CN102600097A - Zolpidem tartrate controlled-release double-layer tablet and preparation process of zolpidem tartrate controlled-release double-layer tablet - Google Patents
Zolpidem tartrate controlled-release double-layer tablet and preparation process of zolpidem tartrate controlled-release double-layer tablet Download PDFInfo
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- CN102600097A CN102600097A CN201110023314XA CN201110023314A CN102600097A CN 102600097 A CN102600097 A CN 102600097A CN 201110023314X A CN201110023314X A CN 201110023314XA CN 201110023314 A CN201110023314 A CN 201110023314A CN 102600097 A CN102600097 A CN 102600097A
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- zolpidem tartrate
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- XWSCOGPKWVNQSV-UHFFFAOYSA-N 5-bromo-2,3-dichloropyridine Chemical compound ClC1=CC(Br)=CN=C1Cl XWSCOGPKWVNQSV-UHFFFAOYSA-N 0.000 title claims abstract description 264
- 229960005111 zolpidem tartrate Drugs 0.000 title claims abstract description 264
- 238000013270 controlled release Methods 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 55
- 239000002245 particle Substances 0.000 claims abstract description 55
- 238000001035 drying Methods 0.000 claims abstract description 46
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- 239000000314 lubricant Substances 0.000 claims abstract description 24
- 238000002156 mixing Methods 0.000 claims abstract description 17
- 239000008187 granular material Substances 0.000 claims description 89
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 80
- 238000013268 sustained release Methods 0.000 claims description 46
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- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 24
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
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- 239000003795 chemical substances by application Substances 0.000 claims description 17
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- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 8
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 7
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 6
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
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- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
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- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 9
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 9
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- 229960002336 estazolam Drugs 0.000 description 1
- CDCHDCWJMGXXRH-UHFFFAOYSA-N estazolam Chemical compound C=1C(Cl)=CC=C(N2C=NN=C2CN=2)C=1C=2C1=CC=CC=C1 CDCHDCWJMGXXRH-UHFFFAOYSA-N 0.000 description 1
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- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a zolpidem tartrate controlled-release double-layer tablet. The tablet comprises a zolpidem tartrate quick-release medicine releasing layer and a zolpidem tartrate controlled-release medicine releasing layer and shows the quick dissolving in 1h and the subsequent slow dissolving in 6h. In addition, the invention also discloses a preparation process of the zolpidem tartrate controlled-release double-layer tablet. The preparation process comprises the steps of 1) preparing zolpidem tartrate quick-release particles and zolpidem tartrate controlled-release particles through wet granulation process, and drying and straightening the particles; 2) respectively mixing the quick-release particles and the controlled-release particles with a flow aid and a lubricant in a mixer through a dry method; and 3) pressing the mixed zolpidem tartrate quick-release mixed particles and the controlled-release mixed particles into the zolpidem tartrate controlled-release double-layer tablet.
Description
Technical field
The invention belongs to the method for preparing of a kind of sustained-release double-layer tablet in the oral drug preparation field, relate in particular to the method for preparing of the medicine Zolpidemtar Trate of sleeping peacefully (Zolpidem Tartrate) sustained-release double-layer tablet; In addition, the dissolution in vitro that the invention still further relates to Zolpidemtar Trate obtained by this method (Zolpidem Tartrate) sustained-release double-layer tablet and showed.
Background technology
Zolpidemtar Trate is a non-benzodiazepine hypnotic and sedative of new generation.Since the nineties in 20th century; (administration after 0.5～2 hour PC arrive peaking) and internal metabolism rapid (the removing half-life has only 1.4～3.8 hours) because its oral absorption takes effect rapidly; And savings less or do not have and to accumulate; Do not produce the characteristics that residual reaction etc. is superior to benzodiazepine hypnotic and sedative thing (like stable and estazolam), the trend that progressively replaces traditional benzodiazepine medicine is arranged in American-European hypnotic market.But oral of existing Zolpidemtar Trate common quick release is in the market used and has still been found much to take medicine afterwards rapid-action in the case but the also phenomenon of fast early awakening that lost efficacy.Also find simultaneously the patient face wake up before nightmare, side effect such as night is restless or awake back is dizzy, dizzy, headache, excitement and daytime are drowsy.The possibility that habituation, dependency, knock-on aypnia also can occur in addition.And the common sustained-release matrix tablets of this medicine is also found the slow and above-mentioned side effect of part of onset in its use.
