CN110251473A - Hydroxyl piperazine pyrrone oral slow-releasing preparation - Google Patents
Hydroxyl piperazine pyrrone oral slow-releasing preparation Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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Abstract
The invention discloses hydroxyl piperazine pyrrone oral slow-releasing preparation, the sustained release preparations, comprising: hydroxyl piperazine pyrrone or its officinal salt；One or more pharmaceutically acceptable excipients；At least contain a kind of polymer with slow releasing function.The present invention has selected pharmaceutical polymers as slow-release material, vitro release test result shows, the hydroxyl piperazine pyrrone sustained release tablets of offer gradually discharged drug in 8-24 hours, to reduce the peak valley phenomenon of drug absorption, blood concentration needed for maintenance therapy, thus compared with ordinary tablet, it can reach reduction and take number, persistent, purpose convenient to take are more advantageous to the treatment of disease.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to hydroxyl piperazine pyrrone oral slow-releasing preparation.
Background technique
Depression be it is a kind of as caused by a variety of causes based on lasting depressed, hebetude, retardation of thinking etc.
The syndrome for wanting Clinical symptoms, because it has high morbidity, high suicide, Gao Fufa, high disability rate and low identification, low go to a doctor, low controls
The features such as treatment rate seriously endanger the physical and mental health of the mankind.As rhythm of life is constantly accelerated, the stress of people also gradually increases
Greatly, depression has become the common disease of modern society, frequently-occurring disease, and disease incidence is rising year by year.
At present, drug therapy is one of main means for the treatment of depression.Clinically common antidepressant, including 5-
HT reuptake inhibitor (SSRIs, such as Prozac), the dual reuptake inhibitor of 5-HT/NE (SNRIs, such as Duloxetine) are equal
In the presence of the delay (2-6 weeks) that works, toxicity obvious (50-70%) low with effective percentage, lead to sex dysfunction and introgression
Etc. more serious defect.Synaptic cleft 5-HT water can be improved in common antidepressant (such as 5-HT reuptake inhibitor) a few hours
It is flat, but presynaptic membrane 5-HT is activated simultaneously1AAutoreceptor generates negative feedback inhibition effect, reduces the synthesis and release of 5-HT.It gives
After medicine 2-4 weeks, 5-HT1AAutoreceptor desensitization, so that antidepressant effect is generated, 5-HT1ANegative-feedback caused by autoreceptor activates
Inhibiting effect is considered playing key effect in antidepressant action deferring procedure.It is reported that 5-HT1AReceptor stimulating agent
It can make neuronal synapse cephacoria 5-HT1AAutoreceptor desensitization, plays antidepressant effect, about 3-7 weeks delayed onset time.
Studies show that, 5-HT reuptake inhibitor and 5-HT1AAcceptor portion agonist use in conjunction can enhance the suppression of 5-HT reuptake
The antidepressant effect of preparation shortens onset time.It may make presynaptic membrane 5-HT since both drugs can act synergistically1AItself
Receptor desensitization, while enhancing postsynaptic membrane Nerve conduction.This kind of compound can be with quick acting and it is possible that drug effect ratio
Individually use 5-HT reuptake inhibitor or 5-HT1AReceptor stimulating agent is stronger.Therefore, the inhibition of 5-HT reuptake and 5-HT are had concurrently1ABy
Body excitement dual-target active medicine becomes the representative direction of novel characteristic antidepressant research.
It is based on " the monoamine strategy of optimization " in recent years, 5-HT1AThe 5-HT reuptake of acceptor portion excitement and selectivity inhibits
Target antidepressants (serotonin partial agonist and reuptake inhibitors, SPARIs), because strong
The features such as effect, quick acting, potential low introgression and adverse reaction (including sex dysfunction and weight gain etc.) occur
The low advantage of rate, it has also become the representative direction of newtype drug.SPARIs specificity accelerates presynaptic membrane 5-HT1AAutoreceptor is de-
It is quick, to achieve the purpose that accelerate to work, heighten the effect of a treatment, reduce toxicity.U.S. FDA was in approval novel antidepressant Wella in 2011
Help ketone (Vilazodone, ViibrydTM) list marketing, for treating depression.The medicine shows ideal antidepressant effects,
Have the characteristics that safe, rapid-action (working within 1 week), high-efficient, side reaction is few.Completely new (the non-me- of the chemical structure of hydroxyl piperazine pyrrone
Too and me-better class formation), it is entirely different with the structural formula of vilazodone, and structure is simpler, mechanism of action and dimension
It draws assistant ketone seemingly, is 1.1 class original new drug of chemical drug.
