CN101496792A - Punailuoer or delayed-release preparation of salt thereof and preparation method thereof - Google Patents
Punailuoer or delayed-release preparation of salt thereof and preparation method thereof Download PDFInfo
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- CN101496792A CN101496792A CNA2008100332660A CN200810033266A CN101496792A CN 101496792 A CN101496792 A CN 101496792A CN A2008100332660 A CNA2008100332660 A CN A2008100332660A CN 200810033266 A CN200810033266 A CN 200810033266A CN 101496792 A CN101496792 A CN 101496792A
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Abstract
The invention discloses a delayed-release preparation of propranolol for treating cardiovascular diseases such as abnormal heart rate, angina, myocardial infarction and the like or a salt thereof. The aim of the invention is to provide a drug preparation which meets the intentions of chrono-pharmacology and chrono-therapeutics and has the delayed and impulse drug-release effects and a method for preparing the same. The delayed-release preparation comprises: a tablet core containing the active component propranolol with effective treating dose or the salt thereof and other auxiliary materials and one or two coating layers which are coated in a coating pan by the rollover method or coated by the fluidization coating method or dry pressing coating method. The composition and the thickness of the coating layers decide the time lag of releasing the drug.
Description
Technical field
The present invention relates to a kind of slowbreak preparation for the treatment of multiple cardiovascular disease such as arrhythmia, angina pectoris, myocardial infarction and hypertensive Propranolol or its salt and preparation method thereof.Described slowbreak preparation comprises label (containing treatment effective amount of actives Propranolol or its salt and adjuvant) and coatings, its release characteristic is the time hysteresis through after a while, can discharge contained active component Propranolol or its salt of doses rapidly, the release effect of so-called delay and pulse is promptly arranged.
Background technology
Propranolol hydrochloride (Propranolol) has another name called propranolol, is beta-receptor blockader.Its chemical name is: 1-isopropylamino-3-(1-naphthoxy)-2-propylate hydrochlorate, and structural formula is as follows, is the crystalline powder of an off-white color or off-white color, odorless, little sweet back of distinguishing the flavor of is bitter, 162～165 ℃ of fusing points.
Propranolol hydrochloride is non-selective epinephrine beta-blocker.Can block the beta receptor of cardiac muscle, decreased heart rate suppresses cardiac contractile force and conduction, reduces circulation volume, reduces myocardial oxygen consumption.Its mainly act on purposes be can the selectivity coronary artery dilator, increase coronary flow, can suppress the conduction of myocardial excitability and chamber.Be used for the treatment of paroxysmal supraventricular tachycardia, also can be used for acute and chronic coronary insufficiency or angina pectoris, effect is preferably also arranged for the treatment of ventricular arrhythmia.Also can be used for the atrial fibrillation atrial flutter, artrial premature beat.
The type of preparation of propranolol hydrochloride exploitation at present is a lot, and the CHP2005 version has been recorded tablet and injection, and UP27 has recorded slow releasing capsule (24 hours), propranolol hydrochloride and hydrogen chlorine saliva tremnble compound sustained release capsules (24 hours) and ordinary tablet thereof etc.In China's slow releasing tablet, slow releasing capsule listing is arranged all, but these dosage forms just reach the purpose of traditional slow release, and do not consider the division of day and night rhythmicity of hypertension angina pectoris morbidity, not in conjunction with the feature of the chronopharmacology of the rhythmicity of seizure of disease and medicine, reach the purpose of delayed release.
Summary of the invention
Therefore, one object of the present invention be to provide a kind of after predetermined lag time with the Propranolol of the mode release of active ingredients of pulsed release or the slowbreak preparation of its salt; Another object of the present invention is to provide a kind of method for preparing the slowbreak preparation of above-mentioned Propranolol or its salt.
The slowbreak preparation of Propranolol provided by the invention or its salt, it is characterized in that, described slowbreak preparation comprises: the label and one deck or the two-layered coating layer that contain treatment effective amount of actives Propranolol or its salt and other adjuvants, wherein the sheet core diameter is 2.0～6.0mm, label weight is 50～110mg, wherein coatings weight is 5%～65% of label weight, and is preferably 10%～45%.The slowbreak preparation of above-mentioned Propranolol or its salt does not have substantial seepage to take place in lag time, after certain lag time, just discharge active pharmaceutical ingredient Propranolol or its salt, it relies on the thickness of component, set of dispense ratio and the coatings of coatings that time lag is carried out reliable and reproducible control, its release mechanism is by the corrosion of coatings or the control time lag that expands, and also can control time lag by breaking of coatings.
