CN101219118A - Impulse released oral medication preparation and method for preparing the same - Google Patents
Impulse released oral medication preparation and method for preparing the same Download PDFInfo
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- CN101219118A CN101219118A CNA2007100564165A CN200710056416A CN101219118A CN 101219118 A CN101219118 A CN 101219118A CN A2007100564165 A CNA2007100564165 A CN A2007100564165A CN 200710056416 A CN200710056416 A CN 200710056416A CN 101219118 A CN101219118 A CN 101219118A
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Abstract
The invention discloses a pulsatile release oral drug product and a preparation method thereof. The product is a multi-layered coating product which consists of a drug-containing core, an alkaline layer and a hysteretic coating; wherein, the drug-containing core contains drug in forms of granule, micro-pill, micro-tablet or troche, etc.; the alkaline layer is alkaline medicinal adjuvant and the hysteretic coating comprises a coating material, polyacrylic resin III. 2-6 hours of delayed time for dug release can be achieved by adjusting the thickness of the hysteretic coating and the proportion of the coating materials. The pulsatile release oral drug product of the invention has the active material which is released suddenly after the preset delayed time, and the pulsatile release effect is good and not affected by the pH value of alimentary canal; meanwhile, the prescription of the pulsatile release oral drug preparation is simple in prescription and mature in process, and easy in realization of mass production.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of dosage form composition of pulse release oral drug preparation and the preparation method of said preparation thereof.
Technical background
Research and development along with chronopharmacology, the outbreak that it is found that numerous disease all presents tangible circadian rhythm variation, if biorhythm according to 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.But the M ﹠ M of some diseases is the highest in morning, as diseases such as hypertension, angina pectoris, myocardial infarction, asthma, Parkinson's disease, insomnias, at this class disease, at dead of night or the administration in morning, can play best prevention and therapeutical effect, but bring very big inconvenience to the patient in administration meeting during this period of time.
Ordinary preparation generally needs day clothes repeatedly (3-4 time), and blood concentration fluctuation is big, and can not guarantee corresponding blood drug level when seizure of disease; General slow release 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 the generation of its untoward reaction on the contrary to a certain extent, so that have reduced curative effect.Especially to being subjected to first pass effect to influence greatly, cause the medicine of a large amount of degradeds, slow release can make degradation amount increase, and reduces bioavailability of medicament then.In addition, drug receptor interaction, long-time stimulus makes it deactivation, produces toleration, also can lessen the curative effect, as nitrate esters medicine.
In order to solve an above difficult problem, open-loop system claims that again intelligent drug delivery system grows up, it is according to chronopharmacology and division of day and night pharmacokinetics principle, regularly discharge the novel form of effective dose medicine, claim timing clock (Time clock) or control prominent release system (Controlled explosion systems) again.The pulse preparation, has the incomparable advantage of ordinary preparation or 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 the prevention morbidity reduces the untoward reaction of medicine, and is difficult for producing toleration, improving the compliance of patient, is the new model of modern medicinal agents research.
Especially, for some at dead of night or the disease that is easy to fall ill morning, relative medicine is made the pulse preparation, before sleep, take medicine, through the delay of the scheduled time, medicine at dead of night or discharge morning will be brought into play the therapeutic effect of medicine to greatest extent and make things convenient for the patient to take.
Existing several different methods prepares the pulse preparation both at home and abroad.Can be divided into coating pulse system, osmotic pumps pulse system and commutator pulse plug capsule.In the coating pulse system, be the effect that reaches the preparation pulsed release by the coatings of control different materials.Adopted erodable clothing layer to reach the pulsed release effect as patent WO9319741, be characterized in containing in the sluggish coatings at least a water-soluble cellulose derivative, by the corrosion gradually of sluggish clothing layer, after after a while, outside the pastille core was exposed to, medicine began to discharge.A kind of pulse formulation preparation method that CN1488332A and CN1188131C describe, it is characterized in that containing osmotic pressure regulator and disintegrating agent in sluggish clothing layer the inside, pulse theory is after water dissolution osmotic pressure regulator and disintegrating agent, expansion by osmotic pressure and disintegrating agent, destroy outermost sluggish clothing tunic, cause the medicine pulse release.Osmotic pumps and commutator pulse plug capsule have very big difficulty in actual applications, mainly are that the said preparation form needs special instrument and equipment on producing, and often can only be difficult to its industrialization is lacked practicality in the laboratory manual preparation.
Summary of the invention
The present invention aims to provide a kind of new pulse release oral drug preparation and preparation method thereof, it belongs to the coating pulse system, more existing pulse preparation, the present invention has prescription simply, and technical maturity is easy to realize suitability for industrialized production, active substance is after sluggish one period scheduled time, characteristics such as discharge suddenly, pulsed release is effective, and the interior digestive tract pH value variable effect of the effect receptor of pulsed release is little.
Technical scheme of the present invention is:
A kind of pulse release oral drug preparation of the present invention is characterized in that said preparation is a coated preparation, and basic structure is respectively pastille core, alkaline layer and sluggish clothing layer from inside to outside and forms.
Another pulse release oral drug preparation of the present invention is characterized in that said preparation is a coated preparation, is made up of pastille core that contains the basic medicinally adjuvant and sluggish clothing layer.
Sluggish clothing layer is 50～200% with respect to the coating weightening finish of pastille core in above-mentioned two kinds of methods; Described alkaline layer is medicinal organic or inorganic basic auxiliary, and its weight is 5～30% of pastille core weight; Contain weight in the described sluggish clothing layer and be 10～90 parts polyacrylic resin III; Can also contain weight in the described as required sluggish clothing layer is 5～80 parts of insoluble polymers.Also can contain weight is 1～10 part of plasticizer.
In the sluggish clothing layer of the present invention for the ease of the preparation of coatings, usually add antiplastering aid, therefore, the present invention further discloses the pulse release oral drug preparation of being convenient to prepare, it is characterized in that said preparation is a coated preparation, basic structure is respectively pastille core, alkaline layer and sluggish clothing layer from inside to outside and forms; Wherein alkaline layer is medicinal organic or inorganic basic auxiliary, and its weight is 5～30% of pastille core weight; Sluggish clothing layer is 50～200% with respect to the coating weightening finish of pastille core, contain weight in the sluggish clothing layer and be 10～90 parts polyacrylic resin III, also can contain weight in the sluggish as required clothing layer and be the antiplastering aid that 10～90 parts polyacrylic resin III and weight are 1～10 part.
Of the present invention another contain the pulse release oral drug preparation of the pastille core of basic medicinally adjuvant, it is characterized in that said preparation is a coated preparation, form by pastille core that contains the basic medicinally adjuvant and sluggish clothing layer; Wherein basic medicinally adjuvant weight is 5～30% of core; Sluggish clothing layer is 50～200% with respect to the coating weightening finish of the pastille core that contains the basic medicinally adjuvant, contains weight in the sluggish clothing layer and be 10～90 parts polyacrylic resin III.Also can contain weight in the sluggish as required clothing layer and be the antiplastering aid that 10～90 parts polyacrylic resin III and weight are 1～10 part.
For the ease of more comprehensively understanding the present invention, it is elaborated as follows:
Sluggish clothing layer and alkaline layer constitute pulse clothing layer jointly, and wherein sluggish clothing layer and alkaline layer are isolating on physical arrangement, and the position of sluggish clothing layer is at the alkaline layer skin.Control the thickness of sluggish clothing tunic and the time that the outside moisture of component may command infiltrates, play a delay effect of 2-6 hour, guarantee that active substance does not discharge or seepage in the given time; Alkaline layer plays the effect that causes inner active substance pulse release, by dissolving the polyacrylic resin III in the sluggish clothing layer, destroy the structure of sluggish clothing tunic, outside moisture can be infiltrated rapidly, inner dosage form (being the pastille core) can be as there not being coating to discharge medicine in the past, simultaneously, do not change the drug release behavior of pastille core itself.
Pulse release oral drug preparation of the present invention, also can be according to the compatibility situation of active substance and basic auxiliary, make pastille core and alkaline layer not necessarily want separately strict, can mix and be one deck, the basic auxiliary that is about in the alkaline layer directly adds in the pastille core, and made preparation is made up of pastille core that contains basic auxiliary and sluggish clothing layer.Also can be divided into two-layerly, also can increase by an isolation coat layer between two-layer and play the effect that strengthens medicine stability.Isolation coat layer material commonly used comprises water-soluble, film-forming coating materials such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol.The compatibility of the present invention refers to medicine and chemical reaction does not take place used basic auxiliary, can not cause content of medicines to descend, and impurity increases.
Pastille core of the present invention is the dosage forms such as granule, micropill, micro chip or tablet that contain medicine, have no particular limits for the medicine in the pastille core, comprise synthetic chemicals, bio-pharmaceutical, the active effective part that from plant, extracts, effective active single component etc.For example can be treatment cardiovascular, arthritis, hypertension, treatment diabetes, antitumor drug, treatment gastric ulcer or the like.Through a large amount of experiment screenings, because different pastille core, the surface area difference, and desired pulse lag time is also different, and (the indication duration of seizure according to Drug therapy is different with corresponding administration time, need the time of delayed release medicine also inequality), so sluggish clothing layer is not quite similar with respect to the coating weightening finish of pastille core, experimental data shows that the coating weightening finish can all can reach good pulse release effect between 50～200%.Coated product by different lag times is used in combination, and can obtain the multiple pulses releasing effect of pastille core drug.For example the different coatings of same pastille core by sluggish clothing layer can be obtained the product that lag time is respectively 2 hours and 6 hours, the two is used in combination the effect that just can obtain twice pulse release of medicine.