Hydroxyl piperazine pyrrone is novel new antidepressant, has serotonin 1A (5-HT1A) receptor agonism and 5-HT reuptake suppression
The reactive compound of (SSRI) dual-target is made, antidepression, antianxiety effect have potent, quick it should be appreciated that having rush cognition activity concurrently
Action, potential low introgression, the features such as adverse reaction rate is low, can be used for preventing or treating depression, anxiety disorder, cognition
Defect, mania, schizophrenia, pain, various forms of stresses, sleep disturbance etc..
Entitled 1- [(- 4 base of 4- hydroxy piperidine) methyl] pyridine -2 (1H) -one of hydroxyl piperazine pyrrone chemistry, structural formula such as following formula institute
Show:
Since hydroxyl piperazine pyrrone only has 3-4 hours intracorporal half-life period in people, lead to the administration frequency of the quick releasing formulation of the medicine
It is designed as one day 2-3 times.Oral number is more daily by patient, takes and is more troublesome, and easily occurs missing and night dosing interval
Overlong time and effective blood concentration cannot be maintained and play lasting therapeutic effect, there is the blind area in treatment.
Summary of the invention
The object of the present invention is to provide the oral slow-releasing preparation of hydroxyl piperazine pyrrone, when extending the intracorporal effect of drug
Between, reduce medicining times, reduce side effects of pharmaceutical drugs and improve patient long-term administration compliance.
It is provided by the invention it is new, conveniently, effectively, action period long oral drugs discharge system, make it longer
In time range, lasting, stabilization quantitatively discharges drug, can be to avoid the generation of above-mentioned unfavorable factor.The invention keeps patient every
Day need to only take once, to improve the compliance of patient, and then reach better therapeutic effect.
Technical solution provided by the invention is as follows:
A kind of hydroxyl piperazine pyrrone oral slow-releasing preparation, which is characterized in that the sustained release preparation, comprising:
Hydroxyl piperazine pyrrone or its officinal salt；
One or more pharmaceutically acceptable excipients；
At least contain a kind of polymer with slow releasing function.
Preferably, the oral slow-releasing preparation further includes barrier layer, and the barrier layer is by following components in percentage by weight
It is prepared:
Preferably, the sustained release preparation shows to release in vitro in the hydroxyl piperazine pyrrone that 1 hour time point discharged no more than 40%
Degree of putting was no more than 80% hydroxyl piperazine pyrrone vitro release 6 hour time point.The detection of the hydroxyl piperazine pyrrone vitro release
Condition are as follows:
Using 50 turns of Chinese Pharmacopoeia II method, revolving speed, using deionized water 1000ml as solvent.
Preferably, the dosage form is sustained-release tablet, and the medicine layer of the sustained-release tablet is by following components in percentage by weight
It is prepared:
The hydroxyl piperazine pyrrone or its officinal salt 5~20%, the framework material 5~70%, can medicine described in remaining use
100% is complemented to excipient.
Preferably, the sustained-release tablet further includes barrier layer, and the barrier layer is prepared by following components in percentage by weight
It forms:
The framework material 20~70% remaining complements to 100% with the pharmaceutically acceptable excipient.
Preferably, the sustained-release tablet is the single layer matrix sustained release tablet of only medicine layer composition,
Or,
The sustained-release tablet is the multilayer matrix sustained release tablet containing medicine layer and barrier layer.
It preferably, include the hydroxyl piperazine pyrrone of 5mg-50mg in the unit dosage forms of the sustained-release tablet, further, it is preferable that
The unit dosage forms of the sustained-release tablet are 10mg-40mg.
Preferably, the framework material of the medicine layer and barrier layer includes:
Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and its sodium salt, sodium alginate, Methyl cellulose
Element, ethyl cellulose, polyacrylic resins, polyvinyl acetate, carbomer, polyoxyethylene, stearic acid, behenyl acid glycerol
One of ester, glycerin monostearate, rilanit special, beeswax, paraffin, Chinese wax, Brazil wax, microwax and octadecyl alcolol
Or it is several.
Further, it is preferable that the framework material of the medicine layer includes: hydroxypropyl methyl cellulose and carboxymethyl cellulose
The combination or hydroxypropyl methyl cellulose of sodium, the combination of sodium carboxymethylcellulose and Compritol 888 ATO.
Preferably, the pharmaceutically acceptable excipient of the sustained-release tablet includes:
Filler, adhesive, glidant and lubricant.
Further, it is preferable that the filler includes: starch, lactose, pregelatinized starch, microcrystalline cellulose, phosphoric acid hydrogen
The combination of one or more of calcium, mannitol, starch milk-sugar mixture, mannitol starch mixture.
Described adhesive includes: polyvinylpyrrolidone, hydroxypropyl cellulose, methylcellulose, hypromellose
One or more of combination.
