CN102247326B - Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts - Google Patents
Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts Download PDFInfo
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Abstract
The invention discloses an oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts. The preparation comprises a quick release pill core containing 40-120mg of propranolol and its salts, a slow release layer, an alkaline layer, and a retardation layer, or comprises a slow release pill core containing 40-120mg of propranolol and its salts, the alkaline layer, and the retardation layer, wherein the retardation layer which contains polyacrylic resin III has a weight of 80-200% of the pill core, and the alkaline layer which is a medicinal water-soluble alkaline accessory has a weight of 10-30% of the pill core. The preparation has a characteristic that a medicament which is not immediately released after being orally taken is slowly released from the mini-pill when going through a time lag for 3-4h, and the slow release time can achieve 12-16h, so the daytime blood pressure can be stably controlled, and a purpose that the blood pressure in ten hours or so of early-morning wakefulness and daytime are stably controlled can be achieved.
Description
Technical field
The present invention relates to Propranolol and salt oral administration preparation thereof, specifically the preparation method of the dosage form of Propranolol salt oral administration timing and controlled release pellet preparations composition and said preparation.
Technical background
Along with the research and development that chronopharmacology, circadian therapy are learned, the outbreak that it is found that numerous disease all presents obvious circadian rhythm and changes, and especially, the cardiovascular disease such as angina pectoris, myocardial infarction, the M ﹠ M of these diseases is the highest in morning.If according to the biorhythm of these seizures of disease, select best administration time, can make medicine when needing most, the maximum therapeutic effect of therapeutic dose performance with minimum farthest reduces toxic and side effects simultaneously.Timing and controlled release formula drug-supplying system claims again intelligent drug delivery system, is according to chronopharmacology and division of day and night pharmacokinetics principle, the novel form of time controlled released effective dose medicine.The timing and controlled release preparation has advantages of that ordinary preparation or slow releasing preparation are incomparable, it can be taken medicine in advance according to the rhythmicity of patient's morbidity, make medicine time and drug release time that a time difference that is complementary with physiological period be arranged, thereby prevention morbidity, reduce the untoward reaction of medicine, and being difficult for producing toleration, improving the compliance of patient, is the new model of Modern Pharmaceutics research.
Ordinary preparation generally needs day clothes, and repeatedly (3～4 times) and blood concentration fluctuation are large and can not guarantee corresponding blood drug level when seizure of disease; General slow releasing preparation or controlled release preparation can be kept stable blood drug level for a long time, but can not satisfy the needs of seizure of disease rhythmicity, therapeutical effect and toxic and side effects that can not separate drug have increased the weight of not the generation of reaction, on the contrary to a certain extent to such an extent as to reduced curative effect.Especially large on the first-pass effect impact, cause degrading in a large number medicine, slow release can make degradation amount increase, and then reduces the bioavailability of medicine.In addition, drug receptor interaction, long-time stimulus descends its sensitivity, produces tolerance, also can lessen the curative effect.
Under the physiological status, human blood-pressure shows as high type in low daytime at night more: namely night, blood pressure level was lower, human blood-pressure increases rapidly before and after the awakening in early morning, and two peak values (when 9:00 and 19:00) are arranged daytime, individual slightly low spot (during 15:00) is arranged afternoon, in the daytime keep higher level, night, blood pressure further descended always, o'clock reached its valley in morning 3～5.Normal human's blood pressure descends 10%～20% more in the daytime in the nighttime sleep process, but in normal part population, and its, blood pressure there is no obvious decline at night.People are called Wood-scoop type blood pressure with the former traditionally, and the latter is called non-Wood-scoop type blood pressure.Research finds to have in addition minority crowd blood pressure drops at night amplitude excessive (surpassing 20%), is referred to as dark Wood-scoop type or super Wood-scoop type.This circadian rhythm feature of blood pressure is that life entity is intrinsic
[2], sleep-waking cycle or movement rest cycle just affect the circadian rhythm of blood pressure to a certain extent.Hypertension in morning and Related Risk Factors produce extremely important impact to cardiovascular event.The rising of control hyperpietic Morning Blood Pressure can reduce the generation of patient's cardiovascular time, to improving hyperpietic's quality of life, reduces mortality rate and has very important significance.
