Background technology
Development along with chronopharmacology, common slow releasing preparation can not satisfy the needs of clinical treatment, study according to chronopharmacology, the all free rhythm and pace of moving things of the therapeutical effect of medicine, toxicity and physiological disposition, the physical signs level of the outbreak of disease and human body also is the rhythmicity variation and (sees The American journal ofCardiology, 1988, Vol.62:635-637:Circulation, 1990, Vol.82:897-902; HearDisease, 1988, Vol.2:1234-1235).
U.S. Alza company in December, 1993 application the patent of releasing osmosis pump sheet when selecting, patent No. US5,252,338, releasing osmosis pump sheet (COER-Verapamil) became the division of day and night controlled release preparation of first listing when the verapamil hydrochloride that uses this patented technology to produce was selected, and what it adopted is the osmotic pump controlled-releasing chip technology.
At home, Kanghong Sci. ﹠ Tech. Industrial (Group) Co., Ltd., Chengdu has applied for " oral formulations of pulse release and preparation method " patent, patent publication No. CN 1488332A.Inst. of Dongyu Enterprise Group Co., Ltd., Shenyang has applied for " new oral timing and controlled release system " patent, patent publication No. CN1261533A.More than two patents all adopt multiple coatings to prepare different time lag granule technologies, discharge medicine with pulse mode.
The present invention adopts the slow-release micro-pill technology of preparing to prepare slow-release micro-pill, at the external packets expanding material of slow-release micro-pill, makes timing slow-releasing micrpill at the external packets timing and controlled release film of expanding material.Releasing mechanism is: after micropill is met water, moisture slowly sees through the timing and controlled release film and enters expanding layer, expanding layer material water-swellable, when the timing and controlled release film can not bear the pressure of expanding layer, the timing and controlled release layer breaks, slow-release micro-pill is exposed in the expanding layer corrosion, and slow-release micro-pill begins to discharge medicine according to the release rule of himself.Composition by adjusting the timing and controlled release film and thickness can the controlling slow release micropill release time, make its dispose procedure produce an interval that matches with physiological period, reach the effect that the division of day and night treats.
Summary of the invention
Purpose one of the present invention be the timing slow-releasing micrpill that has been to provide a kind of timing slow-releasing micrpill and application to make make select the time slow releasing capsule, slow releasing tablet when selecting.Timing slow-releasing micrpill comprises two kinds of basic structures, and basic structure 1 is made up of celphere, medicated layer, slow release layer, expanding layer, timing and controlled release layer; Basic structure 2 is made up of pastille nuclear, slow release layer, expanding layer and timing and controlled release layer.
The component of celphere can be microcrystalline Cellulose, starch, sucrose, lactose, glucose, dextrin, phosphate, acetate, aminoacid, sodium chloride, potassium chloride, mannitol, sorbitol; Above material can use separately also and can be used.
Medicated layer is made up of the mixture of medicine or medicine and adjuvant or the solid dispersion of medicine or the Benexate Hydrochloride of medicine or the hydroxypropyl clathrate of medicine.The operable carrier of the solid dispersion of medicine comprises Polyethylene Glycol, Bo Luoshamu, polyvidone, carbamide, Eudragit resin, ethyl cellulose, acrylic resin.The hydroxypropyl clathrate of the Benexate Hydrochloride of medicine and medicine can adopt solvent method, the polishing preparation.
Slow release layer is made up of slow-release material, plasticizer and porogen, and slow-release material is selected from Eudragit series plastics, cellulose acetate, ethyl cellulose, tacryl element, acrylic resin, cellulose acetate titanate esters, hydroxypropyl emthylcellulose titanate esters; Plasticizer is selected from triethyl citrate, Methyl Benzene-o-dicarboxylate, dibutyl sebacate, diethyl phthalate, dibutyl phthalate; Porogen is selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyvidone, micropowder sodium chloride.