The glidant includes: the combination of one or both of superfine silica gel powder, talcum powder.
The lubricant includes: magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, poly- second
The combination of one or more of glycol.
The present invention also provides the preparation methods of the sustained-release tablet of hydroxyl piperazine pyrrone, include the following steps:
(1) medicine layer: the other components (except lubricant) of hydroxyl piperazine pyrrone and medicine layer are put into wet granulator and are mixed
It closes uniformly, the adhesive of recipe quantity is added, be uniformly mixed, wet granular is made in sieving, dries, and the lubrication of recipe quantity is added in whole grain
Agent is uniformly mixed；
(2) barrier layer: each component (except lubricant) being put into wet granulator and is uniformly mixed, and the viscous of recipe quantity is added
Mixture is uniformly mixed, and wet granular is made in sieving, dries, and the lubricant of recipe quantity is added in whole grain, is uniformly mixed；
(3) drug layer granulation for preparing above-mentioned steps is pressed into single-layer sheet, both obtains single layer matrix sustained release tablet；Or it will be above-mentioned
The drug layer granulation that step prepares is pressed into double-layer tablets or three-layer tablet (medicine layer is middle layer) together with barrier layer granules, both
The double-deck matrix sustained release tablet or three layers of matrix sustained release tablet.
Preferably, the dosage form of the hydroxyl piperazine pyrrone oral slow-releasing preparation further include: sustained release pellet, comprising:
Pellet core comprising hydroxyl piperazine pyrrone or its officinal salt and the sustained-release coating layer comprising coating material.
Preferably, the coating material is one of acrylic resin, polyvinyl acetate or ethyl cellulose.
In the technical program, the sustained release pellet is made by the quick-release capsule core packet sustained release coating film of drug containing, pellet core
By hydroxyl piperazine pyrrone or its officinal salt, auxiliary material, auxiliary material include: blank capsule core (such as: cane sugar core, microcrystalline cellulose pellet
Deng), adhesive (povidone, HPMC etc.), antiplastering aid (such as: talcum powder, titanium dioxide etc.) and other auxiliary materials.
Coating material includes slow-release material and other auxiliary materials；
Slow-release material is one of acrylic resin, polyvinyl acetate or ethyl cellulose.
Preferably, the dosage form is osmotic pump tablet, comprising:
Label comprising hydroxyl piperazine pyrrone or its officinal salt and the semi-transparent film coating comprising coating material.
Preferably, the semi-transparent film coating includes:
The polymer of water-insoluble and water-soluble polymer.
Preferably, the label of the osmotic pump tablet further include:
Penetrating agent, sweller.
In the technical program, the osmotic pump tablet is made by drug containing label packet semi-permeable membrane, and drug containing label includes hydroxyl piperazine pyrrone
Or its officinal salt, auxiliary material；
Auxiliary material include: penetrating agent (such as: D-sorbite, mannitol, lactose etc.), swelling agent (such as: polyoxyethylene, hydroxyl
Ethyl cellulose, crospovidone, cross-linked carboxymethyl cellulose sodium etc.) and other auxiliary materials.
Semi-permeable membrane coating material includes slow-release material and other auxiliary materials；
Slow-release material include water-insoluble polymer (such as: cellulose acetate) and water-soluble polymer (such as: it is poly-
Ethylene glycol, hydroxypropyl cellulose).
The preparation method of the sustained-release tablet can be non-slurry pelletizing, wet granulation, fusion method granulation or direct tablet compressing.
The preparation method of the drug containing quick-release capsule core can be hot-melt extruded, extrusion spheronization or fluidized bed coating medicine-feeding.Described
The preparation process of drug containing label packet semi-permeable membrane can be coating pan coating or fluidized bed coating.
The oral slow-releasing preparation of hydroxyl piperazine pyrrone provided by the invention, can bring it is following the utility model has the advantages that
1, the present invention provides hydroxyl piperazine pyrrone oral slow-releasing preparations, extend action time, reduce medicining times, reduce drug
Side effect and improve patient compliance.
2, the present invention has selected pharmaceutical polymers as slow-release material, and vitro release test result shows to provide
Hydroxyl piperazine pyrrone sustained release tablets gradually discharge drug in 8-24 hours, to reduce the peak valley phenomenon of drug absorption, maintenance therapy
Required blood concentration, to can reach reduction compared with common quick release piece and take number, persistent, mesh convenient to take
, it is more advantageous to the treatment of disease.
3, the slow-release material of the hydroxyl piperazine pyrrone sustained-release tablet in the present invention is hydroxypropyl methyl cellulose and carboxymethyl cellulose
The combination of plain sodium or hydroxypropyl methyl cellulose, sodium carboxymethylcellulose and Compritol 888 ATO can meet close to zero
Grade rate of release, reaches ideal slow release effect.
