CN106137996A - A kind of (+)-Zopiclone secondary delivery formulations - Google Patents
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- CN106137996A CN106137996A CN201510128611.9A CN201510128611A CN106137996A CN 106137996 A CN106137996 A CN 106137996A CN 201510128611 A CN201510128611 A CN 201510128611A CN 106137996 A CN106137996 A CN 106137996A
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Abstract
The invention belongs to technical field of medicine, relate to a kind of (+)-Zopiclone secondary delivery formulations and the preparation method of said preparation thereof.Delivery formulations of the present invention, is mainly made up of kernel, swell layer, controlled release layer, sealing coat and release layer.The most quickly discharge q.s (+)-Zopiclone after said preparation is oral, allow patient quickly fall asleep, afterwards almost without drug release in certain time, after predetermined lag time, again kernel Chinese medicine is the most all discharged, make patient no longer wake up midnight, maintain the sleep of long period.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of (+)-Zopiclone secondary delivery formulations and the preparation method of said preparation thereof.
Background technology
Insomnia is multilated of sleeping normally, and has obvious harmful effect (fatigue, aprosexia, beat ton etc.) to the activity on daytime, and abnormal syndrome occurs in the most objective detection (such as polysomnogram).The difficulty falling asleep that mainly shows as of insomniac maintains difficulty with sleep, and the people i.e. having a sleepless night is usually simultaneously with difficulty falling asleep and early awakening.
The preferred option for the treatment of of insomnia patients is to take sleeping pill, although but many patients reflection can solve difficulty falling asleep problem after taking commercially available sleeping pill, but holding time, shorter (the sleeping pill half-life is generally the shortest, because the half-life is long, residual was still had to affect the orthobiosis on daytime by second day), it is difficult to again fall asleep after waking up at 1-2 o'clock the most at night, therefore, it is difficult to treatment difficulty falling asleep and early awakening symptom cannot be proved effective simultaneously, it is therefore desirable to after waking up midnight, secondary drug administration is to maintain enough length of one's sleep.
In order to reduce medicining times, treatment difficulty falling asleep and early awakening, be developed slow releasing preparation simultaneously.But slow releasing preparation there is also many problems.Under the effect of the sleeping pill of ordinary preparation, patient at least can sleep peacefully 3-4 hour, therefore it is administered continuously by slow releasing preparation, especially being administered within the 3-4 little time that patient originally can sleep peacefully just seems there is no need, slow releasing preparation, to maintaining blood drug level higher being in the patient in the middle of sleep, causes unnecessary side effect and untoward reaction.Simultaneously slow releasing preparation because of its release time longer, because of the individual variation of patient, be difficult to effectively control rational blood levels, cause the symptoms such as most of patients m seq has one's head in the clouds, the normal work of impact and life.
In order to solve the problem of above-mentioned slow releasing preparation, can design by rapid release and postpone the secondary delivery formulations that 2 preparation unit of release form.Wherein, immediate release section plays after taking and discharges immediately, makes the effect that patient quickly falls asleep；Decay part then wouldn't discharge, and midnight of waiting for a period of time discharges again, makes patient maintain the longer length of one's sleep.Have and postpone the preparation then effect of releasing unit more more preferably, the medicine taken before going to bed, to the q.s medicine that again came down in torrents the when that immediate release section medicine will losing efficacy after midnight, thus extends the length of one's sleep, but to morning regain consciousness time medicine analytic metabolism complete, side effect substantially eliminates.
Delay release described here is different with the most described slow release.Any medicine cannot be detected in blood in postponing a period of time that release is administration, until just can measure after the stipulated time, blood drug level afterwards quickly reaches peak as quick releasing formulation；Slow release is the most different, and in quickly measuring medicine, and long period in blood after administration, blood drug level maintains relative high levels always.
Document (preparation of Zaleplon pulse release micropill and release in vitro [J]. Chinese Journal of Modern Applied Pharmacy, 2012,10:924-930.) report the preparation method of Zaleplon pulse release micropill.Chinese patent (application number: 201310178912.3) discloses pulsatile release pellets and preparation method thereof when a kind of Zolpidemtar Trate is selected.All to there is problems of time delay the longest for two reports, external postpones just release in 4h hour, is that time delay may be longer to internal release, more than 7-8 hour, will affect second day morning awake after action.
Chinese patent (application number: 200910068877.3) discloses Zolpidem tartrate controlled-release pellet and preparation method thereof, it is characterised in that the slow-release micro-pill that its slow-release micro-pill being mainly made up of pellet core and the slow release layer playing slow releasing function or the slow release layer by the immediate release outer layer part of rapid-onset, maintaining slow release release and pellet core form.Here it is above-mentioned slow releasing preparation, medicine maintains higher valid density the most always, causes unnecessary side effect and untoward reaction to patient.
Attract most attention now in Non-benzodiazepine sleeping pill is (+)-Zopiclone, also known as (+)-6-(5-chloropyridine-2-base)-7-[(4-methylpiperazine-1-yl) carbonyloxy group] 5,6-pyrrolin [3,4-b] pyrazine-5-ketone is the dextroisomer of zopiclone.(+)-Zopiclone and the affinity of receptor than zopiclone big 50 times.
Summary of the invention
In order to solve to overcome the shortcoming and defect of above-mentioned prior art, the present invention provides a kind of (+)-Zopiclone secondary release pharmaceutical formulations, described preparation can solve treatment difficulty falling asleep and the problem of early awakening, the most quickly discharge q.s (+)-Zopiclone after described preparation oral, allow patient quickly fall asleep, afterwards almost without drug release in certain time, after predetermined lag time, again kernel Chinese medicine is the most all discharged, make patient no longer wake up midnight, maintain the sleep of long period.
The technical scheme is that
(+)-Zopiclone secondary release pharmaceutical formulations of the present invention, is followed successively by kernel, swell layer, controlled release layer, sealing coat and release layer from inside to outside.
Specifically, the secondary delivery formulations of the present invention is to postpone release kernel, hydrophilic gel swell layer, insoluble release-controlled film layer, water solublity sealing coat and (+)-Zopiclone release layer composition containing (+)-Zopiclone.Meeting after water, the (+)-Zopiclone in release layer quickly discharges, but because of controlled release layer and the obstruction of swell layer, interior nuclear pharmaceuticals wouldn't discharge, until after the stipulated time the most rapidly, all discharge.
Its action principle is that said preparation is under water environment (or body fluid), and in release layer, (+)-Zopiclone quickly discharges, but the obstruction kernel Chinese medicine of controlled release layer and swell layer wouldn't discharge.Containing a small amount of water soluble ingredient in controlled release layer, water soluble ingredient leaves tiny duct at release-controlled film layer after dissolving, and water enters swell layer by these passages.Swell layer material is hydrophilic gel polymer, and chance water is the most swelling, effectively prevents moisture from further expanding to kernel.Over time, the water entering swell layer is gradually increased, and swell layer volume increasingly expands, and finally breaks through controlled release layer.In the presence of a large amount of water, swell layer is quickly dissolved, and water enters into inner nuclear layer, and medicine all discharges in the short time.
In the preparation of the present invention, kernel is the circular piece of diameter 5-7mm.Kernel, in addition to containing active medicine, should include filler, disintegrating agent.Can also be containing other adjuvants conventional in oral tablet in kernel, including binding agent, coloring agent, surfactant, fluidizer, lubricant, sweeting agent.
Described active medicine is the 0.67-4% that (+)-Zopiclone accounts for kernel weight ratio, preferably 1-2%.
Filler uses the diluent that tablet is conventional, one or more mixture in lactose, microcrystalline Cellulose, starch based, mannitol, wherein it is preferred that and does not affect dissolving or the filler of disintegrate under the conditions of higher pH (more than 5.0).It is preferably lactose, microcrystalline Cellulose, starch.Described filler loading accounts for weight ratio 80-92% of kernel, preferably 86-89%.