The expanding layer material is selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, polyvidone, phosphate, acetate, can use separately, also can be used.
The timing and controlled release layer is made up of controlled-release material, plasticizer and porogen, and controlled-release material comprises coating materials such as Eudragit series acrylic resin, ethyl cellulose, methylcellulose, Cera Flava, Palmic acid tristearin; Plasticizer comprises triethyl citrate, dibutyl sebacate, diethyl phthalate, dibutyl phthalate.Porogen is selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyvidone, micropowder sodium chloride.
Treatment hypertension, angina pectoris, asthma, arthralgia, diabetes, the medicine of gastric ulcer is fit to make timing slow-releasing micrpill and preparation thereof, and these medicines are including, but not limited to verapamil hydrochloride, the sulphuric acid diltiazem, nitrendipine, nimodipine, nisoldipine, lacidipine, nicardipine, Amlodipine Besylate Tablet, amlodipine maleate, luxuriant and rich with fragrance Lip river Horizon, losartan, Irb, valsartan, Candesartan, telmisartan; Isosorbide acid, isosorbide mononitrate, nitroglycerin, aspirin, glipizide, gliquidone; Salbutamol sulfate, salmaterol, levodropropizine, dextromethorphan hydrobromide; Omeprazole, magnesium omeprazole, Omeprazole Sodium, lansoprazole, Tenatoprazole, Pan draws azoles sodium, famotidine, ranitidine.
One of the preferred technical solution of the present invention (being fit to the medicine of single dose less than 30mg) is as follows.
Medicine accounts for 4%~35% of prescription, and celphere accounts for 30%~50% of prescription, and the sustained release coating material accounts for 5%~20% of prescription, and expanding material accounts for 5%~25% of prescription, and the timing and controlled release coating material accounts for 5%~25% of prescription.
Another optimal technical scheme of the present invention (being fit to the medicine of single dose greater than 20mg) is as follows.
Medicine accounts for 30%~50% of prescription, and celphere accounts for 0~20% of prescription, and the sustained release coating material accounts for 8%~25% of prescription, and expanding material accounts for 5%~25% of prescription, and the timing and controlled release coating material accounts for 10%~30% of prescription.
The method of controlled release preparation when second purpose of the present invention provides above-mentioned the selecting of preparation may further comprise the steps:
The preparation of the timing slow-releasing micrpill of basic structure 1:
1, get the adjuvant of preparation celphere, mix homogeneously is crossed 100 mesh sieves, and mixing is with coating pan or centrifugal coating pelletizing machine or fluid bed system micropill.Taking-up, dry for standby.
2, get and make celphere and put in coating pan or centrifugal granulator machine or the fluid bed, spray into binding agent, add drug powder or the solid dispersion of medicine or the cyclodextrin clathrate of medicine, medicine is wrapped in the outside of celphere; Or with medicine dissolution in binding agent, be sprayed on the surface of celphere.Take out the micropill drying of having wrapped medicated layer, standby.
3, get slow-release material, plasticizer and porogen and dissolve, be mixed with the coating solution of debita spissitudo, the pastille micropill is put in coating pan or centrifugal coating granulator or the fluid bed, spray into coating solution and make slow-release micro-pill with appropriate solvent.
4, in the external packets expanding layer of slow-release micro-pill,, progressively add expanding material, or expanding material is dissolved in the binding agent, be sprayed on the surface of slow-release micro-pill at the surface of slow-release micro-pill spray binding agent, standby.
5, with the timing and controlled release material dissolves, add the dissolving of suitable plasticizer and porogen and make timing and controlled release layer coating solution, coating solution is sprayed on the outside of expanding layer, take out oven dry.
6, can selectively add bag light shield layer or color clothing layer or flavoring layer at micropill
The preparation of the timing slow-releasing micrpill of basic structure 2:
1, medicine is mixed with adjuvant, with coating pan or centrifugal coating pelletizing machine or fluid bed system micropill; Or make micropill, dry for standby with extruding spheronization.