Chronopharmacology studies show that: human blood-pressure, the rhythm of the heart are in the physiology lowstand when falling asleep, and WA blood pressure and the rhythm of the heart sharply rise, and heart and ischemia more easily occur.Comparatively ideal mode of administration is to need at regular time and quantity release according to physiology and treatment.During traditional conventional sustained-release administration medicine in vivo slowly, the lasting high concentration that produces of constant release, and the receptor sensitivity that causes thus reduces and the generation of bacterial drug resistance.The timing and controlled release drug-supplying system can be selected the significant instant of seizure of disease, reaches in the given time higher, effective blood drug concentration, thereby guarantees curative effect, reduces side effect, reduces simultaneously administration number of times, increases patient's compliance.
The timing and controlled release preparation is treated the time factor introducing machine-processed, cooperates physiological rhythm to discharge medicine, thereby prevents to fall ill, alleviate adverse effect, raising patient's compliance, is the new model of Modern Pharmaceutics research.This medicine-releasing system is particularly suitable for the treatment of morning, generation property disease at night (such as cerebral infarction, angina pectoris etc.).What research was more at present is regularly the explosion medicine-releasing system, and namely interval one definite time delay discharges rapidly the effective dose of medicine thing.And for cardiovascular and hyperpietic, particularly get up front and back to noon 11, at 12 o'clock from morning, and the seizure frequency of disease is higher, is in therapeutic domain for making the blood drug level level in this period, and the treatment practice thinks that Best administration time is morning 2, at 3 o'clock.Given this, reserve in vivo the lag time of 3～5h after taking, then keep the preparation of suitable slow release process, namely the timing and controlled release preparation arises at the historic moment.
The preparation of at present Propranolol salt exploitation is a lot, and Chinese Pharmacopoeia version in 2010 is recorded has tablet and injection, USP27 to record slow releasing capsule (24 hours), and ordinary tablet.In China's slow releasing tablet, slow releasing capsule listing is arranged all.(commodity are called InnoPran to the propranolol hydrochloride timing and controlled release capsule of being developed by the trust pharmacy in 2003
), by FDA approval listing, this product is the antihypertensive drug of taking before unique can the sleeping in the U.S..This product and the embodiment of the invention 1 sample release in vitro curve approach, and Beagle dog in vivo test bioequivalence, but the controlled release mechanism of this product and this product has the difference of essence.
CN99814002.3 relates to a kind of many particle release compositions that discharges with timing and controlled release or bimodal mode, control release by excipient and composition that the change coatings contains, but preparation technology is complicated; CN02133886.8 discloses a kind of based on the timing and controlled release delivery formulations of expansion technique in osmotic pump principle, mainly containing core, swelling clothing layer and clothing film three parts forms, penetrate outer water-insoluble clothing film by water, swell layer swelling and make the clothing film release medicine that breaks.CN01804761.0 discloses the time control timing and controlled release drug-supplying system of the multiple multiple coatings granule of being made by one or more beadlet, except the beadlet of quick release, each beadlet contain at least the two-layered coating envelope barrier wherein a kind of envelope barrier formed by enteric polymer.The composition of polymeric film barrier and thickness have determined the interval that sluggish period and medicine discharge from each beadlet.Use contains the organic acid intermediate coat with sluggish period of further adjusting and/or pharmaceutical release time interval.But the life-time service organic acid has stimulation to gastrointestinal tract.CN200410016125.X discloses a kind of albuterol time control timing and controlled release sustained-release oral preparation, and its timing and controlled release partly adopts water-soluble or/and enteric material is made block layer, the outer enteric film coat that coats.CN 101496792A discloses timing and controlled release preparation of a kind of Propranolol or its salt and preparation method thereof, the method preparation of one deck or two-layered coating is carried out in employing to the pastille label, although above-mentioned timing and controlled release formulation system or the timing and controlled release piller technology of preparing of relating to, but the mentality of designing and the composition therefor that adopt with the present invention are all not identical, and supplementary material of the present invention is easy to get, and production technology is simple.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of oral timing and controlled release medicine-releasing system for the treatment of hypertensive medicine Propranolol salt, the oral rear medicine of said preparation does not discharge immediately, but the hysteresis medicine triggers medicament slow release by certain mechanism when certain, and slow-release time reaches 12～16 hours.Patient is as long as taking a medicine at bedtime, and through a period of time (people is in physiological level and hangs down period) not release, in the daytime blood pressure is effectively controlled in slow release when 6～10 blood pressures begin to rise in the morning, and steadily release; And at night, because medicine do not discharge substantially, so blood drug level reaches low spot, effectively avoided excessively reducing blood pressure night and the thrombosis problem that causes, also reduce simultaneously the generation of toxic and side effects and toleration, solved simultaneously patient's hard problem of taking medicine at night.