Summary of the invention
The problem that the present invention will solve and the target of realization provide a kind of Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet (as shown in Figure 1) and preparation method thereof; It is behind drug oral, to discharge medicine rapidly and absorb onset through the release layer of this double-layer tablet in the intravital mechanism of action of insomniac, so that the insomniac gets into sleep state rapidly.Then; The slow drug release of controlling of slow controlled release layer through this double-layer tablet; Follow-uply very effectively keep effective Drug therapy blood drug level and reach the object time; Make insomniac's sleep further controlled (bioavailability is better in the medicine body); Guaranteeing patient's ortho sleep, and reduce significantly simultaneously that existing in the market Zolpidemtar Trate (Zolpidem Tartrate) common oral quick release is fast, dizzy, dizzy with the inefficacy that slow releasing tablet exists, side effect, raising insomniac's sleep quality and quality of life such as headache, excitement and daytime are drowsy.
In order to address the above problem; The present invention provides a kind of Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet; It is characterized in that, comprise the component of following weight percent part: Zolpidemtar Trate (Zolpidem Tartrate) 5.0%, slow controlled release polymer or copolymer (Controlled release polymer/co-polymer) 3.0-25.0%, filler (Filler) 62.5-84.5%, binding agent (Binder) 4.5%, disintegrating agent (Disintegrant) 3.0%, fluidizer (Glidant) 1.0% and lubricant (Lubricant) 0.5%.
Said Zolpidemtar Trate (Zolpidem Tartrate) has been the non-benzodiazepine active constituents of medicine of hypnosis sedation; Said slow controlled release polymer or copolymer (Controlled release polymer/co-polymer) are can slow down and control medicine to control within a certain period of time polymer or copolymer at the intravital rate of release of people or with medicine in the intravital release of people; Being somebody's turn to do slow controlled release polymer or copolymer is xanthan gum (xanthan gum), sodium alginate (sodium alginate), methylcellulose (methyl cellulose), ethyl cellulose (ethyl cellulose), hydroxypropyl cellulose (hydroxypropyl cellulose; HPC), hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose; HPMC), carboxy ethyl copolymer (carboxyvinyl polymer, carbopol/carbomer copolymer Carbopol/Carbomer Polymer), propenoic acid resin series copolymer (acrylic co-polymer or
You Teqi copolymer) or polylactic acid-lactide
(PLGA); Said filler (Filler) is for playing the complementary material of filling and skeleton shaping effect in medicament pellet and the controlled release tablet prescription, this filler is dextrin, maltodextrin, cyclodextrin, lactose, sucrose, mannitol, microcrystalline Cellulose, ethyl cellulose, cellulose acetate, calcium carbonate, calcium phosphate dibasic anhydrous, dicalcium phosphate dehydrate and dalcium biphosphate; Said binding agent (Binder) plays the adjuvant that is bonded into the granule effect for the gentle controlled release granule of medicine rapid release prepares in the process; This binding agent is polyvidone (povidone; PVP), copolyvidone (copovidone) and hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose, HPMC); Disintegrating agent (Disintegrant) is for having good water absorption and dilatancy; Can make tablet in gastro-intestinal Fluid, split the material that is broken into fine particle rapidly; Thereby make functional component dissolve absorption rapidly; The adjuvant that plays a role; This disintegrating agent be dried starch, sodium carboxymethyl cellulose (carboxymethyl cellulose sodium, CMC), low substituted hydroxy-propyl methylcellulose (L-HPC), crospolyvinylpyrrolidone (crospovidone) and cross-linking sodium carboxymethyl cellulose (croscarmellose sodium); Fluidizer (Glidant) is when various materials comprise that pharmaceutically active substance and adjuvant mix, to play between material dryness powder to reduce friction; Prevent the material that the powder adhesion takes place; This fluidizer be Pulvis Talci (talc) and silicon dioxide (silica gel, silicon dioxide, colloidal); Lubricant (Lubricant) is meant after the dryness powder first step is always mixed, to join and carries out the short time mixing in the mixed-powder again; The adjuvant that occurs the phenomenon of tablet sticking during with tabletting; This lubricant be magnesium stearate (magnesium stearate), calcium stearate (calcium stearate) and sodium stearyl fumarate (sodium stearyl fumarate, SSF).