The label of the slowbreak preparation of above-mentioned Propranolol or its salt comprises treatment effective amount of actives Propranolol or its salt, binding agent, disintegrating agent, filler and lubricant, also can add release regulator to regulate the form release of medicine with pulse.Wherein, Propranolol or its salt, binding agent, disintegrating agent, filler, lubricant and the release regulator percentage by weight in label are: 9～17%:0.8～8%:4～40%:20～46%:0.9～5%:0～50%.
Propranolol in the above-mentioned label or its salt are one or both in Propranolol or the propranolol hydrochloride;
Described binding agent is selected from one or more in starch, polyvidone, hydroxypropyl methylcellulose (HPMC) and the microcrystalline Cellulose;
Described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose (CCNa), polyvinylpolypyrrolidone (PVPP), carboxymethyl starch sodium (CMSNa), low-substituted hydroxypropyl cellulose (L-HPC), starch and the microcrystalline Cellulose;
Described filler is selected from one or more in starch, dextrin, Icing Sugar, lactose, mannitol, microcrystalline Cellulose and the calcium chloride etc.;
Described lubricant is selected from one or more in stearic acid, calcium stearate, magnesium stearate, Pulvis Talci and the micropowder silica gel;
Described release regulator is selected from one or more in sodium chloride, potassium chloride, sucrose, lactose, mannitol, fructose, glucose, sorbitol, sodium acetate, succinic acid and the citric acid.
The coatings of the slowbreak preparation of described Propranolol or its salt can be by one deck or two-layer the composition, and the release of the slowbreak preparation of Propranolol or its salt can also can be controlled by breaking of coatings by the corrosion of coatings or the control of expanding.
Described coatings comprises water-soluble polymer, water-soluble plasticizer, insoluble polymer and antiplastering aid, and in coatings, the percentage by weight of water-soluble polymer, water-soluble plasticizer, insoluble polymer, antiplastering aid is: 20～60%:5～30%:20～60%:5～30%, and be preferably: 25～45%:7～25%:25～45%:8～25%.
In coatings, described water-soluble polymer is selected from one or more in hydroxy methocel, hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, Polyethylene Glycol and the carbomer;
Described water-soluble plasticizer is selected from one or more in triethyl citrate, propylene glycol, Polyethylene Glycol, dibutyl phthalate, glycerol triacetate and the sodium alginate;
Described insoluble polymer is selected from one or more in methacrylic resin, ethyl cellulose, Brazil wax, Cera Flava and the octadecanol;
Described antiplastering aid is selected from one or more in Pulvis Talci, magnesium stearate, micropowder silica gel and the glyceryl monostearate.
The objective of the invention is to after certain lag time immediately, the mode with pulsed release discharges active pharmaceutical ingredient, for realizing this purpose, except the composition that will control above mentioned label and coatings, the weight ratio of the thickness of coatings and coatings and label all is to realize this purpose important technology feature.Under existing technical conditions, adopt the weightening finish of coating, i.e. the weight of (weight of the gross weight-label behind the coating)/label is controlled the weight ratio of thickness and the coatings and the label of coatings.It is generally acknowledged that slice, thin piece is under the condition of fixed diameter, the coating weightening finish is big, and coatings thickness is big, and time lag is long.And the time active component that lags behind release, then depend on the composition in the sheet sandwich layer.So-called " weightening finish ", be meant on the heavy basis of the diameter of fixing label and sheet, technical specification in order to control coatings " thickness ", coatings " thickness " can determine the release behavior of preparation, but the in fact very difficult thickness of measuring every coatings, the thickness of tablet is controlled in average " weightening finish " behind the therefore general employing mensuration multi-disc coating.Therefore, need only the fixedly diameter and the sheet weight of label, just can come control thickness with " weightening finish ", in the present invention, the label diameter restrictions is at 2.0～6.0mm, and label weight is limited in 50～110mg, and the coating weightening finish is controlled at 5～65%, is preferably 10～45%.