Containing polyacrylic resin III in the sluggish clothing layer of the present invention is absolutely necessary.Use polyacrylic resin III to be coating material separately, can control the moisture penetration time, reach the pulsatile effect of different lag time by different coating thicknesses; For the ease of the preparation of coatings, can add antiplastering aid 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 not effect of pulse release effect for the medicine of pastille core, and these two kinds of effects only depend on the thickness of sluggish clothing layer and the mutual ratio of polyacrylic resin III and basic auxiliary.
In addition, sluggish clothing layer can also contain insoluble polymer as required, and wherein said insoluble polymer comprises: ethyl cellulose, poly-first ammonium acrylate ester I and poly-one or more mixture of first ammonium acrylate ester II.Wherein poly-first ammonium acrylate ester I[chemical composition is: ethyl acrylate, methyl methacrylate and methacrylic acid chlorination trimethylamine groups ethyl ester (1: 2: 0.2) copolymer], poly-first ammonium acrylate ester II[chemical composition is: ethyl acrylate, methyl methacrylate and methacrylic acid chlorination trimethylamine groups ethyl ester (1: 2: 0.1) copolymer] wait a kind of of the slow controlled release coat filmogen used always or several.
The different proportion combination of these insoluble polymers and polyacrylic resin III can obtain different moisture penetration time, the i.e. lag time of pulsed release.Find that through a large amount of experiments part by weight is in the sluggish clothing layer: polyacrylic resin III is 10 parts-90 parts; Insoluble polymer is 5 parts～80 parts; Plasticizer loading is 1 part-10 parts can reach good sluggish effect.
Sluggish clothing layer of the present invention can also contain plasticizer and antiplastering aid as required; 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.
Alkaline layer of the present invention is medicinal basic auxiliary, and alkaline layer weight is the 5-30% of pastille core weight.Described alkaline layer is necessary, and after basic auxiliary is dissolved, the local pH value that forms should be greater than 7, and commonly used is organic, the inorganic alkaline adjuvant comprises: sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium acetate, potassium acetate, ammonium acetate, calcium acetate, magnesium acetate, cellulose acetate hydrogen sodium, cellulose acetate hydrogen potassium, ammonium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate, calcium phosphate, magnesium phosphate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium phosphate, calcium hydrogen phosphate, one or more mixture of magnesium hydrogen phosphate etc.By test, we find that basic auxiliary that above these alkalescence are not too strong and the combination energy of polyacrylic resin III are extraordinary and reach above designing requirement that the strong basicity adjuvant then can influence the stability of most drug usually, should not adopt.
The preparation of oral drugs pulsation-releasing preparation of the present invention, can adopt following method:
(1) preparation of pastille core: according to tablet, micro chip, micropill or particulate preparation method, active medicine is prepared into above dosage form, as the pastille core.
(2) preparation of alkaline layer: in the water-soluble solution of basic auxiliary, adopt fluid bed that basic auxiliary is wrapped on the pastille core, control coating weightening finish 5-30% makes alkaline pastille core.
(3) preparation of sluggish clothing layer: the polyacrylic resin III that takes by weighing weight and be 10 parts-90 parts, 1 part of-10 parts of antiplastering aid or 5 parts～80 parts insoluble polymers or 1 part～10 parts plasticizers, adopt the organic solution or the aqueous dispersion of above coating material, above-mentioned coating solution is wrapped in alkaline pastille core, control coating weightening finish 50～200%, promptly.
Of the present inventionly add the preparation method of the oral drugs pulsation-releasing preparation of pastille core, it is characterized in that for alkaline layer:
(1) preparation of alkaline pastille core: according to tablet, micro chip, micropill or particulate preparation method, active medicine and basic auxiliary are mixed with into above dosage form, basic auxiliary weight is 5～30% of core, as alkaline pastille core;
(2) preparation of sluggish clothing layer: the polyacrylic resin III that takes by weighing weight and be 5 parts-90 parts, 1 part of-10 parts of antiplastering aid or 5 parts～80 parts insoluble polymers or 1 part～10 parts plasticizers, adopt the organic solution or the aqueous dispersion of above coating material, above-mentioned coating solution is wrapped in alkaline pastille core, control coating weightening finish 50～200%, promptly.
The release mechanism of oral drugs pulsation-releasing preparation of the present invention is: water sees through sluggish clothing tunic slowly to the preparation internal penetration, can control the sluggish time by thickness and the component of controlling sluggish clothing tunic, when alkaline layer is arrived in moisture penetration, the dissolving basic auxiliary, formed a pH value greater than environment in 7 the part, made that the polyacrylic resin III in the sluggish clothing layer dissolves, sluggish clothing tunic is destructurized, outside moisture infiltrates rapidly, the very fast dissolved and release of active substance.Must contain polyacrylic resin III in the sluggish clothing layer of the present invention, chemical composition is: methacrylic acid and methyl methacrylate (1: 2) copolymer, trade name Eudragit S100, 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 hour, and the sluggish design time of pulse preparation is 2-6 hour, preparation is no show colon place still, the pulse release process is finished, though thereby polyacrylic resin III is pH dependency material, the effect of pulsed release is not subjected to the influence of Digestive system pH value in human body.Can contain ethyl cellulose in addition, poly-first ammonium acrylate ester I[chemical composition is: ethyl acrylate, methyl methacrylate and methacrylic acid chlorination trimethylamine groups ethyl ester (1: 2: 0.2) copolymer], poly-first ammonium acrylate ester II[chemical composition is: ethyl acrylate, methyl methacrylate and methacrylic acid chlorination trimethylamine groups ethyl ester (1: 2: 0.1) copolymer] etc. commonly used slow controlled release coat filmogen a kind of or several, the different proportion combination of these materials and polyacrylic resin III, can obtain the different moisture penetration time, i.e. the lag time of pulsed release.Find that through a large amount of experiments part by weight is in the sluggish clothing layer: polyacrylic resin III is 10 parts-90 parts; Insoluble polymer is 5 parts～80 parts; Plasticizer loading is 1 part-10 parts can reach good sluggish effect.
Solids content by regulating polyacrylic resin III in the sluggish clothing layer and the weightening finish of the coating of sluggish clothing layer can make different pastille cores obtain 2-6 hour lag time and pulsatile effect.Here said lag time refers to that medicine accumulative total discharges the time less than content 10% own.
Preparation structure of the present invention is compared with the pulse preparation of existing report with release mechanism has following outstanding feature:
(1) preparation basic structure of the present invention is respectively pastille core, alkaline layer, sluggish clothing layer from inside to outside.Wherein the pastille core there is not specific (special) requirements, must contain polyacrylic resin III in the sluggish clothing layer, after the alkaline layer dissolving, the local pH value that forms is more than 7, such structure can not influence the drug release behavior of pastille core, that is: no matter the pastille core itself is that dissolving discharges rapidly, the preparation that still slow dissolving discharges, after basic auxiliary and the reaction of sluggish clothing layer, drug release is still consistent with pastille core preparation release behavior.
(2) the present invention adopts suitable macromolecule coating material, and the infiltration of moisture is only depended in the influence that the dissolving of this material is not changed by the gastrointestinal tract pH value; Simultaneously on the basis of control moisture penetration time (lag time), with outer macromolecular material generation physical-chemical reaction, form duct or path behind the moisture that penetrates into by inner adjuvant contact, cause the release of preparation of Chinese medicine.
(3) the present invention reaches the effect of oral formulations pulse release by the specific physical structure of design preparation; the physical arrangement of proof preparation is the key element that obtains the pulse release effect in the implementation process; the pulse preparation of the present invention's preparation can guarantee that the release lag time of active substance is controlled; active substance finishes quick and complete from beginning to be discharged into release; pulsatile effect is obvious, favorable reproducibility.
(4) the present invention is used in combination by the coated product of different lag times, can obtain the multiple pulses releasing effect of pastille core drug.
(5) adjuvant of the present invention is commercial easy acquisition pharmaceutic adjuvant commonly used, and preparation technology of the present invention is simply ripe, easily realizes suitability for industrialized production.
Figure of description:
Fig. 1 is the release of pulse preparation in different medium.
Fig. 2 is the influence that the different weightening finish of alkaline layer paired pulses discharges.
Fig. 3 is the influences of the different weightening finish of sluggish clothing layer to discharging.
Fig. 4 is the influence that polyacrylic resin III resin demand paired pulses discharges.
Fig. 5 is the pulse release curve of slow releasing preparation pastille core.
Fig. 6 is the influence that different basic auxiliary paired pulses discharge.
Fig. 7 is a micro chip pulse coating releasing curve diagram.
Fig. 8 is a tablet pulse coating releasing curve diagram.
Fig. 9 is a granule pulse coating releasing curve diagram.
Figure 10 adds the pulse release curve chart of pastille core for alkaline layer.
For further specifying of accompanying drawing among the embodiment:
(1) release conditions of sample in following release medium of embodiment 1 preparation seen accompanying drawing 1: the phosphate buffer of pure water, pH5.0, pH6.8 and putting again after 2 hours in the hydrochloric acid solution of 0.1mol/L in the phosphate buffer of pH6.8.As shown in Figure 1, sample discharges no significant difference at the aqueous solution Chinese medicine of different pH value.
(2) release profiles of sample in the phosphate buffer of pH6.8 of embodiment 1 and 2 preparations seen accompanying drawing 2, as shown in Figure 2, the example pharmaceuticals that does not contain bicarbonate sodium alkaline layer did not discharge in 3 hours, slowly discharge after 3 hours, and the sample that is surrounded by the sodium bicarbonate alkaline layer did not discharge in 3 hours, discharge fully rapidly after 3 hours, a tangible pulse release process is arranged.Sodium bicarbonate weightening finish is discharged into completely at the sample 5% below that the time slightly prolongs as shown in Figure 2, and increasing weight does not have notable difference in the sample release conditions more than 5%.
(3) release profiles of sample in the pH6.8 phosphate buffer of embodiment 3 preparations seen Fig. 3, and as seen from the figure, along with the increase of sluggish clothing layer coating weightening finish, the lag time of medicine prolongs, and the time does not have significant change completely and medicine is from beginning to be discharged into.
(4) embodiment 4-6 and 1 preparation sample release profiles are seen accompanying drawing 4, and as seen from the figure, under the identical condition of weightening finish, the lag time difference is little; Along with the increase of polyacrylic resin III content, the time also increases medicine to some extent from beginning to be discharged into completely, and pulsatile effect improves, and high-load polyacrylic resin III releasing effect is more or less the same.
(5) embodiment 7 preparation sample release in vitro curves are seen accompanying drawing 5, behind the slow-release pill coating tangible lag time are arranged as seen from the figure, and the back slow release effect is good simultaneously.
(6) embodiment 8 after measured release profiles see accompanying drawing 6, as seen from the figure, the prescription releasing effect of different alkali is more or less the same.
(7) embodiment 9 releasing effects are seen accompanying drawing 7, and as seen from the figure, the micro chip behind the coating had discharge fully rapidly behind the lag time in obvious 2 hours, obtained the releasing effect of pulse.
(8) embodiment 10 discharges and the results are shown in accompanying drawing 8, and tablet discharges behind sluggish clothing layer coating tangible lag time, discharges fully rapidly after a period of time, reaches the effect of pulse.
(9) embodiment 11 discharges and the results are shown in accompanying drawing 9, and granule discharges behind sluggish clothing layer coating tangible lag time, discharges fully rapidly after a period of time, reaches the effect of pulse.
(10) embodiment 12 is for adding alkaline layer the release conditions of pastille core, and release profiles is seen accompanying drawing 10 after measured, can reach good pulse release effect equally.
The specific embodiment
The present invention will be further described below in conjunction with embodiment.Enumerated as general representative in the embodiments of the invention but be not limited to medicines such as sorbide nitrate, propranolol hydrochloride, salbutamol sulfate, the said medicine tabulation is not to be detailed, many other medicines also are applicable to the present invention, both can use separately also can combine with other drug to mix and use.
Polyacrylic resin III of the present invention, ethyl cellulose, poly-first ammonium acrylate ester I and poly-first ammonium acrylate ester II, triethyl citrate, dibutyl sebacate, dibutyl phthalate, glycerol triacetate, Oleum Ricini, glycerol or the like all can buy from the market.
(1), sorbide nitrate impulse pellet
The release conditions of working sample adopts and changes basket method, 100 rev/mins, 37 ± 0.5 ℃, 900ml release medium according to " Chinese Pharmacopoeia version in 2005 " appendix relevant regulations among the embodiment.
Pastille core prescription:
Starch sucrose celphere 400g
Sorbide nitrate 100g
Water 1kg
Preparation technology:
Sorbide nitrate is soluble in water, adopt fluidized bed coating, 50 ± 2 ℃ of intake air temperatures, flow velocity 5mL/min is wrapped in sorbide nitrate on the celphere, makes the pastille core.
The alkaline layer prescription:
Preparation technology:
Sodium bicarbonate is water-soluble, adopt fluidized bed coating, sodium bicarbonate is wrapped on the pastille core, coating weightening finish 10% makes alkaline pastille core.
Sluggish clothing layer prescription % (w/v)
Polyacrylic resin III (Eudragit S100) 9
Pulvis Talci 0.9
Add 95% ethanol to 100%, polyacrylic resin III (Eudragit S100) weight is about 90 grams (the sluggish clothing layer of per 100 grams)
Preparation technology:
Adopt fluidized bed coating, 40 ± 1 ℃ of intake air temperatures, flow velocity 5mL/min is wrapped in above-mentioned coating solution on the alkaline pastille core, coating weightening finish 100%.
According to sample raw and auxiliary material and preparation method among the embodiment 1, preparing the weightening finish of alkaline layer coating respectively is 0%, 3%, 5%, 10%, 20%, 30%, and sluggish clothing layer weightening finish is 100% sample.
According to sample raw and auxiliary material preparation method among the embodiment 1, the weightening finish of preparation alkaline layer coating is 10%, and sluggish clothing layer weightening finish is respectively 50%, 100%, 200% sample.
Pastille core prescription, preparation technology are according to embodiment 1
The alkaline layer prescription:
Preparation technology:
Dipotassium hydrogen phosphate is water-soluble, adopt fluidized bed coating, dipotassium hydrogen phosphate is wrapped on the alkaline layer pastille core, coating weightening finish 10% makes the pastille core.
Sluggish clothing layer prescription % (w/v)
Polyacrylic resin III (Eudragit S100) 1.3
Ethyl cellulose 6.3
Dibutyl sebacate 1.5
Pulvis Talci 0.9
Add 95% ethanol to 100%, polyacrylic resin III weight is about 13 grams (the sluggish clothing layer of per 100 grams)
Preparation technology:
Adopt fluidized bed coating, 40 ± 1 ℃ of intake air temperatures, flow velocity 5mL/min is wrapped in above-mentioned coating solution on the above-mentioned pastille core, coating weightening finish 100%.
Pastille core prescription, preparation technology are according to embodiment 1
The alkaline layer prescription:
Cellulose acetate hydrogen sodium 10% (w/v) adds water to 100%
Preparation technology:
Cellulose acetate hydrogen sodium is water-soluble, adopt fluidized bed coating, cellulose acetate hydrogen sodium is wrapped on the alkaline layer pastille core, coating weightening finish 10% makes pastille core 5.
Sluggish clothing layer prescription % (w/v)
Polyacrylic resin III (Eudragit S100) 8.0
Poly-first ammonium acrylate ester I 4.1
Dibutyl phthalate 0.5
Magnesium stearate 0.7
Add 95% ethanol to 100%, polyacrylic resin III weight is about 60 grams (the sluggish clothing layer of per 100 grams).
Preparation technology:
Adopt fluidized bed coating, 40 ± 1 ℃ of temperature, flow velocity 10mL/min is wrapped in above-mentioned coating solution on the above-mentioned pastille core, coating weightening finish 100%.
Pastille core prescription, preparation technology are according to embodiment 1
The alkaline layer prescription:
Preparation technology:
Sodium carbonate is water-soluble, adopt fluidized bed coating, sodium carbonate is wrapped on the alkaline layer pastille core, coating weightening finish 10% makes pastille core 6.
Sluggish clothing layer prescription % (w/v)
Polyacrylic resin III (Eudragit S100) 8
Poly-first ammonium acrylate ester II 1
Glycerol triacetate 0.6
Micropowder silica gel 0.4
Add 95% ethanol to 100%, polyacrylic resin III weight is about 80 grams (the sluggish clothing layer of per 100 grams).
Preparation technology:
Adopt fluidized bed coating, 40 ± 1 ℃ of temperature, flow velocity 10mL/min is wrapped in above-mentioned coating solution on the above-mentioned pastille core, coating weightening finish 100%.
(2) Propranolol postpones slow-release micro-pill
The release conditions of working sample adopts oar method, 50 rev/mins, 37 ± 0.5 ℃, 900ml release medium according to " Chinese Pharmacopoeia version in 2005 " appendix relevant regulations among the embodiment.
The slow-release micro-pill prescription
Ball core prescription % (w/w)
Microcrystalline Cellulose 70
Preparation technology:
Add 20% alcoholic solution and make wet feed, wet feed is extruded through extruder sieve plate (aperture 0.8mm), strip particle is put in the spheronizator round as a ball, and the ball core sieves 18-24 order medicated core in 50 ℃ of dry 5h.
Sustained release coating liquid prescription: % (v/v)
Surelease aqueous dispersion (solids content 25%) 60
Preparation technology:
Spray coating at the bottom of adopting fluid bed, the coating solution flow velocity is 3mL/min, and intake air temperature is 30 ± 1 ℃.The slow-release pill that makes is as the pastille core.
Alkaline layer and sluggish clothing layer prescription and preparation technology are with embodiment 1
(3) salbutamol sulfate pulse preparation
The release conditions of working sample adopts oar method, 50 rev/mins, 37 ± 0.5 ℃, 900ml release medium according to " Chinese Pharmacopoeia version in 2005 " appendix relevant regulations among the embodiment.
Pastille core prescription: % (w/w)
Microcrystalline Cellulose 98
Preparation technology:
Add 20% alcoholic solution and make wet feed, wet feed is extruded through extruder sieve plate (aperture 1.0mm), strip particle is put in the spheronizator round as a ball, and the ball core sieves 18-24 order medicated core in 50 ℃ of dry 5h.
The sealing coat prescription:
Hydroxypropyl emthylcellulose 5% (w/v) adds water to 100%.
Preparation technology:
Hydroxypropyl emthylcellulose is soluble in water, adopt fluidized bed coating, hydroxypropyl emthylcellulose is wrapped on the above-mentioned pastille core, weightening finish 2% makes alkaline pastille core.
Alkaline layer, sluggish clothing layer prescription are seen embodiment 1, and wherein alkaline layer is selected sodium bicarbonate, potassium acetate, dipotassium hydrogen phosphate or diammonium phosphate for use.
Miniature label prescription: % (w/w)
Amylum pregelatinisatum 15.4
4% polyvidone 1
Magnesium stearate 0.6
Preparation technology:
In above-mentioned prescription ratio, salbutamol sulfate and microcrystalline Cellulose are put in the blender dry blending 8 minutes, with amylum pregelatinisatum, carboxymethyl starch sodium is put in the blender again, does and mixes 15 minutes, binding agent is added in the mixture, make soft material, be screened into granule of uniform size, put into oven drying 5 hours, add magnesium stearate and mixed 6 minutes, be pressed into label, the heavy 120mg of sheet, diameter 5mm is as the pastille core.
Alkaline layer and sluggish clothing layer prescription seen and with fluid bed miniature label carried out spray coating by embodiment 1, alkaline layer weightening finish 15%, sluggish clothing layer weightening finish 100%.
Salbutamol sulfate label prescription % (w/w)
Salbutamol sulfate 2.1
Pregelatinized starch 43.0
Microcrystalline Cellulose 47.0
Sodium lauryl sulphate 0.5
Carboxymethyl starch sodium 5.8
4% hypromellose 1.2
Micropowder silica gel 0.4
Preparation technology:
In above-mentioned prescription ratio, salbutamol sulfate and microcrystalline Cellulose, sodium lauryl sulphate are put in the blender, and dry blending 10 minutes is put pregelatinized starch, carboxymethyl starch sodium in the blender again, dry blending 10 minutes, binding agent 4% hypromellose is added in the mixture, make soft material, sieve and make granule of uniform size, put into 50 ℃ of dryings of baking oven 3 hours, add micropowder silica gel and mixed 5 minutes, be pressed into micro chip pastille core.
The alkaline layer prescription:
Preparation technology:
Sodium carbonate is water-soluble, adopt the coating pan coating, sodium carbonate is wrapped on the micro chip pastille core, coating weightening finish 18% makes alkaline pastille core.
Sluggish clothing layer prescription % (w/v)
Polyacrylic resin III (Eudragit S100) 9
Triethyl citrate 0.6
Pulvis Talci 0.4
Add 95% ethanol to 100%
Preparation technology:
Adopt the high-efficiency coating pan coating, 40 ± 1 ℃ of temperature, flow velocity 5mL/min is wrapped in above-mentioned coating solution on the alkaline pastille core, and the coating weightening finish is respectively 50%, 90%, 120%.Release profiles is seen accompanying drawing 8
Embodiment 11
Salbutamol sulfate granule prescription: % (w/w)
Salbutamol sulfate 25
Sucrose 45
Preparation technology:
After above-mentioned supplementary material crossed 120 mesh sieves respectively, make wetting agent, make soft material, usefulness 16# nylon screen granulate with 50% ethanol.Sealing coat, alkaline layer and sluggish clothing layer prescription are seen embodiment 1,
Ball core prescription: % (w/w)
Microcrystalline Cellulose 70
Sodium bicarbonate 28
Preparation technology:
Add 20% alcoholic solution and make wet feed, wet feed is extruded through extruder sieve plate (aperture 1.0mm), strip particle is put in the spheronizator round as a ball, and the ball core sieves 18-24 order alkalescence pastille core in 50 ℃ of dry 5h,
Sluggish clothing layer prescription: % (w/v)
Polyacrylic resin III (Eudragit S100) 6
Dibutyl sebacate 0.6
Pulvis Talci 1.5
Add 95% ethanol to 100%
Preparation technology:
Adopt end spray fluidized bed coating, the coating solution flow velocity is 6mL/min, and intake air temperature is 40 ± 1 ℃, coating weightening finish 100%, and release profiles is seen accompanying drawing 10 after measured.
Though being in the clear purpose of understanding, the mode of foregoing by embodiment be described in detail, but those skilled in the art obviously understand some changes and improvements, can from foregoing, understand and obtain, and can realize within the scope of the appended claims and not need too much experiment, the foregoing description only is representationally to illustrate rather than limit.
Claims (14)
1. a pulse release oral drug preparation is characterized in that said preparation is a coated preparation, and basic structure is respectively pastille core, alkaline layer and sluggish clothing layer from inside to outside and forms.
2. a pulse release oral drug preparation is characterized in that said preparation is a coated preparation, is made up of pastille core that contains the basic medicinally adjuvant and sluggish clothing layer.
3. as the described pulse release oral drug preparation of claim 1-2, wherein said pastille core is granule, micropill, micro chip or the tablet that contains medicine.
4. as the described pulse release oral drug preparation of claim 1-2, it is characterized in that sluggish clothing layer is 50～200% with respect to the coating weightening finish of pastille core.
5. as the described pulse release oral drug preparation of claim 1-2, wherein said alkaline layer is medicinal organic or inorganic basic auxiliary, and its weight is 5～30% of pastille core weight.
6. as the described pulse release oral drug preparation of claim 1-2, contain weight in the wherein said sluggish clothing layer and be 10～90 parts polyacrylic resin III.
7. as the described pulse release oral drug preparation of claim 1-2, contain weight in the wherein said sluggish clothing layer and be the antiplastering aid that 10～90 parts polyacrylic resin III and weight are 1～10 part.
8. pulse release oral drug preparation as claimed in claim 1 or 2, also containing weight in the wherein said sluggish clothing layer is 5～80 parts of insoluble polymers or 1～10 part of plasticizer.
9. pulse release oral drug preparation as claimed in claim 8 or 9, wherein insoluble polymer comprises: ethyl cellulose, poly-first ammonium acrylate ester I, poly-one or more mixture of first ammonium acrylate ester II; 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.
10. a pulse release oral drug preparation is characterized in that said preparation is a coated preparation, and basic structure is respectively pastille core, alkaline layer and sluggish clothing layer from inside to outside and forms; Wherein alkaline layer is medicinal organic or inorganic basic auxiliary, and its weight is 5～30% of pastille core weight; Contain weight in the sluggish clothing layer and be 10～90 parts polyacrylic resin III, sluggish clothing layer is 50～200% with respect to the coating weightening finish of pastille core.
11. a pulse release oral drug preparation is characterized in that said preparation is a coated preparation, basic structure is respectively pastille core, alkaline layer and sluggish clothing layer from inside to outside and forms; Wherein alkaline layer is medicinal organic or inorganic basic auxiliary, and its weight is 5～30% of pastille core weight; Sluggish clothing layer is 50～200% with respect to the coating weightening finish of pastille core, contains weight in the sluggish clothing layer and be the antiplastering aid that 10～90 parts polyacrylic resin III and weight are 1～10 part.
12. a pulse release oral drug preparation is characterized in that said preparation is a coated preparation, is made up of pastille core that contains the basic medicinally adjuvant and sluggish clothing layer; Wherein basic medicinally adjuvant weight is 5～30% of core weight; Sluggish clothing layer is 50～200% with respect to the coating weightening finish of the pastille core that contains the basic medicinally adjuvant, contains weight in the sluggish clothing layer and be 10～90 parts polyacrylic resin III.
13. a pulse release oral drug preparation is characterized in that said preparation is a coated preparation, is made up of pastille core that contains the basic medicinally adjuvant and sluggish clothing layer; Wherein basic medicinally adjuvant weight is 5～30% of core weight; Sluggish clothing layer is 50～200% with respect to the coating weightening finish of the pastille core that contains the basic medicinally adjuvant, contains weight in the sluggish clothing layer and be the antiplastering aid that 10～90 parts polyacrylic resin III and weight are 1～10 part.
14. as the described pulse release oral drug preparation of claim 11-14, it is characterized in that also containing in the described sluggish clothing layer weight is 5～80 parts of insoluble polymers or 1～10 part of plasticizer.
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| CN2007100564165A CN101219118B (en) | 2007-01-08 | 2007-01-08 | Impulse released oral medication preparation |
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| CN2007100564165A CN101219118B (en) | 2007-01-08 | 2007-01-08 | Impulse released oral medication preparation |
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| CN101219118B CN101219118B (en) | 2011-05-25 |
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Cited By (1)
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2558535A1 (en) * | 2004-03-03 | 2005-10-06 | Teva Pharmaceutical Industries Ltd. | A stable pharmaceutical composition comprising an acid labile drug |
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Cited By (2)
| 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 |
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| CN101219118B (en) | 2011-05-25 |
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