In addition; The present invention also provides the method for preparing of this Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet, and this method is to prepare the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles respectively with wet granulation, fluid bed drying, the blended technology of dried granule.On bi-layer tablet press, suppress Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet then.
As shown in Figure 2, the method for preparing of Zolpidemtar Trate of the present invention (Zolpidem Tartrate) sustained-release double-layer tablet mainly comprises the steps:
(1) every batch of total amount is half the Zolpidemtar Trate (Zolpidem Tartrate) and disintegrating agent, filler and binding agent are processed immediate-release granules through wet granulation technology on the high shear wet granulator, use fluid bed drying and pelletizing machine granulate then;
(2) Zolpidemtar Trate (Zolpidem Tartrate) that every batch of total amount is in addition half the delays controlled release polymer with the 1-2 kind or copolymer, filler and binding agent are processed immediate-release granules through wet granulation technology on the high shear wet granulator, uses fluid bed drying and pelletizing machine granulate then;
(3) dry granulate is the good gentle control of Zolpidemtar Trate (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with fluidizer and lubricant respectively in mixing machine;
(4) the gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.
In step (1) and (2), said wet granulation technology is on a high shear wet granulator, to carry out, and major parameter is operator rotating speed 150-350rpm in the technology, and the side tool rotating speed is 1000-2500rpm.Granulation solvent is a purified water, and its amount ranges is 30-40% (weight ratio), and the adding speed through an atomizer is the 5-25g/ branch.Before adding purified water, under the operating condition of operator 50-150rpm and side tool 1000-2000rpm, carry out 5 minutes premix, will keep operator and side tool to turn round and continue after the purified water adding finishes and mix 2-5 minute.Baking temperature is set to 50-60 ℃ during fluid bed drying, and contained humidity should be no more than 5% behind the particle drying.Make dry back granule on pelletizing machine, carry out granulate at last through 18-25 order USP standard screen cloth.
In the step (3), said lubricant and Zolpidemtar Trate (Zolpidem Tartrate) rapid release or slow controlled release granule are in a dried granule mixing machine, to mix.Incorporation time is 5-10 minute.
In the step (4), the every target patch of double-layer tablet of suppressing in the said tabletting process heavily is 250mg, and span of control is 237.5-262.5mg; Target patch hardness is 15kgf, and span of control is 8-21kgf.
The present invention compares with common Zolpidemtar Trate (Zolpidem Tartrate) oral quick release sheet or sustained-release matrix tablets, and following beneficial effect is arranged:
1. a kind of Zolpidemtar Trate disclosed by the invention (Zolpidem Tartrate) sustained-release double-layer tablet can release layer rapid disintegrate discharge the gentle follow-up slow controlled release of controlled release layer and put and more effectively control medicine release in vivo.
2. owing to more effectively control the intravital release of medicine, this Zolpidemtar Trate disclosed by the invention (Zolpidem Tartrate) sustained-release double-layer tablet can be controlled at blood drug level in a stable state and the effective scope in the time at ortho sleep after the insomniac takes medicine in vivo more effectively.This has just significantly improved medicine bioavailability in vivo than other common oral Zolpidemtar Trate (Zolpidem Tartrate) rapid release or slow releasing tablet.
3. the safety that simultaneously, has also therefore significantly reduced contingent side effect and significantly improved drug use than other common oral Zolpidemtar Trate (Zolpidem Tartrate) rapid release or slow releasing tablet.