Concrete technical scheme of the present invention is as follows:
A kind of Propranolol salt oral administration timing and controlled release pellet preparations of the present invention is characterized in that said preparation is the multiple coatings preparation, and basic structure is respectively pastille rapid release ball core, slow release layer, alkaline layer and sluggish layer from inside to outside.
Another Propranolol salt oral administration timing and controlled release pellet preparations of the present invention is characterized in that said preparation is the multiple coatings preparation, and basic structure is respectively pastille slow-release ball core, alkaline layer and sluggish layer from inside to outside.
The medicine that reaches of the present invention is Propranolol salt and other salts of Propranolol and the derivant that pharmaceutically has pharmacologically active.The therapeutic dose that sets is generally 40～120mg.
The pastille rapid release ball core of addressing is to be surrounded by the pill core that contains that the celphere of medicine layer or medicine and pharmaceutic adjuvant be mixed with, and the rapid release ball core of addressing discharges at 1 hour giving drugs into nose and reaches more than 90%.
The pastille slow-release ball core of addressing is having containing the pill core slow releasing function and can reaching 12～16 hours of slow releasing function of adopting that medicine and slow-release material prepare.
Aforesaid slow release layer, for the macromolecular material coating with slow-release function forms, after pastille rapid release ball core was coated with by slow release layer, medicine can present 12～16 hours slow release effect.Its slow release layer is comprised of the macromolecule medical coating adjuvant that possesses sustained release performance, and its sustained release performance is not affected by environment pH, comprising: ethyl cellulose, acrylic resin.The slow release layer weightening finish is 5%～15% of rapid release ball core.
Aforesaid pastille slow-release ball core is for to be comprised of slow-releasing medicated adjuvant and active medicine, and medicine can present 12～16 hours slow release effect.Its sustained release performance is not affected by environment pH, specifically comprises: ethyl cellulose, acrylic resin, hydroxypropyl emthylcellulose.The weight of slow-release auxiliary material accounts for 5%～30% of pastille slow-release ball core.
Above-mentioned Propranolol oral timing and controlled release pellet preparations neutral and alkali layer is necessary, and alkaline layer is medicinal soluble organic or inorganic basic auxiliary, and weight is 10～30% of pastille rapid release ball core weight.More excellent coating weightening finish alkaline layer is 15～20%.And after basic auxiliary is dissolved, the local pH value that forms should be greater than 7, and available basic auxiliary comprises one or more mixture of sodium carbonate, potassium carbonate, ammonium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium acetate, potassium acetate, ammonium acetate, magnesium acetate, cellulose acetate hydrogen sodium, cellulose acetate hydrogen potassium, cellulose acetate hydrogen ammonium, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium phosphate, magnesium oxide, magnesium carbonate, magnesium hydroxide etc.
Sluggish layer is necessary in the above-mentioned timing and controlled release pellet preparations.Mainly contain polyacrylic resin III, sluggish layer is 80～200% with respect to the coating weightening finish of pastille rapid release ball core; Preferred its weightening finish is 100～150%.Sluggish layer also contains plasticizer or antiplastering aid as required: its plasticizer comprises triethyl citrate, dibutyl sebacate, dibutyl phthalate, glycerol triacetate, Oleum Ricini, glycerol, one or more mixture of propylene glycol; Antiplastering aid comprises Pulvis Talci, magnesium stearate, micropowder silica gel, one or more mixture of glyceryl monostearate.Contain weight in the preferred sluggish clothing layer of the present invention and be 80～90 parts polyacrylic resin III, can also contain weight and be antiplastering aid and 0～10 part of plasticizer of 1～10 part.Relevant auxiliary materials of the present invention refers to Propranolol and is mixed and made into the rapid release ball core that contains principal agent, such as one or more mixture of low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sucrose, starch etc.
