CN102247326A - 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
- Publication number
- CN102247326A CN102247326A CN2010101739830A CN201010173983A CN102247326A CN 102247326 A CN102247326 A CN 102247326A CN 2010101739830 A CN2010101739830 A CN 2010101739830A CN 201010173983 A CN201010173983 A CN 201010173983A CN 102247326 A CN102247326 A CN 102247326A
- Authority
- CN
- China
- Prior art keywords
- release
- layer
- slow
- timing
- ball core
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
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 chronopharmacology, therapeutic research and development of division of day and night, the outbreak that it is found that numerous disease all presents tangible circadian rhythm and changes, and especially, 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 intelligent drug delivery system again, is according to chronopharmacology and division of day and night pharmacokinetics principle, regularly discharges the novel form of effective dose medicine.The timing and controlled release preparation has ordinary preparation or the incomparable advantage of slow releasing preparation, 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 medicinal agents research.
Ordinary preparation generally needs day clothes, and repeatedly (3～4 times) and blood concentration fluctuation are big 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 big to the first-pass effect influence, cause degrading in a large number medicine, slow release can make degradation amount increase, and reduces bioavailability of medicament then.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: promptly 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 low spot (during 15:00) is slightly 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 crowd, 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.Discovering has minority crowd blood pressure drops at night amplitude excessive (surpassing 20%) in addition, is referred to as dark Wood-scoop type or super Wood-scoop type.This circadian rhythm feature of blood pressure is that life entity institute is inherent
[2], sleep-waking cycle or movement rest cycle just affect the circadian rhythm of blood pressure to a certain extent.Early morning, hypertension and hazard factor produced extremely important influence to cardiovascular event.The rising of control hyperpietic blood pressure in early morning 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 the WA blood pressure and the rhythm of the heart sharply rise, and heart and ischemia more easily take place.Comparatively ideal mode of administration is to need release at regular time and quantity according to physiology and treatment.The lasting high concentration that medicine is in vivo slowly during traditional conventional sustained-release administration, constant release produced, 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 higher, effective blood drug concentration in the given time, thereby guarantees curative effect, reduces side effect, reduces administration number of times simultaneously, 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 medicinal agents research.This medicine-releasing system is particularly suitable for the treatment of morning, generation property disease at night (as cerebral infarction, angina pectoris etc.).What research was more at present is regularly the explosion medicine-releasing system, and lagging behind when promptly certain at interval discharges the effective dose of medicine thing rapidly.And, particularly get up front and back at 11,12 o'clock at noon from morning for cardiovascular and hyperpietic, 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 2,3 o'clock mornings.Given this, reserve the release time lag of 3～5h after taking in vivo, keep the preparation of suitable slow release process then, promptly the timing and controlled release preparation arises at the historic moment.
The preparation of Propranolol salt exploitation at present 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 are approaching, 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, and the excipient and the composition that contain by the change coatings come sustained release, 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 particulate time control timing and controlled release of the multiple multiple coatings drug-supplying system of being made by one or more beadlet, except the beadlet of rapid release, each beadlet contains wherein a kind of envelope barrier of two-layered coating envelope barrier at least to be made up of 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, though above-mentioned timing and controlled release formulation system or the timing and controlled release piller technology of preparing of relating to, but it is all inequality with mentality of designing and composition therefor that the present invention adopts, 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 back of said preparation medicine 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, through a period of time (people is in physiological level and hangs down period) not release, slow release when 6～10 blood pressures begin to rise in the morning, and steadily release, effectively blood pressure between controll day; And at night, because medicine do not discharge substantially, so blood drug level reaches low spot, effectively avoided excessively bringing high blood pressure down night and the thrombosis problem that causes, also reduce simultaneously the generation of toxic and side effects and toleration, solved take medicine at the night problem of difficulty of patient simultaneously.
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 being addressed 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 being addressed discharges at 1 hour giving drugs into nose and reaches more than 90%.
The pastille slow-release ball core of being addressed 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, pastille rapid release ball core by by the slow release layer bag by after, medicine can present 12～16 hours slow release effect.Its slow release layer is made up of the macromolecule medical coating adjuvant that possesses sustained release performance, and its sustained release performance is not influenced 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 to be made up of slow-releasing medicated adjuvant and active medicine, and medicine can present 12～16 hours slow release effect.Its sustained release performance is not influenced 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 a 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 as required layer also contains plasticizer or antiplastering aid: 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, for example mixture of one or more 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 influenced by pH, as ethyl cellulose, acrylic resin etc.Also can be the hydrophilic or hydrophobic polymeric material that constitutes macromolecular scaffold structure control drug release jointly as hydroxypropyl emthylcellulose, ethyl cellulose, acrylic resin etc.