Description of drawings
Fig. 1 is the structure chart of Zolpidem tartrate controlled-release double-layer tablet disclosed by the invention;
Fig. 2 is the flow chart of the method for preparing of Zolpidem tartrate controlled-release double-layer tablet disclosed by the invention;
Fig. 3 be the embodiment of the invention 1 mesotartaric acid zolpidem the dissolution curve chart;
Fig. 4 be the embodiment of the invention 2 mesotartaric acid zolpidems the dissolution curve chart;
Fig. 5 be the embodiment of the invention 3 mesotartaric acid zolpidems the dissolution curve chart;
Fig. 6 be the embodiment of the invention 4 mesotartaric acid zolpidems the dissolution curve chart;
Fig. 7 be the embodiment of the invention 5 mesotartaric acid zolpidems the dissolution curve chart;
Fig. 8 be the embodiment of the invention 6 mesotartaric acid zolpidems the dissolution curve chart;
Fig. 9 be the embodiment of the invention 7 mesotartaric acid zolpidems the dissolution curve chart;
Figure 10 be the embodiment of the invention 8 mesotartaric acid zolpidems the dissolution curve chart;
Figure 11 be the embodiment of the invention 9 mesotartaric acid zolpidems the dissolution curve chart.
The specific embodiment
Through embodiment the present invention is done further detailed explanation below:
Embodiment 1:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 1 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 1 and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 2000rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 15g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 55 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with Pulvis Talci (fluidizer) and magnesium stearate (lubricant) respectively according to consumption shown in the table 1 respectively in mixing machine.Incorporation time is 5 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 245.0-255.0mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 10-21kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 3).
Table 1 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 1
Embodiment 2:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 2 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 2 and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 2000rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 15g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 55 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with Pulvis Talci (fluidizer) and magnesium stearate (lubricant) respectively according to consumption shown in the table 2 respectively in mixing machine.Incorporation time is 5 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 245.0-255.0mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 10-21kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 4).
Table 2 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 2
Embodiment 3:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 3 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 3 and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 2000rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 15g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 55 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with Pulvis Talci (fluidizer) and magnesium stearate (lubricant) respectively according to consumption shown in the table 3 respectively in mixing machine.Incorporation time is 5 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 245.0-255.0mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 10-21kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method I I (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 5).
Table 3 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 3
Embodiment 4:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 4 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 4 and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 2000rpm, and prior load weighted 350g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 15g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 55 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with Pulvis Talci (fluidizer) and magnesium stearate (lubricant) respectively according to consumption shown in the table 4 respectively in mixing machine.Incorporation time is 5 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 245.0-255.0mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 10-21kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 6).
Table 4 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 4
Embodiment 5:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 5 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 5 and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 2000rpm, and prior load weighted 350g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 15g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 55 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with Pulvis Talci (fluidizer) and magnesium stearate (lubricant) respectively according to consumption shown in the table 5 respectively in mixing machine.Incorporation time is 5 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 245.0-255.0mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 10-21kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 7).
Table 5 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 5
Embodiment 6:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 6 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose and carbopol 974 (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 6 with polyvidone (binding agent) and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 200rpm and the side tool rotating speed is brought up to 2000rpm, and prior load weighted 300g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 10g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 50 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 25 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with silica gel (fluidizer) and sodium stearyl fumarate (lubricant) respectively according to consumption shown in the table 6 respectively in mixing machine.Incorporation time is 8 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 237.5-262.5mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 8-18kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 8).
Table 6 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 6
Embodiment 7:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 7 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose and carbopol 974 (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 7 with polyvidone (binding agent) and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 200rpm and the side tool rotating speed is brought up to 2000rpm, and prior load weighted 300g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 10g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 50 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 25 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with silica gel (fluidizer) and sodium stearyl fumarate (lubricant) respectively according to consumption shown in the table 7 respectively in mixing machine.Incorporation time is 8 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 237.5-262.5mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 8-18kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 9).
Table 7 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 7
Embodiment 8:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 8 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose and sodium alginate (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 8 with polyvidone (binding agent) and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 350rpm and the side tool rotating speed is brought up to 2500rpm, and prior load weighted 300g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 5g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 50 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 20 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with silica gel (fluidizer) and sodium stearyl fumarate (lubricant) respectively according to consumption shown in the table 8 respectively in mixing machine.Incorporation time is 10 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 237.5-262.5mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 8-18kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet 30,60,120,180,240 and 360 minutes drug dissolution (see figure 10).
