CN104840439B - A kind of bionical drug release preparation of epiphysin and preparation method thereof - Google Patents

Abstract

The present invention provides bionical drug release preparations of a kind of epiphysin and preparation method thereof.Specifically, the drug release preparation contains epiphysin and pharmaceutically acceptable carrier as active constituent, and the drug release preparation discharges the active constituent with two-phase delivery mode, wherein the two-phase release includes the first release stage that zero order release rate is v1 and the second release stage that zero order release rate is v2, and the trend reverse point of two-phase release is 4-6 hour after medication, and 2 hours active constituent Accumulation dissolution≤20% after medication.Present invention drug release preparation can effectively simulate young normal population endogenous melatonin release and plasma concentration curve, sufficiently achieve bionical purpose, and dosage used is only 1/20-1/10 in the prior art or so, can be effectively prevented from drug-induced " being still drank after a night " phenomenon.

Description

A kind of bionical drug release preparation of epiphysin and preparation method thereof

Technical field

The present invention relates to field of pharmaceutical preparations, specifically, the present invention relates to one kind based on the life of human endogenous's property epiphysin The two-phase of reason pharmacokinetics time-histories feature discharges the design and preparation of bionical medicine-releasing system.

Background technique

Epiphysin (Melatonin, MT, melatonin) also known as epiphysin are loose in vertebrate brain The endogenous indole hormone of fruit body gland cell synthesis and secretion, has extensive physiological function and immunoregulation effect, mainly For adjusting, by objective factor (jet lag syndrome and shift-work system) or inherent cause, (familial sleep period integrates in advance Seek peace and postpone sleep period syndrome) circadian system upset and eliminates depression to promote sleep, improve sleep quality Shape, in addition its there are also oxidation resistant effects.The secretion of epiphysin has the characteristics that apparent circadian rhythm, and people and mammal are just Under normal physiological status, the rhythmicity fluctuation of " day at low night is high " is presented in the melatonin secretion in serum, since evening 18:00 It gradually rises, midnight 2:00-3:00 is the top of secretion in one day, is then gradually reduced again, to a morning 6:00-7:00 left side The right side reaches the lowest point [WARD D, JOHN M, STEVEN W.Smart Drugs II [M] .First edition.Health Freedom Publ ications,1993]。

The normal epiphysin secreted daily only about 115 μ g in younger age group, and the epiphysin dosage form listed at present is main There are conventional tablet, chewable tablets, oral disnitegration tablet, sustained-release preparation, soft capsule, oral solution etc., these dosage forms belong to primary Hormone replacement therapy, and its dosage is usually 2mg, significantly larger than needed for normal physiologic levels, excessive epiphysin may be led It causes " effect of being still drank after a night ", i.e., still has the epiphysin of higher concentration in vivo during the day, human body occurs strong sleep signal, causes to sleep Disorder, or hypothermia can be generated, the excessive galactin of release leads to infertile adverse reaction, influence next day work with it is normal raw It is living.In addition, the epiphysin ordinary preparation product of quick release that there are oral absorptions is unstable, distribution with remove fastly that (half-life period is 30-50min) the problem of, therefore the melatonin dosage in preparation is difficult to reduce.

For example, 0213388.6 melatonin two-layer release-controlled tablet of patent CN), it is a kind of double-deck control characterized by early stage quick-release Release piece；Patent US 20100120887/CN 200880100059.0 is a kind of epiphysin preparation with bionical drug release concept, It proposes the concept of imitation young man's endogenous levels, extracts blood at regular intervals from 19:00 to next day 12:00 after subject's medication Slurry detection epiphysin blood concentration, but its take after discharge same very fast, 22:00 or so reaches peak to blood concentration at night Value, and keep higher about 5 to 6 hours horizontal.Patent US 5498423 is a kind of bionical drug release granular preparation of epiphysin, but its The sustained release time is shorter (22:00pm-6:00am), wherein being always maintained at maximum concentration, said preparation from 24:00pm-4:00am For itself there are also the crowd of part endogenous melatonin secretion, long-term use is likely to result in own endogenous melatonin secretion It is abnormal.Patent CN 98113169.7 is also a kind of melatonin slow-releasing agent for proposing bionical drug release concept, but it includes quick-release system Agent part, takes rear blood concentration and improves rapidly, then keeps stable again.Patent US 20120195968/WO 2012103411 It is the melatonin slow-releasing agent of a kind of single layer, bilayer or multilayer, has the characteristics that single-phase release；Patent WO 1995003043 It is also a kind of sustained release preparation of single-phase release, such preparation is taken rear blood concentration and risen comparatively fast.Patent US 20080171085 It is the epiphysin preparation that a kind of release early period is rapid, the later period discharges slow two-phase release, includes two parts of quick-release and sustained release, Immediate release section can make rapid increase in the blood concentration short time reach peak.Patent EP 2598124/US 20130122092 is a kind of Epiphysin tablet with three-phase release characteristic, but its dosage is larger, and i.e. release reaches 1mg in 10 minutes, therefore after taking Blood concentration meeting rapid increase, patent US 20080254121 are also a kind of multi-layer preparation with multiphase release characteristic, tool There are immediate release outer layer and inner sustained-release layer, so that blood concentration is peaked in a short time.

It can be seen that the simple combination of general preparation is usually used only in the prior art, including skeleton type sustained release preparation etc. absolutely Most types of sustained-release preparation be all often discharge rapidly the incipient stage, latter stage rate of release it is slow, therefore in order to take The peak of epiphysin is maintained after medicine in a few hours, often preparation uses large dosage of medication (2-3mg), but this dosage and human endogenous Property melatonin dosage (115 μ g) differ as many as decades of times, easily cause the side effect of next day, i.e., above-mentioned " being still drank after a night " phenomenon.

Therefore, there is an urgent need in the art to develop one kind to meet human body natural's melatonin secretion and action rule and can Side effect is reduced to the epiphysin delivery formulations of minimum.

Summary of the invention

The present invention provides a kind of controlled release epiphysins according to the design of young normal person's endogenous melatonin Secretion Rhyme to release Put preparation.

First aspect present invention, provides a kind of bionical drug release preparation of epiphysin, and the drug release preparation contains as work The epiphysin and pharmaceutically acceptable carrier of property ingredient,

And the drug release preparation discharges the active constituent with two-phase delivery mode, wherein two-phase release includes The second release stage that the first release stage and zero order release rate that zero order release rate is v1 are v2, and the two-phase discharges Trend reverse point be 4-6 hour after medication, and after taking medicine 2 hours active constituent Accumulation dissolution≤20% it is (preferable Ground≤15%, more preferably≤10%).

In another preferred example, the V1 < V2.

In another preferred example, the ratio of the V2/V1 is 1.2-5, preferably 1.5-3, is more preferably 1.75- 2.5。

In another preferred example, the content of epiphysin is 0.05-0.5mg/ agent (or piece) in the drug release preparation.

In another preferred example, the content of epiphysin is 0.1-0.3mg/ agent (or piece) in the drug release preparation.

In another preferred example, two-phase release refers to: the drug release preparation being placed in water or digestive juice, first Rate of release is v1 when drug release stage T1, and in the second drug release stage T2, rate of release is v2, wherein a length of 4-6 as T1 Hour, T2 when 4-8 hours a length of (preferably 8-6 hours).

In another preferred example, first drug release stage T1 in, active constituent Accumulation dissolution be 10-45% (preferably 15-40%)；In the second drug release stage T2, active constituent Accumulation dissolution is 55-90% (preferably 60-85%), by described The total weight of active constituent in preparation.

In another preferred example, (4-4.5 hours a length of when T1), v1 when 4-4.5 is small after trend reverse point is medication For 4.37-5.93%/h, it is preferable that be 4.92%/h；V2 is 6.30-20.89%/h, preferably 11.09%/h.

In another preferred example, (a length of 4.5-5.5 is small when T1 when 4.5-5.5 is small after trend reverse point is medication When), v1 4.37-7.21%/h, it is preferable that be 5.19%/h；V2 is 6.30-20.89%/h, preferably 11.48%/h.

In another preferred example, (5.5-6 hours a length of when T1), v1 when 5.5-6 is small after trend reverse point is medication For 4.37-8.25%/h, it is preferable that be 5.54%/h；V2 is 6.30-20.89%/h, preferably 11.64%/h.

In another preferred example, the Accumulation dissolution of the active constituent of the preparation meets the following conditions: 2 hours after medication Accumulation dissolution be not higher than 10%, 4 hours Accumulation dissolutions are 14-30%, and 6 hours Accumulation dissolutions are 35%- 45%, 8 hours Accumulation dissolutions are 60-70%, and 12 hours Accumulation dissolutions are not less than 90%.

In another preferred example, the Accumulation dissolution curve L1 of the epiphysin of the drug release preparation and young normal population Epiphysin release profiles L0 coincide or coincide substantially.