Sluggish layer and alkaline layer constitute timing and controlled release clothing layer jointly in the timing and controlled release preparation of the present invention, and wherein sluggish layer and alkaline layer are isolating on physical arrangement, and the position of sluggish layer is at the alkaline layer skin.Control the time of the outside moisture infiltration of thickness (being the weightening finish of coating) may command of sluggish tunic, 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, release complete substantially (cumulative release is greater than 90% of setting dosage) rapidly 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), promptly Zhi Bei timing and controlled release piller is not subjected to the influence 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, promptly with the coating solution that contains isosorbide dinitrate; 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 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 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 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 the 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 promptly.
Mentality of designing of the present invention: adopt suitable macromolecule coating material, the infiltration of moisture is only depended in the influence 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 contact the moisture that penetrates into by inner adjuvant after, or form duct, path or by corrosion 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 take place to destroy the constraint of clothing layer to medicine.By a large amount of tests, find that alkaline not too strong water-soluble inorganic alkali and the combination of polyacrylic resin III can extraordinaryly reach above designing requirement, strong basicity then can influence 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 of 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 is no show colon place still, the timing and controlled release dispose procedure is finished substantially, and the environment that arrives colon pH＞7 can quicken the dissolving of the sluggish layer of timing and controlled release micropill, makes drug release more complete.Though thereby polyacrylic resin III is pH dependency material, the timing and controlled release process is not influenced by the Digestive system pH value, can reach ideal release effect in human body.
The release mechanism 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, make the polyacrylic resin III in the time lag layer dissolve, 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 destroyed substantially this moment, thereby the effect of the drug release that no longer makes a difference this moment, sluggish thickness of structure is only influential to the medicine lag time, and the slow release after the sluggishness is not had influence substantially.。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 division of day and night rhythmicity that changes according to the circadian rhythm of blood pressure rhythm and pace of moving things of hypertension and medicine, and not influenced by the pH value of intestines and stomach, sustained release time comparatively accurately, 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, form 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, so 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, taking the back lag time 3～5 hours, medicine does not discharge (cumulative release is less than 10% of setting dosage) substantially, slow release reaches the effect of treatment 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, with import propranolol hydrochloride timing and controlled release capsule is 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 the high performance liquid chromatography 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; Absorb half-life 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 two-way one-side t check analysis, trial target and reference product bioequivalence.
Figure of description:
Fig. 1 is embodiment 1 a 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 that replace medium with preceding 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 about 3 hours, discharged fully in 14 hours then.
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 about 4 hours, discharged fully in 12 hours then.
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, and 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, and 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 about 3.5 hours, discharged fully in 12 hours then.
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, add an amount of 95% dissolve with ethanol, dissolving back adds propranolol hydrochloride, starch and sucrose mixing fine powders, makes 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 about 4 hours, discharged fully in 13 hours then.
Claims (14)
1. Propranolol and salt oral timing and controlled release pellet preparations thereof 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.
2. Propranolol and salt oral timing and controlled release pellet preparations thereof 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.
3. timing and controlled release pellet preparations according to claim 1, pastille rapid release ball core wherein are to be surrounded by the ball core that the celphere of medicine layer or medicine and pharmaceutic adjuvant are mixed with; 1 hour giving drugs into nose of described pastille rapid release ball core discharges and reaches more than 90%.Rapid release ball core contains 40～120mg Propranolol and its esters.
4. timing and controlled release pellet preparations according to claim 1, its slow release layer is made up of general medicinal sustained release coating macromolecular material, and the drug release of may command rapid release ball core reaches 12～16 hours slow release.
5. timing and controlled release pellet preparations according to claim 2, pastille slow-release ball core wherein is the ball core that active medicine and slow-releasing medicated adjuvant are mixed with; Described pastille slow-release ball core may command medicine slow release in 12～16 hours, and release reaches more than 90% eventually.Slow release ball core contains 40～120mg Propranolol salt.
6. timing and controlled release pellet preparations according to claim 1, it is characterized in that slow release layer is medicinal sustained release coating high polymer adjuvant, its sustained release performance is not influenced by environment pH, comprising: ethyl cellulose, acrylic resin etc., its weightening finish is 5%～15% of pastille rapid release ball core.
7. timing and controlled release pellet preparations according to claim 2, it is characterized in that pastille slow-release ball core is that active medicine and medicinal slow-release auxiliary material are formed, its sustained release performance is not influenced by environment pH, comprising: ethyl cellulose, acrylic resin, hydroxypropyl emthylcellulose etc., its weight accounts for and is 5%～35% of pastille slow-release ball core.
8. according to claim 1,2 described timing and controlled release pellet preparations, it is characterized in that alkaline layer.Be medicinal soluble organic or inorganic basic auxiliary, weight is 10～30% of slow release ball weight.
9. according to claim 1,2 described timing and controlled release pellet preparations, it is characterized in that sluggish layer contains polyacrylic resin III, its weightening finish is 80～200% of slow release ball.
10. according to claim 1,2,7 described timing and controlled release pellet preparations, wherein sluggish layer weightening finish is for containing 100～150% of pill core.
11. according to claim 1,2,7 or 8 described timing and controlled release pellet preparations, it is characterized in that sluggish layer also contains antiplastering aid and plasticizer: 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.