The present invention also provides the preparation method of the slowbreak preparation of Propranolol or its salt, and this method comprises: prepare label by the tablet machine tabletting; Carry out the coating process then, it can be finished by rollover in coating pan, also can finish by fluidized coating or dry-pressing coating.The coating weightening finish is controlled at 5～65%, and preferred coating weightening finish is controlled at 10～45%.
The slowbreak preparation of described Propranolol or its salt can be prepared into the tablet of coating or further be filled to capsule.
Description of drawings
Fig. 1 is the external release curve chart of measuring in the embodiment of the invention 1.
Fig. 2 is the external release curve chart of measuring in the embodiment of the invention 2.
Fig. 3 is the external release curve chart of measuring in the embodiment of the invention 4.
Fig. 4 is the external release curve chart of measuring in the embodiment of the invention 5.
Fig. 5 be the embodiment of the invention 11 and common Propranolol sheet measure body in the release curve chart.
The specific embodiment
Below, will the present invention be further specified by embodiment, but the present invention is not limited to these embodiment, in the illustrated scope of claim of the present invention, can carry out various changes or be equal to replacement.
Supplementary material and equipment:
Propranolol and salt changzhou Ya Bang pharmaceutical Co. Ltd thereof
Lianyun Harbour, mannitol Jiangsu iodine factory
Cross-linking sodium carboxymethyl cellulose Anhui Shanhe Medical Accessary Material Co., Ltd.
Polyvinylpolypyrrolidone American I SP
Carboxymethyl starch sodium Anhui Shanhe Medical Accessary Material Co., Ltd.
Low-substituted hydroxypropyl cellulose Anhui Shanhe Medical Accessary Material Co., Ltd.
Microcrystalline Cellulose PH101 Japan Asahi Chemical Industry
Hydroxypropyl methylcellulose K100 U.S. Dow company
Hydroxyethyl-cellulose U.S. Natrsol HEC
Hydroxypropyl cellulose Anhui Shanhe Medical Accessary Material Co., Ltd.
Gao Nan chemical plant, Macrogol 4000 Shanghai
Carbomer 934 U.S. NOVEN
Triethyl citrate U.S. Aldrich company
Dibutyl phthalate Kaifeng gold is rich
The grand chemical industry company limited in glycerol triacetate Shanghai
Sodium alginate Qingdao bright moon seaweed industry Co., Ltd
The German ROhm of methacrylic resin (EUDRAGIT RL100) company
The German ROhm of methacrylic resin (EUDRAGIT RS100) company
Ethyl cellulose Shanghai Ka Lekang coating company limited
Brazil wax Beijing Li Kang great achievement
Cera Flava Beijing Li Kang great achievement
Octadecanol Nanjing Kanbon Science Co., Ltd
Sky, TDP single punch tablet machine Shanghai and pharmaceutical machine factory
BY300A type coating pan Shanghai Huanghai Sea medicine inspection instrument plant
Fluidized-bed coating machine Changzhou XianFeng drying equipment Co., Ltd
Preparation embodiment
Embodiment 1
Prescription 1:
Get propranolol hydrochloride, mannitol, L-HPC, sodium chloride and cross 80 eye mesh screens, mix homogeneously respectively; Get starch, add water 10mL and boil, put the cold starch slurry of making, add the supplementary material mix and prepare soft material, cross 16 mesh sieves and granulate, 65 ℃ of dryings 4 hours, 18 order granulate add magnesium stearate and mix.Dash with the shallow arc of 5.0mm and to be punch die, suppress on the tablet machine (TDP single punch tablet machine) label.The 101mg of plate core weight, hardness 3.5 ± 0.5kg.
Hydroxy methocel, Brazil wax, Pulvis Talci, Macrogol 4000 are suspended in the water of 20mL and make coating solution; Label is placed in the coating pan, and adjusting lift-over coating pan (BY300A type coating pan) angle is 30 degree, and rotating speed 30rpm is added in aligning label spraying in the spray gun with coating solution, send 85～100 ℃ of hot air dryings with heat gun simultaneously.The weight of record label in the coating process is about 15% to the weightening finish of label, promptly makes propranolol hydrochloride slowbreak sheet.