Slow-release material of the present invention can be the coating slow release macromolecular material that slow releasing function is not affected by pH, such as ethyl cellulose, acrylic resin etc.Also can be the hydrophilic or hydrophobic polymeric material that jointly consists of macromolecular scaffold structure control drug release such as hydroxypropyl emthylcellulose, ethyl cellulose, acrylic resin etc.
Sluggish layer and alkaline layer consist of timing and controlled release clothing layer jointly in the timing and controlled release preparation of the present invention, and wherein sluggish layer separates in physical arrangement with alkaline layer, and the position of sluggish layer is outer at alkaline layer.Control the thickness (being the weightening finish of coating) of sluggish tunic and can control the time that external water divides infiltration, play a delay effect of 3～4 hours, guarantee that active substance seldom discharges in the given time or seepage (cumulative release is less than 10% of setting dosage); Alkaline layer plays and causes the effect that inner active substance timing and controlled release discharges, by the polyacrylic resin III in the dissolving time lag clothing layer, destroy the structure of sluggish tunic, outside moisture can be infiltrated rapidly, the very fast dissolved and diffusion release of active substance, rapidly release substantially complete (cumulative release is greater than 90% of setting dosage) in 3 hours.Experimental result shows: the piller of preparation discharges indifference in water, in simulated gastric fluid (pH=1.0) and the simulated intestinal fluid (pH=6.8), namely the timing and controlled release piller of preparation is not subjected to the impact of human gastrointestinal tract pH environment.
The preparation method of isosorbide dinitrate oral administration timing and controlled release pellet preparations of the present invention comprises the steps:
(1) preparation pastille rapid release ball core: method one: get some celphere and place in fluid bed or the coating pan, be sprayed on the celphere with the coating solution that contains isosorbide dinitrate, and get final product; Method two: according to the method for the common ball core of preparation, isosorbide dinitrate is mixed with relevant auxiliary materials, the employing routine is extruded the method such as round as a ball and can be made; Resulting pastille rapid release ball core is measured (900ml water is dissolution medium, basket method, 75 rev/mins) under the conventional capsule leaching condition of pharmacopeia regulation: cumulative leaching rate is greater than 90% in 1 hour;
(2) sustained release coating ball: the macromolecular material that will have slow releasing function is dissolved in the appropriate solvent, can add plasticizer (as: triethyl citrate, Polyethylene Glycol etc.) and antiplastering aid (as: Pulvis Talci) if needed; Adopt fluid bed or coating pan, pastille rapid release ball core is carried out coating;
(3) pastille slow-release ball core: method one: medicine is mixed with the adjuvant with slow releasing function and other respective secondary material, and adopting routine to extrude the method such as round as a ball can make.Method two: medicine is mixed with the adjuvant with slow releasing function and other respective secondary material, adopt appropriate solvent dissolving part binding agent, spending the tangent line spray Granulation Equipments of seed-coating machine to carry out pelletize with multi-functional stream can make;
(4) alkaline layer coating: in the water-soluble solution of basic auxiliary, adopt fluid bed or coating pan, sustained release coating ball and pastille slow-release ball core are carried out coating;
(5) sluggish layer coating: adopt organic solution or the aqueous dispersion of sluggish layer coating material, adopt fluid bed or coating pan that the slow releasing function micropill that has that is surrounded by alkaline layer is carried out coating and get final product.
