CN104856971B - A kind of pulse dual-release preparation and the preparation method and application thereof - Google Patents
A kind of pulse dual-release preparation and the preparation method and application thereof Download PDFInfo
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- CN104856971B CN104856971B CN201510249751.1A CN201510249751A CN104856971B CN 104856971 B CN104856971 B CN 104856971B CN 201510249751 A CN201510249751 A CN 201510249751A CN 104856971 B CN104856971 B CN 104856971B
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Abstract
本发明属于药物制剂技术领域，公开了一种脉冲双释放制剂及其制备方法与应用。该脉冲制剂包括双释放片芯和薄膜包衣层，所述的双释放片芯是由药物、含药固体分散体和内层辅料组成。本发明的脉冲双释放制剂在达到时滞后，呈现明显的脉冲双释放行为，双释放片芯快速崩解，速释部分迅速释放药物以达到有效血药浓度，含药固体分散体缓慢释放药物维持有效血药浓度，从而减少服药次数，提高患者的顺应性。达预定时滞后，1h内累积释药百分率大于40％，12h累积释药百分率大于80％。本发明的脉冲双释放制剂的释药时滞通过改变双释放片芯与薄膜包衣层的处方工艺控制时滞为1～13h，以满足任意本领域常规药物防治疾病的高发节律性要求。
The invention belongs to the technical field of pharmaceutical preparations, and discloses a pulsed double-release preparation and a preparation method and application thereof. The pulse preparation comprises a dual-release tablet core and a film coating layer, and the dual-release tablet core is composed of a drug, a drug-containing solid dispersion and an inner layer of auxiliary materials. The pulsed dual-release preparation of the present invention has a delay in reaching, and exhibits obvious pulsed dual-release behavior, the dual-release tablet core disintegrates rapidly, the immediate-release part rapidly releases the drug to achieve an effective blood drug concentration, and the drug-containing solid dispersion slowly releases the drug to maintain Effective blood drug concentration, thereby reducing the frequency of medication and improving patient compliance. There is a delay in reaching the predetermined time, the cumulative drug release percentage within 1 hour is greater than 40%, and the cumulative drug release percentage within 12 hours is greater than 80%. The drug release time delay of the pulsed dual-release preparation of the present invention is controlled to be 1-13 hours by changing the prescription process of the dual-release tablet core and the film coating layer, so as to meet the high-incidence rhythm requirements of any conventional drugs in the field for disease prevention and treatment.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of pulse dual-release preparation and preparation method thereof with answer
With.
Background technique
There is the 1950s scholar to propose the concept of " chronopharmacology ", it is research drug and biorhythmicity phase
The a science of mutual relation is mainly studied according to the curative effect of drug, adverse reaction, pharmacokinetics process and body itself
The temporal rhythm having selects suitable medication time, to reach minimum dose, optimum curative effect, minimum toxicity, to improve disease
The life quality of people.Pulsed drug delivery system is one kind based on chronobiology, chronopharmacology and circadian therapy, from disease
Pathogenetic daily rhythmicity sets out, and single or multiple drug-loading systems for quantitatively discharging drug can be lagged when scheduled.Arteries and veins
Rush drug-delivery preparation has many positive effects in clinical use.Firstly, for some onset peak times, at night, inconvenience is given
The pharmaceutical preparation of the disease of medicine, Pulsed drug delivery system can easily be administered in patient awoke, and drug release when selecting, and realize best
The clinical administration time.Secondly, being avoided that some drugs as long-time stable bacterial drug resistance caused by high blood concentration
Generation and receptor susceptibility decline and generate adverse reaction and drug resistance.In addition, administration number of times can be reduced, improve patient's
Compliance.
The principle that Pulsed drug delivery system designs lag time has diversity, has through magnetic field, temperature, electric field, ultrasound etc.
The pulsatile administration system that polymer architecture is controlled by external factor also has dissolution and Penetration Signature, body according to coating material
Be osmotic pressure variation, material hydrophilic swelling character etc. realize the pulsatile administration system of lag time, and pass through material
The self-adjustable Pulsed drug delivery system of the preparations such as pH sensitive property, competitive binding, zymolyte reaction, concentration of metal ions variation.