In another preferred example, the young normal population is the normal population for being 20-35 years old the age.

In another preferred example, " coincide or coincide substantially " refers to that the Accumulation dissolution curve L1 and youth are normal Related coefficient >=0.9 of the epiphysin release profiles L0 of crowd.

In another preferred example, the Accumulation dissolution curve refers to after medication 0-14 hours, preferably 1-12 hours The release curve of period.

In another preferred example, after the drug release preparation is taken, in the plasma concentration curve of the intracorporal active constituent of people In unimodal and described unimodal peak value be located at medication after 5-10 hour, be preferably located at take medicine after 6-9 hours, more preferably for 6-8 hours.

In another preferred example, the drug release preparation occurs after 18:00-20:00 takes in next day 0:00-3:00 The unimodal peak value of epiphysin blood concentration.

In another preferred example, there is epiphysin in next day 1:00-3:00 after 18:00 takes in the drug release preparation The unimodal peak value of blood concentration.

In another preferred example, there is epiphysin in next day 1:00-3:00 after 20:00 takes in the drug release preparation The unimodal peak value of blood concentration.

In another preferred example, the preparation includes osmotic pump tablet preparation, gel skeleton tablet preparation.

In another preferred example, the label of the preparation is interior outer double-layer structure label.

In another preferred example, the content of active constituent is 0.035- based on label weight in the internal layer label 1.8wt%；The content of active constituent is 0.005-0.6wt% based on label weight in the outer layer label, and it is described it is interior, The weight ratio internal layer of active constituent in outer layer label: outer layer 10:0-7:3.

In another preferred example, the outer layer release in the interior outer double-layer structure corresponded to for the first release stage, and outer layer is released It puts and corresponded to for the second release stage.

In another preferred example, inside and outside layer gross mass ratio is 4:1-1:4.

In another preferred example, when the drug release preparation is osmotic pump tablet preparation, inside and outside layer gross mass ratio preferably 3: 1-1:2, most preferably 2:1-1:2.

In another preferred example, when the drug release preparation is gel skeleton tablet preparation, inside and outside layer ratio is 3:1-1:4, It is preferred that 2:1-1:4, most preferably 1:1-1:4.

In another preferred example, based on the label total weight of osmotic pump tablet preparation, the label includes 0.1-2wt%, excellent Select 0.1-1.5wt%, the most preferably epiphysin of 0.1-1wt%；5-25wt%, preferably 5-20wt%, most preferably 5-15wt%'s Play the controlled release agent of controlled-release function；70-90wt%, preferably 75-90wt%, the osmotic pressure promotor of most preferably 80-90wt% and 0.1-5wt%, preferably 0.1-3wt%, most preferably 0.1-1wt% pharmaceutically acceptable carrier.

In another preferred example, it is based on gel matrix tablet label total weight, the label includes 0.05-2wt%, preferably 0.05-1.5wt%, the most preferably epiphysin of 0.05-1wt%；30-70wt%, preferably 30-60wt%, most preferably 30-50wt% Rise controlled-release function controlled release agent；30-70wt%, preferably 40-70wt%, the most preferably filler of 50-70wt% and 0.1- The pharmaceutically acceptable auxiliary material of 5wt%, preferably 0.1-3wt%, most preferably 0.1-1wt%.

In another preferred example, the pharmaceutically acceptable carrier includes controlled release agent, filler, osmotic pressure promotion Agent.

In another preferred example, the pharmaceutically acceptable carrier further includes colorant, opacifier, adhesive, lubrication Agent.

In another preferred example, the controlled release agent includes polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethyl Cellulose, sodium carboxymethylcellulose, povidone, copolyvidone, acrylic resin, stearic acid, octadecyl alcolol, carbomer or its group It closes；Preferably, include polyoxyethylene, hydroxypropyl methylcellulose, or combinations thereof；And/or

The osmotic pressure promotor include lactose, fructose, glucose, mannitol, sodium chloride, potassium chloride, potassium sulfate or its Combination；Preferably, include lactose, mannitol, or combinations thereof；And/or

The filler includes lactose, fructose, glucose, mannitol, sodium chloride, potassium chloride, potassium sulfate, microcrystalline cellulose Element, starch, dextrin calcium carbonate, or combinations thereof；Preferably, including lactose, microcrystalline cellulose or combinations thereof.

Described adhesive includes starch slurry, povidone, copolyvidone, ethyl cellulose, hydroxypropylcellulose, hypromellose Element, methylcellulose, gelatin, polyethylene glycol, or combinations thereof；Preferably, including povidone；And/or

The lubricant include magnesium stearate, talcum powder, superfine silica gel powder, polyethylene glycol, or combinations thereof, preferably include hard Fatty acid magnesium, talcum powder or combinations thereof；And/or

In another preferred example, when the drug release preparation is osmotic pump tablet preparation, the osmotic pressure promotor is Lactose；And/or the filler is microcrystalline cellulose.

In another preferred example, the opacifier includes one of titanium dioxide, talcum powder and silica or a variety of, It is preferred that titanium dioxide.

In another preferred example, the colorant is red ferric oxide or yellow ferric oxide.

In another preferred example, when the drug release preparation is osmotic pump tablet preparation, the piece of the osmotic pump tablet preparation Core appearance has semi permeability coating membrane, and the semi permeability coating membrane has drug releasing pores.

In another preferred example, the weight gain of the semi permeability coating membrane is the 3%-10% of label weight, preferably, being 3%-8%.

In another preferred example, the semi permeability coating membrane includes filmogen, pore-foaming agent, plasticizer.

In another preferred example, the filmogen includes cellulose acetate, ethyl cellulose, cellulose acetate phthalandione Ester, acrylic resin, hydroxypropyl cellulose phthalate ester, or combinations thereof, preferred cellulose acetate.

In another preferred example, the pore-foaming agent include polyethylene glycol, povidone, copolyvidone, hydroxypropylcellulose or its Combination, preferably polyethylene glycol；

In another preferred example, the plasticizer includes phthalate, triethyl citrate, preferably O-phthalic Diethyl phthalate.

In another preferred example, the mass ratio of filmogen and pore-foaming agent is 8:1-3:1 in the semi permeability coating membrane, excellent Select 6:1-3:1.

In another preferred example, the diameter of the drug releasing pores is 0.2mm-1.2mm.

In another preferred example, the osmotic pump tablet preparation preparation step includes:

(a) epiphysin being sieved, osmotic pressure promotor and can pharmaceutically connect in addition to lubricant are weighed by recipe quantity The auxiliary material received is uniformly mixed, and granulation adds suitable lubricant, is mixed to get inner layer granule, spare；

(b) epiphysin being sieved, controlled release agent, osmotic pressure promotor and the pharmacy in addition to lubricant are weighed by recipe quantity Upper acceptable auxiliary material is uniformly mixed, and granulation adds suitable lubricant, is mixed to get skin granulate, spare；

(c) inside and outside layer particle is made to double-layer tablets label after tabletting twice；

(d) packet semi-permeable membrane clothing, until label weight gain reaches design flow；

(e) punch, use laser or mechanical punching mode the medicated layer one side or the multi-lateral of coating tablet beat diameter for 0.2mm-1.2mm aperture.

In another preferred example, the preparation step of the gel matrix tablet includes:

(i) epiphysin being sieved, controlled release agent, filler and in addition to lubricant are weighed respectively by inside and outside layer recipe quantity Pharmaceutically acceptable auxiliary material be uniformly mixed, pelletize respectively, add suitable lubricant, mix to get inside and outside layer Grain, it is spare；

(ii) inside and outside layer particle is made to two-layer gel matrix tablet after tabletting twice.

Second aspect of the present invention provides a kind of method for preparing the bionical drug release preparation of epiphysin, the drug release preparation Meet young normal population endogenous melatonin circadian rhythm, and comprising steps of

(a) according to endogenous melatonin blood concentration changing course in young normal population body, Exogenous Melatonin is obtained Ideal biphasic release curve；

(b) formula of the bionical drug release preparation of epiphysin is determined according to the curve that (a) is obtained and prepares the drug release preparation, The drug release preparation is interior outer double-layer structure and has bi-phasic release characteristics, and the drug release preparation meets with next or more A feature:

(i) related coefficient of the drug release preparation cumulative release curve and ideal biphasic release curve obtained in (a) For 0.9-1.0；

(ii) the two-phase release of the delivery formulations has trend reverse point, and trend reverse point is 4-6 after medication Hour；Or

(iii) the drug release preparation 2 hours active constituent Accumulation dissolution≤20% after the tablet has been ingested；

(c) the drug release preparation in (b) is calculated or is measured its Accumulation dissolution R_iWith rate of release constant k_i, and root According to the R_iAnd k_iAnd formula: (1), (3), (4), (6) calculate human body blood concentration changing course and its curve l'1；Its In, i is different timing node, wherein k_aFor absorption rate constant, k_eFor elimination rate constant, k_iFor zero order release rate, V For apparent volume of distribution, F is absorptivity, C_{R, i}For the absorption strength of i timing node, C_E,iFor the elimination concentration of i timing node, C_{S, i}For the residual concentration of i timing node；t_iRepresent the duration of different nodes:

C=C_R+C_E+C_S(6)；

(d) the blood concentration changing course curve l'1 obtained will be calculated in (c) to take off with endogenous in young normal population body Melanocyte blood concentration changing course curve l'0 compares, if related coefficient >=0.9 of l'1 and l'0, shows design in (b) The preparation that releases the drug is the drug release preparation for meeting young normal population endogenous melatonin circadian rhythm；If the related coefficient of l'1 and l'0 <0.9, then return step (b)-(d) is needed, until related coefficient>=0.9 of l'1 and l'0.