Mentality of designing of the present invention: adopt suitable macromolecule coating material, the infiltration of moisture is only depended in the impact that requires the dissolving of this material not changed by the gastrointestinal tract pH value; Simultaneously on the basis of control moisture penetration time (lag time), suddenly change with outer macromolecular material generation physical-chemical reaction generation film character contacted the moisture that penetrates into by inner adjuvant after, or form duct, path or be dissoluted etc., inner release structures is exposed in the solvent, causes the slow release of preparation of Chinese medicine.Enforcement to scheme is included in the satisfactory medical substance of screening in numerous macromolecular materials, and the adjuvant that impels film to undergo mutation, and the two physical-chemical reaction can occur to destroy the clothing layer to the constraint of medicine.By a large amount of tests, the water-soluble inorganic alkali that discovery alkalescence is not too strong and the combination of polyacrylic resin III can extraordinaryly reach above designing requirement, and strong basicity then can affect the stability of most drug usually, should not adopt; The polyacrylic resin III that contains in the time lag layer among the present invention, its chemical composition is: methacrylic acid and methyl methacrylate (1: 2) copolymer, because polyacrylic resin III does not dissolve in less than 7 environment at pH value, and the little intestinal segment of human body alimentary canal from stomach to colon top, the pH value of Digestive system is all less than 7, beginning pH value from colon just begins greater than 7, usually gastric content arrives colon and needs 6～8 hours, and the time lag design time of timing and controlled release preparation is 3～5 hours, preparation not yet arrives colon, the timing and controlled release dispose procedure is finished substantially, and the environment that arrives colon pH＞7 can accelerate the dissolving of the sluggish layer of timing and controlled release micropill, makes drug release more complete.Although thereby polyacrylic resin III is pH dependency material, the timing and controlled release process is not affected by the Digestive system pH value, can reach desirable release effect in human body.
The release Mechanisms of Propranolol of the present invention and salt oral administration timing and controlled release pellet preparations thereof is: water sees through sluggish tunic slowly to the preparation internal penetration, can control the time of time lag by the thickness of controlling sluggish tunic, when alkaline layer is arrived in moisture penetration, the dissolving basic auxiliary, formed a pH value greater than 7 inside microenvironment, so that the dissolving of the polyacrylic resin III in the time lag layer, sluggish tunic is destructurized, release structures is exposed in the solvent, active substance slowly discharges under the control of release structures, forms slow release.Because sluggish structure is substantially destroyed this moment, thereby the effect of the drug release that no longer makes a difference this moment, the thickness of sluggish structure is only influential to the medicine lag time, and on the slow release after the sluggishness substantially without affecting.。For the ease of the preparation of coatings, can add antiplastering aid such as Pulvis Talci etc. as required, the experimental result screening shows: the part by weight of polyacrylic resin III and antiplastering aid is 10 parts～90 parts polyacrylic resin III and 1 part～10 parts antiplastering aid.But antiplastering aid is sluggish and almost not effect of timing and controlled release releasing effect for the medicine of pastille core.
The present invention is the timing and controlled release preparation that designs according to hypertension circadian rhythm Changing Pattern.Its advantage is: (1) is on dosage form design, the prepared Propranolol salt oral administration timing and controlled release pellet preparations of the present invention is the chronopharmacology characteristic Design of the Attack time that changes according to the blood circadian of hypertension and medicine, and not affected by the pH value of intestines and stomach, can control comparatively accurately release time, for angina pectoris and patient's treatment, improve the compliance of taking medicine and have great importance.(2) on formulation characteristic, the prepared Propranolol salt oral administration timing and controlled release pellet preparations of the present invention belongs to the multiple-unit dosage form, formed by many pillers, these pillers, just as one by one little diffusion cell release, error or the defective of indivedual pillers in preparation is unlikely to drug release behavior to whole preparation and produces and have a strong impact on, and the change of digestive tract microenvironment can be cancelled out each other generally, therefore the repeatability of its release rule, concordance aspect are better than ordinary preparation.(3) the present invention adopts the technology of innovation to prepare Propranolol salt timing and controlled release micropill according to hypertensive division of day and night pathology, lag time is 3～5 hours after taking, medicine does not discharge (cumulative release is less than 10% of setting dosage) substantially, slow release reaches the effect for the treatment of to complete (cumulative release is greater than 90% of setting dosage) in ensuing 12～16 hours.Adopt simultaneously and extrude rolling circle equipment, fluid bed or coating pan coating, preparation technology is simple and easy to realize suitability for industrialized production.