4, the hydroxyl piperazine pyrrone sustained-release tablet in the present invention can be realized by single layer matrix sustained release tablet, can also be by list
A barrier layer or two barrier layers are added on the basis of layer matrix sustained release tablet, reduce the surface area that medicated layer is contacted with the external world,
To reach zero level or nearly Zero order release.Wherein, medicine layer is made of hydroxyl piperazine pyrrone, slow-release material and other auxiliary materials, barrier layer by
Slow-release material and other auxiliary materials form.
5, include sustained release pellet and osmotic pump tablet the present invention also provides other sustained-release dosage types of hydroxyl piperazine pyrrone, can all meet
It is sustained releasing effect.
Detailed description of the invention
Below by clearly understandable mode, preferred embodiment is described with reference to the drawings, to above-mentioned characteristic of the invention, skill
Art feature, advantage and its implementation are further described.
Fig. 1 is the release rate profile figure of the single layer matrix sustained release tablet in the embodiment of the present invention 1.
Fig. 2 is the release rate profile figure of the double-deck matrix sustained release tablet in the embodiment of the present invention 2.
Fig. 3 is the rate of release of three layers of matrix sustained release tablet of the HPMC K100M of different content in the embodiment of the present invention 3
Curve graph.
Fig. 4 is the release rate profile figure of the sustained release pellet in the embodiment of the present invention 4.
Fig. 5 is in the embodiment of the present invention 5 using the release rate profile figure of the osmotic pump tablet of different content coating weight gain.
Fig. 6 is the release rate profile figure for containing different hydrochloric acid hydroxyl piperazine pyrrone dosage in the embodiment of the present invention 8.
Specific embodiment
Representational example is intended to help to illustrate the present invention below, and is not necessarily to be construed as limiting the scope of the invention.
In fact, other than those occur and is described herein, the full content of file in the present invention, including according to cited herein
The example and resulting various modifications and many of scientific and technical literature and patent are further change in general technology in this profession
Personnel are clearly clear.Following example contains important supplemental information, example and guidance, is adaptable in the present invention
Various change and similar situation.
Embodiment 1 (single layer matrix sustained release tablet)
The present embodiment is the common single layer matrix sustained release tablet of hydroxyl piperazine pyrrone, and the composition and content of medicine layer are as shown in table 1:
Table 1
Preparation process:
1, the hydrochloric acid hydroxyl piperazine pyrrone of recipe quantity, hydroxypropyl methyl cellulose, carmethose, microcrystalline cellulose and pre- are taken
Gelling starch is uniformly mixed；
2, with 5%PVPK30 aqueous solution softwood, the sieve wet granular of 2.0mm is crossed；
3, gained wet granular is dried to water content less than 2% in a fluidized bed.
4, after dry particl to be crossed to the sieve whole grain of 1.2mm, the magnesium stearate with recipe quantity is mixed, and carries out tabletting, theoretical piece
Weight is 150mg.
Release experiment, using deionized water 1000ml as solvent, is surveyed using 50 turns of Chinese Pharmacopoeia II method (slurry processes), revolving speed
The release profiles of the release of random sample product, sample are shown in Fig. 1.
As shown in Figure 1, in single layer matrix sustained release tablet, 20% HPMC K100M and the combination of 10% carmethose,
1h release can be reached and be no more than the sustained release releasing effect that 40%, 8h discharges 80% or more.
Embodiment 2 (the double-deck matrix sustained release tablet)
The present embodiment is hydroxyl piperazine pyrrone bilayer matrix sustained release tablet, and the composition and content of medicine layer are as shown in table 2:
Table 2
The barrier layer of hydroxyl piperazine pyrrone bilayer matrix sustained release tablet forms and content, as shown in table 3:
Table 3
| Component | Dosage (mg) |
| Single water and milk sugar | 47.7 |
| Yellow iron oxide | 0.3 |
| Hydroxypropyl methyl cellulose (HPMC, K4M) | 60 |
| Compritol 888 ATO | 37.5 |
| Polyvinylpyrrolidone (PVP, K30) | 3 |
| Magnesium stearate | 1.5 |
| Total amount | 150 |
The medicine layer preparation process of hydroxyl piperazine pyrrone bilayer matrix sustained release tablet:
1, hydrochloric acid hydroxyl piperazine pyrrone, hydroxypropyl methyl cellulose, carmethose, single water and milk sugar and the behenyl of recipe quantity are taken
Acid glyceride is uniformly mixed；
2, with 5%PVPK30 aqueous solution softwood, the sieve wet granular of 2.0mm is crossed；
3, gained wet granular is dried to water content less than 2% in a fluidized bed.