In another preferred example, first stage rate of release v1 < second stage rate of release v2 of the two-phase release.

In another preferred example, C_RFor absorption strength, C_E, to eliminate concentration, C_s, it is residual concentration.

In another preferred example, the C is the blood concentration of specific time node, and C=C_R+C_E+C_S, that is, work as t=t_i When, C=C_i, C=C_i=C_{R, i}+C_{E, i}+C_{S, i}。

In another preferred example, the drug release preparation is drug release preparation described in first aspect present invention.

In another preferred example, the drug release preparation has ectonexine double-layer structure, and epiphysin in double-layer structure Mass ratio is internal layer: outer layer 10:0-7:3.

In another preferred example, the method further include: (c1) after volunteer takes the drug release preparation, measurement is not With the blood concentration of time-histories, it is depicted as curve l'2, and the blood concentration changing course curve l'1 with calculating acquisition in (c) Or endogenous melatonin blood concentration changing course curve l'0 compares in young normal population body.

It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.

Detailed description of the invention

Fig. 1 be all ages and classes, sex population endogenous melatonin concentration changes with time curve.

Fig. 2 is that its secretion song of gained is calculated according to the curve of the endogenous melatonin concentration changes with time of different crowd Line, the i.e. ideal release profiles of epiphysin bio-preparation.

Fig. 3 is that the release curve of the bionical patch of epiphysin osmotic pumps prepared by 1 prescription of embodiment and ideal discharge Curve (Fig. 3 A), the plasma concentration curve of the bionical patch of epiphysin osmotic pumps and ideal young state epiphysin blood concentration Curve (Fig. 3 B).

Fig. 4 is that the release curve of the bionical patch of epiphysin osmotic pumps prepared by 2 prescription of embodiment and ideal discharge Curve (Fig. 4 A), the plasma concentration curve of the bionical patch of epiphysin osmotic pumps and ideal young state epiphysin blood concentration Curve (Fig. 4 B).

Fig. 5 is that the release curve of the bionical patch of epiphysin gel skeleton prepared by 3 prescription of embodiment is released with ideal It puts curve (Fig. 5 A), the plasma concentration curve of the bionical patch of epiphysin gel skeleton and ideal young state epiphysin blood medicine are dense Write music line (Fig. 5 B).

Fig. 6 is that the release curve of the bionical patch of epiphysin gel skeleton prepared by 4 prescription of embodiment is released with ideal It puts curve (Fig. 6 A), the plasma concentration curve of the bionical patch of epiphysin gel skeleton and ideal young state epiphysin blood medicine are dense Write music line (Fig. 6 B).

Fig. 7 is the blood concentration song that the elderly men of different endogenous melatonin levels takes epiphysin osmotic pumps bionical Line and ideal young state epiphysin blood medicine curve.

Fig. 8 is that the old women of different endogenous melatonin levels takes entirety after the bionical patch of epiphysin gel skeleton Blood concentration and ideal young state epiphysin blood medicine curve.

Fig. 9 is the release curve and desirable release profile of the epiphysin osmotic pumps patch prepared by 7 prescription of embodiment (Fig. 9 A), the plasma concentration curve of epiphysin osmotic pumps patch and ideal young state epiphysin plasma concentration curve (figure 9B)。

Specific embodiment

The present inventor after extensive and in-depth study, for the first time it was unexpectedly observed that the ideal release of endogenous melatonin is bent Line has first slow rear fast two-phase Zero order release feature, and the rate of release of first stage is less than the rate of release of second stage, The general release characteristic of such two-phase Zero order release feature sustained-release preparation different from the past first quick and back slow, needs to take spy Fixed preparation research means are just able to achieve.The present inventor is according to the discovery, by osmotic pumps/gel skeleton technology and compound suppressing packet The multilayer chip technology for wrapping up in type combines, and the physiologic secretion dynamics spy of healthy human body is followed in the selection of the dosage of active material Sign demand, design, which obtains, can make the elderly population for lacking melatonin secretion realize young state epiphysin plasma concentration curve feature Drug release preparation, can occur within 4-6 hours after the tablet has been ingested preparation two-phase release two kinds of showing zero-order release patterns turning point, and Make the epiphysin physiology of the epiphysin plasma concentration curve obtained by the biphasic release preparation and young state to the full extent Plasma concentration curve is consistent.The bionical drug release preparation of the epiphysin that the present invention designs only need using in the prior art 1/10 activity at Divide dosage (i.e. 0.1-0.3mg), drug release patterns and human endogenous's property epiphysin release profiles similarity can either be made good, And blood concentration changes with time similar to young normal population, and epiphysin can be made to reach in morning 0:00-3:00 The top of blood concentration, so that the epiphysin plasma concentration curve degree of fitting with higher of elderly population and young crowd, To obtain the purpose of bionical drug release, the effect of being still drank after a night of overdose is avoided well.On this basis, this hair is completed It is bright.

Term

As used herein, term " epiphysin as active constituent ", " active constituent ", " Exogenous Melatonin " are interchangeable It uses, refers both to the epiphysin that can be used in present invention drug release preparation.

As used herein, term " Zero order release " refers to the epiphysin discharged with constant or substantially invariable rate Release process.Wherein, the substantially constant refers to that the different time nodes in a certain stage, drug release rate error do not surpass Cross ± 20%.

As used herein, term " two-phase Zero order release " refers to release first stage and the second stage of present invention drug release preparation It is Zero order release.Wherein, the rate of release of first stage is v1, and the rate of release of second stage is v2, and wherein v1 is less than v2, And the turning point of v1 and v2 releasing trend betides the 4-6 hour after medication.V1 and v2 can also be respectively seen as the first and second ranks The average rate of release of section.

As used herein, term " Accumulation dissolution " refers in drug release process, on each specific time node, from system The summation of the amount of the active constituent released in agent accounts for the percentage of active constituent total amount in preparation.

As used herein, during term " trend reverse point " refers to present invention drug release preparation release, the first release rank Section is converted into the point in the second release stage, and the 4-6 that the trend reverse point of preparation betides after medication in general, the present invention releases the drug is small When.

As used herein, term " drug release preparation ", " medicine-releasing system ", " the bionical medicine-releasing system of epiphysin " are used interchangeably, Refer both to the present invention and contain epiphysin as active constituent, and the drug release preparation with following characteristics: (a) release has two-phase zero Grade release characteristic；(b) first stage rate of release v1 is less than v2；(c) the trend reverse point of two-phase release is the after medication 4-6 hours；(d) 2 hours active constituent Accumulation dissolution≤20% and after taking medicine.Drug release preparation for use in the present invention Including osmotic pump preparation, gel skeleton preparation.

As used herein, term " osmotic pumps ", " osmotic pump tablet ", " osmotic pump preparation " " osmotic pump tablet preparation " are interchangeable It uses, refers to the osmotic pump preparation for being capable of providing active constituent Zero order release with inside and outside double-deck core structure, form can be with For tablet, pill, granule.Wherein, the outer layer release of the double-deck core structure corresponds to the first of delivery formulations release Stage, internal layer release correspond to the second stage of delivery formulations release.When osmotic pump tablet preparation of the present invention is in the work of outer-skin sheet core Before property ingredient releases, internal layer label will not discharge active component.

As used herein, term " gel skeleton ", " gel matrix tablet ", " gel skeleton preparation " " gel skeleton tablet preparation " It is used interchangeably, refers to the gel skeleton preparation for being capable of providing active constituent Zero order release with inside and outside double-deck core structure, Its form can be tablet, pill, granule.Wherein, the outer layer release of the double-deck core structure corresponds to delivery formulations The first stage of release, internal layer release correspond to the second stage of delivery formulations release.When inventive gel skeleton preparation outside Before the active constituent of synusia core releases, internal layer label will not discharge active component.