Table 8 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 8
Embodiment 9:
At first Zolpidemtar Trate (Zolpidem Tartrate) and lactose and microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) and polyvidone (binding agent) are accurately weighed respectively by the consumption shown in table 9 release layer and carefully join in the pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 250rpm and the side tool rotating speed is brought up to 1800rpm, and prior load weighted 400g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 25g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift Zolpidemtar Trate (Zolpidem Tartrate) rapid release soft material to fluid bed dryer, then this soft material is carried out drying at 60 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good immediate-release granules carries out granulate through 18 purpose USP standard screen clothes on pelletizing machine.Similarly, Zolpidemtar Trate (Zolpidem Tartrate) and hydroxypropyl emthylcellulose and sodium alginate (slow controlled release polymer or copolymer), lactose and microcrystalline Cellulose (filler) are accurately weighed respectively by the consumption shown in the slow controlled release layer of table 9 with polyvidone (binding agent) and carefully join in pot body of high shear wet granulator.Before adding purified water, premix is 5 minutes under setting operator rotating speed 150rpm and side tool rotating speed 1500rpm.Then, the rotating speed of will operating is brought up to 350rpm and the side tool rotating speed is brought up to 2500rpm, and prior load weighted 300g purified water is joined in the same pot body to carry out wet granulation through an atomizer with the speed that 5g/ divides simultaneously.After water adding to be purified finishes, keep operator and side tool to remain in operation, and continue to mix 2 minutes.Stop granulation and shift the slow controlled release soft material of Zolpidemtar Trate (Zolpidem Tartrate) to fluid bed dryer, then this soft material is carried out drying at 50 ℃ of following use fluid beds and be not higher than 5% up to made particulate water content.Again that drying is good slow controlled release granule carries out granulate through 20 purpose USP standard screen clothes on pelletizing machine.The gentle control of the Zolpidemtar Trate that dry granulate is good (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with silica gel (fluidizer) and sodium stearyl fumarate (lubricant) respectively according to consumption shown in the table 9 respectively in mixing machine.Incorporation time is 10 minutes.The gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.This batch double-layer tablet is in the sampling Detection sheet focuses on 237.5-262.5mg (the heavy 250.0mg of target patch) scope, and sheet hardness is in 8-18kgf (target patch hardness 15kgf) scope.Simultaneously; Use the medicine dissolving device of American Pharmacopeia USP dissolving-out method II (slurry method); At 37 ℃, change oar rotating speed 100rpm down and in the 900mL0.1M hydrochloric acid dissolution medium, measure this double-layer tablet at 30,60,120,180,240 and 360 minutes drug dissolution (seeing Figure 11).
Table 9 Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet recipe 9
Claims (10)
1. a Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet; It is characterized in that, comprise the component of following weight percent part: Zolpidemtar Trate (Zolpidem Tartrate) 5.0%, slow controlled release polymer or copolymer (Controlled release polymer/co-polymer) 3.0-25.0%, filler (Filler) 62.5-84.5%, binding agent (Binder) 4.5%, disintegrating agent (Disintegrant) 3.0%, fluidizer (Glidant) 1.0% and lubricant (Lubricant) 0.5%.This sustained-release double-layer tablet is using American Pharmacopeia dissolution method of testing II (oar method; USP dissolution method II; Paddle); And change dissolution under the oar speed conditions at 37 ℃, 900 milliliters 0.01M hydrochloric acid dissolution mediums and 100rpm and show as that drug dissolution is 55.0-85.0% in 1 hour, and drug dissolution is not less than 90.0% in 6 hours.