The kernel prescription of the present invention is not suitable for using this kind of basic auxiliary of calcium hydrogen phosphate.Otherwise kernel rate of release in intestinal substantially reduces, this is because (+)-Zopiclone is alkalescent medicine, increases its dissolubility at higher pH and substantially reduces.Specifically can be seen that from embodiment 1.
Disintegrating agent uses superdisintegrantes class, selects one or more mixture in carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone.Preferably intumescent disintegrating agent, the one in carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose or 2 mixture.Disintegrating agent consumption accounts for kernel weight ratio and is preferably 5%-10%, most preferably 6%-8%.In the disintegrating agent of q.s is conducive to, the whole of nuclear pharmaceuticals discharge.
In kernel, other adjuvant accounts for the 0.5-3.5% of kernel weight ratio, preferably 1-2%.
Kernel can be obtained by conventional tablet technique, including wet granulation technology, dry granulation process, direct compression technique.
In the present invention, swell layer is indispensable.When preparation just contacts water, swell layer plays the effect stoping moisture diffusion to enter kernel.Later stage swell layer plays breaks through controlled release layer, reaches the pivotal role of explosion release.It addition, swell layer also acts as the effect modifying tablet sharp edges, it is to avoid controlled release layer is the thinnest at tablet edges, the problem causing rapid crack propagation.
Swell layer uses chance water quickly to form the hydrophilic polymer of gel, such as vitamins, Sargassum acids, polyoxyethylene, Carbomer.These are all to sell on market, have chance water and quickly form the adjuvant for oral use of gel.Preferably hydroxypropyl methyl cellulose, calcium alginate, polyoxyethylene, carbomer.Most preferably select the many elegant E5 (Colorcon company) of hydroxypropyl methyl cellulose (HPMC), especially beauty competition.In order to improve the film property of swell layer material, reduce glass transition temperature and be preferably added plasticizer.Plasticizer selects a kind of or any mixture of more than two kinds in triethyl citrate, dibutyl sebacate, Polyethylene Glycol (PEG), preferably PEG400.
Because it is fast that HPMC meets hydrogel speed, it is ensured that swell layer intercepts the effect of water.Additionally U.S. many elegant E5 prepare viscosity number, beneficially industrialized production after solution, and this is to meet the commercial oral adjuvant that GMP requires.
When swell layer coating weight gain reaches certain thickness, could obtain and preferably postpone releasing effect.Swell layer weightening finish is too low, and drug release is similar to ordinary preparation, the most all discharges.Swell layer coating weight gain is too much, is unfavorable for production efficiency and cost control.
In order to investigate the swell layer weightening finish impact on release, kernel is carried out swell layer coating with weightening finish listed by according to the form below, and carry out controlled release layer coating to obtaining coating, after controlled release layer coating completes, the mensuration (dissolution method surveys release) (phosphate buffer of pH6.8 is release medium, and speed of agitator is 50rpm) of release is carried out by Chinese Pharmacopoeia dissolution the second method.Result see table
| Sample number into spectrum | Swell layer weightening finish % | Controlled release layer weightening finish % | 6 average legs T1/min |
| a | 0 | 12.7 | 8 |
| b | 5 | 14.0 | 14 |
| c | 8 | 13.1 | 47 |
| d | 18 | 13.2 | 124 |
| e | 23 | 12.8 | 164 |
| f | 28 | 14.0 | 172 |
Find out that swell layer thickness and hang-over delay relation are not proportional relations, the when that swell layer being thin from result, it is impossible to realize medicine controlled releasing, but swell layer is further added by weightening finish and the most not affects time delay after reaching certain thickness.
Therefore swell layer weightening finish controls as 15%-30%, preferably 18%-28%.
The swell layer of the present invention is by the equipment of preparation workshop routine, including pan coater, rotates seed-coating machine, and fluidized-bed coating machine all can realize.
Controlled release layer in the present invention includes water-insoluble polymer and water-soluble substances.
Water-insoluble polymer can use the conventional slow release controlling coating material sold on market, preferably ethyl cellulose, polyacrylic resin, polyvinyl acetate.Most preferably Aquacoat.Such as Sulisi (Colorcon company, the Aquacoat of concentration 25%).