Epiphysin

Epiphysin (Melatonin) is mainly a kind of amine bormones generated by the pineal body of mammal and the mankind.It takes off The biosynthesis of melanocyte is restricted by the photoperiod.Pineal body is melted into 5-hydroxyryptophan under the control of light nerve, by tryptophan transfer, It is further converted into serotonin, under the action of N- acetyltransferase, is then converted into N-acetyl-5-hydroxytryptamine, finally Epiphysin is synthesized, so that intracorporal content be made to change in the rhythm and pace of moving things of property round the clock.

Night melatonin secretion amount is 5~10 times more than daytime, and early morning, 2:00 to 3:00 reached peak value.Hakola etc. is to night shift The result of study of melatonin content in worker's saliva also demonstrates this daily rhythmicity variation.WARD D etc. (WARD D, JOHN M,STEVEN W.Smart Drugs II[M].First edition.Health Freedom Publications, 1993.) it points out under normal circumstances, healthy year less serious case about starts to secrete epiphysin in 18:00, and morning next day 2:00 concentration reaches The appearance of peak value, older's peak value lags one hour relative to year less serious case, and the epiphysin maximum plasma concentration of older is only The half of year less serious case.Certain difference, young man is presented in the blood concentration variation of epiphysin in crowd's body in all ages and classes stage Group is apparently higher than elderly population, and AUC is about 2 times (Fig. 1) of elderly population.

The design and calculating of relationship between endogenous melatonin blood concentration and exogenous drugs release

The elderly population for lacking melatonin secretion can be made to realize young state epiphysin plasma concentration curve feature in order to obtain Drug delivery system, the present invention according to the absorption of internal endogenous material epiphysin, eliminate process, it is black to have calculated that exogenous drugs take off The calculation method of the release process of element.

1. epiphysin is calculated by pharmacokinetic curve in epiphysin common quick release preparation body using method of residual Internal pharmacokinetic parameter:

Absorption rate constant k_a, elimination rate constant k_e, apparent volume of distribution V and absorptivity F ratio:

I.e. according to (BECOM-JIN L, KEITH A P, JAMES W A, the ROBERT L S.Design and such as Lee evaluation of an oral controlled release delivery system for melatonin in human subjects[J].International Journal of Pharmaceutics,1995,124(1):119- 127.) population provided, which takes the plasma concentration curve after 0.5mg epiphysin quick releasing formulation and calculates through method of residual, obtains:

The k of epiphysin_a=1.36h^-1、k_e=1.21h^-1With F/V=3.07 × 10^-6mL^-1。

2. it is dense that derivation meets young state (20-35 years old age youth normal population) epiphysin blood medicine according to split dose method The release in vitro feature for spending horizontal bio-preparation calculates the Accumulation dissolution R at each time point_i, rate of release constant k₀。

If corresponding to the time [0, t₁, t₂..., t_n] internal blood concentration be [0, C₁, C₂..., C_n], then Release Division method The process for calculating drug release kinetics in slow-release controlled-release preparation body is exactly the internal zero level for calculating preparation in each time interval Rate of release k_i。

Burst size in first time period is segmented into two parts, and a part is absorbed by the body, and another part is then present in Absorption site, it is to be absorbed, and in t > t₁It is gradually absorbed afterwards.Deenergized period is absorbed part to vivo medicine concentration curve in t =t₁When contribution are as follows:

Rate of release

Absorb the blood concentration C obtained_R,1Elimination relatively subsequent each time point blood concentration contribution margin are as follows:

This release absorption site residual quantity to the contribution margin at subsequent each time point are as follows:

According to above-mentioned (3), (4) two formulas, corresponding to time [t₂..., t_n] internal blood concentration [C₂..., C_n] in point It Kou Chu not C₁C_E,iAnd k₁t₁C_S,iContribution margin, obtain by rate of release [k₁..., k_n] caused by vivo blood concentration be [C_R,2..., C_R,n], according to formula (1) by C_R,2K is calculated₂.And so on, calculate separately out medicine in subsequent each period Object rate of release constant [k₂..., k_n].Accumulation dissolution can be denoted as:

3. it is same, according to known drug Accumulation dissolution R_iWith rate of release constant k_i, it can be reversed derivation blood concentration, C is found out according to formula (3), (4)_E,iAnd C_S,i。

The blood medicine dynamics of the outer Zero order release of single blood vessel are as follows:

C_i=C_R+C_E+C_S (6)

C_RContribution of the part to vivo medicine concentration curve in various time points to blood concentration is absorbed for deenergized period Value, the blood concentration of various time points can be found out according to formula (6).

4. secretion time 18:00 is set as 0h, utilizes agent according to different crowd endogenous melatonin plasma concentration curve The Accumulation dissolution that split plot design calculates 0-12h each time point after administration is measured, the internal epiphysin of all ages and classes stage crowd is obtained Release characteristic.All ages and classes, different sexes crowd epiphysin body in release time-histories be in " first slow after fast " bi-phasic release characteristics.

Through Similarity measures, the similar factors f of the epiphysin release profiles of young woman and older women₂It is 59.04；Year The similar factors f of the epiphysin release profiles of light women and young men₂It is 77.35；Young woman and taking off for older male are black The similar factors f of plain release profiles₂It is 61.96；The similar factors f of young men and older male's epiphysin release profiles₂For 60.90.According to the relevant regulations of U.S. FDA, similar factors f₂Indicate that two release profiles are similar, illustrate above four greater than 50 Curve is similar between any two, i.e., all ages and classes, the internal release time-histories of different sexes crowd's epiphysin are similar (Fig. 2).

Since the endogenous melatonin kinetics of secretion of four kinds of crowds is approximate, only intensity is different, so the present invention uses The internal epiphysin release time-histories of young crowd (such as young woman) is designed, and the design of the bionical drug delivery system of other crowds can Reached with adjustment by dosage.

For example, various dose preparation may be selected according to different patient's own endogenous melatonin levels, specifically, when disease When level is respectively 0,25%, 50%, 100% and the 150% of the elderly's average level in people's epiphysin body, it is computed corresponding choosing Selecting taking dose is respectively 228,207,143,115,57 μ g.Patient 18:00 take epiphysin prepared by the present invention it is bionical to Medicine system, epiphysin enters enteron aisle with first slow rear fast two-phase delivery mode and is absorbed after medication, and blood concentration starts slowly Rise, reach peak value in 2:00-3:00am or so, then begin to decline, 6:00am or so restores to reduced levels.

The dosage form design of drug release preparation

The present invention provides the first slow rear fast two-phase zero levels for meeting young state epiphysin physiological drug dynamics time-histories feature Epiphysin preparation of release and preparation method thereof, used preparation includes double-layer osmotic pump tablet and gel matrix tablet:

Osmotic pump tablet preparation

Osmotic pump tablet is made of drug, semipermeable membrane material, osmotic pressure active material and push agent etc., is made with osmotic pressure For the controlled release tablet for the energy that releases the drug.Its basic structure is that drug and proper auxiliary materials are first pressed into label, one layer of semi permeability object of outsourcing Plasma membrane, and an aperture is generated on film.Taking orally gastrointestinal water after the medicine and entering label through semi-permeable membrane dissolves drug, medicine The permeable semi-permeable membrane of osmotic pressure is generated after object dissolution, moisture is endlessly entered into label, due to the limit of semi-permeable membrane internal volume The nearly saturated concentration solution of system, drug is constantly shifted to outside piece by drug releasing pores again, thus makes drug with constant speed Rate is discharged into outside piece, because of referred to herein as osmotic pumps.

The drug of osmotic pump tablet is discharged with Zero order rate, and relative to other sustained-release preparations its rate of releasing drug by extraneous ring Border factor (such as pH value, gastrointestinal motility) influence is small, therefore individual difference is small, and inside and outside drug release behavior correlation is good, body Inside and outside related coefficient is up to 0.9 or more (Kaushik Thanki, Sushant Kulthe, Yogesh Mandge, et al.Formulation Development and IVIVC of Controlled Porosity Osmotic Pump Tablets of Carvedilol Phosphate[J]Journal of Pharmacy Research 2011,4(12), 4736-4740).According to this theory, aqueous solution substitution gastric juice or intestinal juice etc. can be used in vitro and be used as dissolution solvent for osmotic pump tablet, Its interior medicine dynamics feature can be effectively predicted by external release characteristic.

The present invention by designing there is the osmotic pump preparation of two-phase typical case Zero order release feature to reach bionical release epiphysin Purpose.

Osmotic pump tablet preparation for use in the present invention is interior outer double-layer structure preparation, and outer in the interior outer double-layer structure Layer release corresponded to for the first release stage, and outer layer release corresponded to for the second release stage.

In general, osmotic pump tablet preparation of the present invention, the label total weight based on osmotic pump tablet preparation, the label include 0.1- 2wt%, preferably 0.1-1.5wt%, the most preferably epiphysin of 0.1-1wt%；5-25wt%, preferably 5-20wt%, most preferably 5- The controlled release agent for playing controlled-release function of 15wt%；The osmotic pressure of 70-90wt%, preferably 75-90wt%, most preferably 80-90wt% promote Into agent and 0.1-5wt%, preferably 0.1-3wt%, most preferably 0.1-1wt% pharmaceutically acceptable carrier.