There are a variety of Pulsed drug delivery systems after the 1980s, wherein the more typical pulsatile administration for tablet and capsule form
System, the pulse preparation including osmotic pump type, coating type and plunger piston type delayed release, such as pulse of the preparation of multiple-unit pulse at present are micro-
The research of ball also gradually increases.
Currently, there is the late into the night and morning high-incidence rhythmicity mainly around treatment to the research of pulsatile drug delivery system both at home and abroad
The pharmaceutical preparation of disease is unfolded, such as angina pectoris, hypertension, myocardial infarction and cerebral infarction, gastric ulcer, asthma, arthritis, rheumatism
Deng.The pulse preparation listed has Verapamil osmotic pump tablet (Covera-HS, Searle/Alza), Verapamil controlled release glue
Capsule (Verela PM, Elan), diltiazem controlled release tablet (Cardizem XL, Biovail), propranolol controlled release piece
(InnoPran XL, Reliant Pharm), prednisone controlled release tablet (Lodotra, Nitec) etc..
Arthritis is a kind of higher common disease of disease incidence, frequently-occurring disease in the world, is to drastically influence human life quality
Major health problems.Arthritis common sympton has pain, swelling, morning stiffness etc..Modern medicine has been carried out largely arthritis
Research, but pathogenesis is not yet clear, it is considered that the synovial tissue of joint of patient is since many reasons (such as grind for a long time by joint
Damage, immune, environment, heredity etc.) lesion occurs, cause it to ooze out and generate a large amount of inflammatory synovia, arthroedema is caused to increase,
Lead to inflammation and pain.According to chronopharmacology and circadian therapy, arthritis breaking-out has regular hour regularity, patient's
Cardinal symptom such as arthralgia and the stiff pain for mostly aggravating in morning to early morning, keeping patient's receiving very big, seriously affect life
Quality.Development is facilitating administration just before going to bed, in the pulse preparation of the arthritis treatment drug of morning next day drug release, is expected to preferably
Improve these arthritic rhythmicity symptoms, treats patient more effectively.
Diclofenac (Diclofenac), its chemical name is: 2- [(2,6- dichlorophenyl) amino]-phenylacetic acid, point
Minor is C14H11Cl2NO2, structural formula is as follows:
Diclofenac belongs to the potent non-steroidal anti-inflammatory drugs of the third generation, be clinically usually used in rheumatoid arthritis, flesh it is strong scorching,
The anti-inflammatory and analgesia of osteoarthritis, bursal synovitis and other joints or periarticular illness, anti-inflammatory, analgesic activity are compared with other non-steroids
Body anti-inflammatory agent has stronger anti-inflammatory effect and safety.
The indication arthritis of Diclofenac is the disease that morbidity has Attack time.It is related research shows that when morning 2
Left and right medication is more effective compared with other times, which can not only mitigate the pain of patient, and drug is at this moment
It is less side effects.According to chronopharmacology and circadian therapy, in order to mitigate side effect, and because half-life short and morning occur
Peak pain is inconvenient to patient's bring, and present invention design, which is more advantageous to, alleviates morning peak pain, while continuing slowly to release the drug
The pulse dual-release preparation of curative effect on the one is maintained, patient need to only take a medicine at bedtime once, can reach timely and continued treatment
Effect, with realize optimum curative effect, minimum dose, minimal side effect purpose, improve the compliance of patient's long-term administration.
Currently, the dosage form that Diclofenac lists both at home and abroad has tablet (enteric, sustained release), suppository, capsule (common, double to release
Put enteric), granule, cream, liniment, spray etc.；It include liposome, impulse pellet, controlled release tablet and controlled release in lapping compound type
Pellet etc..But it is most of only only around single double releases, sustained release or controlled release.Only have in Dai Fenwei commercialized product at present
The dual drug release feature that enteric is combined with sustained release mainly realizes slow release long-acting effect while avoiding gastrointestinal stimulation.