In order to verify release in vitro repeatability in vivo, investigate this timing and controlled release capsule characteristics of pharmacokinetics and relative bioavailability in the beasle dog body: adopt method of randomization that 6 of beasle dogs are divided into two groups, take import propranolol hydrochloride timing and controlled release capsule as control formulation, intersect and gavage self-control this timing and controlled release capsule (embodiment 1) and commercially available propranolol hydrochloride timing and controlled release capsule (120mg/ grain), adopt High Performance Liquid Chromatography with Fluorescence Detection to measure blood drug level, the main pharmacokinetic parameter of result: 6 Beagle dog oral test product T (120mg/1 grain/bar) and reference product R (120mg/1 grain/bar) is calculated as: plasma drug level peak time Tpeak (measured value) is respectively (10.2 ± 3.4) and (11.3 ± 2.0) h; Peak concentration Cmax (measured value) is respectively (57.2 ± 36.0) and (51.3 ± 27.2) ng/mL; Area (AUC under the concentration-time curve
0 → 24h) be respectively (417.9 ± 200.8) and (411.8 ± 201.7) ngh/mL; Absorption halftime T
1/2kaBe respectively (2.7 ± 0.6) and (2.7 ± 0.6) h; Eliminate half-life T
1/2keBe respectively (4.3 ± 1.4) and (5.1 ± 1.5) h; Apparent volume of distribution Vd is respectively (279.9 ± 144.0) and (274.6 ± 153.9) L/kg, and clearance rate CL is respectively (51.9 ± 37.7) and (43.7 ± 34.7) L/ (kgh).The relative bioavailability of the relative reference product of trial target is (100.3 ± 18.0) %.Through the two one-sided t tests analysis, trial target and reference product bioequivalence.
Figure of description:
Fig. 1 is embodiment 1 gained timing and controlled release piller release profiles
Fig. 2 is embodiment 2 gained timing and controlled release piller release profiles
Fig. 3 is embodiment 3 gained timing and controlled release piller release profiles
Fig. 4 is embodiment 4 gained timing and controlled release piller release profiles
Fig. 5 is the release profiles of embodiment 1 sample in different pH medium
The specific embodiment
The used supplementary material of the present invention is the commercially available prod.The stripping of working sample photograph among the embodiment " Chinese pharmacopoeia version appendix in 2010 relevant regulations:
The stripping condition determination of pastille rapid release ball core, sustained release coating ball and pastille slow-release ball core: slurry method, 50 rev/mins, 37 ± 0.5 ℃; 900ml water is dissolution medium.Final timing and controlled release piller stripping condition determination: slurry method, 50 rev/mins, 37 ± 0.5 ℃, 900ml release medium: after 2 hours medium is replaced with the pH6.8 phosphate buffer of prior preheating in the hydrochloric acid solution of 0.1mol/L, sample adopts ultraviolet visible spectrophotometry to measure.
Sample drug release determination method in embodiment 1 sample and the different pH medium, except replace medium from front different, other conditions are identical.
Embodiment 1
Pastille rapid release ball core prescription:
Starch sucrose celphere 200g
Propranolol hydrochloride 240g
80% ethanol 1kg
Preparation technology: isosorbide dinitrate is dissolved in 95% ethanol, adopts fluidized bed coating, 32 ± 1 ℃ of temperature, flow velocity 8mL/min is wrapped in propranolol hydrochloride on the celphere, makes pastille rapid release ball core.45 minutes average accumulated dissolution rates 90%.
Slow release layer prescription: ethyl cellulose 4% (w/v) 80% alcoholic solution.
Preparation technology: ethyl cellulose is dissolved in 80% ethanol, adopts fluidized bed coating, 35 ± 2 ℃ of temperature, flow velocity 8mL/min is wrapped in ethyl cellulose on the pastille rapid release ball core, and coating increases weight 8%, makes to contain slow-release micro-pill.
The alkaline layer prescription: sodium bicarbonate 10% (w/v) adds water to 100%
Preparation technology: sodium bicarbonate is water-soluble, adopt fluidized bed coating, 45 ± 1 ℃ of temperature, flow velocity 3mL/min is wrapped in sodium bicarbonate on the slow-release micro-pill, and coating increases weight 20%, makes to contain alkaline layered pills core.
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 6.5
Magnesium stearate 1.2
Add 95% ethanol to 100%.
Preparation technology: adopt fluidized bed coating, 35 ± 1 ℃ of temperature, flow velocity 10mL/min is wrapped in above-mentioned coating solution and contains on the alkaline layered pills core, coating weightening finish 90%.Embodiment 1 gained timing and controlled release piller release profiles is seen appendix Fig. 1: sluggish approximately 3 hours, then discharged fully in 14 hours.