The water-soluble substances of controlled release layer leaves thin channel in controlled release layer after dissolving, and hydrone can enter swell layer by this passage.Water-soluble substances is selected from hydroxypropyl methyl cellulose, polyacrylic resin, a kind of or the most two or more combination in polyvinyl alcohol, preferably hydroxypropyl methyl cellulose.
By changing the weightening finish of controlled release layer and insoluble polymer and the ratio of water-soluble substances, can obtain different postponing lag time.Controlled release layer weightening finish is the longest for the most time delays, and in controlled release layer, the water-soluble substances ratio more high latency time is the shortest.Therefore the ratio that can increase weight or reduce water-soluble substances by increasing controlled release layer all can increase time delay.In view of the increase of production cost, controlled release layer weightening finish is difficult to too much.But it is less to increase weight, it is difficult to ensure the uniformity of film, therefore controls coating weight gain scope and be preferably 8%-25%.Controlled release layer coating weight gain optimum for controlling at 10-20%, most preferably 13-14%.
In order to investigate the hydroxypropyl methylcellulose ratio impact on release in Aquacoat, same component, preparation method are obtained kernel, and after with same composition identical swell layer coating weight gain, with Aquacoat, hydroxypropyl methylcellulose for controlled release layer composition, measuring dissolution according to two annex XC dissolution determination the second methods of " Chinese Pharmacopoeia " version in 2010, result see table
| Numbering | Hydroxypropyl methylcellulose: ethyl cellulose | 6 average lag-time T1/min |
| 1 | 1:4.5 | 124 |
| 2 | 1:1 | 29 |
| 3 | 1:6.7 | 224 |
| 4 | 1:8.4 | 308 |
At this moment, it is proper that hydroxypropyl methylcellulose and ethyl cellulose weight ratio are preferably 1:4.2-1:4.8, and optimum is 1:4.4-1:4.6.
Controlled release layer coating is by operating on conventional coating equipment.
Sealing coat outside controlled release layer, play obstruct controlled release layer and the effect of release layer in the present invention, can not quickly discharge to prevent release layer medicine from directly contacting water-insoluble controlled release layer, i.e. lack sealing coat and the (+)-Zopiclone in release layer will be caused quickly not discharge.
Sealing coat uses conventional gastric solubility coating material, can be selected from hydroxypropyl methyl cellulose, polyvinyl alcohol, and a kind of or any compositions of more than two kinds in polyacrylic acid, its coating weight gain is 2-4%.
Release layer is the medicine layer containing binding agent, can use hydroxypropyl methyl cellulose, the mixture of one or more in polyvidone (PVP) and polyacrylic acid.Not having notable difference between these binding agents, preferably U.S. many elegant E are as binding agent.
Described release layer drug dose: kernel drug dose=1.5-3:1-2.
To different coating materials, coating temperature role is different, for the coating of kernel and swell layer, coating temperature primarily serves the effect accelerating moisture evaporation, so ensure coating process is smooth, adhesion is few, coating efficiency high in the case of can select relatively low temperature, to save energy loss.For filmogen is such as ethyl cellulose, the dual function that in coating process, temperature plays and makes moisture evaporation, assembles film forming, it is to ensure that the key of clothing film quality.If coating temperature is the highest, before being uniformly distributed in whole core surface film forming completely, coating solution has been dried and has become powder, causes coating solution utilization rate to reduce, and causes the waste of coating material, and core surface clothing film quality is the most bad, and brittleness increases；If coating temperature is the lowest, the coating solution of core surface is dried slowly, and kernel adhesion is obvious.
Preferably, (+)-Zopiclone secondary delivery formulations preparation method comprises the steps:
Step one, the preparation of kernel
Take (+)-Zopiclone and diluent lactose and microcrystalline Cellulose, Surfactant SDS, fluidizer micropowder silica gel, super-disintegrant cross-linking sodium carboxymethyl cellulose and carboxymethyl starch sodium join two-dimensional mixing machine, mix 15 minutes.Add magnesium stearate lubricant and remix 10 minutes.The powder of mix homogeneously is put into rotary tablet machine and is pressed into the circular piece of diameter 5-7mm.Tablet hardness controls between 30-40N.