The ectonexine label total mass ratio that can be used for osmotic pump tablet preparation of the present invention is 4:1-1:4, preferably 3:1-1: 2, it is more preferably 2:1-1:2.And active constituent contained in ectonexine label is calculated as 0.035- by the weight of label 1.8wt%；The content of active constituent is calculated as 0.005-0.6wt% by the weight of label in the outer layer label, and described The weight ratio of active constituent is 10:0-7:3 in inside and outside synusia core.

It can be used in the double-deck core of osmotic pump tablet preparation of the present invention, internal layer includes epiphysin and osmotic pressure promotor；Outside Layer includes epiphysin, controlled release agent and osmotic pressure promotor.

The osmotic pressure promotor include lactose, fructose, glucose, mannitol, sodium chloride, potassium chloride, in potassium sulfate or A combination thereof, preferably lactose and/or mannitol, most preferably lactose.

The controlled release agent includes polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethyl cellulose, carboxymethyl cellulose One of plain sodium, povidone, copolyvidone, acrylic resin, stearic acid, octadecyl alcolol, carbomer are a variety of, preferably polyoxy second Alkene, hydroxypropyl methylcellulose, or combinations thereof.

The osmotic pressure promotor include lactose, fructose, glucose, mannitol, sodium chloride, potassium chloride, potassium sulfate or its Combination, preferably lactose and/or mannitol, most preferably lactose.

Other pharmaceutically acceptable carriers further include one in adhesive, lubricant, opacifier, filler and colorant Kind is a variety of.

Wherein, the adhesive includes starch slurry, povidone, copolyvidone, ethyl cellulose, hydroxypropylcellulose, hydroxyl One of third methylcellulose, methylcellulose, gelatin and polyethylene glycol are a variety of, preferably povidone；The lubricant packet Include one of magnesium stearate, talcum powder, superfine silica gel powder and polyethylene glycol or a variety of, preferably include magnesium stearate, talcum powder or A combination thereof；The opacifier include titanium dioxide, talcum powder, silica, or combinations thereof, preferred titanium dioxide；Described Filler include microcrystalline cellulose, starch, dextrin, mannitol, calcium carbonate, or combinations thereof, preferably microcrystalline cellulose；Described Toner includes red ferric oxide or yellow ferric oxide.

Label appearance has semi permeability coating membrane, and semi permeability coating membrane is made of filmogen, pore-foaming agent, plasticizer.Institute It states semi-permeable membrane coating material and is selected from cellulose acetate, ethyl cellulose, cellulose acetate phthalate, acrylic resin and hydroxypropyl One of cellulose phthalate is a variety of, preferably cellulose acetate；The pore-foaming agent is selected from polyethylene glycol, povidone, copolymerization Tie up one of ketone and hydroxypropylcellulose or a variety of, preferably polyethylene glycol.The semi permeability coating membrane further includes medicine Acceptable plasticizer on, the plasticizer are selected from phthalate and triethyl citrate, preferably phthalic acid Diethylester.

The weight gain of the semi permeability film coating is the 3%-10%, preferably 3%-8% of label weight；Filmogen with The ratio of pore-foaming agent is 8:1-3:1, preferably 6:1-3:1.

In determining osmotic pump tablet preparation ectonexine structure of the present invention after the different weight ratio of active constituent, ability can be passed through Domain conventional technical means prepares osmotic pump tablet preparation of the present invention.It is a kind of preferred the preparation method is as follows:

(a) epiphysin being sieved, osmotic pressure promotor and can pharmaceutically connect in addition to lubricant are weighed by recipe quantity The auxiliary material received is uniformly mixed, and granulation adds suitable lubricant, is mixed to get inner layer granule, spare；

(b) epiphysin being sieved, controlled release agent, osmotic pressure promotor and the pharmacy in addition to lubricant are weighed by recipe quantity Upper acceptable auxiliary material is uniformly mixed, and granulation adds suitable lubricant, is mixed to get skin granulate, spare；

(c) inside and outside layer particle is made to double-layer tablets label after tabletting twice；

(d) packet semi-permeable membrane clothing, until label weight gain reaches design flow；

(e) punch, use laser or mechanical punching mode the medicated layer one side or the multi-lateral of coating tablet beat diameter for 0.2mm-1.2mm aperture.

Gel skeleton preparation

Gel matrix tablet is one kind of sustained-release preparation matrix tablet, that is, selects suitable colloid skeletal material tabletting, piece Meet the gel that certain viscosity is formed after water, drug by spread or (and) gel skeleton corrosion mode releases the drug, its main feature is that skeleton It can finally be completely dissolved, drug all discharges, therefore bioavilability is high.But the drug release process of general gel matrix tablet is in Higuchi release, early period, release had the feature of burst release, was in the canonical trend of " first quick and back slow ".And present invention discover that it is outer The desirable release profile of endogenous melatonin has the two-phase Zero order release feature of " fast after first slow ", and general gel matrix tablet can not Reach this release characteristic, therefore there is certain difficulty in terms of preparation preparation.The present invention is by gel matrix tablet and compound packet The double-deck chip technology for wrapping up in tabletting combines, and solves the problems, such as general gel matrix tablet " burst release ", and the double of " fast after first slow " may be implemented Phase zero-order release kinetics process.

Gel skeleton preparation for use in the present invention is interior outer double-layer structure preparation, and outer in the interior outer double-layer structure Layer release corresponded to for the first release stage, and outer layer release corresponded to for the second release stage.

In general, inventive gel skeleton preparation, based on the total weight of gel skeleton preparation, the label includes 0.05- 2wt%, preferably 0.05-1.5wt%, the most preferably epiphysin of 0.05-1wt%；30-70wt%, preferably 30-60wt%, it is optimal Select the controlled release agent for playing controlled-release function of 30-50wt%；30-70wt%, preferably 40-70wt%, the most preferably filling of 50-70wt% Agent and 0.1-5wt%, preferably 0.1-3wt%, most preferably 0.1-1wt% pharmaceutically acceptable carrier.

The ectonexine label total mass ratio that can be used for inventive gel skeleton preparation is 4:1-1:4, preferably 3:1-1: 4, more preferably 2:1-1:4, most preferably 1:1-1:4.And active constituent contained in ectonexine label is calculated as by the weight of label 0.035-1.8wt%；The content of active constituent is calculated as 0.005-0.6wt% by the weight of label in the outer layer label, and The weight ratio of active constituent is 10:0-7:3 in the inside and outside synusia core.

In the double-deck core of gel skeleton preparation for use in the present invention, internal layer includes epiphysin, controlled release agent and filler； Outer layer includes epiphysin, controlled release agent and filler.

The filler includes lactose, fructose, glucose, mannitol, sodium chloride, potassium chloride, potassium sulfate, microcrystalline cellulose Element, starch, dextrin, calcium carbonate, or combinations thereof, preferably lactose and/or microcrystalline cellulose.

The controlled release agent includes polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethyl cellulose, carboxymethyl cellulose Plain sodium, povidone, copolyvidone, acrylic resin, stearic acid, octadecyl alcolol, carbomer, or combinations thereof, preferably polyoxyethylene and/ Or hydroxypropyl methylcellulose.

Other pharmaceutically acceptable carriers further include one in adhesive, lubricant, opacifier, filler and colorant Kind is a variety of, wherein the adhesive includes starch slurry, povidone, copolyvidone, ethyl cellulose, hydroxypropylcellulose, hydroxyl Third methylcellulose, methylcellulose, gelatin, polyethylene glycol, or combinations thereof, preferred povidone；The lubricant includes tristearin Sour magnesium, talcum powder, superfine silica gel powder, polyethylene glycol, or combinations thereof, preferably include magnesium stearate and/or talcum powder；The shading Agent includes titanium dioxide, talcum powder, silica or combinations thereof, preferably titanium dioxide；The colorant includes red ferric oxide Or yellow ferric oxide.

The preparation method of the epiphysin gel matrix tablet includes:

1) epiphysin being sieved, controlled release agent, filler and in addition to lubricant are weighed respectively by inside and outside layer recipe quantity Pharmaceutically acceptable auxiliary material is uniformly mixed, and is pelletized respectively, and suitable lubricant is added, and is mixed to get inside and outside layer particle, It is spare；

2) inside and outside layer particle is made to two-layer gel matrix tablet after tabletting twice.

The drug release characteristic of drug release preparation and application

The bionical drug release preparation of epiphysin of the present invention has the behavior of two-phase Zero order release, the turnover of two-phase releasing trend Point is between 4-6h, and preferably trend reverse point is in 4h.