The 3rd method of pressing Chinese Pharmacopoeia (2005 editions) drug release determination method is measured the release in vitro curve of propranolol hydrochloride slowbreak sheet.Get the slowbreak sheet and place the 180ml release medium, medium temperature (37 ± 1) ℃, rotating speed is 100rpm.Sampling 5ml at the fixed time, 0.8 μ m filtering with microporous membrane is added simultaneously with volume isothermal medium, and subsequent filtrate is measured peak area with the HPLC method.All drug release determination experiments all repeat 3 times.
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-0.02molL
-1Potassium dihydrogen phosphate (50:50) is a mobile phase, and the detection wavelength is 290nm.
The release in vitro curve of propranolol hydrochloride slowbreak sheet is seen accompanying drawing 1.As seen, the time lag of propranolol hydrochloride slowbreak sheet is 3 hours, and propranolol hydrochloride rapid release in 30 minutes reaches the effect of pulse.
Embodiment 2
Prescription 2:
Get propranolol hydrochloride, starch, PVPP, potassium chloride and cross 80 eye mesh screens respectively, mix homogeneously is got polyvidone k29 and is dissolved in ethanol 10mL, adds the supplementary material system soft material that mixes, and cross 16 mesh sieves and granulate, 65 ℃ of dryings 3 hours, 18 order granulate add the magnesium stearate mixing.With the shallow arc of 5.0mm dash be punch die, tablet machine suppress label.The 102mg of plate core weight, hardness 4.5 ± 0.5kg.
Hydroxyethyl-cellulose, ethyl cellulose, glyceryl monostearate, triethyl citrate are dissolved in the ethanol of 50mL and make coating solution; Label is placed fluid bed, feed air-flow, borrow the air-flow that rises rapidly to make label be in fluidized state, coating solution is imported fluid bed and atomizing, make label surface adhesion one deck coating material, feed 40～60 ℃ of air dryings then.The weight of documentary film, to the weightening finish of label be 35%, promptly make propranolol hydrochloride slowbreak sheet.
With with embodiment 1 in identical method measure the release in vitro curve of propranolol hydrochloride slowbreak sheet, the results are shown in accompanying drawing 2.Digital proof, coating weightening finish increases, and the time lag of propranolol hydrochloride slowbreak sheet also increased to 5 hours, and later propranolol hydrochloride rapid release embodies the effect of pulse.
Embodiment 3
Prescription 3:
Get propranolol hydrochloride, microcrystalline Cellulose PH101, CCNa, polyvidone k29, micropowder silica gel, sorbitol, mannitol and cross 80 eye mesh screens respectively, mix homogeneously with the method for direct powder compression, dashes to punch die with the shallow arc of 5.0mm, makes label.The 102mg of plate core weight, hardness 3.5 ± 0.5kg.
With various component mixings such as Polyethylene Glycol, Cera Flava, glyceryl monostearate, glycerol triacetate, ethyl celluloses, 65 ℃ of heating in water bath fusions, mix homogeneously, slowly cooling at room temperature makes it to solidify, and grinds; Get the label that 10.2mg coating material and a slice prepare, direct dry-pressing coating on tablet machine, the heavy 112.2mg of sheet, hardness 5.5 ± 0.5kg, the coating weightening finish is 10%, promptly makes propranolol hydrochloride slowbreak sheet.
Embodiment 4
Prescription 4:
Get propranolol hydrochloride, starch, CMS Na, Pulvis Talci and cross 80 eye mesh screens respectively, mix homogeneously is got polyvidone k29 and is dissolved in ethanol 10mL, adds the supplementary material system soft material that mixes, and cross 16 mesh sieves and granulate, 65 ℃ of dryings 3 hours, 18 order granulate add the Pulvis Talci mixing.With the shallow arc of 5.0mm dash be punch die, tablet machine suppress label.The 101mg of plate core weight, hardness 4.5 ± 0.5kg.
Get carbomer and be dissolved in the 20mL ethanol, make the ground floor coating solution; Label is placed in the coating pan, and adjusting lift-over coating pan angle is 35 degree, rotating speed 60rpm, coating solution is added in aligning label spraying in the spray gun, send 45～65 ℃ of hot air dryings with heat gun simultaneously, the weight of record label in the coating process, to the weightening finish of label be 6%; After waiting to do, be dissolved in the 30mL acetone, add Pulvis Talci and make the second layer (skin) coating suspension with methacrylic resin EUDRAGIT RL100 and EUDRAGIT RS100, triethyl citrate; Carry out second layer coating, the coating pan angle is 35 degree, and rotating speed 60rpm is added in coating solution in the spray gun and aims at the label spraying, send 35～45 ℃ of hot air dryings with heat gun simultaneously, to the weightening finish of label be 9%, promptly make propranolol hydrochloride slowbreak sheet.