Step 2, swell layer coating
Coating solution is prepared: by hydrophilic gel material hydroxypropyl methyl cellulose, putting into the batch tank equipped with ethanol solution, being configured to concentration is solution, adds plasticizer, mix homogeneously.
Coating: add the (+)-Zopiclone pressure kernel that step one prepares in high-efficiency coating machine, adjust hydrojet speed and hot air temperature, the coating solution that parcel has configured.Hydrojet speed is about 3-8ml/min, heating-up temperature 55-45 DEG C.I.e. obtain swelling synusia.
Step 3, controlled release layer coating
Coating solution is prepared: is dissolved by purified water in batch tank by hydroxypropyl methylcellulose, adds mix homogeneously in Aquacoat.
Coating: add the swelling synusia obtained in step 2 in high-efficiency coating machine, adjusting hydrojet speed is about 3-8ml/min, and heating-up temperature 65-50 DEG C is wrapped up controlled release layer, obtained (+)-Zopiclone controlled release tablet.
Step 4, sealing coat coating
Coating solution is prepared: putting into hydroxypropyl methylcellulose equipped with in the batch tank of purified water, stirring is completely dissolved.
Coating: add the (+)-Zopiclone controlled release tablet that step 3 obtains in high-efficiency coating machine, adjusts hydrojet speed and hot air temperature, the coating solution that parcel has configured.Obtain shaping piece.
Step 5, the cladding of immediate release drug
The preparation of pastille binder solution: in step 3, the preparation of coating solution compound method takes hydroxypropyl methylcellulose, dissolves by purified water, opens stirring, add (+)-Zopiclone raw material, be uniformly dispersed in batch tank.
Coating: add the shaping piece obtained in step 4 in high-efficiency coating machine, adjusts hydrojet speed and hot air temperature, sprays pastille binder solution, makes medicaments uniformity be coated on tablet surface.Obtain (+)-Zopiclone secondary delivery formulations.
Release of the present invention specifies according to Chinese Pharmacopoeia, measures release conditions with medicament dissolution instrument.Specifically, be placed in by preparation in 37 DEG C of release medium, suitable speed stirs, and measures release medium Chinese medicine total amount in different time sections.
Preferably retard formulation should meet the most several condition: (1) release starts (T0) to specifying interior (T lag time1) drug-eluting amount is few, such as less than the 10% of total amount；(2) arrive T1In the rear medicine short time, whole dissolutions, such as T1In latter 30 minutes, drug-eluting amount is more than 70%；(3) medicine release profiles in different pH release medium does not has notable difference；(4), under rational dissolution stirring intensity, drug release does not has notable difference.
The delayed release preparation T of the present invention1Prodrug burst size is less than 5%, T1After+30 minutes, drug release is close to 100%.The preparation of the present invention is at pH1.2 hydrochloric acid solution, aqueous solution, T in pH6.8 phosphate buffer1Being not changed in, illustrating that release is not changed by gastrointestinal tract pH is affected.
The preparation of the present invention is at Chinese Pharmacopoeia slurry processes 50 turns, slurry processes 75 turns, basket method 100 turns, the T that basket method is 125 turns1It is not changed in, illustrates that internal gastrointestinal motility is on release not impact.
Above 2 understand again, and it is less that environment postpones release impact to the preparation of the present invention.As patients diet or fasting, pH in digestive tract can occur significant change, and this preparation can realize the most predetermined lag time, and release process does not relies on pH.
Preparation of the present invention, external time delay is 2-2.5 hour, and 4-5 hour blood drug level reaches peak value in vivo.See accompanying drawing 2.
Beneficial effects of the present invention
Preparation the most of the present invention can realize the most predetermined lag time, and release process does not relies on pH.
Preparation the most of the present invention, external time delay is 2-2.5 hour, and 4-5 hour blood drug level reaches peak value in vivo, plays effect, but will not excessively delay and affect the mental status after getting up early when such time is conducive to previous drug effect to disappear..
