CN104721162A - Prednisone oral pulsatile tablet and preparation method thereof - Google Patents
Prednisone oral pulsatile tablet and preparation method thereof Download PDFInfo
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- CN104721162A CN104721162A CN201510151639.4A CN201510151639A CN104721162A CN 104721162 A CN104721162 A CN 104721162A CN 201510151639 A CN201510151639 A CN 201510151639A CN 104721162 A CN104721162 A CN 104721162A
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Abstract
The invention discloses a prednisone oral pulsatile tablet and a preparation method thereof. The oral pulsatile tablet comprises a rapid-release tablet core, a swelling coating layer and a controlled-release film coating layer, wherein the rapid-release tablet core is composed of a main medicine and pharmaceutically acceptable auxiliary materials, the main medicine is pulsatile, the dosage specification is 1-20mg per tablet metered by pulsatile, and the tablet core weight is 120-220mg; the swelling coating layer is composed of hydroxypropyl methylcellulose, and the coating weight increment relative to the weight of the rapid-release tablet core is 1-20%; the controlled-release film coating layer is composed of a water-insoluble film coating material which is insoluble under different pH values and other pharmaceutically acceptable auxiliary materials, and the coating weight increment relative to the total weight of the rapid-release tablet core and the swelling coating layer is 1-15%. According to the prednisone oral pulsatile tablet and the preparation method thereof disclosed by the invention, the tablet core is prepared by a direct powder tableting process, the swelling coating layer and the controlled-release layer are prepared by a film coating method, the preparation is stable, and the process is simple and practicable, and high in reproducibility.
Description
Technical field
The present invention relates to a kind of Orally taken pulsed preparation of prednisone for the treatment of rheumatoid arthritis joint deadlock in morning and preparation method thereof, namely according to the daily rhythmicity of disease incidence, select suitable lag time, and time the prescription composition of pulse preparation of delayed blasting type complete release and preparation method.
Background technology
Large quantity research confirms, slow effect antirheumatic (DMARD) can delay the destruction of joint of rheumatoid arthritis (RA), it is the key agents for the treatment of RA, but its onset is slower, if Small dose injection hormone therapy, just can symptom management earlier, stop destruction of joint, the patient for early stage RA is especially useful.
Prednisone is Aeroseb-Dex.Be mainly used in anaphylaxis and diseases associated with inflammation.Most important medicine in the autoimmune diseasees such as treatment rheumatism.Its chemistry 17 α, 21-dimonohydric pregnant-Isosorbide-5-Nitrae diene-3,11,20-triketone by name.Molecular formula is C
21h
26o
5, molecular weight is 358.43, and structural formula is:
Preparation prepared by the present invention for early stage rheumatoid arthritis (RA) there is daily rhythmicity, the ankylosis caused by it is the most serious with early morning.But existing dosage form is not division of day and night rule design, the administration of morbidity according to rheumatoid arthritis, can not the therapeutical effect of separate drug and toxic and side effects, increase the weight of its untoward reaction to a certain extent on the contrary, so that reduce curative effect.Therefore, best dosage regimen should take into full account the various factors affecting curative effect of medication, the therapeutical effect of medicine is reached with toxic and side effects and is farthest separated, and outstanding curative effect, reduces toxic and side effects.
The time function rule of " chronopharmacology " main drugs effect, comprises pharmacodynamics effect, pharmacokinetics, body sensitivity etc., and its basic goal improves drug level.Grasp the change of these rhythm and pace of moving things, work out best therapeutic scheme at reasonable time according to the rhythm and pace of moving things change of pharmacokinetics, pharmacodynamics, according to circadian time schedule, the curative effect improving medicine will be conducive to, reduce the generation of adverse effect.Pulse controlled-release administrating system according to the biorhythmic feature of seizure of disease in conjunction with division of day and night pathology, can carry out time optimization to release scheme, provides required blood drug level.It can be taken medicine in advance according to the rhythmicity of patient's morbidity, makes medicine time and drug release time have a time difference matched with physiological period, thus prevention morbidity, reduce the untoward reaction of medicine, and not easily produce drug resistance, improve the compliance of patient.
Research in recent years finds, if dosage <10mgPd (by prednisone Rapid Dose Calculation), then the incidence rate of untoward reaction obviously reduces, and prolonged application also may have the effect slowing down lesion growth.At present, the dosage form of (acetic acid) prednisone is tablet, eye ointment, and prednisolone acetate has tablet, emulsifiable paste, injection, the domestic listing of the pulse-controlled release preparations there are no prednisone.Because prednisone drug treating time is shorter, conventional tablet generally needs day to take repeatedly (3 ~ 4 times), and blood concentration fluctuation is large.By the research to external pulse release control and division of day and night pharmacokinetic model, solve drug release and absorb relation between behavior and seizure of disease incubation period, drug release is absorbed match with the seizure of disease rhythm and pace of moving things, for the late into the night or daystart morbidity crowd medication are provided convenience, by significant.
Summary of the invention
Primary and foremost purpose of the present invention is to provide Orally taken pulsed of a kind of prednisone, this Orally taken pulsed is for the Attack time of seizure of disease and chronopharmacology principle design, delayed when 3 ~ 5h, release completely, reaching the effect of pulse release, patient can being facilitated in taking a medicine at bedtime rapidly, in the release completely rapidly of high-incidence season in morning, blood drug level is reached fast and effectively treats concentration, treat the joint deadlock in morning caused by RA early morning in time, alleviate patient painful.
Another object of the present invention is to the preparation method that Orally taken pulsed of above-mentioned prednisone is provided.The method mature preparation process, simple, the lag time of prepared prednisone pulsatile tablets and time delayed drug release behavior stablize controlled, favorable reproducibility, is applicable to suitability for industrialized production.
Object of the present invention is achieved through the following technical solutions:
A kind of Orally taken pulsed of prednisone, this Orally taken pulsed rapid release label comprising internal layer, middle swell layer and outer field controlled release membranes coatings.Wherein label weight is 120 ~ 220mg, and swell layer is 1% ~ 20% relative to the coating weight gain of rapid release label weight; Controlled release membranes coatings is 1% ~ 15% relative to the coating weight gain of rapid release label and swell layer gross weight.
The Orally taken pulsed preparation of above-mentioned prednisone does not have substantial seepage in lag time, after certain lag time, can quick and complete release medicine, it relies on the thickness of the component of coatings, component proportion and coatings can control reliably time lag, and its Mechanism of Drug Release is by the control gains that breaks of controlled release coating layer.
The label of the Orally taken pulsed preparation of above-mentioned prednisone comprises the active component prednisone for the treatment of effective dose, and label adjuvant filler, disintegrating agent, release regulator, lubricant, the percentage by weight of adjuvant in label is respectively (60 ~ 80) %, (5 ~ 20) %, (2 ~ 15) %, (0.2 ~ 5) %.
Described filler is selected from one in lactose, microcrystalline Cellulose, pregelatinized Starch or several mixture;
Described disintegrating agent is selected from one in cross-linking sodium carboxymethyl cellulose (crosslinked CMC-Na), crospolyvinylpyrrolidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC) or several mixture;
Described release regulator is selected from one in mannitol, sodium chloride, sorbitol, citric acid or several mixture;
Described lubricant is selected from one in magnesium stearate, Pulvis Talci, micropowder silica gel or several mixture;
The coatings of the Orally taken pulsed preparation of described prednisone is made up of two-layer: HPMC swell layer and water-insoluble controlled release coating layer, and the release of prednisone can be controlled by breaking of coatings;
Described swell layer is made up of HPMC, and coating weight gain is 1% ~ 20% relative to the coating weight gain of rapid release label weight, is more preferably 5 ~ 12%;
Described thin film controlled release coating layer is by water-insoluble coating material ethyl cellulose or especially strange Eudragit RL and Eudragit RS mixing coating material form, coating weight gain is 1% ~ 15% relative to the coating weight gain of rapid release label and swell layer gross weight, is more preferably 4 ~ 10%;
Described thin film controlled release coating layer plasticizer is selected from one in triethyl citrate, Polyethylene Glycol, dibutyl phthalate or several mixture;
Described thin film controlled release coating layer porogen is selected from one in Polyethylene Glycol, carbomer or several mixture;
Orally taken pulsed of prednisone of the present invention, after reaching lag time, all presents obvious pulsed release behavior, label fater disintegration, and completely, in 5min, cumulative release percentage rate is greater than 95% in release rapidly.According to the present invention for the stiff symptom in morning in RA early morning, the lag time of preferred prednisone pulsatile tablets is 3 ~ 5h.
The present invention designs according to the principle of chronopharmacology and circadian therapy, use Orally taken pulsed medicine being taken at bed time, active substance is after sluggish one period of scheduled time, blasting type discharges, ensure that the therapeutic effect of this medicine, make to reach balance between the biorhythm of patient self and curative effect, while having given full play to therapeutical effect, reduce the toxic and side effects of medicine.Thus it is low to solve traditional therapeutic regimen curative effect, the problems such as side effect is larger.
Orally taken pulsed of the prednisone utilizing the present invention to prepare has release performance when selecting, and lag time is pH variable effect in receptor not, its release Mechanisms is: adopt water-insoluble and under different pH all undissolved macromolecular material to prepare controlled release membranes coatings, clothing layer decides the time lag of pulsed release to the transmission rates of water, the toughness of clothing layer and the swelliong power of label, and drug release rate delayed when reaching depends primarily on the disintegrate ability of label.When prednisone pulsatile tablets touches release medium, water through controlled release coating layer slowly to preparation internal penetration, label expands after absorbing moisture gradually, when label absorb abundant moisture fully expand time, produce powerful expansive force, make controlled release film coat layer cannot bear and finally cause clothing film rupture, label contact release medium, fater disintegration release.Lag time and drug release rate are mainly controlled by the kind of disintegrating agent, controlled release membranes coating layer material, consumption, plasticizer and porogen kind and consumption and coating weight gain rate.
High spot reviews of the present invention:
(1) label disintegrating agent consumption is on the impact of lag time and drug release
(2) controlled release coat layer thickness is on the impact of lag time and drug release
(3) controlled release coating layer plasticizer and porogen consumption are on the impact of lag time and drug release
Investigate and find, select crosslinked CMC-Na and PVPP mixing disintegrating agent, within the scope of optimizing prescriptions, rapid release label can be made to obtain enough swelliong powers, label can discharge completely in 5min, and can coating membrane be made in the given time to break, and reaches explosion releasing effect; In controlled release coat layer thickness and coatings, plasticizer, porogen consumption have appreciable impact to lag time, Orally taken pulsed of the preferred prednisone of the present invention, lag time can be made to be 4h, in lag time 0.5 ~ 1h, medicine can discharge completely, and optimizing prescriptions is made up of (every 100 parts) the raw material of following portions by weight:
The present invention is the principle design according to chronopharmacology and circadian therapy, label adopts direct powder compression preparation, then coating process is carried out, it can be completed by rollover in coating pan, also can be completed by fluidized bed coating, mature production technology, simple, adapt to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the tablets in vitro curve chart of prednisone pulsatile tablets in embodiment 1;
Fig. 2 is the tablets in vitro curve chart of prednisone pulsatile tablets in embodiment 2;
Fig. 3 is the tablets in vitro curve chart of prednisone pulsatile tablets in embodiment 3;
Fig. 4 is the tablets in vitro curve chart (pH1.0) of prednisone pulsatile tablets in embodiment 3;
Fig. 5 is the tablets in vitro curve chart (pH4.5) of prednisone pulsatile tablets in embodiment 3;
Fig. 6 is the tablets in vitro curve chart (pH6.8) of prednisone pulsatile tablets in embodiment 3;
Fig. 7 is the tablets in vitro curve chart of prednisone ordinary tablet.
Detailed description of the invention
Below, by embodiment, the present invention will be further described, but the present invention is not limited to these embodiments, in the scope illustrated by the claims in the present invention, various change or equivalent replacement can be carried out.
Embodiment 1
Label (10000):
Supplementary material used is crossed 80 mesh sieves, to progressively increase method by equivalent, by the prednisone of recipe quantity, PVPP, crosslinked CMC-Na, sorbitol, add recipe quantity SiO2 after pregelatinized Starch and MCC mix homogeneously, be placed in multinomial movement mixer and mix 30min, then add recipe quantity magnesium stearate mixing 10min namely obtain mixed material, by the material of mix homogeneously with the shallow arc punching of 5.0mm, required label is suppressed and obtained to single punch tablet machine.Plate core weight is about 125mg, hardness 2.8kg ± 0.5kg.
HPMC is dissolved in 60% ethanol and makes coating solution, be mixed with concentration be 5% HPMC alcoholic solution namely obtain swell layer coating solution; By label as in coating pan, adjustment rolling coating pan angle is 30 °, and rotating speed 25 ~ 35/min, be added in by coating solution in spray gun and aim at label spraying, atomizing pressure 0.1MPa, send 80 ~ 100 DEG C of hot air dryings with heat gun simultaneously.In coating process, record label weight, the weightening finish to label is about 5%.
By PEG-400, triethyl citrate, ethyl cellulose be dissolved in the alcoholic solution of 90% be mixed with concentration be 5% EC alcoholic solution namely obtain controlled release layer coating solution, carry out coating by above-mentioned coating parameter, be about 7% namely obtain Orally taken pulsed of prednisone to label weightening finish.By Chinese Pharmacopoeia 2010 editions drug release determination methods the 2nd method, prednisone pulsatile tablets is added sedimentation basket, measure the In-vitro release curves of prednisone pulsatile tablets.Leaching condition: 500mL release medium, medium temperature (37 ± 0.2) DEG C, rotating speed 100rpm, at predetermined point of time sampling 2mL, 0.45 μm of membrane filtration, adds same volume isothermal medium simultaneously, and subsequent filtrate HPLC method measures.
Chromatographic condition: octadecylsilane chemically bonded silica is filler, acetonitrile-water (45:55) is mobile phase, and determined wavelength is 240nm, sample size 20 μ L.
Embodiment 2
Label (10000):
Supplementary material used is crossed 80 mesh sieves, to progressively increase method by equivalent, by the prednisone of recipe quantity, L-HPC, crosslinked CMC-Na, mannitol, adds recipe quantity SiO after lactose and MCC mix homogeneously
2, be placed in multinomial movement mixer and mix 30min, then add recipe quantity Pulvis Talci mixing 10min and namely obtain mixed material, by the material of mix homogeneously with the shallow arc punching of 5.0mm, required label is suppressed and obtained to single punch tablet machine.Plate core weight is about 125mg, hardness 2.1kg ± 0.5kg.
HPMC is dissolved in 60% ethanol and makes coating solution, be mixed with concentration be 5% HPMC alcoholic solution namely obtain swell layer coating solution; By label as in coating pan, adjustment rolling coating pan angle is 30 °, and rotating speed 25 ~ 35/min, be added in by coating solution in spray gun and aim at label spraying, atomizing pressure 0.1MPa, send 80 ~ 100 DEG C of hot air dryings with heat gun simultaneously.In coating process, record label weight, the weightening finish to label is about 5%.
By PEG-400, PEG-6000, ethyl cellulose be dissolved in the alcoholic solution of 90% be mixed with concentration be 5% EC alcoholic solution namely obtain controlled release layer coating solution, carry out coating by above-mentioned coating parameter, be about 9.5% namely obtain Orally taken pulsed of prednisone to label weightening finish.In-vitro release curves mensuration is carried out according to embodiment 1 stripping condition determination.
Embodiment 3
Label (10000):
Supplementary material used is crossed 80 mesh sieves, to progressively increase method by equivalent, by the prednisone of recipe quantity, PVPP, crosslinked CMC-Na, mannitol, adds recipe quantity SiO after lactose and MCC mix homogeneously
2, be placed in multinomial movement mixer and mix 30min, then add recipe quantity magnesium stearate mixing 10min and namely obtain mixed material, by the material of mix homogeneously with the shallow arc punching of 5.0mm, required label is suppressed and obtained to single punch tablet machine.Plate core weight is about 125mg, hardness 2.5kg ± 0.5kg.
HPMC is dissolved in 60% ethanol and makes coating solution, be mixed with concentration be 5% HPMC alcoholic solution namely obtain swell layer coating solution; By label as in coating pan, adjustment rolling coating pan angle is 30 °, and rotating speed 25 ~ 35/min, be added in by coating solution in spray gun and aim at label spraying, atomizing pressure 0.1MPa, send 80 ~ 100 DEG C of hot air dryings with heat gun simultaneously.In coating process, record label weight, the weightening finish to label is about 5%.
By PEG-400, PEG-6000, ethyl cellulose be dissolved in the alcoholic solution of 90% be mixed with concentration be 5% EC alcoholic solution namely obtain controlled release layer coating solution, carry out coating by above-mentioned coating parameter, be about 10.5% namely obtain Orally taken pulsed of prednisone to label weightening finish.In-vitro release curves mensuration is carried out according to embodiment 1 stripping condition determination.
Embodiment 4
Core formulation and coating weight gain, parameter are with embodiment 3, and the release in vitro that Orally taken pulsed of gained prednisone carries out in different pH medium investigates (being respectively pH1.0, pH4.5, pH6.8).
From the tablets in vitro curve of prednisone pulsatile tablets, along with the increase of controlled release layer coating weight gain, the lag time of prednisone pulsatile tablets extends gradually, can the lag time of control impuls sheet change at 3 ~ 5h by regulating the thickness of coatings, and rapid release label has stronger disintegrating property, medicine can be discharged rapidly after coatings is broken, reach pulsatile effect.
Embodiment 5 comparative test:
Conclusion:
(1) prednisone pulsatile tablets comparatively ordinary tablet release to have 3 ~ 5h sluggish, can by the required medicine of premorbid release;
(2) prednisone pulsatile tablets only needs to take 1 time every day, treats convenient;
(3) prednisone pulsatile tablets blood drug level is only at premorbid peaking, curative effect is separated with side effect, reaches optimum therapeuticing effect.
Claims (7)
1. Orally taken pulsed an of prednisone, is characterized in that: this Orally taken pulsed rapid release label adjuvant comprising internal layer, the swelling coatings in intermediate layer and outer field controlled release membranes coatings;
The lag time that described prednisone is Orally taken pulsed is 1-7h; Described rapid release label is made up of principal agent and pharmaceutically acceptable adjuvant, and principal agent is prednisone, and the dosage strengths of described principal agent counts 1 ~ 20mg with prednisone; Swelling coatings is made up of hypromellose, is 1% ~ 20% relative to the coating weight gain of rapid release label weight; Controlled release membranes coatings all undissolved thin film coating material and other pharmacy by water-insoluble and under different pH can accept adjuvant and form, and are 1% ~ 15% relative to the coating weight gain of rapid release label and swell layer gross weight;
The adjuvant of described rapid release label is at least one in filler, disintegrating agent, release regulator, lubricant; Described swelling coatings is cellulosic polymer; Described thin film coating material is at least one in cellulosic polymer or acrylic resin base polymer; Described coatings adjuvant is at least one in plasticizer, porogen;
Described core filler is one in lactose, microcrystalline Cellulose, pregelatinized Starch or several mixture, and described filler accounts for rapid release label weight for (60 ~ 80) %;
Described label disintegrating agent is one in cross-linking sodium carboxymethyl cellulose (crosslinked CMC-Na), crospolyvinylpyrrolidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC) or several mixture, and described disintegrating agent accounts for rapid release label weight for (5 ~ 20) %;
Described label release regulator is one in mannitol, sodium chloride, sorbitol, citric acid or several mixture, and described release regulator accounts for rapid release label weight for (2 ~ 15) %;
Described label lubricant is one in magnesium stearate, Pulvis Talci, micropowder silica gel or several mixture, and described lubricant accounts for rapid release label weight for (0.2 ~ 5) %;
Described controlled release coating layer thin film coating material is ethyl cellulose or especially strange Eudragit RL and Eudragit RS mixing coating material;
Described controlled release coating layer plasticizer is one in triethyl citrate, Polyethylene Glycol, dibutyl phthalate or several mixture; Described controlled release coating layer porogen is Polyethylene Glycol, carbomer.
2. Orally taken pulsed of a kind of prednisone according to claim 1, is characterized in that: in described controlled release membranes coatings, the weight ratio of thin film coating material, plasticizer, porogen is (50 ~ 90) %:(1 ~ 10) %:(1 ~ 10) %.
3. Orally taken pulsed of a kind of prednisone according to claim 1, is characterized in that: the lag time that described prednisone is Orally taken pulsed is 3-5h.
4. the preparation method of Orally taken pulsed of a kind of prednisone according to claim 1, is characterized in that comprising following operating procedure:
(1) prepare rapid release label: after being mixed homogeneously with label adjuvant by principal agent, adopt direct powder compression to prepare rapid release label;
(2) prepare swelling coatings: HPMC is made coating feed liquid, adopt fluid bed or coating pan to carry out coating to rapid release label;
(3) prepare controlled release layer coating: thin film coating material and plasticizer, porogen are mixed and made into coating feed liquid, adopt fluid bed or coating pan to carry out coating, obtained Orally taken pulsed of prednisone to bag swell layer label.
5. preparation method according to claim 4, is characterized in that the drug release time of Orally taken pulsed of described prednisone does not affect by pH.
6. Orally taken pulsed of prednisone according to claim 1, is characterized in that it is made up of (every 100 parts) the raw material of following portions by weight:
。
7. the preparation method of Orally taken pulsed of prednisone according to claim 4, is characterized in that the preparation of Orally taken pulsed of described prednisone before release is no more than 10%.
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Cited By (2)
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| CN109674794A (en) * | 2017-10-19 | 2019-04-26 | 上海复星星泰医药科技有限公司 | A kind of Amlodipine benazepil pulsatile tablets and preparation method thereof |
| CN109925288A (en) * | 2017-12-18 | 2019-06-25 | 江苏开元药业有限公司 | A kind of glucocorticoid medicine tablet and preparation method thereof |
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Application publication date: 20150624 |