Reported about the research of Diclofenac Pulsed drug delivery system, be up to lag time after simple quick-release or slow
The Pulsed drug delivery system released cannot play lag fast-pulse drug release when specific simultaneously and relieve pain and continue the dimension that slowly releases the drug
Hold the effect of blood concentration.The representational such as preparation of C14H10Cl2NNaO2 pulsatile release tablets and the research of release Mechanisms, drug release
Time lag is about 4h, when lag 2h when cumulative release up to 90% or so, be simple quick-releasing type pulsatile tablets (Zhang Yi, Qu Yong, Lin Ning
The preparation of C14H10Cl2NNaO2 pulsatile release tablets and the research Hubei College Of Traditional Chinese Medicine journal .2009 of release Mechanisms, 11 (6), 29-
32.).The research of diclofenac sodium pulsatile release pellets, lag time in 0.1%SDS solution are 3.1h, when lag 1.5h
Drug release 80% or so is that (Guo Tao, Zheng Chunli, Song Hongtao, Sui Yin, Chang great Sheng, Sun Xuehui are bis- for simple quick-releasing type impulse pellet
The research Acta Pharmaceutica Sinica .2003 of the fragrant sour sodium pulsatile release pellets of chlorine, 38 (9), 707-710.).Diclofenac Potassium delay sustained release is micro-
The preparation of ball, lag time 4h, when 90% or more lag 6h drug release, for simple slow-release impulse pellet (Hu Xiao, Wu Rui,
Zong Li Diclofenac Potassium postpones preparation and the release in vitro China Medicine University journal .2010 of sustained release pellet, 41 (2), 135-
140.)。
Summary of the invention
In order to overcome the shortcomings and deficiencies of the prior art described above, the primary purpose of the present invention is that providing that a kind of pulse is double to be released
Put preparation.The pulse dual-release preparation is designed according to the Attack time and chronopharmacology principle of disease incidence, through 3~
It is lagged when 5h, double release characteristics with quick-release and sustained release reach the drug release effect of pulsatile once, double releases, can facilitate patient
In just before going to bed (20:00~22:00P.M.) take medicine, onset peak the circadian rhythm period realize pulsed release and when lag
Quick-release and be sustained dual drug release feature, especially arthritic's onset peak the circadian rhythm period (1:00~3:
00A.M.), make blood concentration be rapidly achieved effective treatment concentration to relieve pain, subsequent slow-released part can slowly release the drug and remain effective
Blood concentration realizes maintenance therapy.
Another object of the present invention is to provide a kind of preparation method of above-mentioned pulse dual-release preparation.This method preparation process
It is simple and easy, the lag time of prepared pulse dual-release preparation and up to when the drug release behavior that lags is stably and controllable, reappears
Property it is good, be suitble to industrialized production.
The purpose of the present invention is realized by following proposal:
A kind of pulse dual-release preparation, the pulse preparation include double releasing pieces core and based calcium, double releases
Label is made of drug, drug containing solid dispersions and internal layer auxiliary material.The time lag of drug release is mainly by label internal layer auxiliary material
Type and dosage and the type of based calcium coating material and coating weight gain rate co- controlling.
In the double releasing pieces core, the mass ratio of drug is preferably 1:(0.1 in the drug and drug containing solid dispersions
~10).
The drug containing solid dispersions include mass fraction 3~50% drug and 50~97% carrier material.
Preferably, the drug containing solid dispersions include mass fraction 5~30% drug and 70~95% carrier
Material, each component mass fraction total content are 100%.
The carrier material may include stearic acid, stearyl alcohol, glycerin monostearate, glyceryl monooleate, acrylic acid
Resin, ethyl cellulose, polyethylene glycol, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose and carboxylic first
At least one of base ethyl cellulose.
Preferably, the carrier material includes stearic acid, glycerin monostearate, Utech Eudragit RL, especially
Odd Eudragit RS, cetomacrogol 1000, polyethylene glycol 2000, Macrogol 4000, Macrogol 6000, ethyl cellulose,
At least one of hydroxypropyl methylcellulose phthalate and hydroxypropyl methyl cellulose.
Carrier material of the invention has both carrying medicament and adjusts the effect of rate of releasing drug.It is carried by reasonably combined and adjustment
The drug containing solid dispersions of different rate of releasing drug can be obtained in the composition of body material.
The internal layer auxiliary material may include at least one of filler, disintegrating agent, adhesive and lubricant.
The filler is preferably starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, phosphorus
At least one of sour hydrogen calcium, calcium carbonate, mannitol and sorbierite, more preferably starch, dextrin, lactose, pregelatinized starch and
At least one of microcrystalline cellulose.The dosage of the filler is preferably the 5~80% of double releasing pieces core gross mass, more preferably
It is 10~60%.