3. the preparation of the present invention can allow and take a preparation unit before patient falls asleep but the release of internal secondary, the most respectively after taking and cross release in 2 hours, it is ensured that quickly fall asleep, it is thus also avoided that midnight wakes up.
Accompanying drawing explanation
The release profiles of accompanying drawing 1 (+)-Zopiclone controlled release tablet
Accompanying drawing 2 (+)-Zopiclone secondary delivery formulations release profiles
Detailed description of the invention
Embodiment 1
Step one, the preparation of kernel
All adjuvants outside by above-mentioned recipe quantity (+)-Zopiclone and removing magnesium stearate join two-dimensional mixing machine, mix 15 minutes.Add recipe quantity magnesium stearate and remix 10 minutes.The powder of mix homogeneously is put into rotary tablet machine and is pressed into the circular piece of diameter 6mm.Tablet hardness controls between 30-40N.Obtain kernel by A prescription and be referred to as A, by B prescription obtain kernel be referred to as B by according to Chinese Pharmacopoeia dissolution method (slurry processes) measure, in pH1.2 hydrochloric acid solution and pH6.8 phosphate buffer, measure dissolution situation respectively, see table
Visible, obtain kernel by A prescription and be referred to as A effect more preferably.
Step 2, swell layer coating
Coating solution is prepared: by 2kg hydroxypropyl methyl cellulose (HPMC E5), putting into the batch tank equipped with 23kg 85% ethanol solution, being configured to concentration is 8% solution, adds PEG4000.2kg, mix homogeneously.
Coating: add the above-mentioned (+)-Zopiclone pressure kernel prepared by prescription A of 10kg in high-efficiency coating machine, adjust hydrojet speed and hot air temperature, the coating solution that parcel has configured.Hydrojet speed is about 3-8ml/min, heating-up temperature 55-45 DEG C.I.e. obtain swelling synusia.Coating weight gain is 18%.
Step 3, controlled release layer coating
Coating solution is prepared: is dissolved by 6kg purified water in batch tank by 0.28kg hydroxypropyl methylcellulose (U.S. many elegant E5), adds mix homogeneously in 5kg_ Aquacoat (Sulisi).
Coating: add the swelling synusia 11kg obtained in step 2 in high-efficiency coating machine, adjusting hydrojet speed is about 3-8ml/min, and heating-up temperature 65-50 DEG C is wrapped up controlled release layer, obtained (+)-Zopiclone controlled release tablet, and coating weight gain is 13.2%.
Step 4, sealing coat coating
Coating solution is prepared: being put in the batch tank equipped with 5kg purified water by 0.4kg hydroxypropyl methylcellulose (U.S. many elegant E5), stirring is completely dissolved.
Coating: add (+)-Zopiclone controlled release tablet 10kg that step 3 obtains in high-efficiency coating machine, adjusts hydrojet speed and hot air temperature, the coating solution that parcel has configured.Obtain shaping piece.Coating weight gain 3.7%.
Step 5, the cladding of immediate release drug
The preparation of pastille binder solution: coating solution compound method preparation 15kg hydroxypropyl methylcellulose (U.S. many elegant E5) binder aqueous solution in step 4, opens stirring, adds 1.5kg (+)-Zopiclone raw material, be uniformly dispersed.
Coating: add the shaping piece 10kg obtained in step 4 in high-efficiency coating machine, adjusts hydrojet speed and hot air temperature, sprays pastille binder solution, makes medicaments uniformity be coated on tablet surface.Obtain (+)-Zopiclone secondary delivery formulations.
Embodiment 2 (+)-Zopiclone secondary delivery formulations
With the prescription described in following table and percent increase in weight, prepare according to the method for embodiment 1.
Embodiment 3
The mensuration of external controlled release tablet release
It is measured by Chinese Pharmacopoeia dissolution the second method.The phosphate buffer of pH6.8 is release medium, and speed of agitator is 50rpm.Embodiment 1 step 3 obtains the release profiles of (+)-Zopiclone controlled release tablet and sees accompanying drawing 1.