12., it is characterized in that consisting of of sluggish layer: 80～90 parts of polyacrylic resin III, 1～10 part of antiplastering aid and 0～10 part of plasticizer according to claim 1,2 or 9 described timing and controlled release pellet preparations.
13. the application in preparation treatment hypertension drug of Propranolol and salt oral administration timing and controlled release pellet preparations thereof, wherein said timing and controlled release micropill is made up of the rapid release ball core that contains 40～120mg Propranolol salt, slow release layer, alkaline layer and sluggish layer.Its slow release layer is medicinal sustained release coating high polymer adjuvant, and its sustained release performance is not influenced by environment pH, and its weight is to contain 5%～15% of pill core.Alkaline layer is medicinal organic or inorganic adjuvant, its weight is 5%～30% of rapid release ball core, contain 80%～90% polyacrylic resin III in the sluggish clothing layer, 1～10 part of antiplastering aid and 0～10 part of plasticizer, sluggish clothing layer is 50%～200% with respect to the coating weightening finish of pastille core.
14. the application in preparation treatment hypertension drug of Propranolol and salt oral administration timing and controlled release pellet preparations thereof, wherein said timing and controlled release micropill is made up of the pastille slow-release ball core that contains 40～120mg Propranolol salt, alkaline layer and sluggish layer.Pastille slow-release ball core is that active medicine and medicinal slow-release auxiliary material are formed, and its sustained release performance is not influenced by environment pH, and wherein slow-release auxiliary material weight accounts for and is 5%～35% of pastille slow-release ball core.Alkaline layer is medicinal organic or inorganic adjuvant, its weight is 5%～30% of rapid release ball core, contain 80%～90% polyacrylic resin III in the sluggish clothing layer, 1～10 part of antiplastering aid and 0～10 part of plasticizer, sluggish clothing layer is 50%～200% with respect to the coating weightening finish of pastille core.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101739830A CN102247326B (en) | 2010-05-17 | 2010-05-17 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101739830A CN102247326B (en) | 2010-05-17 | 2010-05-17 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102247326A true CN102247326A (en) | 2011-11-23 |
| CN102247326B CN102247326B (en) | 2013-10-23 |
Family
ID=44975138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101739830A Expired - Fee Related CN102247326B (en) | 2010-05-17 | 2010-05-17 | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102247326B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114053218A (en) * | 2020-08-06 | 2022-02-18 | 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 |
-
2010
- 2010-05-17 CN CN2010101739830A patent/CN102247326B/en not_active Expired - Fee Related
Patent 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 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114053218A (en) * | 2020-08-06 | 2022-02-18 | 武汉科福新药有限责任公司 | Nadolol sustained-release oral liquid 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102247326B (en) | 2013-10-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2015204313B2 (en) | Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors | |
| CA2462637C (en) | Timed, sustained release multi-particulate dosage forms of propranolol | |
| CN100579525C (en) | Sustained release preparation of licardipine hydrochloride and its preparing process | |
| US5496561A (en) | Controlled release-initiation and controlled release-rate pharmaceutical composition | |
| CN103211779B (en) | Comprise alkalescence selectivity 5-hydroxy tryptamine 5-HT 3blocker and organic acid drug delivery system | |
| US20040052844A1 (en) | Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins | |
| JP6976946B2 (en) | A pharmaceutical composition containing an inhibitor of URAT1 having strong bioactivity. | |
| JPS61501151A (en) | Diffusion coated multiple unit dose | |
| JP2015098477A (en) | Compositions comprising weakly basic drugs and controlled-release dosage forms | |
| KR20110075011A (en) | Slow-release particle and a production method therefor | |
| AU2002330211A1 (en) | Timed, sustained release multi-particulate dosage forms of propranolol | |
| CN103417505A (en) | Huperzine A controlled release preparation having biphasic release behavior, and preparation method thereof | |
| HU227490B1 (en) | Sustained release pharmaceutical preparation containing carvedilol | |
| CN102247326B (en) | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts | |
| RU2452472C2 (en) | Delayed fixed-time pulsatile release dosage forms | |
| CN101269056B (en) | Metoprolol salt oral administration impulse pellet preparation | |
| CN101773482B (en) | Three-stage pulsed release controlled release tablet and preparation method thereof | |
| WO2015196956A1 (en) | Metoprolol sustained-release composition and preparation method thereof | |
| EP3796908B1 (en) | Controlled release propiverine formulations | |
| CN101269059B (en) | Isosorbide dinitrate oral administration impulse pellet preparations | |
| CN110638791A (en) | Topiramate sustained-release capsule and preparation method thereof | |
| CN101219118B (en) | Impulse released oral medication preparation | |
| CN115569125B (en) | Sinomenine hydrochloride oral delayed release pulse micropill, its preparation and preparation method | |
| CN102429886B (en) | Indapamide osmotic pump preparation and preparation method thereof | |
| KR840000692B1 (en) | Process for preparing dipyridamol sustained release forms |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20131023 Termination date: 20210517 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |