CN104127401A - Osmotic pump control-released composition containing desmethylvenlafaxine benzoate compound - Google Patents
Osmotic pump control-released composition containing desmethylvenlafaxine benzoate compound Download PDFInfo
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- CN104127401A CN104127401A CN201410400501.9A CN201410400501A CN104127401A CN 104127401 A CN104127401 A CN 104127401A CN 201410400501 A CN201410400501 A CN 201410400501A CN 104127401 A CN104127401 A CN 104127401A
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- 230000003204 osmotic effect Effects 0.000 title claims abstract description 43
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- -1 benzoate compound Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 238000000576 coating method Methods 0.000 claims description 79
- 239000012943 hotmelt Substances 0.000 claims description 55
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 42
- 235000002639 sodium chloride Nutrition 0.000 claims description 30
- 239000011780 sodium chloride Substances 0.000 claims description 21
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims description 19
- 239000008118 PEG 6000 Substances 0.000 claims description 18
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 18
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 17
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 17
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 11
- 239000002671 adjuvant Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 229920000642 polymer Polymers 0.000 claims description 11
- 230000008961 swelling Effects 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 239000013543 active substance Substances 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000013270 controlled release Methods 0.000 claims description 5
- 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 4
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- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
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- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 2
- 238000002372 labelling Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
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- 238000012360 testing method Methods 0.000 description 28
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- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 6
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 5
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
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- 239000005711 Benzoic acid Substances 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention provides an osmotic pump control-released composition containing a desmethylvenlafaxine benzoate compound, and a preparation method of the composition. The preparation method comprises the following steps: firstly, preparing active compounds into hot-molten extrudate, and subsequently performing later preparation. The osmotic pump control-released composition provided by the invention has the characteristics that the composition can be relatively completely released and the zero-grade release of a control-released preparation is met; moreover, relatively high bioavailability is achieved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to the osmotic pump controlled-releasing composition and method of making the same that contains ODV benzoate compounds.
Background technology
Depression is a kind of common and serious mental sickness, has become the fourth-largest disease of harm humans health, and at present the sickness rate of whole world depression can reach 5%～12%, approximately has 15% depressive patients to commit suicide and die every year.Pharmaceutical intervention is alleviate depression disease patient symptom, the effective means that improves patients ' life quality.The medicine of traditional treatment depression is a lot, but all because erious adverse reaction, compliance be poor etc., reason is restricted the treatment of depression.Widely used novel antidepressant is reuptake inhibitor (SSRIs) and the 5-hydroxy tryptamine-norepinephrine reuptake inhibitor (SNRIs) of selectivity 5-hydroxy tryptamine clinically at present, and its curative effect has obtained clinical sure.
Venlafaxine, chemistry 1-[2-(dimethylamino)-1-(4-anisyl) ethyl by name] encircle alcohol, the medicine that represents for SNRIs class antidepressants, by the exploitation listing in 1994 of U.S. Hui Shi (Wyeth) company, trade name Effexor, dosage form is oral sustained release sheet, slow releasing capsule and slow-release pill.Venlafaxine has the norepinephrine of inhibition and heavily absorbs the dual function with antagonism 5-HT, be widely used in the diseases such as Cure of depression, to various depressions, comprise that unipolar depression, the depression with anxiety, Bipolar Depression, refractory depression have good curative effect.
Venlafaxine oral administration biaavailability is 45%, extensively metabolism in liver, main metabolites is O-DMV (ODV), main by renal excretion [Klamerus KJ, Maloney K, Rudolph RL, et al.Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite[J] .Journal of Clinical Pharmacology.1992,32 (8): 716-724]
U.S. Wyeth started to develop the succinate peroral dosage form (DVS-233) of ODV in 2000, as antidepressants of new generation, and FDA approved listing at present.With respect to taking in venlafaxine, directly take in O-DMV and treat the advantage that relevant central nervous system disease has single compound principle, be conducive to adjust better dosage and curative effect, reduce side effect, reduce and the interactional risk of other drug.But, in O-DMV chemical constitution, having increased a hydroxyl, hydrophilic increases, thereby has reduced its oral bioavailability, and the increase of (Pre-system) side effect before the system that may cause not absorbing the drug.In order to overcome the defect of above relevant O-DMV, by the prodrug of synthetic O-DMV, likely effectively increase the bioavailability of O-DMV, improve curative effect, reduce side effect.
CN1955159 discloses O-DMV benzoate compounds, and due to than ODV few hydroxyl in structure, lipotropy increases, and be conducive to see through gastrointestinal mucosal and absorb, and the bioavailability of compound all increases than ODV.
Summary of the invention
The invention provides a kind of osmotic pump controlled-releasing compositions that contains ODV benzoate compounds, it discharges more completely, bioavailability is higher.
Specifically, described osmotic pump controlled-releasing compositions contains logical formula I compound or its salt, is carrying out follow-up preparation after formula I compound or its salt is prepared into hot-melt extruded thing.
r=phenyl, p-methylphenyl, p-methoxyphenyl
Described salt is hydrochlorate, tartrate, maleate, fumarate, acetate or succinate.
Wherein, in described hot-melt extruded thing, contain hot melt adjuvant, the weight ratio of hot melt adjuvant and logical formula I compound or its salt is 20:1-3:1, is preferably 10:1-5:1.
Described hot melt adjuvant is one or both in polyvidone (PVP), Polyethylene Glycol (PEG), is preferably PVP S630, PEG4000, PEG6000; The compositions of PVP and PEG more preferably, its weight ratio is 4:1-10:1; Especially PVP S630:PEG6000=8:1.Particularly, PVP S630:PEG6000 in hot-melt extruded thing: logical formula I compound=8:1:1.
Described osmotic pump controlled-releasing compositions contains plate core weight and coatings, and label comprises hot-melt extruded thing, osmotic pressure active substance and swelling type polymer.
Osmotic pressure active substance is selected from mannitol, potassium chloride, sodium chloride, preferred sodium chloride, and while selecting sodium chloride, Cumulative release amount is larger, discharges more complete; Swelling polymer is selected from polyvidone (PVP), sodium alginate (SA) or polyoxyethylene (PEO), preferably PVP K30, PEO, more preferably PEO, while selecting PEO, the cumulative release amount of osmotic pumps compositions is larger, discharges more completely, and zero level is the longest release time.
The 10-65% of hot-melt extruded Wu Zhan plate core weight weight content, is preferably 20-55%; Osmotic pressure active substance accounts for 10～60% of plate core weight's weight content, and preferably 15～40%, 20-25% more preferably; Swelling type polymer accounts for 1～20% of plate core weight's weight content, and preferably 3～15%, more preferably 7-11%.
According to clinical needs, can also add other adjuvants, as filler, filler is selected from: starch, sucrose, dextrin, lactose, pregelatinized Starch, microcrystalline Cellulose, inorganic salts, mannitol, calcium phosphate, calcium hydrogen phosphate; Binding agent is selected from: starch slurry, methylcellulose (MC), hydroxypropyl cellulose (HPC), hypromellose (HPMC), sodium carboxymethyl cellulose (CMC-Na), polyvidone (PVP), gelatin, Polyethylene Glycol; Lubricant is selected from: magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, Polyethylene Glycol, sodium laurylsulfate, hard acyl fumaric acid sodium.
The coating adjuvant of coatings is selected from the compositions of one or more materials in cellulose acetate, ethyl cellulose, polrvinyl chloride and Merlon, Polyethylene Glycol (PEG), diethyl phthalate (DEP), dibutyl phthalate (DBP), glyceride, succinate, is preferably the compositions of cellulose acetate and Polyethylene Glycol.Coatings, with respect to the label 8-12% that increases weight, is preferably 12%.
Infiltration controlled release pharmaceutical compositions of the present invention adopts following methods preparation:
The preparation of hot-melt extruded thing: can adopt conventional method to prepare, but preferred following methods: will lead to after formula I compound or its salt and hot melt adjuvant are pulverized and cross 60～100 mesh sieves, mix homogeneously, makes physical mixture.The extrusion temperature of setting extruder is 50～250 ℃, and temperature starts screw rod after being raised to setting value, and physical mixture is added in extruder, through melting, extruding, finally with ribbon, extrudes; After ribbon extrudate is cooling, pulverization process is crossed 20-80 mesh sieve, standby.
The preparation of plate core weight: by hot-melt extruded thing and osmotic pressure active substance, swelling type polymer, and other adjuvants mix, and make single or multiple lift plate core weight by pelletizing press sheet or direct compression process;
The preparation of coating solution: coating powder be dissolved in or be suspended in solvent, stirring certain hour, obtaining coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8-1.2mm in the one side of tablet.Make osmotic tablet.