Embodiment 4
The mensuration of internal controlled release tablet blood drug level
Selecting 3 healthy beasle dogs (male, body weight 10.0～10.7kg), be orally administered to the controlled release synusia that 1 embodiment 1 is obtained by A recipe step three respectively, drinking water takes.Before test, fasting about 16 hours, freely drinks water.After being administered 4 lab scales, unification gives feedstuff.Within 1,2,2.5,3,3.5,4,5,8,10,12 hours, taking blood 1.5mL through cephalic vein before being administered and after being administered, put in K3EDTA centrifuge tube, under the conditions of 4 DEG C, 3200g is centrifuged 5min separated plasma.During sample analysis, all plasma samples are collected and are placed on-20 DEG C of Refrigerator stores.Gather plasma sample in different time points, use Liquid Chromatography-Tandem Mass Spectrometry to determine the concentration in blood plasma respectively after organic solvent processes, result such as following table:
Article 3, beasle dog blood drug level (ng/mL)
BLQ: less than lower limit of quantitation；NA: inapplicable；ND: do not detect
Embodiment 5
Secondary delivery formulations drug release determination
Example 1 obtains (+)-Zopiclone secondary delivery formulations, measures dissolution according to two annex XC dissolution the second methods of " Chinese Pharmacopoeia " version in 2010.The phosphate buffer of pH6.8 is release medium, and speed of agitator is 50rpm, and release curve is shown in accompanying drawing 2.
Claims (10)
1. the secondary delivery formulations containing (+)-Zopiclone, it is characterised in that said preparation mainly by kernel, swell layer, controlled release layer,
Sealing coat and release layer composition.
Secondary delivery formulations the most according to claim 1, it is characterised in that described kernel mainly by (+)-Zopiclone, filler,
Disintegrating agent forms.
Secondary delivery formulations the most according to claim 1, it is characterised in that described swell layer uses chance water quickly to form gel
Hydrophilic polymer, the preferred hydroxypropyl methyl cellulose of described hydrophilic polymer, calcium alginate, polyoxyethylene, carbomer；
Most preferably hydroxypropyl methyl cellulose.
Secondary delivery formulations the most according to claim 1, it is characterised in that described controlled release layer include water-insoluble polymer and
Water-soluble substances, water-insoluble polymer is preferably ethyl cellulose, polyacrylic resin, polyvinyl acetate, most preferably second
Base cellulose aqueous dispersions；Described water-soluble substances is selected from hydroxypropyl methyl cellulose, and polyacrylic resin, in polyvinyl alcohol
A kind of or the most two or more combinations, preferably hydroxypropyl methyl cellulose.
Secondary delivery formulations the most according to claim 1, it is characterised in that described sealing coat uses conventional gastric solubility coating material
Material, a kind of or the most two or more compositions in hydroxypropyl methyl cellulose, polyvinyl alcohol, polyacrylic acid.
Secondary delivery formulations the most according to claim 1, it is characterised in that release layer mainly contains the bonding of (+)-Zopiclone
Agent, the binding agent a kind of or the most two or more compositions in hydroxypropyl methyl cellulose, polyvidone, polyacrylic acid.
Secondary delivery formulations the most according to claim 2, it is characterised in that the filler of described kernel uses the dilute of tablet routine
Release agent, including a kind of or the most two or more mixture in lactose, microcrystalline Cellulose, starch based, mannitol, further
It is preferably lactose, microcrystalline Cellulose, starch；Described filler loading accounts for the 80-92%% of kernel；Kernel is possibly together with oral tablet
Other adjuvants conventional in agent, including binding agent, coloring agent, surfactant, fluidizer, lubricant, sweeting agent.
8. according to the secondary delivery formulations described in claim 1-7 any one, it is characterised in that described swell layer heavily control be
15%-30%, preferably 18%-28%.
9. according to the secondary delivery formulations described in claim 1-7 any one, it is characterised in that described controlled release layer coating weight gain
8%-25%, preferably 10-20%.
10. according to the secondary delivery formulations described in claim 1-7 any one, it is characterised in that described controlled release layer is mainly by hydroxypropyl
Methylcellulose and ethyl cellulose composition.
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