation adds lubricant to mix, spare；
(3) it suppresses slowbreak piece: punch die bottom first is added in the coated granule of half amount, double-deck core is placed in central location, then plus
Enter the coated granule of remaining half amount, tabletting to obtain the final product.
5. epiphysin slowbreak piece described in -4 according to claim 1, it is characterised in that: said preparation can be achieved at the same time slowbreak and hold
The sustained release release of continuous 4~5h, drug release characteristic are as follows: Accumulation dissolution is between 50% when Accumulation dissolution is no more than 5%, 5h when 3h
Accumulation dissolution is not less than 85% when~70%, 7h.
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