Sustained release pharmaceutical composition provided by the invention is taked oral administration, and dosage is to contain anhydrous active matter, 20-80mg/ days.
Accompanying drawing explanation
Fig. 1-9: the release in vitro curve comparison of osmotic pump controlled release tablet prepared by employing embodiment 1-9 hot-melt extruded method and non-hot melt extrusion molding, show to adopt the standby osmotic pump controlled release tablet release in vitro of hot-melt extruded legal system more complete, more meet zero level release characteristic
Figure 10: be the inside and outside dependency collection of illustrative plates of embodiment 6
Figure 11: osmotic pump tablet extracorporeal releasing test curve prepared by different osmotic active substance
Figure 12: osmotic pump tablet extracorporeal releasing test curve prepared by different swelling polymers
The specific embodiment
Further illustrate the present invention with test example by the following examples, but be not limited to this.
Embodiment 1
Prescription: p-Methoxybenzoic acid 4-[2-dimethyl amido-1-(1-hydroxyl cyclohexyl)-ethyl] phenyl ester hydrochlorate 21g, PVPS630 420g, mannitol 101g, PEO130g, magnesium stearate 6.5g
Preparation method:
The preparation of hot-melt extruded thing: reactive compound and PVPS630 are crossed respectively to 60 mesh sieves; after mixing; be placed in the loading hopper of extruder; rotating speed is 20r/min, and temperature is 120 ℃, and material is extruded with form of strips via head nib; room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Label preparation: claim hot-melt extruded thing 441g, mannitol 101g, PEO130g mix homogeneously, add magnesium stearate 6.5g as lubricant, tabletting after mixing, the heavy 680mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder Opradry CA97.2g is dissolved in 94% acetone, and magnetic agitation 45min, obtains coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Embodiment 2
Prescription: p-Methoxybenzoic acid 4-[2-dimethyl amido-1-(1-hydroxyl cyclohexyl)-ethyl] phenyl ester hydrochlorate 30g, PVPS630 300g, mannitol 200g, PVP K30 124g, magnesium stearate 6.0g
Preparation method:
The preparation of hot-melt extruded thing: the reactive compound of recipe quantity and PVPS630 are crossed respectively to 60 mesh sieves; after mixing; be placed in the loading hopper of extruder; rotating speed is 20r/min, and temperature is 120 ℃, and material is extruded with form of strips via head nib; room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Label preparation: take hot-melt extruded thing 330g, mannitol 200g, PVP K30 124g mix homogeneously, add suitable magnesium stearate 6.0g as lubricant, tabletting after mixing, the heavy 660mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder Opradry CA66g is dissolved in 94% acetone, and magnetic agitation 45min, obtains coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Embodiment 3
Prescription: p-Methoxybenzoic acid 4-[2-dimethyl amido-1-(1-hydroxyl cyclohexyl)-ethyl] phenyl ester hydrochlorate 21g, PVPS630 63g, mannitol 150g, PVP K30 77g, lactose 200g, hydroxypropyl methylcellulose (K100M) 200g, microcrystalline Cellulose (pH102) 119g, magnesium stearate 10g
Preparation method:
The preparation of hot-melt extruded thing: reactive compound and PVPS630 are crossed respectively to 60 mesh sieves; after mixing; be placed in the loading hopper of extruder; rotating speed is 20r/min, and temperature is 120 ℃, and material is extruded with form of strips via head nib; room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Plate core weight's preparation: take hot-melt extruded thing 84g, lactose 200g, microcrystalline Cellulose 50g mix homogeneously, add magnesium stearate 5.0g as lubricant, standby after mixing.
By after hydroxypropyl methylcellulose (K100M) 200g, mannitol 150g, PVPK30 77g, microcrystalline Cellulose 69g, a small amount of color lake mix homogeneously, add appropriate alcoholic solution soft material processed, 20 mesh sieves are granulated, dry 1h under 50 ℃ of fluid beds, 20 mesh sieve granulate, add magnesium stearate, mix standby.
Adopt the method for twice pressurization of twice filler of single punch tablet machine to suppress double-deck label, the heavily about 830mg of sheet, makes 1000.