The release in vitro curve of propranolol hydrochloride slowbreak sheet is seen accompanying drawing 3.As seen, the time lag of propranolol hydrochloride slowbreak sheet is 2 hours, compares with embodiment 1, adopts different coating fluid prescription, the time lag asynchronism(-nization).
Prescription 5:
Get Propranolol, lactose, calcium chloride, CMS Na and cross 80 eye mesh screens respectively, mix homogeneously is got HPMC and is dissolved in the 10mL water, adds the supplementary material system soft material that mixes, and cross 16 mesh sieves and granulate, 65 ℃ of dryings 5 hours, 18 order granulate add the stearic acid mixing.With the shallow arc of 2.5mm dash be punch die, tablet machine suppress label.The 61mg of plate core weight, hardness 5.5 ± 0.5kg.
Get hydroxypropyl cellulose and be dissolved in the 15mL ethanol, make the ground floor coating solution; Label is placed in the coating pan, and adjusting lift-over coating pan angle is 35 degree, rotating speed 60rpm, coating solution is added in aligning label spraying in the spray gun, send 45～65 ℃ of hot air dryings with heat gun simultaneously, the weight of record label in the coating process, to the weightening finish of label be 15%; After waiting to do, be dissolved in the 30mL acetone, make the second layer (skin) coating suspension with methacrylic resin EUDRAGIT RL100 and EUDRAGIT RS100, propylene glycol, glyceryl monostearate; Carry out second layer coating, the coating pan angle is 35 degree, and rotating speed 60rpm is added in coating solution in the spray gun and aims at the label spraying, send 35～45 ℃ of hot air dryings with heat gun simultaneously, to the weightening finish of label be 12%, promptly make Propranolol slowbreak sheet; Getting 5 Propranolol slowbreak sheets is filled in No. 0 capsule and promptly makes Propranolol slowbreak capsule.
The capsular release in vitro curve of propranolol hydrochloride slowbreak is seen accompanying drawing 4.The release in vitro song is S-type, and the capsular time lag of propranolol hydrochloride slowbreak is 6 hours, subsequently pulse release.
Embodiment 6
Prescription 6:
Get propranolol hydrochloride, Propranolol, dextrin, PVPP, low-substituted hydroxypropyl cellulose, fructose and cross 80 eye mesh screens respectively, mix homogeneously, getting starch is dissolved in the 10mL water, heated and boiled is put the cold starch slurry of making, and adds the supplementary material system soft material that mixes, crossing 16 mesh sieves granulates, 65 ℃ of dryings 4 hours, 18 order granulate add stearic acid and mix.Dash with the shallow arc of 5.0mm, on tablet machine, suppress label.The 100mg of plate core weight, hardness 4.5 ± 0.5kg.
Hydroxyethyl-cellulose, sodium alginate, Pulvis Talci, ethyl cellulose, propylene glycol are crossed 80 mesh sieves respectively, evenly mixed, make coating material; Get 10mg and a slice label, tabletting once more on tablet machine, the dry-pressing coating, the weightening finish of control coating is 10%, promptly makes propranolol hydrochloride slowbreak sheet.
Embodiment 7
Prescription 7:
Get propranolol hydrochloride, lactose, CCNa, citric acid, succinic acid and cross 80 eye mesh screens respectively, mix homogeneously, getting starch is dissolved in the 10mL water, heated and boiled is put the cold starch slurry of making, and adds the supplementary material system soft material that mixes, crossing 16 mesh sieves granulates, 65 ℃ of dryings 4 hours, 18 order granulate add magnesium stearate and mix.Dash with the shallow arc of 5.0mm, on tablet machine, suppress label.The 100mg of plate core weight, hardness 4.5 ± 0.5kg.
Methacrylic resin EUDRAGIT RL100 and EUDRAGIT RS100, Pulvis Talci, dibutyl phthalate, carbomer, micropowder silica gel are suspended in the water of 50mL and make coating solution; Label is placed in the coating pan, and adjusting lift-over coating pan angle is 30 degree, and rotating speed 30rpm is added in aligning label spraying in the spray gun with coating solution, send 85～100 ℃ of hot air dryings with heat gun simultaneously.The weight of record label in the coating process, to the weightening finish of label be 25%, promptly make propranolol hydrochloride slowbreak sheet.