4, after dry particl to be crossed to the sieve whole grain of 1.2mm, the magnesium stearate with recipe quantity is mixed.
The barrier layer preparation process of hydroxyl piperazine pyrrone bilayer matrix sustained release tablet:
1, take single water and milk sugar, yellow iron oxide (crossing 80 meshes), hydroxypropyl methyl cellulose and the behenic acid of recipe quantity sweet
Grease is uniformly mixed；
2, with 5% PVP K30 aqueous solution softwood, the sieve wet granular of 2.0mm is crossed；
3, gained wet granular is dried to water content less than 2% in a fluidized bed.
4, after dry particl to be crossed to the sieve whole grain of 1.2mm, the magnesium stearate with recipe quantity is mixed.
Tabletting:
The above-mentioned drug layer granulation prepared and barrier layer granules are pressed into double-layer tablets, wherein drug layer weight is
150mg, barrier layer weight are 150mg.
Release experiment, using deionized water 1000ml as solvent, is surveyed using 50 turns of Chinese Pharmacopoeia II method (slurry processes), revolving speed
The release profiles of the release of random sample product, sample are shown in Fig. 2.
As shown in Figure 2, HPMC K100M, 10% carboxylic first fibre in the double-deck matrix sustained release tablet, in medicated layer using 40%
Tie up plain sodium and the combination of 10% Compritol 888 ATO, so that it may reach 1h release and be no more than the sustained release that 40%, 20h discharges 80% or more
Releasing effect.
Embodiment 3 (three layers of matrix sustained release tablet)
The present embodiment is three layers of matrix sustained release tablet of hydroxyl piperazine pyrrone of different hypromellose contents, the group of medicine layer
At ingredient and content, as shown in table 4:
Table 4
The medicine layer preparation process of three layers of matrix sustained release tablet of hydroxyl piperazine pyrrone: with embodiment 2.
The composition and preparation process of the barrier layer of hydroxyl piperazine three layers of matrix sustained release tablet of pyrrone: with embodiment 2.
Tabletting:
The above-mentioned drug layer granulation prepared and barrier layer granules are pressed into three-layer tablet, first layer is by 150mg barrier layer group
At the second layer is made of 150mg medicine layer, and the hydroxyl piperazine pyrrone comprising 20mg, third layer is made of the barrier layer of 150mg.
Coating:
Above-mentioned tablet is coated again with hydroxypropyl cellulose coating solution, until weight gain 3% or so, obtains hydroxyl piperazine pyrrone
Three layers of matrix sustained release tablet.
Release experiment is carried out to 3 resulting hydroxyl piperazine pyrrone of embodiment, three layers of matrix sustained release tablet, using Chinese Pharmacopoeia II method
50 turns of (slurry processes), revolving speed measure the release of sample using deionized water 1000ml as solvent, and the release profiles of sample are shown in Fig. 3.
From experimental result as can be seen that the hydroxypropyl cellulose (HPMC K100M) of different amounts is available in medicine layer
Different drug release patterns, HPMC K100M dosage is fewer, and drug release rate is faster, the HPMC of 5%-40% dosage
The releasing result that 1h release is no more than 40%, 8-24h release 80% can be obtained in K100M respectively, reaches ideal slow release effect.
Embodiment 4 (sustained release pellet)
The present embodiment is hydroxyl piperazine pyrrone sustained release pellet, and composition and content are as shown in table 5:
Table 5
Sustained release pellet uses art for coating, and hydrochloric acid hydroxyl piperazine pyrrone, hypromellose and talcum powder are configured to add medicine to
Layer solution, wraps one layer of medicine accommodation layer for sugar-pill in a fluidized bed, then wraps sustained release coating film again on upper pill core, until packet
Clothing weight gain 25% continues to be dried in a fluidized bed to moisture that hydroxyl piperazine pyrrone sustained release pellet is made less than 2%.
To the resulting hydroxyl piperazine pyrrone sustained release pellet of embodiment 4 carry out release experiment, using Chinese Pharmacopoeia II method (slurry processes),
50 turns of revolving speed, using distilled water 1000ml as solvent, the release of sample is measured, the release profiles of sample are shown in that Fig. 4 shows.
As shown in Figure 4, make Sustained release coating materials with Kollicoat SR 30D, coating weight gain is 25% or so, so that it may
Reach 1h release and is no more than the sustained release releasing effect that 40%, 8h discharges 80% or more.
Embodiment 5 (osmotic pump tablet)
The present embodiment is hydroxyl piperazine pyrrone osmotic pump tablet, and composition and content are as shown in table 6:
Table 6
Label uses direct tablet compressing technique, and the label suppressed is coated with semi-permeable membrane coating solution, until coating increases
Weight 8%-10% then removes tablet from coating pan, and 24 hours dry in 45 DEG C of baking ovens.It is bored in the end of tablet surface
Single hole, aperture 0.6mm.