A kind of preferred rate of release and the relationship of trend reverse point time of origin are as follows:

For turning point in 4-4.5h, the rate of release of first stage (0-4h) is 4.37-5.93%/h, preferably 4.92%/h；It is 6.30-20.89%/h, preferably 11.09%/h in the rate of release of second stage (4-12h).

For turning point in 4.5-5.5h, the rate of release of first stage (0-5h) is 4.37-7.21%/h, preferably 5.19%/h；It is 6.30-20.89%/h, preferably 11.48%/h in the rate of release of second stage (5-12h).

For turning point in 5.5-6h, the rate of release of first stage (0-6h) is 4.37-8.25%/h, preferably 5.54%/h；It is 6.30-20.89%/h, preferably 11.64%/h in the rate of release of second stage (6-12h).

The bionical drug release preparation of epiphysin of the present invention, the release of epiphysin usually have the feature that 2h is not higher than 10%, 4h 14-30%, 6h 35%-45%, 8h 60-70%, 12h are not less than 90%.

The release characteristic of the bionical drug release preparation of epiphysin of the invention in the medium meet taken off with young crowd's endogenous it is black Element internal release characteristic it is consistent, and according to different patient's own endogenous melatonin levels (such as the elderly's average level 0, 25%, various dose preparation 50%, 100% and 150% etc.) may be selected, make its drug release close to young crowd's endogenous melatonin The physiological level curvilinear characteristic generated is secreted, after patient's medication, blood concentration is gradually increasing, in morning 0:00-3:00 or so (being more preferably morning 2:00 effect) reaches peak value, and 6:00-7:00 point is down to low-level in the morning, can bring in the treatment more Good therapeutic effect simultaneously reduces side effect.

When the time that patient takes present invention drug release preparation is 18:00-20:00, internal blood medicine after medication can be obtained Concentration time curve is similar to endogenous melatonin, and internal time front of blood concentration has similar with endogenous melatonin Unimodal feature.

Beneficial effects of the present invention:

Present invention drug release preparation can make the elderly population for lacking melatonin secretion realize that young state epiphysin blood concentration is bent Line feature can occur the trend reverse point of preparation two-phase release for 4-6 hours after the tablet has been ingested.Importantly, the present invention releases Medicine preparation only need using in the prior art 1/10 active constituent dosage (i.e. 0.1-0.3mg is more preferably 0.115- 0.2mg), drug release patterns and human endogenous's property epiphysin release profiles degree of fitting can be made good, and blood concentration It changes with time similar to young normal population, and epiphysin can be made to reach blood concentration most in morning 0:00-3:00 Peak to obtain the purpose of bionical drug release, and avoids the effect of being still drank after a night of overdose well.

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, no Then percentage and number are weight percent and parts by weight.

Embodiment 1: the bionical patch of epiphysin osmotic pumps

Core formulation: based on 1000

Outer layer:

Internal layer:

Coating solution:

Preparation method: epiphysin and remaining auxiliary material are sieved with 100 mesh sieve, and first press recipe quantity for epiphysin, lactose and tristearin Sour magnesium is uniformly mixed, and as internal layer core material, the scrobicula shape formed punch for being 5mm with diameter is in blocks by its direct pressing.Again by place PEO N80, lactose and magnesium stearate are uniformly mixed, as outer layer core material by side's amount.Half cladding material is set into punching Mould bottom, after internal layer label is then set punch die center, outside upper die part and surrounding one fixed gap of generation, remaining half Layer material fills punch die side gap and covering upper space, the scrobicula shape formed punch for being 6mm with diameter are tabletted.Piece is set In coating pan, it is blown into hot-air, when label temperature is 40 DEG C or so, is coated, coating weight gain continues to blow up to after 5% Enter hot-air 15min.Coating tablet is placed in 40 DEG C of dry 4h in aeration cabinet, carries out laser boring, hole in coating tablet one side Diameter is 0.6mm.

Vitro release measurement:

Using the device of dissolution method (2010 editions two annex of Chinese Pharmacopoeia, Ⅹ C third method cuvette paddle method), to steam Distilled water 100mL is dissolution medium, and revolving speed 100rpm, temperature is 37 ± 0.5 DEG C.Operate according to methods, respectively 0.5,1,2,4,6, 8,10,12h respectively takes solution 1mL, is filtered with 0.22 μm of miillpore filter, discards primary filtrate, take subsequent filtrate spare, and operating immediately Blank medium solution under supplement same volume is synthermal in container.Sample is using efficient liquid phase-Mass Spectrometry measurement.Chromatography with Mass Spectrometry Conditions: chromatographic column is Diamonsil C₁₈(150 × 4.6mm, 5 μm), mobile phase are -0.1% aqueous formic acid of methanol (60:40), 40 DEG C of column temperature, flow velocity 0.6mLmin^-1, 1 μ L of sample volume.Ion source: the source ESI；Detection mode: positive ion detection； Scanning mode: multiple reaction ion detection (MRM) mode；233 → m/z of epiphysin m/z 174；Fragmentation voltage: 95V；Collision Can: 12V；Capillary voltage 3500V；Dry gas (N₂) flow velocity 5Lmin^-1, 300 DEG C of temperature；Sheath gas (N₂) flow velocity 11Lmin^-1, 400 DEG C of temperature；Nebulizer pressure 45psi.Average accumulated, which is calculated, according to result discharges percentage.

Due to epiphysin absorption in animal body, eliminate process and people it is intracorporal absorb, elimination process it is different, nothing Method detects the requirement whether pharmacokinetics behavior in epiphysin bio-preparation body meets simulation of human body using experimental animal.This Patent pushes away blood concentration in human body, plasma concentration curve obtained by comparative experiments and ideal plasma concentration curve according to releasing result is counter Similitude.By split dose method formula (3), (4), (6), C is found out respectively_E,i、C_S,i、C_R、C₁.To start medication time as 0 When, rate of release k₀=0, C_E,i、C_S,i、C_RIt is 0；After experiment gained medication 1 hour, k₁=2.13 μ g/h, by formula (3), (4), (6) obtain C respectively_E,i=0, C_S,i=0, C_R=C₁=2.38pg/mL successively calculates to obtain C₂、C₃、…、C₁₈.The elderly due to A small amount of epiphysin is still secreted in pineal degeneration.This patent is young man's secretory volume according to the secretory volume of the elderly's epiphysin 50% calculate, then test gained 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) blood The sum of concentration and the elderly's secretory volume be respectively 0,3.06,17.60,26.65,28.22,48.76,82.47,99.18, 103.20,98.87,86.45,81.01,58.32,14.23,1.24,0.06pg/mL.Young man 0-18h each time point (0,1, 2,3,4,5,6,7,8,9,10,11,12,14,16,18h) blood concentration be respectively 0,6.66,16.20,25.83,30.83, 38.33,45.83,56.66,82.08,109.16,89.16,63.33,49.16,19.16,0.41,0pg/mL.Experiment gained is imitative Each time point blood concentration of raw preparation and the blood concentration at young man's each time point are almost the same, coefficient R=0.937. Being averaged for experiment gained 0-12h (18:00pm-6:00am) each time point (0,1,2,3,4,5,6,7,8,9,10,11,12h) is released Putting rate is respectively 0,2.13,5.94,4.05,2.17,7.38,12.60,10.97,9.35,7.83,6.30,4.35,2.40 μ g/h.As can be seen from the results, the rate of release of early period (0-4h) is smaller, and the later period rate of release of (4-12h) is larger, in first slow rear fast Bi-phasic release characteristics.

The vitro release curve of the bionical patch of gained osmotic pumps is shown in that Fig. 3 A, plasma concentration curve are shown in Fig. 3 B.

Embodiment 2: the bionical patch of epiphysin osmotic pumps

Core formulation: based on 1000

Outer layer:

Internal layer:

Coating solution:

Preparation method: epiphysin and remaining auxiliary material are sieved with 100 mesh sieve, and first press recipe quantity for epiphysin, lactose and tristearin Sour magnesium is uniformly mixed, and as internal layer core material, the scrobicula shape formed punch for being 5mm with diameter is in blocks by its direct pressing.Again by place Epiphysin, HPMC K4M, lactose and magnesium stearate are uniformly mixed, as outer layer core material by side's amount.By half outer layer Material sets punch die bottom, after internal layer label is then set punch die center, generates a fixed gap, residue two in upper die part and surrounding / mono- cladding material fills punch die side gap and covering upper space, the scrobicula shape formed punch for being 6mm with diameter are tabletted. Piece is placed in coating pan, hot-air is blown into, when label temperature is 40 DEG C or so, is coated, coating weight gain is up to 5% Afterwards, continue to be blown into hot-air 15min.Coating tablet is placed in 40 DEG C of dry 4h in aeration cabinet, is swashed on one side in coating tablet Light punching, aperture 0.6mm.