Embodiment 8
Prescription 8:
Get propranolol hydrochloride, Icing Sugar, PVPP, sodium acetate and cross 80 eye mesh screens respectively, mix homogeneously, getting starch is dissolved in the 10mL water, heated and boiled is put the cold starch slurry of making, and adds the supplementary material system soft material that mixes, crossing 16 mesh sieves granulates, 65 ℃ of dryings 4 hours, 18 order granulate add micropowder silica gel and Pulvis Talci and mix.5.0mm shallow arc punching press makes label.The 100mg of plate core weight, hardness 4.5 ± 0.5kg.
Hydroxy methocel, methacrylic resin EUDRAGIT RL100 and EUDRAGIT RS100, Pulvis Talci, triethyl citrate are suspended in the water of 50mL and make coating solution; Label is placed in the coating pan, and adjusting lift-over coating pan angle is 30 degree, and rotating speed 30rpm is added in aligning label spraying in the spray gun with coating solution, send 85～100 ℃ of hot air dryings with heat gun simultaneously.The weight of record label in the coating process, to the weightening finish of label be 15%, promptly make propranolol hydrochloride slowbreak sheet.
Embodiment 9
Prescription 9:
Get propranolol hydrochloride, starch, L-HPC, sodium chloride and cross 80 eye mesh screens respectively, mix homogeneously is got polyvidone k29 and is dissolved in the 10mL ethanol, add the supplementary material system soft material mix, cross the granulation of 16 mesh sieves, 45 ℃ of dryings 3 hours, 18 order granulate, magnesium stearate is mixed.Get the shallow arc of 5.0mm and dash, the tablet machine tabletting makes label.The 100mg of plate core weight, hardness 4.5 ± 0.5kg.
Hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, Pulvis Talci, dibutyl phthalate are suspended in 75% ethanol of 50mL and make coating solution; Label is placed in the coating pan, and adjusting lift-over coating pan angle is 30 degree, and rotating speed 30rpm is added in aligning label spraying in the spray gun with coating solution, send 45～65 ℃ of hot air dryings with heat gun simultaneously.The weight of record label in the coating process, to the weightening finish of label be 20%, promptly make propranolol hydrochloride slowbreak sheet.
Prescription 10:
Get propranolol hydrochloride, starch, CCNa, sucrose and cross 80 eye mesh screens respectively, mix homogeneously is got polyvidone k29 and is dissolved in the 10mL ethanol, adds the supplementary material system soft material that mixes, and crosses 16 mesh sieves and granulates, 45 ℃ of dryings 3 hours, 18 order granulate, calcium stearate mixing.With the shallow arc of 5.0mm be punched in suppress on the tablet machine label.The 100mg of plate core weight, hardness 4.5 ± 0.5kg.
With carbomer, octadecanol, Macrogol 4000, micropowder silica gel, be suspended in the water of 50mL and make coating solution; Label is placed in the coating pan, and adjusting lift-over coating pan angle is 30 degree, and rotating speed 30rpm is added in aligning label spraying in the spray gun with coating solution, send 85～95 ℃ of hot air dryings with heat gun simultaneously.The weight of record label in the coating process, to the weightening finish of label be 42%, promptly make propranolol hydrochloride slowbreak sheet.
Embodiment 11
Test instrunment: Agilent1100 chromatograph of liquid (hewlette-packard)
6 healthy volunteer's single doses are intersected oral propranolol hydrochloride slowbreak sheet (embodiment 6 preparation) and commercially available ordinary tablet, adopt propranolol hydrochloride concentration in the reversed-phase HPLC method mensuration blood plasma, the HPLC condition is C
18The ODS post, 5 μ m, 150 * 4.6mm; Mobile phase is methanol-water (containing 0.06% phosphoric acid, octane semi-annular jade pendant acid sodium IPR-B80.005molL-1)=65:35 (V/V); Flow velocity is 0.9mLmin-1; The fluoroscopic examination wavelength is λ ex=296nm, λ em=340nm; 35 ℃ of column temperatures.