The disintegrating agent is preferably dried starch, sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl cellulose (L-
HPC), at least one of croscarmellose sodium (CC-Na), crospovidone (PVPP) and gas-producing disintegrant, it is more excellent
It is selected as sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (CC-Na)
At least one of with crospovidone (PVPP).The dosage of the disintegrating agent be preferably double releasing pieces core gross mass 0~
40%, more preferably 0~25%.
The adhesive is preferably starch slurry, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose
At least one of sodium, ethyl cellulose, povidone, gelatin, Macrogol 4000, Macrogol 6000 and sodium alginate, more
Preferably at least one of starch slurry, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and sodium carboxymethylcellulose.It is described viscous
The dosage of mixture is preferably the 0~30% of double releasing pieces core gross mass, and more preferably 0~20%.
The lubricant is preferably magnesium stearate, superfine silica gel powder, talcum powder, hydrogenated vegetable oil, polyethylene glycols and the moon
At least one of at least one of lauryl sulfate, more preferably talcum powder, magnesium stearate and superfine silica gel powder.The lubrication
The dosage of agent is preferably the 0~30% of double releasing pieces core gross mass, and more preferably 0~10%.
Preferably, in the double releasing pieces core, the content of filler is 10~45wt%, the content of disintegrating agent is 2~
20wt%, the content of adhesive are 0~18wt%, and the content of lubricant is 1~8wt%.
The weight of the based calcium of dual-release preparation of the invention is preferably the 1~50% of double releasing pieces core weight, more
Preferably 3~45%.The based calcium includes coating material and plasticizer, the weight of the coating material, plasticizer
Than being preferably 1:(0~0.5), more preferably 1:(0.05~0.4).The based calcium can also include other packets
The weight ratio of clothing auxiliary material, the coating material, plasticizer and other coating auxiliary materials is preferably 1:(0~0.5): (0~0.6), more
Preferably 1:(0.05~0.4): (0~0.6).
The coating material may include acrylic resin quasi polymer, cellulosic polymer and polyvinyl alcohol Type of Collective
At least one of object；Preferably include Utech Eudragit RL, Utech Eudragit RS, Utech Eudragit RD,
Utech Eudragit NE, Utech Eudragit L100, Utech Eudragit S100, ethyl cellulose, acetate fiber
Element, cellulose acetate phthalate, cellulose acetate benzenetricarboxylic acid ester, hydroxypropyl methylcellulose phthalate and poly-
At least one of vinyl alcohol phthalic acid ester；More preferably include Utech Eudragit RL, Utech Eudragit RS,
Utech Eudragit L100, Utech Eudragit S100, ethyl cellulose and hydroxypropyl methyl cellulose O-phthalic
At least one of acid esters.
The plasticizer may include cochin oil, castor oil, corn oil, liquid paraffin, glyceryl monoacetate, glycerol
Triacetate, triethyl citrate, tributyl citrate, dibutyl sebacate, dibutyl phthalate, phthalic acid two
At least one of ethyl ester, glycerol, propylene glycol and polyethylene glycol；Preferably include castor oil, triethyl citrate, two fourth of decanedioic acid
At least one of ester, dibutyl phthalate, diethyl phthalate, glycerol and propylene glycol.
Other described coating auxiliary materials can be auxiliary material commonly used in the art, such as include antiplastering aid, speed regulator, shading
At least one of agent and pigment.
The double releasing pieces core that pulse dual-release preparation of the invention is made of drug, drug containing solid dispersions and internal layer auxiliary material
It is collectively constituted with based calcium, the present invention provides a kind of formulation systems of the double releases of pulse, wherein the drug and contain
Drug in medicine solid dispersions can be any this field conventional medicine, as may be the same or different be respectively Verapamil,
That sulphur Zhuo, Propranolol, prednisone, theophylline, salbutamol, Lansoprazole and its active optical isomers, dissolve support at Omeprazole
Azoles, Rabeprazole, ranitidine or Diclofenac and its at least one of pharmaceutical salts and its solvate are drawn, it is preferably double
At least one of the fragrant acid of chlorine, its pharmaceutical salts and its solvate.The dosage strengths of the pulse dual-release preparation are total with drug
Content is calculated as 0.5~300mg every.