Vitro release measurement such as embodiment one, pushes away blood concentration step such as embodiment one by average rate of release is counter.With When beginning medication time is 0, rate of release k₀=0, C_E,i、C_S,i、C_RIt is 0；k₁=0 μ g/h is divided by formula (3), (4), (6) C is not obtained_E,i=0, C_S,i=0, C_R=C₁=2.22pg/mL successively calculates to obtain C₂、C₃、…、C₁₈.The elderly is moved back due to pineal Change, still secretes a small amount of epiphysin.This patent is calculated according to 50% that the secretory volume of the elderly's epiphysin is young man's secretory volume, Then test the blood concentration of gained 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) and old The sum of year people's secretory volume is respectively 0,0.68,11.92,26.20,39.74,61.75,89.16,105.26,113.18, 110.54,108.58,100.53,89.85,21.60,2.19,0.16pg/mL.Young man 0-18h each time point (0,1,2,3, 4,5,6,7,8,9,10,11,12,14,16,18h) blood concentration be respectively 0,6.66,16.20,25.83,30.83, 38.33,45.83,56.66,82.08,109.16,89.16,63.33,49.16,19.16,0.41,0pg/mL.Experiment gained is imitative Each time point blood concentration of raw preparation and the blood concentration at young man's each time point are almost the same, coefficient R=0.934. Being averaged for experiment gained 0-12h (18:00pm-6:00am) each time point (0,1,2,3,4,5,6,7,8,9,10,11,12h) is released Putting rate is respectively 0,0,4.45,5.17,5.90,9.23,12.56,12.08,11.59,9.91,8.21,8.67,9.13 μ g/ h.As can be seen from the results, the rate of release of early period (0-4h) is smaller, and the later period rate of release of (4-12h) is larger, in first slow rear fast Bi-phasic release characteristics.

The vitro release curve of the bionical patch of gained osmotic pumps is shown in that Fig. 4 A, plasma concentration curve are shown in Fig. 4 B.

Embodiment 3: the bionical patch of epiphysin gel skeleton

Core formulation: based on 1000

Outer layer:

Internal layer:

Preparation method: epiphysin and remaining auxiliary material are sieved with 100 mesh sieve, and first press recipe quantity for epiphysin, microcrystalline cellulose It mixes with PEO WSR303, is pelletized with appropriate PVP K30 ethanol solution, magnesium stearate is added and is uniformly mixed, as inner layer piece Grain.Epiphysin, PEO WSR303 and lactose are uniformly mixed by recipe quantity again, pelletized with appropriate PVP K30 ethanol solution, is added Magnesium stearate is uniformly mixed, as outer-skin sheet particle.The scrobicula shape formed punch for being first 5mm with diameter is tabletted by inner layer granule, Portion outer layer material is set into punch die bottom again, after internal layer label is then set punch die center, generates one in upper die part and surrounding Fixed gap, another part cladding material fill punch die side gap and covering upper space, the scrobicula shape formed punch for being 8mm with diameter It is pressed into double-layer tablets.

Vitro release measurement such as embodiment one, pushes away blood concentration step such as embodiment one by average rate of release is counter.With When beginning medication time is 0, rate of release k₀=0, C_E,i、C_S,i、C_RIt is 0；k₁=1.59 μ g/h, by formula (3), (4), (6), C is obtained respectively_E,i=0, C_S,i=0, C_R=C₁=2.22pg/mL successively calculates to obtain C₂、C₃、…、C₁₈.The elderly is due to pine nut A small amount of epiphysin is still secreted in the degeneration of body.This patent is young man's secretory volume according to the secretory volume of the elderly's epiphysin 50% calculates, then tests gained 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) blood medicine The sum of concentration and the elderly's secretory volume be respectively 0,2.47,7.53,17.41,31.73,54.06,80.81,101.41, 117.23,122.62,128.52,114.64,89.52,20.62,2.05,0.14pg/mL.Young man 0-18h each time point (0, 1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) blood concentration be respectively 0,6.66,16.20,25.83, 30.83,38.33,45.83,56.66,82.08,109.16,89.16,63.33,49.16,19.16,0.41,0pg/mL.Experiment Each time point blood concentration of gained bio-preparation and the blood concentration at young man's each time point are almost the same, and coefficient R= 0.952.Experiment gained 0-12h (18:00pm-6:00am) each time point (0,1,2,3,4,5,6,7,8,9,10,11,12h) Average rate of release is respectively 0,1.59,1.67,3.30,4.92,8.02,11.12,12.25,13.39,12.90,12.40, 9.64,6.89μg/h.As can be seen from the results, the rate of release of early period (0-4h) is smaller, and the later period rate of release of (4-12h) is larger, In first slow rear fast bi-phasic release characteristics.

The vitro release curve of the bionical gel skeleton sustained release tablets of gained is shown in that Fig. 5 A, plasma concentration curve are shown in Fig. 5 B.

Embodiment 4: the bionical patch of epiphysin gel skeleton

Core formulation: based on 1000

Outer layer:

Internal layer:

Preparation method such as embodiment three.

Vitro release measurement such as embodiment one；Blood concentration step such as embodiment one is pushed away by average rate of release is counter.With When beginning medication time is 0, rate of release k₀=0, C_E,i、C_S,i、C_RIt is 0；k₁=2.39 μ g/h, by formula (3), (4), (6), C is obtained respectively_E,i=0, C_S,i=0, C_R=C₁=2.22pg/mL successively calculates to obtain C₂、C₃、…、C₁₈.The elderly is due to pine nut A small amount of epiphysin is still secreted in the degeneration of body.This patent is young man's secretory volume according to the secretory volume of the elderly's epiphysin 50% calculates, then tests the blood of gained 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) The sum of concentration and the elderly's secretory volume be respectively 0,3.36,9.68,20.84,36.44,56.01,77.32,94.13, 107.54,111.53,115.52,103.79,83.29,19.61,1.93,1.34pg/mL.Young man 0-18h each time point (0, 1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) blood concentration be respectively 0,6.66,16.20,25.83, 30.83,38.33,45.83,56.66,82.08,109.16,89.16,63.33,49.16,19.16,0.41,0pg/mL.Experiment Each time point blood concentration of gained bio-preparation and the blood concentration at young man's each time point are almost the same, and coefficient R= 0.953.Experiment gained 0-12h (18:00pm-6:00am) each time point (0,1,2,3,4,5,6,7,8,9,10,11,12h) Average rate of release is respectively 0,2.39,2.25,4.05,5.85,7.80,9.75,10.67,11.58,10.85,10.12, 8.36,6.59μg/h.As can be seen from the results, the rate of release of early period (0-4h) is smaller, and the later period rate of release of (4-12h) is larger, In first slow rear fast bi-phasic release characteristics.

The vitro release curve of the bionical sustained-release gel matrix tablet of gained is shown in that Fig. 6 A, plasma concentration curve are shown in Fig. 6 B.

Embodiment 5: the low elderly men of endogenous melatonin levels takes epiphysin osmotic pumps bionical blood concentration With the similitude of young state epiphysin In vivo kinetics curve

If this patent calculates (i.e. old male according to 50% that the secretory volume of elderly men epiphysin is young men secretory volume Property itself secretes epiphysin), it is only necessary to epiphysin osmotic pumps bionical 1 is taken, that is, can reach epiphysin in young men body Secretion level.The blood medicine of experiment gained 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) Concentration is respectively 0,3.06,17.55,26.61,28.21,48.75,78.33,93.66,96.99,98.87,101.28, 69.98,45.22,8.71,1.24,0pg/mL.Young men 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11, 12,14,16,18h) blood concentration be respectively 0,3.43,8.28,15.86,31.73,45.52,53.11,63.45,81.38, 98.63,66.21,52.42,40.00,17.25,0.41,0pg/mL.Each time point blood concentration of experiment gained bio-preparation It is similar with the blood concentration at young men each time point, coefficient R=0.961 between the two.

Gained take epiphysin osmotic pumps bionical 1 after male senile patient group plasma concentration curve and ideal young state Epiphysin plasma concentration curve is shown in Fig. 7.

Embodiment 6: the low old women of endogenous melatonin levels whole blood after taking epiphysin gel skeleton bionical The similitude of concentration and young state epiphysin In vivo kinetics curve

Various dose preparation may be selected according to different patient's own endogenous melatonin levels.This patent is according to old women The secretory volume of epiphysin is 0% calculating (i.e. old women itself does not secrete epiphysin) of young woman's secretory volume, it is only necessary to be taken The bionical patch of epiphysin gel skeleton 1, that is, can reach the secretion level of epiphysin in young woman's body.Experiment gained 0- The blood concentration at 18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) is respectively 0,3.57, 10.93、25.18、44.16、73.64、109.21、135.23、154.47、156.88、158.26、140.76、112.76、 21.94,2.73,0.29pg/mL.Young woman 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14, 16,18h) blood concentration be respectively 0,6.66,16.20,25.83,30.83,38.33,45.83,56.66,82.08, 109.16,89.16,63.33,49.16,19.16,0.41,0pg/mL.Each time point blood concentration of experiment gained bio-preparation It is similar with the blood concentration at young woman's each time point, coefficient R=0.951 between the two.