Coating solution preparation: coating powder (ethyl cellulose 76.5g+PEG400 25.5g) 102g is dissolved in 95% medicinal alcohol, magnetic agitation 12h, 200 order filter-cloth filterings obtain coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of colourless medicated layer.
Embodiment 4
Prescription: 4-ar-Toluic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] phenyl ester hydrochlorate 20g, PVPS630320g, PEG6000 80g, sodium chloride 140g, sodium alginate 133g, magnesium stearate 7g
Preparation method:
Hot-melt extruded thing preparation: reactive compound and PVPS630, PEG6000 are crossed respectively to 60 mesh sieves; after mixing; be placed in the loading hopper of extruder; rotating speed is 20r/min, and temperature is 120 ℃, and material is extruded with form of strips via head nib; room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Label preparation: claim hot-melt extruded thing 420g, sodium chloride 140g, PEO133g mix homogeneously, add appropriate alcohol granulation, 40 ℃ of oven drying 2h, 20 mesh sieve granulate, add magnesium stearate 7g as lubricant, tabletting after mixing, the heavy 700mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder Opradry CA70g is dissolved in 94% acetone, and magnetic agitation 45min, obtains coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Embodiment 5
Prescription: 4-ar-Toluic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] phenyl ester hydrochlorate 44g, PVPS630160g, PEG6000 16g, sodium chloride 120g, PEO150g, lactose 234g, magnesium stearate 9g
Preparation method:
Hot-melt extruded thing preparation: reactive compound and PVPS630, PEG6000 are crossed respectively to 60 mesh sieves; after mixing; be placed in the loading hopper of extruder; rotating speed is 20r/min, and temperature is 120 ℃, and material is extruded with form of strips via head nib; room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Label preparation: claim hot-melt extruded thing 220g, sodium chloride 120g, PEO150g, lactose 234g, magnesium stearate 9g mix homogeneously, tabletting, the heavy 730mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder (ethyl cellulose 75g+PEG400 25g) 100g is dissolved in 95% medicinal alcohol, magnetic agitation 12h, 200 order filter-cloth filterings obtain coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Embodiment 6
Prescription: 4-ar-Toluic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] phenyl ester hydrochlorate 25g, PVPS630200g, PEG6000 25g, sodium chloride 116g, PEO32g
Preparation method:
Hot-melt extruded thing preparation: reactive compound and PVPS630, PEG6000 are crossed respectively to 60 mesh sieves; after mixing; be placed in the loading hopper of extruder; rotating speed is 20r/min, and temperature is 120 ℃, and material is extruded with form of strips via head nib; room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Label preparation: claim hot-melt extruded thing 250g, sodium chloride 116g, PEO32g mix homogeneously, add appropriate amount of ethanol and granulate, 40 ℃ of oven drying 2h, 20 mesh sieves arrange, tabletting, the heavy 400mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder Opradry CA48g is dissolved in 94% acetone, and magnetic agitation 45min, obtains coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Embodiment 7
Prescription: benzoic acid 4-[2-dimethyl amido-1-(1-hydroxyl cyclohexyl)-ethyl] phenyl ester hydrochlorate 20g, PEG6000 300g, sodium chloride 80g, PVP K30 150g, microcrystalline Cellulose (pH102) 242g, magnesium stearate 8g
Preparation method:
Hot-melt extruded thing preparation: reactive compound and PEG6000 are crossed respectively to 60 mesh sieves, after mixing, be placed in the loading hopper of extruder, rotating speed is 20r/min; temperature is 55 ℃, and material is extruded with form of strips via head nib, and room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Label preparation: claim hot-melt extruded thing 320g, sodium chloride 80g, PVP K30 150g, microcrystalline Cellulose 242g mix homogeneously, add hard magnesium 8g, tabletting, the heavy 800mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder (ethyl cellulose 60g+PEG400 20g) 80g is dissolved in 95% medicinal alcohol, magnetic agitation 12h, 200 order filter-cloth filterings, obtain coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Embodiment 8
Prescription: benzoic acid 4-[2-dimethyl amido-1-(1-hydroxyl cyclohexyl)-ethyl] phenyl ester hydrochlorate 20g, PEG6000160g, sodium chloride 100g, PVP K30 150g, lactose 461g, magnesium stearate 9g
Preparation method:
Hot-melt extruded thing preparation: reactive compound and PEG6000 are crossed respectively to 60 mesh sieves, after mixing, be placed in the loading hopper of extruder, rotating speed is 20r/min; temperature is 160 ℃, and material is extruded with form of strips via head nib, and room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Label preparation: claim hot-melt extruded thing 180g, sodium chloride 100g, PVP K30 150g, lactose 461g mix homogeneously, add hard magnesium 9g, tabletting, the heavy 900mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder Opradry CA100g is dissolved in 94% acetone, and magnetic agitation 45min, obtains coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Embodiment 9
Prescription: benzoic acid 4-[2-dimethyl amido-1-(1-hydroxyl cyclohexyl)-ethyl] phenyl ester hydrochlorate 50g, PEG6000 250g sodium chloride 100g, PEO95g, magnesium stearate 5g
Preparation method:
Hot-melt extruded thing preparation: reactive compound and PEG6000 are crossed respectively to 60 mesh sieves, after mixing, be placed in the loading hopper of extruder, rotating speed is 20r/min; temperature is 65 ℃, and material is extruded with form of strips via head nib, and room temperature is cooling; with pelletizing machine granulate, cross 40 mesh sieves, take out, standby.