Pastille slow-release ball core prescription:
Starch sucrose celphere 200g
Propranolol hydrochloride 240g
95% ethanol 1kg
Art for coating is with embodiment 1.Get pastille rapid release ball core.45 minutes average accumulated dissolution rates 90%.
The slow release layer prescription: NE 30D thin up is to solid content 10%, and the Pulvis Talci that adding accounts for solid content 10% stirs and makes mix homogeneously as antiplastering aid.
Preparation technology: will measure a certain amount of NE 30D thin up to solid content 10%, add and account for the Pulvis Talci of solid content 10% as antiplastering aid, stirring makes mix homogeneously, adopt fluidized bed coating, 20 ± 2 ℃ of temperature, flow velocity 6mL/min is wrapped in NE 30D on the pastille rapid release ball core, coating increases weight 6%, makes to contain slow-release micro-pill.
Alkaline layer: potassium dihydrogen phosphate 10% (w/v), add water to 100%, art for coating is with embodiment 1.Coating weightening finish 12% must contain alkaline layered pills core.
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 6
Micropowder silica gel 1.4
Add 95% ethanol to 100%,
Art for coating is with embodiment 1.Coating weightening finish 100%.
Gained timing and controlled release piller release profiles is seen appendix Fig. 2: sluggish approximately 4 hours, then discharged fully in 12 hours.
Embodiment 3
Whole pastille rapid release ball core prescription w/w (%)
Propranolol hydrochloride 240g
Low-substituted hydroxypropyl cellulose 100g
Microcrystalline Cellulose 100g
Preparation technology: 70% alcoholic solution of the HPMC of adding 5% is made soft material, soft material is extruded through extruder sieve plate (aperture 0.8mm), and strip particle is put in the spheronizator round as a ball, and the ball core is in 50 ℃ of dry 5h, screening 18～24 order medicated core make pastille rapid release ball core.45 minutes average accumulated dissolution rates 5%.
Slow release layer prescription: ethyl cellulose 4% (w/v) 80% alcoholic solution.
Preparation technology: ethyl cellulose is dissolved in 80% ethanol, adopts fluidized bed coating, 35 ± 2 ℃ of temperature, flow velocity 8mL/min is wrapped in ethyl cellulose on the pastille rapid release ball core, and coating increases weight 8%, makes to contain slow-release micro-pill.
Alkaline layer: sodium carbonate 10% (w/v), add water to 100%, art for coating is with embodiment 1.Coating weightening finish 25%;
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 8
Dibutyl sebacate 1
Glycerol 0.2
Pulvis Talci 1.5
Add 95% ethanol to 100%, art for coating is with embodiment 1, and coating increases weight 160%.Gained timing and controlled release piller release profiles is seen appendix Fig. 3: sluggish approximately 3.5 hours, then discharged fully in 12 hours.
Pastille slow-release ball core prescription:
Ethyl cellulose 25g
Acrylic resin 25g
Sucrose 50g
Starch 100g
Propranolol hydrochloride 240g
95% ethanol 1kg
Preparation technology: ethyl cellulose is mixed with acrylic resin, adds an amount of 95% dissolve with ethanol, add propranolol hydrochloride, starch and sucrose mixing fine powders after the dissolving, make soft material, adopt extrude, rolling circle equipment prepares slow-release micro-pill, sieve, drying.
Alkaline layer: sodium acetate 10% (w/v), add water to 100%, art for coating is with embodiment 1.
Coating weightening finish 28% must contain alkaline layered pills core.
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 7
Triethyl citrate 1.8
Pulvis Talci 1
Magnesium stearate 0.5
Add 95% ethanol to 100%, art for coating is with embodiment 1, and coating increases weight 200%.Gained timing and controlled release piller release profiles is seen appendix Fig. 3: sluggish approximately 4 hours, then discharged fully in 13 hours.