Gained takes the female old aged people crowd plasma concentration curve after the bionical patch of epiphysin gel skeleton 1 and ideal Young state epiphysin plasma concentration curve is shown in Fig. 8.

Embodiment 7

According to the method for the present invention, double-layer osmotic pump tablet system is prepared in the ectonexine ratio progress preparation of prior art prompt Agent, the side of going out and its result are as follows:

Core formulation: based on 1000

Outer layer:

Internal layer:

Coating solution:

Preparation method such as embodiment two.

Vitro release measurement such as embodiment two；Blood concentration step such as embodiment one is pushed away by average rate of release is counter.With When beginning medication time is 0, rate of release k₀=0, C_E,i、C_S,i、C_RIt is 0；k₁=0 μ g/h is divided by formula (3), (4), (6) C is not obtained_E,i=0, C_S,i=0, C_R=C₁=0pg/mL successively calculates to obtain C₂、C₃、…、C₁₈.The elderly due to pineal degeneration, Still secrete a small amount of epiphysin.This patent is calculated according to 50% that the secretory volume of the elderly's epiphysin is young man's secretory volume, then The blood concentration of experiment gained 0-18h each time point (0,1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) and old age The sum of people's secretory volume be respectively 0,0.68,278.92,568.84,752.15,976.42,1239.09,1429.73,1569.40, 1432.87,1279.76,1118.38,976.99,200.05,24.62,2.59pg/mL.Young man 0-18h each time point (0, 1,2,3,4,5,6,7,8,9,10,11,12,14,16,18h) blood concentration be respectively 0,6.66,16.20,25.83, 30.83,38.33,45.83,56.66,82.08,109.16,89.16,63.33,49.16,19.16,0.41,0pg/mL.Experiment The average release speed at gained 0-12h (18:00pm-6:00am) each time point (0,1,2,3,4,5,6,7,8,9,10,11,12h) Rate is respectively 0,0,124.85,132.11,139.37,183.30,227.22,242.72,258.21,212.41,166.59, 149.71,132.28μg/h.As can be seen from the results, the blood concentration at the osmotic pump preparation resulting each time point obviously compares young man The secretory volume of group's endogenous melatonin is much bigger (Fig. 9).

Embodiment 8

In the present embodiment, according to the method for embodiment 1 and 4, by adjusting active constituent in label internal layer and label outer layer The mass ratio (epiphysin gross mass is between 100-300mg/1000 piece) of epiphysin, is prepared for the osmotic pump tablet system of different batches Agent and gel skeleton tablet preparation, and whether the Accumulation dissolution curve for measuring these batch preparations meets ideal release song Line, the ratio (based on every 1000) of specific epiphysin and the results are shown in Table 1:

Table 1

Epiphysin ratio by the preparation of 10 batches in table 1 it can be found that the present invention releases the drug in preparation ectonexine label When in a certain range, can obtain meet ideal drug release profiles as a result, and when except its range, then be unable to reach the effect Fruit.

The application test of the drug release preparation of embodiment 9

Recruiting has sleep disturbance and sleeps organic or psychotic disorder 50-70 year old volunteer without other influences, is total to 40, be randomly divided into test group (20) and placebo (20), using double-blind study, advise its in 18:00-20:00 it Between take present invention drug release preparation, and acquire it respectively for sleep quality is evaluated before taking medicine and after medication, it is specific to evaluate Table index includes difficulty falling asleep degree, Yi Xing, wake up after be not easy to fall asleep again, early awakening and the Sleepiness on daytime, it is desirable that patient Above-mentioned each index is given a mark by severity 0-10 points.

Result of study discovery, the sleep disturbance symptom for taking the volunteer of invention formulation can be significantly improved, sleep Dormancy improvement rate is more than 80% (P < 0.1).

All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (9)

1. a kind of bionical drug release preparation of epiphysin, which is characterized in that the drug release preparation contains black as taking off for active constituent Element and pharmaceutically acceptable carrier,

And the drug release preparation discharges the active constituent with two-phase delivery mode, wherein two-phase release includes zero level The second release stage that the first release stage and zero order release rate that rate of release is v1 are v2, and the two-phase release become Gesture turning point is 4-6 hour after medication, and 2 hours active constituent Accumulation dissolution≤20% after medication；

The preparation is osmotic pump tablet preparation, and the label of the preparation is interior outer double-layer structure label；The inner layer piece The content of active constituent is 0.035-1.8wt% based on label weight in core；The content of active constituent in the outer layer label Be 0.005-0.6wt% based on label weight, and in the inside and outside synusia core active constituent weight ratio internal layer: outer layer is 10:0-7:3；Label total weight based on osmotic pump tablet preparation, the label include 0.1-2wt% epiphysin, and 5-25wt% rises The controlled release agent of controlled-release function, 70-90wt% osmotic pressure promotor and the pharmaceutically acceptable other carriers of 0.1-5wt%；It is described The ectonexine label total mass ratio of osmotic pump tablet preparation is 4:1-1:4；The label appearance of the osmotic pump tablet preparation has half Permeability coating membrane, and the semi permeability coating membrane has drug releasing pores, the diameter of the drug releasing pores is 0.2mm- 1.2mm；Or

The preparation is gel skeleton tablet preparation, and the label of the preparation is interior outer double-layer structure label, the internal layer The content of active constituent is 0.035-1.8wt% based on label weight in label；Active constituent contains in the outer layer label Amount based on label weight is 0.005-0.6wt%, and in the inside and outside synusia core active constituent weight ratio internal layer: outer layer For 10:0-7:3；Based on gel matrix tablet label total weight, the label includes 0.05-2wt% epiphysin, and 30-70wt% rises The controlled release agent of controlled-release function, 30-70wt% filler and the pharmaceutically acceptable other carriers of 0.1-5wt%；The gel bone The ectonexine label total mass ratio of frame tablet preparation is 4:1-1:4；

The controlled release agent is selected from the group: polyoxyethylene, hydroxypropyl methylcellulose, or combinations thereof；

The filler is selected from the group: lactose, microcrystalline cellulose, or combinations thereof.

2. drug release preparation as described in claim 1, which is characterized in that the content of epiphysin is in the drug release preparation 0.05-0.5mg/ piece.

3. drug release preparation as described in claim 1, which is characterized in that after the drug release preparation is taken, in the intracorporal work of people Property ingredient plasma concentration curve in unimodal and described unimodal peak value be located at medication after 5-10 hours.

4. drug release preparation as described in claim 1, which is characterized in that 2 hours active constituent Accumulation dissolutions after medication≤ 15%.

5. drug release preparation as described in claim 1, which is characterized in that 2 hours active constituent Accumulation dissolutions after medication≤ 10%.

6. drug release preparation as claimed in claim 3, which is characterized in that the unimodal peak value is located at after medication 6-9 hours.

7. drug release preparation as claimed in claim 3, which is characterized in that the unimodal peak value is located at after medication 6-8 hours.

8. drug release preparation as described in claim 1, which is characterized in that the osmotic pressure promotor is selected from the group: lactose, fruit Sugar, glucose, mannitol, sodium chloride, potassium chloride, potassium sulfate, or combinations thereof.

9. a kind of method for preparing the bionical drug release preparation of epiphysin as described in claim 1, which is characterized in that

Wherein, the osmotic pump tablet preparation preparation step includes:

(a) epiphysin being sieved, osmotic pressure promotor and pharmaceutically acceptable in addition to lubricant are weighed by recipe quantity Auxiliary material is uniformly mixed, and granulation adds suitable lubricant, is mixed to get inner layer granule, spare；

(b) epiphysin being sieved, controlled release agent, osmotic pressure promotor and pharmaceutically may be used in addition to lubricant are weighed by recipe quantity The auxiliary material of receiving is uniformly mixed, and granulation adds suitable lubricant, is mixed to get skin granulate, spare；

(c) inside and outside layer particle is made to double-layer tablets label after tabletting twice；

(d) packet semi-permeable membrane clothing, until label weight gain reaches design flow；

(e) it punches, laser or mechanical punching mode is used to beat diameter in the medicated layer one side or the multi-lateral of coating tablet as 0.2mm- 1.2mm aperture；

Wherein, the preparation step of the gel matrix tablet includes:

(i) epiphysin being sieved, controlled release agent, filler and the medicine in addition to lubricant are weighed respectively by inside and outside layer recipe quantity Acceptable auxiliary material is uniformly mixed on, is pelletized respectively, and suitable lubricant is added, and is mixed to get inside and outside layer particle, standby With；

(ii) inside and outside layer particle is made to two-layer gel matrix tablet after tabletting twice.