2. Zolpidemtar Trate as claimed in claim 1 (Zolpidem Tartrate) sustained-release double-layer tablet is characterized in that said Zolpidemtar Trate (Zolpidem Tartrate) is the active constituents of medicine in the controlled release tablet; Said slow controlled release polymer or copolymer (Controlled release polymer/co-polymer) are can slow down and control medicine to control within a certain period of time polymer or copolymer at the intravital rate of release of people or with medicine in the intravital release of people; Being somebody's turn to do slow controlled release polymer or copolymer is xanthan gum (xanthan gum), sodium alginate (sodium alginate), methylcellulose (methyl cellulose), ethyl cellulose (ethyl cellulose), hydroxypropyl cellulose (hydroxypropyl cellulose; HPC), hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose; HPMC), carboxy ethyl copolymer (carboxyvinyl polymer, carbopol/carbomer copolymer Carbopol/Carbomer Polymer), propenoic acid resin series copolymer (acrylic co-polymer or
You Teqi copolymer) or polylactic acid-lactide (PLGA); Said filler (Filler) is for playing the complementary material of filling and skeleton shaping effect in medicament pellet and the controlled release tablet prescription, this filler is dextrin, maltodextrin, cyclodextrin, lactose, sucrose, mannitol, microcrystalline Cellulose, ethyl cellulose, cellulose acetate, calcium carbonate, calcium phosphate dibasic anhydrous, dicalcium phosphate dehydrate and dalcium biphosphate; Said binding agent (Binder) plays the adjuvant that is bonded into the granule effect for the gentle controlled release granule of medicine rapid release prepares in the process; This binding agent is polyvidone (povidone; PVP), copolyvidone (copovidone) and hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose, HPMC); Disintegrating agent (Disintegrant) is for having good water absorption and dilatancy; Can make tablet in gastro-intestinal Fluid, split the material that is broken into fine particle rapidly; Thereby make functional component dissolve absorption rapidly; The adjuvant that plays a role; This disintegrating agent be dried starch, sodium carboxymethyl cellulose (carboxymethyl cellulose sodium, CMC), low substituted hydroxy-propyl methylcellulose (L-HPC), crospolyvinylpyrrolidone (crospovidone) and cross-linking sodium carboxymethyl cellulose (croscarmellose sodium); Fluidizer (Glidant) is when various materials comprise that pharmaceutically active substance and adjuvant mix, to play between material dryness powder to reduce friction; Prevent the material that the powder adhesion takes place; This fluidizer be Pulvis Talci (talc) and silicon dioxide (silica gel, silicon dioxide, colloidal); Lubricant (Lubricant) is meant after the dryness powder first step is always mixed, to join and carries out the short time mixing in the mixed-powder again; The adjuvant that occurs the phenomenon of tablet sticking during with tabletting; This lubricant be magnesium stearate (magnesium stearate), calcium stearate (calcium stearate) and sodium stearyl fumarate (sodium stearyl fumarate, SSF).
3. the method for preparing of Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet according to claim 1 or claim 2 is characterized in that, comprises the steps:
(1) every batch of total amount is half the Zolpidemtar Trate (Zolpidem Tartrate) and disintegrating agent, filler and binding agent are processed immediate-release granules through wet granulation technology and are used fluid bed drying and the pelletizing machine granulate;
(2) Zolpidemtar Trate (Zolpidem Tartrate) that every batch of total amount is in addition half the delays controlled release polymer with the 1-2 kind or copolymer, filler and binding agent are processed immediate-release granules through wet granulation technology and used fluid bed drying and the pelletizing machine granulate;
(3) dry granulate is the good gentle control of Zolpidemtar Trate (Zolpidem Tartrate) immediate-release granules granule is mixed into the gentle controlled release hybrid particles of Zolpidemtar Trate (Zolpidem Tartrate) rapid release hybrid particles with fluidizer and lubricant respectively in mixing machine;
(4) the gentle controlled release hybrid particles of the Zolpidemtar Trate that mixes (Zolpidem Tartrate) rapid release hybrid particles is pressed into Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet on bi-layer tablet press.
4. the method for preparing of Zolpidemtar Trate as claimed in claim 3 (Zolpidem Tartrate) sustained-release double-layer tablet; It is characterized in that: in step (1) and (2); Said wet granulation technology is on a high shear wet granulator, to carry out; And major parameter is operator rotating speed 150-350rpm in the technology, and the side tool rotating speed is 1000-2500rpm.Granulation solvent is a purified water, and its amount ranges is 30-40% (weight ratio), and the adding speed through an atomizer is the 5-25g/ branch.Baking temperature is set to 50-60 ℃ during fluid bed drying, and contained humidity should be no more than 5% behind the particle drying.The granulate process is to make granule pass through 18-25 order USP standard screen cloth.
5. like the method for preparing of claim 3 or 4 described Zolpidemtar Trates (Zolpidem Tartrate) sustained-release double-layer tablet; It is characterized in that: in step (1) and (2); Said with in the wet-granulation process; Before adding purified water, to carry out the premix purified water add finish after, keep operator with the side tool running and continue mixing 2-5 minute.