Plate core weight's preparation: claim hot-melt extruded thing 300g, sodium chloride 100g, PEO95g mix homogeneously, add alcohol granulation, dry 2h, 20 mesh sieve granulate, add hard magnesium 5g, tabletting, the heavy 500mg of sheet, hardness 4-8kg, makes 1000.
Coating solution preparation: coating powder (ethyl cellulose 37.5g+PEG400 12.5g) 50g is dissolved in 95% medicinal alcohol, magnetic agitation 12h, 200 order filter clothes obtain coating solution.
Coating: the plate core weight making is placed in to high-efficiency coating pot, coating pan rotating speed 10rpm, 25 ℃ of kettle temperatures, until coating is complete, then beat the small delivery aperture of 0.8mm in the one side of tablet.
Test example 1 release in vitro contrast test
1) test material
Trial drug:
Hot-melt extruded osmotic pump tablet: prepare according to embodiment 1-9
Non-hot-melt extruded osmotic pump tablet: according to the prescription of embodiment 1-9, adopt and not add the osmotic pump tablet that the method for hot-melt extruded is directly prepared into according to the preparation technology of tablet in embodiment 6.
Test apparatus:
Intelligence digestion instrument (sending out for huge day); Agilent1100 high performance liquid chromatograph (column oven, automatic sampler, quaternary pump, online degasser, DAD detector, Agilent company, the U.S.); Mettler ToledoXS105 100,000/analytical balance (Mei Tele company, Switzerland)
2) method and result
Get respectively the osmotic pump tablet of hot-melt extruded and non-hot-melt extruded, with reference to the second subtraction unit under the dissolution determination item of < < Pharmacopoeia of People's Republic of China > > version appendix XC regulation in 2010, take deionized water as dissolution medium, bath temperature is 37 ℃, rotating speed is 50r/min, respectively at 1,2,4,6,8,10,12h, 18h sample 10mL, add synthermal medium 10mL simultaneously, with 0.45 μ m filter, filter, precision measures subsequent filtrate 20 μ l injection liquid chromatographies.
Chromatographic condition: chromatographic column be take octadecylsilane chemically bonded silica as filler (C18 100mm * 4.6mm, 3.0 μ m), take 0.2% phosphoric acid water as mobile phase A, take acetonitrile as Mobile phase B, in 60:40 ratio, carry out eluting, column temperature is 30 ℃, and detection wavelength is 247nm, and flow velocity is 1.0ml/min.
Take respectively 4-methoxybenzoic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] phenyl ester hydrochlorate, 4-ar-Toluic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] phenyl ester hydrochlorate, 4-Phenylbenzoic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] phenyl ester hydrochlorate is reference substance, preparation reference substance solution, injection liquid chromatography, record chromatogram calculation stripping quantity, draw dissolution curve.Stripping the results are shown in Figure 1-9.
From Fig. 1-9, the osmotic pump tablet that reactive compound is prepared after hot-melt extruded, its accumulation stripping quantity is higher than the osmotic pump tablet of preparing without hot-melt extruded, illustrates that the controlled release osmotic pump tablet preparing through hot-melt extruded discharges more complete, more meets controlled release preparation zero level release characteristic.