2 slow-release materials, plasticizer and porogen dissolve with appropriate solvent, are mixed with the coating solution of debita spissitudo, and the pastille micropill is put in coating pan or centrifugal coating granulator or the fluid bed, spray into coating solution and make slow-release micro-pill.
3, at the surface of slow-release micro-pill spray binding agent, progressively add expanding material, or expanding material is dissolved in the binding agent, be sprayed on the surface of slow-release micro-pill, standby.
4, with the timing and controlled release material dissolves, add the dissolving of suitable plasticizer and porogen and make timing and controlled release layer coating solution, coating solution is sprayed on the outside of expanding layer, take out oven dry.
5, can selectively add bag light shield layer or color clothing layer or flavoring layer at micropill
The timing and controlled release micropill hard capsule of packing into is promptly got the timing and controlled release capsule.
The drug release determination method of preparation is referring to two appendix XD first methods of Chinese Pharmacopoeia version in 2000.
The specific embodiment
Further describe the present invention by the following examples, should be noted that, these embodiment provide as the purpose of illustration, do not constitute limitation of the scope of the invention.
Embodiment 1The verapamil hydrochloride timing slow-releasing micrpill
Prescription of preparation and preparation method thereof is:
Prescription
Verapamil hydrochloride 120g
The blank pill heart (40 order) 20g
Eudragit?Rl100 30g
Triethyl citrate 5.5g
Propylene glycol 2.5g
Hydroxypropyl emthylcellulose (HPMC) 36g
Propylene glycol 4g
Eudragit?RS100 30g
Triethyl citrate 5.5g
Propylene glycol 2.5g
Polyvidone 8g
Ethanol is an amount of
Preparation method:
Get the verapamil hydrochloride raw material and cross 100 mesh sieves, standby.Get polyvidone and add 80% ethanol 100ml dissolving, standby as binding agent; Eudragit Rl100, triethyl citrate, propylene glycol add the 1000ml dissolve with ethanol, and be standby as sustained release coating liquid; It is standby as extender that hydroxypropyl emthylcellulose is crossed 100 mesh sieves; Eudragit (RS100) 30g, triethyl citrate 5.5g, propylene glycol 2.5g add ethanol 260ml dissolving, and be standby as outer controlled release coat liquid.
Get celphere, put in the coating pan or in the centrifugal coating granulator, spraying into 10% polyvidone ethanol liquid is binding agent, add verapamil hydrochloride medicated powder, make micropill.Spray into sustained release coating liquid, with micropill bag release membranes, coating finishes after drying 1 hour.Slow-release micro-pill is put in coating pan or the centrifugal granulator machine, sprays into 10% polyvidone ethanol liquid, adds hydroxypropyl emthylcellulose, the bag expanding layer.Spray into outer controlled release coat liquid bag controlled release layer.Coating finishes the back in 40 ℃ of dryings 12 hours, obtains timing slow-releasing micrpill.
With timing slow-releasing micrpill 1000 hard capsules slow releasing capsule when promptly getting verapamil hydrochloride and selecting of packing into.
Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, record this preparation and postpone 4 hours release medicines, discharged fully in 20 hours.
Present embodiment is model drug with the verapamil hydrochloride, patient at night 10 take said preparation, medicine second day morning the 2-3 point begin to discharge, can well treat normal hypertension in early morning and the anginal outbreak of fine control patient that occurs of patient.