Claims (2)
1. a Propranolol and salt oral timing and controlled release pellet preparations thereof is characterized in that said preparation
Formed by following prescription:
Pastille rapid release ball core prescription:
Starch sucrose celphere 200g
Propranolol hydrochloride 240g
95% ethanol 1kg
Preparation technology: propranolol hydrochloride is dissolved in 95% ethanol, adopts fluidized bed coating, 32 ± 1 ℃ of temperature, flow velocity 8mL/min is wrapped in propranolol hydrochloride on the celphere, makes pastille rapid release ball core; 45 minutes average accumulated dissolution rates 90%;
The slow release layer prescription: NE 30D thin up is to solid content 10%, and the Pulvis Talci that adding accounts for solid content 10% stirs and makes mix homogeneously as antiplastering aid;
Preparation technology: will measure a certain amount of NE 30D thin up to solid content 10%, add and account for the Pulvis Talci of solid content 10% as antiplastering aid, stirring makes mix homogeneously, adopt fluidized bed coating, 20 ± 2 ℃ of temperature, flow velocity 6mL/min is wrapped in NE 30D on the pastille rapid release ball core, coating weightening finish 6% makes the pastille slow-release micropill;
Alkaline layer: potassium dihydrogen phosphate 10%(w/v), add water to 100%;
Preparation technology: potassium dihydrogen phosphate is water-soluble, adopt fluidized bed coating, 45 ± 1 ℃ of temperature, flow velocity 3mL/min is wrapped in potassium dihydrogen phosphate on the slow-release micro-pill, and coating weightening finish 12% must contain alkaline layered pills core;
Sluggish layer prescription w/v(%)
Polyacrylic resin Ⅲ Eudragit S100 6
Micropowder silica gel 1.4
Add 95% ethanol to 100%;
Preparation technology: adopt fluidized bed coating, 35 ± 1 ℃ of temperature, flow velocity 10mL/min is wrapped in above-mentioned coating solution and contains on the alkaline layered pills core, coating weightening finish 100%; Sluggish 4 hours, then in 12 hours, discharge fully.
2. a Propranolol and salt oral timing and controlled release pellet preparations thereof is characterized in that said preparation
Formed by following prescription:
Pastille slow-release ball core prescription:
Preparation technology: ethyl cellulose is mixed with acrylic resin, adds an amount of 95% dissolve with ethanol, add propranolol hydrochloride, starch and sucrose mixing fine powders after the dissolving, make soft material, adopt extrude, rolling circle equipment prepares slow-release micro-pill, sieve, drying;
Alkaline layer: sodium acetate 10%(w/v), add water to 100%;
Preparation technology: sodium acetate is water-soluble, adopt fluidized bed coating, 45 ± 1 ℃ of temperature, flow velocity 3mL/min is wrapped in sodium acetate on the slow-release micro-pill, and coating increases weight 28%, makes to contain alkaline layered pills core;
Preparation technology: adopt fluidized bed coating, 35 ± 1 ℃ of temperature, flow velocity 10mL/min is wrapped in above-mentioned coating solution and contains on the alkaline layered pills core, coating weightening finish 200%; Sluggish 4 hours, then in 13 hours, discharge fully.
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| CN2010101739830A CN102247326B (en) | 2010-05-17 | 2010-05-17 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
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| CN2010101739830A CN102247326B (en) | 2010-05-17 | 2010-05-17 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
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| CN102247326B true CN102247326B (en) | 2013-10-23 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104224859A (en) * | 2014-10-13 | 2014-12-24 | 北京人福军威医药技术开发有限公司 | Ginkgo biloba extract sustained-release pellet preparation |
| CN105287394A (en) * | 2015-11-19 | 2016-02-03 | 哈尔滨圣吉药业股份有限公司 | Propranolole hydrochloride sustained-release pellets and preparation method thereof |
| CN114053218B (en) * | 2020-08-06 | 2022-11-15 | 武汉科福新药有限责任公司 | Nadolol sustained-release oral liquid and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219118A (en) * | 2007-01-08 | 2008-07-16 | 天津药物研究院 | Impulse released oral medication preparation and method for preparing the same |
| CN101496792A (en) * | 2008-01-30 | 2009-08-05 | 中国科学院上海药物研究所 | Punailuoer or delayed-release preparation of salt thereof and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101219118A (en) * | 2007-01-08 | 2008-07-16 | 天津药物研究院 | Impulse released oral medication preparation and method for preparing the same |
| CN101496792A (en) * | 2008-01-30 | 2009-08-05 | 中国科学院上海药物研究所 | Punailuoer or delayed-release preparation of salt thereof and preparation method thereof |
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