6 healthy volunteers issue propranolol hydrochloride slowbreak sheet at random, and (1 once, 10mg/ time), (1 once for commercially available propranolol hydrochloride ordinary tablet, 10mg/ time, Tianjin Lisheng Pharmaceutical Co., Ltd.), one group of per 3 people, the intersection administration is measured blood drug level at a plurality of interval points after each administration.Referring to accompanying drawing: Fig. 5 (n=6).
The HPLC data show: the interior blood drug level of patient's body of taking propranolol hydrochloride slowbreak sheet has an obvious hysteresis peak, be approximately 5～7 hours lag time, have significantly extended release impulse action, as take before sleeping, medicine will a cardiovascular disease high-incidence season discharges in morning 2～3.
Embodiment 12
According to the Wagner-Nelson formula, record the blood drug level data (embodiment 11) of each time point according to single oral dose propranolol hydrochloride slowbreak sheet, calculate PA (Fa).PA (Fa) in 3～12 hours the body is carried out linear regression (data see Table 1) to cumulative in vitro release (Ft), must regression equation be: Fa=0.9137Ft+1.4067, r=0.9963.When degree of freedom df=n-2=4, marginal value r4,0.05=0.811, correlation coefficient r〉r4,0.05.
The inside and outside correlation table of measuring among table 1 embodiment 12
Experimental result shows: it is good to absorb dependency in the release in vitro of propranolol hydrochloride slowbreak sheet and the body.
Claims (12)
1, the slowbreak preparation of a kind of Propranolol or its salt, it is characterized in that, described preparation comprises: the label that contains treatment effective amount of actives Propranolol or its salt and adjuvant, with one deck or two-layered coating layer, wherein the sheet core diameter is 2.0～6.0mm, label weight is 50～110mg, and coatings weight is 5～65% of label weight.
2, the slowbreak preparation of Propranolol as claimed in claim 1 or its salt is characterized in that, described coatings weight is 10～45% of described label weight.
3, the slowbreak preparation of Propranolol as claimed in claim 1 or 2 or its salt is characterized in that,
Described label comprises treatment effective amount of actives Propranolol or its salt, binding agent, disintegrating agent, filler and lubricant.
4, the slowbreak preparation of Propranolol as claimed in claim 3 or its salt is characterized in that, described label further comprises release regulator.
5, the slowbreak preparation of Propranolol as claimed in claim 4 or its salt, it is characterized in that, in described label, the percentage by weight of Propranolol or its salt, binding agent, disintegrating agent, filler, lubricant, release regulator is: 9～17%:0.8～8%:4～40%:20～46%:0.9～5%:0～50%.
6, as the slowbreak preparation of claim 4 or 5 described Propranolol or its salt, it is characterized in that,
Propranolol in the described label or its salt are one or both in Propranolol or the propranolol hydrochloride;
Described binding agent is selected from one or more in starch, polyvidone, hydroxypropyl methylcellulose and the microcrystalline Cellulose;
Described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, starch and the microcrystalline Cellulose;
Described filler is selected from one or more in starch, dextrin, Icing Sugar, lactose, mannitol, microcrystalline Cellulose and the calcium chloride;
Described lubricant is selected from one or more in stearic acid, calcium stearate, magnesium stearate, Pulvis Talci or the micropowder silica gel;
Described release regulator is selected from one or more in sodium chloride, potassium chloride, sucrose, lactose, mannitol, fructose, glucose, sorbitol, sodium acetate, succinic acid and the citric acid.
As the slowbreak preparation of the described Propranolol of one of claim 1 to 5 or its salt, it is characterized in that 7, described coatings comprises water-soluble polymer, water-soluble plasticizer, insoluble polymer and antiplastering aid; And in coatings, the percentage by weight of water-soluble polymer, water-soluble plasticizer, insoluble polymer, antiplastering aid is: 20～60%:5～30%:20～60%:5～30%.
8, the slowbreak preparation of Propranolol as claimed in claim 7 or its salt, it is characterized in that the percentage by weight of water-soluble polymer, water-soluble plasticizer, insoluble polymer, antiplastering aid is in the described coatings: 25～45%:7～25%:25～45%:8～25%.
9, as the slowbreak preparation of claim 7 or 8 described Propranolol or its salt, it is characterized in that,
Described water-soluble polymer is selected from one or more in hydroxy methocel, hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, Polyethylene Glycol and the carbomer;
Described water-soluble plasticizer is selected from one or more in triethyl citrate, propylene glycol, Polyethylene Glycol, dibutyl phthalate, glycerol triacetate and the sodium alginate;
Described insoluble polymer is selected from one or more in methacrylic resin, ethyl cellulose, Brazil wax, Cera Flava and the octadecanol;
Described antiplastering aid is selected from one or more in Pulvis Talci, magnesium stearate, micropowder silica gel and the glyceryl monostearate.
10, the slowbreak preparation of Propranolol as claimed in claim 1 or 2 or its salt is characterized in that, described Propranolol slowbreak preparation is tablet or is capsule.
11, the preparation method of the slowbreak preparation of each described Propranolol or its salt in the claim 1～10, this method comprises: prepare label by the tablet machine tabletting; Carry out the coating process then, finish by rollover in coating pan, perhaps finish by fluidized coating or dry-pressing coating, the coating weightening finish is controlled at 5～65%.
12, the preparation method of the slowbreak preparation of Propranolol as claimed in claim 11 or its salt is characterized in that, described coating weightening finish is controlled at 10～45%.
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| CN2008100332660A CN101496792B (en) | 2008-01-30 | 2008-01-30 | Punailuoer or delayed-release preparation of salt thereof and preparation method thereof |
Applications Claiming Priority (1)
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| CN2008100332660A CN101496792B (en) | 2008-01-30 | 2008-01-30 | Punailuoer or delayed-release preparation of salt thereof and preparation method thereof |
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| Publication Number | Publication Date |
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| CN101496792A true CN101496792A (en) | 2009-08-05 |
| CN101496792B CN101496792B (en) | 2012-05-23 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102247326A (en) * | 2010-05-17 | 2011-11-23 | 天津药物研究院 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
| CN102525981A (en) * | 2012-02-21 | 2012-07-04 | 常州康普药业有限公司 | Propranolol hydrochloride tablets and preparation method thereof |
| CN105030718A (en) * | 2015-08-18 | 2015-11-11 | 石家庄格瑞药业有限公司 | Arotinolol hydrochloride preparation and preparation method thereof |
| CN113104941A (en) * | 2021-04-18 | 2021-07-13 | 广西博世科环保科技股份有限公司 | Sewage dephosphorization and sterilization composite sustained-release tablet and preparation method thereof |
| WO2024022382A1 (en) * | 2022-07-26 | 2024-02-01 | 中国科学院上海药物研究所 | Osmotic pump controlled release preparation, osmotic pump controlled release composition, preparation method and use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1052397C (en) * | 1987-04-28 | 2000-05-17 | E·R·斯奎布父子公司 | Pharmaceutical compositions in form of beadlets and method |
| US6350471B1 (en) * | 2000-05-31 | 2002-02-26 | Pharma Pass Llc | Tablet comprising a delayed release coating |
| CN1511515A (en) * | 2002-12-27 | 2004-07-14 | 蔡玉臣 | Novel medicine slow releasing preparation and its preparing method |
-
2008
- 2008-01-30 CN CN2008100332660A patent/CN101496792B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102247326A (en) * | 2010-05-17 | 2011-11-23 | 天津药物研究院 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
| CN102247326B (en) * | 2010-05-17 | 2013-10-23 | 天津药物研究院 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
| CN102525981A (en) * | 2012-02-21 | 2012-07-04 | 常州康普药业有限公司 | Propranolol hydrochloride tablets and preparation method thereof |
| CN102525981B (en) * | 2012-02-21 | 2014-05-21 | 常州康普药业有限公司 | Propranolol hydrochloride tablets and preparation method thereof |
| CN105030718A (en) * | 2015-08-18 | 2015-11-11 | 石家庄格瑞药业有限公司 | Arotinolol hydrochloride preparation and preparation method thereof |
| CN113104941A (en) * | 2021-04-18 | 2021-07-13 | 广西博世科环保科技股份有限公司 | Sewage dephosphorization and sterilization composite sustained-release tablet and preparation method thereof |
| WO2024022382A1 (en) * | 2022-07-26 | 2024-02-01 | 中国科学院上海药物研究所 | Osmotic pump controlled release preparation, osmotic pump controlled release composition, preparation method and use |
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| Publication number | Publication date |
|---|---|
| CN101496792B (en) | 2012-05-23 |
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