Test example 2 inside and outside correlation tests
1) test material
Trial drug: according to the prescription of embodiment 6 and technique preparation
Test apparatus: intelligent digestion instrument (sending out for huge day); Agilent1100 high performance liquid chromatograph (column oven, automatic sampler, quaternary pump, online degasser, DAD detector, Agilent company, the U.S.); Mettler ToledoXS105 100,000/analytical balance (Mei Tele company, Switzerland); API4000 type triple quadrupole bar tandem mass spectrometer, is furnished with ionspray ionization source and Analyst1.4.1 data processing software (U.S. Applied Biosystem company); L-128 type nitrogen blows concentrating instrument (Beijing technology development center of Lai Heng science and trade Co., Ltd)
2) method and result
The detection method of release in vitro is with test example 1.
In vivo assay Cells: with the male Beagle dog of health (10kg ± 0.5kg, n=3), oral (4-ar-Toluic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] 1 of the osmotic pump tablet (25mg/ sheet) of phenyl ester hydrochlorate; Before administration after (0 hour), administration 0.25,0.5,1,1.5,2,3,4,6,10,12,24h gets blood 2ml in dog forelimb, be placed in calparine pipe, centrifuging and taking supernatant, put in refrigerator freezing stand-by in-35 ℃, measure the blood drug level of metabolite O-DMV, and calculate the absorption fraction of tablet in dog body according to the area under curve of blood drug level, the result of calculating and inside and outside correlation results are in Table 1 and Figure 10.
The cumulative in vitro release absorption fraction in abscissa, body of take is vertical coordinate, and inside and outside data are carried out to matching, and fit equation is y=1.122x-14.339, correlation coefficient r=0.9938.
Result shows: in the release in vitro curve that the external test method that the present invention formulates obtains and body, absorption fraction has good inside and outside dependency, can reflect preparation emission and absorption rule in vivo.
The cumulative in vitro of table 1: embodiment 6 tablets discharges and the interior absorption fraction of body
Test example 3: bioavailability study
1) test material
Trial drug:
Hot-melt extruded is prepared osmotic pump tablet: according to table 2 prescription, adopt the technique of embodiment 6 to prepare
Non-hot-melt extruded osmotic pump tablet: do not add the osmotic pump tablet that the method for hot-melt extruded is directly prepared into according to the preparation technology of tablet in embodiment 6 according to writing out a prescription 1 and prescription 3 in table 2, adopting.
Table 2: prescription table (g/1000 sheet)
Test apparatus: intelligent digestion instrument (sending out for huge day); Agilent1100 high performance liquid chromatograph (column oven, automatic sampler, quaternary pump, online degasser, DAD detector, Agilent company, the U.S.); Mettler ToledoXS105 100,000/analytical balance (Mei Tele company, Switzerland); API4000 type triple quadrupole bar tandem mass spectrometer, is furnished with ionspray ionization source and Analyst1.4.1 data processing software (U.S. Applied Biosystem company); L-128 type nitrogen blows concentrating instrument (Beijing technology development center of Lai Heng science and trade Co., Ltd)
2) method and result
In vivo assay Cells: with the male Beagle dog of health (10kg ± 0.5kg), oral 4-ar-Toluic acid 4-[2-dimethyl amido-1-(1-hydroxy-cyclohexyl) ethyl] 1 of the osmotic pump tablet (30mg/ sheet) of phenyl ester hydrochlorate; Before administration after (0 hour), administration 0.25,0.5,1,1.5,2,3,4,6,10,12,24h gets blood 2ml in dog forelimb, be placed in calparine pipe, centrifuging and taking supernatant, put in refrigerator freezing stand-by in-35 ℃, measure the blood drug level of metabolite O-DMV, calculate the area under curve of blood drug level-time.In body medicine for parameter in Table 3.
The table 3 osmotic pump tablet kinetic parameter of respectively writing out a prescription
Result shows: with respect to the osmotic pump tablet of non-hot-melt extruded, adopt the osmotic pump tablet of hot-melt extruded can improve bioavailability; Wherein during hot melt adjuvant PVPS630:PEG6000=8:1, the bioavailability of osmotic pump tablet is the highest.
Test example 4: osmotic pump tablet extracorporeal releasing test prepared by different osmotic active substance
1) trial drug: according to table 4 prescription, prepare osmotic pump tablet according to the technique of embodiment 6.