To the resulting hydroxyl piperazine pyrrone osmotic pump tablet of embodiment 5 carry out release experiment, using Chinese Pharmacopoeia II method (slurry processes),
50 turns of revolving speed, using distilled water 1000ml as solvent, the release of sample is measured, the release profiles of sample are shown in Fig. 5.
As shown in Figure 5, make Sustained release coating materials with cellulose acetate, coating weight gain is in 8%-10% or so, so that it may reach
It is no more than the sustained release releasing effect that 40%, 18h-24h discharges 80% or more to 1h release.
Embodiment 6
In order to verify the requirement whether prepared hydroxyl piperazine pyrrone sustained release tablets meet sustained release, in embodiment 3 the 3rd group
Three layers of matrix sustained release tablet of hydroxyl piperazine pyrrone do pharmacokinetic studies, compare the absorption of fast-release tablet and sustained release tablets in vivo under Isodose
Rate and degree.
The composition of hydroxyl piperazine pyrrone fast-release tablet is as shown in table 7: preparation process is wet granulation, resulting particle and magnesium stearate
Tabletting is carried out after mixing.Using 50 turns of Chinese Pharmacopoeia II method (slurry processes), revolving speed, using deionized water 1000ml as solvent, sample is measured
The dissolution rate of product, the results show that fast-release tablet just has reached 95% or more in 5 minutes dissolution rates.
Table 7
| Component | Dosage (mg) |
| Hydrochloric acid hydroxyl piperazine pyrrone | 20 |
| Single water and milk sugar | 180 |
| Microcrystalline cellulose | 60 |
| Hydroxypropyl methyl cellulose (E5) | 5 |
| Low-substituted hydroxypropyl cellulose (L-HPC) | 40 |
| Magnesium stearate | 3 |
| Total amount | 308 |
The composition of three layers of matrix sustained release tablet is as shown in table 8, and preparation process is the same as embodiment 3.Using Chinese Pharmacopoeia II method (slurry
Method), 50 turns of revolving speed, liquor capacity 1000ml, respectively in deionized water, pH1.2, in the buffer solution of pH4.5 and pH 6.8
The release of sample is measured, the results show that three layers of matrix sustained release tablet release profiles in different solvents are similar, each release profiles
Between there is no notable difference.
Table 8
Pharmacokinetic experiments design: Beagle dog (half male and half female) 6 is randomly divided into 2 groups, every group 3.Fasting before testing
12h, free water, first group is given hydroxyl piperazine pyrrone fast-release tablet (daily a piece of), is given three layers of skeleton of hydroxyl piperazine pyrrone for second group and is delayed
Piece (daily a piece of) is released, intersects administration after a week.Dosage be 20mg/ piece/only.Blood is acquired from left fore femoral vein after administration
Liquid.
Fast-release tablet: acquisition blank blood before administration, 10mim, 20min, 40min, 1h, 2h, 3h, 4h, 6h, 8h after administration,
10h, 12h acquire blood sample for 24 hours.3000rpm is centrifuged 10min, separated plasma.
Sustained release tablets: acquisition blank blood before administration, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 12h after administration,
For 24 hours, 30h acquires blood sample.3000rpm is centrifuged 10min, separated plasma.
As a result: Beagle dog is oral give 20mg/ piece/hydroxyl piperazine pyrrone fast-release tablet and hydroxyl piperazine pyrrone sustained release tablets after, hydroxyl piperazine
The T of pyrrone fast-release tabletmaxFor 0.87 ± 0.18h；The T of hydroxyl piperazine pyrrone sustained release tabletsmaxFor 5.17 ± 2.48h.Wherein TmaxBe expressed as to
Time needed for reaching peak concentration of drug after medicine, the parameter reflect that drug enters intracorporal speed, infiltration rate then peak time fastly
It is short.
The C of hydroxyl piperazine pyrrone fast-release tabletmaxFor 543.6 ± 127.4ng/ml；The C of hydroxyl piperazine pyrrone sustained release tabletsmaxFor 122.3 ±
84.9ng/ml.Wherein, CmaxThe blood concentration peak occurred after administration, the parameter be reflection drug in vivo absorption rate and
The important indicator of degree of absorption.
The AUC of hydroxyl piperazine pyrrone fast-release tablet0-24hFor 1634.7 ± 787.8ng.h/ml；The AUC of hydroxyl piperazine pyrrone sustained release tablets0-24h
For 1119.7 ± 775.2ng.h/ml.Wherein, AUC0-24hIt is expressed as the area that plasma concentration curve surrounds time shaft.The ginseng
Number is the important indicator for evaluating extent of drug absorption, the exposure characteristic of reflection drug in vivo.