6. the method for preparing of Zolpidemtar Trate as claimed in claim 3 (Zolpidem Tartrate) sustained-release double-layer tablet; It is characterized in that: in the step (3), said lubricant and Zolpidemtar Trate (Zolpidem Tartrate) rapid release or slow controlled release granule carry out the blended time in mixing machine be 5-10 minute.
7. the method for preparing of Zolpidemtar Trate as claimed in claim 3 (Zolpidem Tartrate) sustained-release double-layer tablet; It is characterized in that: in the step (4); Every sheet of double-layer tablet of suppressing in the said tabletting process heavily is controlled in the 237.5-262.5mg scope, and the sheet Hardness Control is in the 8-21kgf scope simultaneously.
8. Zolpidemtar Trate as claimed in claim 1 (Zolpidem Tartrate) dissolution in vitro that sustained-release double-layer tablet showed, it is characterized in that: said dissolution in vitro is divided into two stages.Phase I is the rapid release stage, and the medicine stripping in this stage is mainly by the release layer disintegrate in Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet and discharge medicine and realize; Second stage is for delaying the controlled release stage, and the medicine stripping in this stage is mainly realized by the drug release that slow controlled release polymer or copolymer in the slow controlled release layer in Zolpidemtar Trate (Zolpidem Tartrate) sustained-release double-layer tablet are controlled in this layer with the mode of diffusion controlled release and/or erosion controlled release.
9. like claim 1 and 8 described Zolpidemtar Trates (Zolpidem Tartrate) dissolution in vitro that sustained-release double-layer tablet showed, it is characterized in that: saidly be used to realize that slow controlled release polymer that the second stage medicine sustained and controlled release discharges or copolymer are the combinations of a kind of hydrophilic or lipophilic slow controlled release polymer or copolymer or two kinds of hydrophilic or lipophilic slow controlled release polymers or copolymer.The combination of this a kind of hydrophilic or lipophilic slow controlled release polymer or copolymer or two kinds of hydrophilic or lipophilic slow controlled release polymers or copolymer be through with active component Zolpidemtar Trate (Zolpidem Tartrate) and other adjuvant through granulation, mix and the formed slow controlled release matrix of technology of tabletting is controlled the release of medicine.
10. like claim 1 and 8 described Zolpidemtar Trates (Zolpidem Tartrate) dissolution in vitro that sustained-release double-layer tablet showed, it is characterized in that: said second stage drug release is a zero level or one-level drug release pattern.
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| CN103690505A (en) * | 2013-12-23 | 2014-04-02 | 闻晓光 | Hypnotic double-layer controlled release tablet and preparation method thereof |
| US10137092B2 (en) * | 2013-12-23 | 2018-11-27 | Xiaoguang WEN | Double-layer tablet and preparation method thereof |
| CN116251069A (en) * | 2021-12-10 | 2023-06-13 | 山东新时代药业有限公司 | A kind of zolpidem tartrate gastric floating release tablet and preparation method thereof |
| CN117357493A (en) * | 2023-11-21 | 2024-01-09 | 鲁南贝特制药有限公司 | Zolpidem tartrate orally disintegrating sustained-release tablet and preparation method thereof |
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2011
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| CN103690505A (en) * | 2013-12-23 | 2014-04-02 | 闻晓光 | Hypnotic double-layer controlled release tablet and preparation method thereof |
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| US10137092B2 (en) * | 2013-12-23 | 2018-11-27 | Xiaoguang WEN | Double-layer tablet and preparation method thereof |
| US10925836B2 (en) * | 2013-12-23 | 2021-02-23 | Overseas Pharmaceuticals (Guangzhou) Ltd. | Double-layer tablet and painkiller tablet with same structure |
| US10940114B2 (en) * | 2013-12-23 | 2021-03-09 | Overseas Pharmaceuticals (Guangzhou) Ltd. | Hypnotics tablet with double-layer structure |
| CN116251069A (en) * | 2021-12-10 | 2023-06-13 | 山东新时代药业有限公司 | A kind of zolpidem tartrate gastric floating release tablet and preparation method thereof |
| CN117357493A (en) * | 2023-11-21 | 2024-01-09 | 鲁南贝特制药有限公司 | Zolpidem tartrate orally disintegrating sustained-release tablet and preparation method thereof |
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