Table 4 prescription table (g/1000 sheet)
2) test method and result
Test method: with test example 1
Result of the test: in Table 5 and Figure 11
Table 5 cumulative in vitro release (%) the result comparison of respectively writing out a prescription
Result shows: when osmotic pressure active substance is selected sodium chloride, Cumulative release amount is larger, discharges more complete.
Test example 5: osmotic pump tablet extracorporeal releasing test prepared by different swelling polymers
1) trial drug: according to table 6 prescription, adopt the technique of embodiment 6 to prepare
Table 6 prescription table (g/1000 sheet)
2) result of the test and method
Test method: with test example 1
Result of the test: see Figure 12 and table 7
Table 7 cumulative in vitro release (%) the result comparison of respectively writing out a prescription
Result shows: when swelling polymer is selected PEO, cumulative release amount is larger, discharges more completely, and zero level is the longest release time.
Test example 6: formulation optimization test
1) trial drug:
Adopt sodium chloride as osmotic pressure active substance, PEO is as swelling type polymer, and Opadry CA is coating material.Hot-melt extruded thing consumption is 250mg, appropriate microcrystalline Cellulose, and sheet is heavily 450mg, release aperture is 0.8mm, according to the technique preparation of experimental example 6
2) test method:
Selective chlorination sodium consumption, PEO consumption and coating weightening finish are as empirical factor, with Orthogonal Experiment and Design, be optimized prescription, according to the method for test example 1, measure release in vitro situation, judging quota is the drug accumulation release of the cumulative release amount of 0-12 hour and the linearly dependent coefficient of time and 12 hours.EXPERIMENTAL DESIGN factor level table and result of the test are in Table 8 and table 9
Table 8 factor level experiment table
Table 9 orthogonal experiments
Result shows: by integrated survey, best testing program is A
2b
3c
3, optimum prescription is PEO32mg, sodium chloride 116mg, and coating weightening finish 12%, PEO accounts for 7.1% of label, and sodium chloride accounts for 25.8% of label, and coatings the relative weight gain 12% has best releasing effect.
Claims (10)
1. an osmotic pump controlled-release medicinal composition that contains logical formula I compound or its salt, carries out follow-up preparation after it is characterized in that formula I compound or its salt is prepared into hot-melt extruded thing again.
r=phenyl, p-methylphenyl, p-methoxyphenyl.
2. pharmaceutical composition according to claim 1, is characterized in that containing hot melt adjuvant in described hot-melt extruded thing.
3. pharmaceutical composition according to claim 2, is characterized in that in described hot-melt extruded thing, the weight ratio of hot melt adjuvant and logical formula I compound or its salt is 20:1-3:1, is preferably 10:1-5:1.
4. according to the pharmaceutical composition described in claim 2-3, it is characterized in that described hot melt adjuvant is one or both in polyvidone, Polyethylene Glycol, is preferably PVP S630, PEG4000 or PEG6000; The compositions of polyvidone and Polyethylene Glycol more preferably.
5. pharmaceutical composition according to claim 4, the weight ratio that it is characterized in that polyvidone and Polyethylene Glycol is 4:1-10:1.
6. according to the pharmaceutical composition described in claim 4 or 5, it is characterized in that being preferably PVP S630:PEG6000=8:1.
7. the pharmaceutical composition of stating according to claim 2, is characterized in that PVP S630:PEG6000 in described hot-melt extruded thing: logical formula I compound=8:1:1.
8. according to the arbitrary described pharmaceutical composition of claim 1-7, it is characterized in that containing label and coatings, label comprises hot-melt extruded thing, osmotic pressure active substance and swelling type polymer.
9. arbitrary described pharmaceutical composition according to Claim 8, is characterized in that osmotic pressure active substance is selected from mannitol, potassium chloride, sodium chloride, preferably sodium chloride; Swelling polymer is selected from polyvidone, sodium alginate or polyoxyethylene, is preferably polyoxyethylene.
10. the pharmaceutical composition described according to Claim 8-9, is characterized in that the weight content that hot-melt extruded thing accounts for label is 10-65%, preferably 20-55%; The weight content that osmotic pressure active substance accounts for label is 10～60%, preferably 15～40%, and 20-25% more preferably; The weight content that swelling type polymer accounts for label is 1～20%, preferably 3～15%, and more preferably 7-11%.
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