Compared with hydroxyl piperazine pyrrone fast-release tablet, hydroxyl piperazine pyrrone sustained release tablets bioavilability of the invention is good, peak time Tmax
Obvious postpone reaches Cmax CmaxIt is substantially reduced, body absorption is similar to ordinary tablet, it was demonstrated that hydroxyl piperazine pyrrone sustained release tablets of the invention
Good slow release effect is reached, to further highlight creative place of the invention.
Embodiment 7
This specific embodiment respectively screens the slow-release material in single layer matrix sustained release tablet.Each group is at being shown in Table 9.
Table 9
Release experiment, using deionized water 1000ml as solvent, is surveyed using 50 turns of Chinese Pharmacopoeia II method (slurry processes), revolving speed
The release of random sample product, sampling time point 1,2,4,6,8,10,14,16,20 and 24 hour, resulting experimental result such as table 10
It is shown.
Table 10
As can be seen from Table 10, since the solubility of hydrochloric acid hydroxyl piperazine pyrrone is about in 240mg/ml or so, belong to Gao Rong
Solution degree drug, is individually extremely difficult to ideal releasing effect with hydroxypropyl methyl cellulose, and 6h just has reached 80% or more
Release, and the carmethose of hydroxypropyl methyl cellulose and ionic is selected to share, it can satisfy 80% or more 8h release
Releasing result, this is because the hydroxypropyl in the carmethose and hydroxypropyl methyl cellulose of ionic interacts,
Thus hydration and the expansion rate that collaboration promotes hydroxypropyl methyl cellulose reduce to produce bigger gel strength
The rate of release of the hydrochloric acid hydroxyl piperazine pyrrone of highly-water-soluble, reaches the drug release for being similar to zero level.Simultaneously present invention discover that locating
After being added to lipophilicity slow-release material Compritol 888 ATO in side 3, it can satisfy the releasing result that 10h discharges 80% or more, make
Release profiles have reached ideal slow release effect compared to lipophilicity slow-release material is not added closer to Zero order release.Therefore, hydroxyl
The combination of propyl methocel, sodium carboxymethylcellulose and Compritol 888 ATO has excellent on medicament slow release releasing effect
Gesture.
In order to further improve slow release effect, the present invention also provides a kind of Releasing Mechanisms, i.e., by single layer skeleton
A barrier layer or two barrier layers are added on the basis of sustained release tablets, the surface area contacted by reducing medicated layer with the external world comes
Reach more preferably Zero order release effect.The composition of the medicated layer and barrier layer is shown in Table 11.
Table 11
Double-layer tablets or three-layer tablet are suppressed according to above-mentioned prescription, release experiment is detected according to the above method, resulting reality
It is as shown in table 12 to test result.
Table 12
As can be seen from Table 12, select double-deck or three layers of sustained release tablets, can single layer sustained release tablets rate of release it is enterprising
The raising slow release effect of one step meets 1h release and is no more than the release conditions that 40%, 20-24h reaches 80%, reaches and more approach
In the slow release effect of Zero order release.
Embodiment 8
This specific embodiment discloses the dosage of the hydrochloric acid hydroxyl piperazine pyrrone each component in the sustained release preparation of 10-40mg and contains
Amount, as shown in table 13:
Table 13
Preparation process is with embodiment 3, using 50 turns of Chinese Pharmacopoeia II method (slurry processes), revolving speed, is with deionized water 1000ml
Solvent, measures the release of sample, and the release profiles of sample are shown in that Fig. 6 shows.
It will be appreciated from fig. 6 that slow release effect is suitable, can reach 1h when the dosage of hydrochloric acid hydroxyl piperazine pyrrone is between 10-40mg
Release is no more than the sustained release releasing effect that 40%, 14h release is greater than 80%.
Finally, it is stated that above embodiments further illustrate invention and are in no way limiting of, although referring to preferred embodiment
It describes the invention in detail, those skilled in the art should understand that, invention is not limited to these embodiments
And the preparation method used.And those skilled in the art's description according to the present invention can to technical solution of the present invention into
Row equivalent replacement, combination, improvement or modification should all be covered without departing from the objective and range of technical solution of the present invention
In scope of the presently claimed invention.
Claims (14)
1. a kind of hydroxyl piperazine pyrrone oral slow-releasing preparation, which is characterized in that the sustained release preparation, comprising:
Hydroxyl piperazine pyrrone or its officinal salt；
One or more pharmaceutically acceptable excipients；
At least contain a kind of polymer with slow releasing function.
2. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 1, it is characterised in that:
The officinal salt of the hydroxyl piperazine pyrrone is hydroxyl piperazine pyrrone hydrochloride or hydroxyl piperazine pyrrone sulfate；
The polymer with slow releasing function is framework material and/or coating material.
3. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 2, it is characterised in that:
The sustained release preparation showed to discharge the hydroxyl piperazine pyrrone vitro release no more than 40% 1 hour time point, at 6 hours
Time point is no more than 80% hydroxyl piperazine pyrrone vitro release；
The testing conditions of the hydroxyl piperazine pyrrone vitro release are as follows:
Using 50 turns of Chinese Pharmacopoeia II method, revolving speed, using deionized water 1000ml as solvent.
4. hydroxyl piperazine pyrrone oral slow-releasing preparation according to any one of claims 1 to 3, which is characterized in that described dose
Type is sustained-release tablet, and the medicine layer of the sustained-release tablet is prepared by following components in percentage by weight:
The hydroxyl piperazine pyrrone or its officinal salt 5~20%, the framework material 5~70%, the remaining pharmaceutically acceptable tax
Shape agent complements to 100%.
5. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 4, which is characterized in that the sustained-release tablet further includes screen
Barrier layer, the barrier layer are prepared by following components in percentage by weight:
The framework material 20~70% remaining complements to 100% with the pharmaceutically acceptable excipient.
6. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 5, it is characterised in that:
The sustained-release tablet is the single layer matrix sustained release tablet of only medicine layer composition,
Or,
The sustained-release tablet is the multilayer matrix sustained release tablet containing medicine layer and barrier layer.
7. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 6, which is characterized in that the medicine layer and barrier layer
Framework material includes:
Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and its sodium salt, sodium alginate, methylcellulose, second
Base cellulose, polyacrylic resins, polyvinyl acetate, carbomer, polyoxyethylene, stearic acid, Compritol 888 ATO, list are hard
One or more of glycerol, rilanit special, beeswax, paraffin, Chinese wax, Brazil wax, microwax and octadecyl alcolol.
8. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 7, which is characterized in that the framework material of the medicine layer
Include:
The combination of hydroxypropyl methyl cellulose and sodium carboxymethylcellulose；
Or,
The combination of hydroxypropyl methyl cellulose, sodium carboxymethylcellulose and Compritol 888 ATO.
9. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 5, which is characterized in that the sustained-release tablet it is pharmaceutically acceptable
Excipient includes:
Filler, adhesive, glidant and lubricant.
10. hydroxyl piperazine pyrrone oral slow-releasing preparation according to any one of claims 1 to 3, which is characterized in that described dose
Type is sustained release pellet, comprising:
Pellet core comprising hydroxyl piperazine pyrrone or its officinal salt and the sustained-release coating layer comprising coating material.
11. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 10, it is characterised in that:
The coating material is one of acrylic resin, polyvinyl acetate or ethyl cellulose.
12. hydroxyl piperazine pyrrone oral slow-releasing preparation according to any one of claims 1 to 3, which is characterized in that described dose
Type is osmotic pump tablet, comprising:
Label comprising hydroxyl piperazine pyrrone or its officinal salt and the semi-transparent film coating comprising coating material.
13. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 12, which is characterized in that the semi-transparent film coating packet
It includes:
The polymer of water-insoluble and water-soluble polymer.
14. hydroxyl piperazine pyrrone oral slow-releasing preparation according to claim 13, which is characterized in that the label of the osmotic pump tablet
Further include:
Penetrating agent, sweller.
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| CN112826798A (en) * | 2019-11-25 | 2021-05-25 | 上海博志研新药物技术有限公司 | Ibuprofen pharmaceutical composition, preparation method and application |
| CN113350340A (en) * | 2021-07-05 | 2021-09-07 | 中国人民解放军军事科学院军事医学研究院 | Medical application of hydroxypyrazine hydrochloride in attention-alertness improvement |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112826798A (en) * | 2019-11-25 | 2021-05-25 | 上海博志研新药物技术有限公司 | Ibuprofen pharmaceutical composition, preparation method and application |
| CN112826798B (en) * | 2019-11-25 | 2023-04-07 | 上海博志研新药物技术有限公司 | Ibuprofen pharmaceutical composition, preparation method and application |
| CN113350340A (en) * | 2021-07-05 | 2021-09-07 | 中国人民解放军军事科学院军事医学研究院 | Medical application of hydroxypyrazine hydrochloride in attention-alertness improvement |
| CN113350340B (en) * | 2021-07-05 | 2022-07-26 | 中国人民解放军军事科学院军事医学研究院 | Medical application of hydroxypyrazine hydrochloride in attention-alertness improvement |
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