Embodiment 2The valsartan timing slow-releasing micrpill
Prescription of preparation and preparation method thereof is:
Prescription
Valsartan 80g
The blank pill heart (40 order) 12g
Eudragit?RS100 20g
Triethyl citrate 4g
Polyethylene glycol 6000 4g
Hydroxypropyl emthylcellulose (HPMC) 30g
Propylene glycol 3g
Eudragit?RS100 25g
Triethyl citrate 5g
Propylene glycol 1g
Polyvidone 8g
Ethanol is an amount of
Preparation method:
Get the valsartan raw material and cross 100 mesh sieves, standby.Get polyvidone and add 80% ethanol 100ml dissolving, standby as binding agent; Eudragit RS100, triethyl citrate, 650ml dissolve with ethanol, polyethylene glycol 6000 are dissolved in the 50ml water, add in the above-mentioned solution standby as sustained release coating liquid; It is standby as extender that hydroxypropyl emthylcellulose is crossed 100 mesh sieves; Eudragit (RS100) 25g, triethyl citrate 5g, propylene glycol 1g add ethanol 200ml dissolving, and be standby as outer controlled release coat liquid.
Get celphere, put in the coating pan or in the centrifugal coating granulator, spraying into 10% polyvidone ethanol liquid is binding agent, add valsartan medicated powder, make micropill.Spray into sustained release coating liquid, with micropill bag release membranes, coating finishes after drying 1 hour.Slow-release micro-pill is put in coating pan or the centrifugal granulator machine, sprays into 10% polyvidone ethanol liquid, adds hydroxypropyl emthylcellulose, the bag expanding layer.Spray into encrust controlled release coat liquid bag controlled release layer.Coating finishes the back in 40 ℃ of dryings 12 hours, obtains timing slow-releasing micrpill.
With timing slow-releasing micrpill 1000 hard capsules slow releasing capsule when promptly getting valsartan and selecting of packing into.
Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, record this preparation and postpone 4 hours release medicines, discharged fully in 18 hours.
Embodiment 3The nifedipine timing slow-releasing micrpill
Prescription of preparation and preparation method thereof is:
Prescription
Nifedipine 10g
Polyvidone k-30 30g
Ethanol 300ml
The blank pill heart (30~24 order) 110g
Ethyl cellulose 20g
Propylene glycol 5g
Polyethylene glycol 1500 5g
Hydroxypropyl emthylcellulose (HPMC) 20g
Propylene glycol 3g
Eudragit?RS100 25g
Triethyl citrate 5g
Propylene glycol 1g
Polyvidone 6g
Iron oxide red 3g
HPMC 6g
Distilled water 100ml
Ethanol is an amount of
Preparation method:
Get the nifedipine raw material and add ethanol 300ml dissolving, add polyvidone and dissolve standby; Ethyl cellulose, propylene glycol, polyethylene glycol 1500 add the 800ml dissolve with ethanol, and be standby as sustained release coating liquid; It is standby as extender that hydroxypropyl emthylcellulose is crossed 100 mesh sieves; Eudragit (RS100) 25g, triethyl citrate 5g, propylene glycol 1g add ethanol 200ml dissolving, and be standby as the timing and controlled release coating solution; HPMC is dissolved in the 100ml distilled water, adds iron oxide red and stirs standby as the light shield layer coating solution.
Get celphere, put in the coating pan or in the centrifugal coating granulator,, make the pastille micropill at micropill surface spray nifedipine and polyvidone ethanol liquid.Spray into sustained release coating liquid, with micropill bag release membranes, coating finishes after drying 1 hour.Slow-release micro-pill is put in coating pan or the centrifugal granulator machine, sprays into 10% polyvidone ethanol liquid, adds hydroxypropyl emthylcellulose, the bag expanding layer.Spray into encrust controlled release coat liquid bag controlled release layer, bag light shield layer, coating finish the back in 40 ℃ of dryings 12 hours, obtain nitre benzene timing slow-releasing micrpill.
With timing slow-releasing micrpill 1000 hard capsules slow releasing capsule when promptly getting nifedipine and selecting of packing into.
Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, record this preparation and postpone 4 hours release medicines, discharged fully in 18 hours.
Above embodiment 1, embodiment 2, embodiment 3 release profiles see Figure of description for details.