Pulse dual-release preparation of the invention can be Diclofenac pulse dual-release preparation, be dispersed by drug, drug containing solid
The double releasing pieces core that body and internal layer auxiliary material are constituted is collectively constituted with based calcium, in the drug and drug containing solid dispersions
Drug is at least one of Diclofenac, its pharmaceutical salts and its solvate, dosage strengths are calculated as 5 with Diclofenac~
200mg every.
The present invention also provides a kind of preparation methods of above-mentioned pulse dual-release preparation, comprising the following steps:
(1) preparation of drug containing solid dispersions: weighing drug, carrier material in proportion, first according to carrier material property,
After making it dissolve or melting, drug is added thereto, and is uniformly dispersed, solvent or cooling are removed, drug containing solid point is prepared
Granular media；
Or drug and carrier material are weighed in proportion, it is mixed rear hot-melt extruded, drug containing solid dispersions are prepared；
(2) preparation of double releasing pieces core: weighing drug, drug containing solid dispersions and internal layer auxiliary material in proportion and be uniformly mixed,
Double releasing pieces core is prepared using powder pressing method or granulating tabletting process；
(3) film coating: weighing coating material, plasticizer is mixed and made into coating feed liquid in proportion, with fluidized bed or coating
Pot is coated double releasing pieces core, obtains pulse dual-release preparation.
The double release behaviors of apparent pulse are presented after reaching lag time in pulse dual-release preparation of the invention, double to release
Film releasing core fater disintegration, immediate release section discharge rapidly drug to reach effective blood drug concentration, drug containing solid dispersions slow release
Drug maintains effective blood drug concentration in turn, to reduce medicining times, improves the compliance of patient.Up to it is predetermined when lag, in 1h
Cumulative release percentage is greater than 40%, 12h cumulative release percentage and is greater than 80%.The drug release of pulse dual-release preparation of the invention
Time lag can be 1~13h by changing the formulation and technology of double releasing pieces core and based calcium come control gains, to meet any
The high-incidence rhythmicity requirement for the disease that field conventional medicine is prevented and treated.The double release systems of the Diclofenac pulse provided according to the present invention
The compliance that the morning for the arthritis disease that the drug of agent is prevented and treated high-incidence rhythmicity and patient take, preferably Diclofenac arteries and veins
The lag time for rushing dual-release preparation is 3~5h.
The present invention compared with the existing technology, have the following advantages and the utility model has the advantages that
(1) pulse dual-release preparation structure of the invention is simple, and preparation method is simple, is suitble to industrialization demand.
(2) pulse dual-release preparation of the invention can according to the specific needs of clinical different rhythmicity disease Selecting times,
By adjusting coating material, coating auxiliary material, internal layer auxiliary material, drug containing solid dispersions carrier material etc. type and dosage adjust
Save lag time and drug release rate.It can be used conveniently to prepare arthritis treatment drug or other medicines for having Attack time disease
The pulse preparation of object.
(3) pulse dual-release preparation provided by the invention can realize the time lag of delay drug release, and lag is double when reaching releases
Clearance is that label is disintegrated rapidly, and immediate release section discharges rapidly drug and reaches effective blood drug concentration, and slow-released part slow release maintains
Effective blood drug concentration realizes the timely and effectively preventing to rhythmicity disease.It is more convenient patient's medication feasible, moreover it is possible to reduce
Medicining times improve medication compliance.
Detailed description of the invention
Fig. 1 is the tablets in vitro curve graph of Diclofenac solid dispersions in embodiment 5.
Fig. 2 is the tablets in vitro curve graph of Diclofenac solid dispersions in embodiment 6.
Fig. 3 is the tablets in vitro curve graph of Diclofenac solid dispersions in embodiment 7.
Fig. 4 is the tablets in vitro curve graph of Diclofenac solid dispersions in embodiment 9.
Fig. 5 is the tablets in vitro curve graph of Diclofenac pulse dual-release preparation in embodiment 11,14,17,18, wherein
A, B, C, D respectively correspond embodiment 11,14,17,18.
Fig. 6 is the tablets in vitro curve graph of Diclofenac pulse dual-release preparation in embodiment 20,23,26,27, wherein
A, B, C, D respectively correspond embodiment 20,23,26,27.
Fig. 7 is the tablets in vitro curve graph of Diclofenac pulse dual-release preparation in embodiment 32,39,42,43, wherein
A, B, C, D respectively correspond embodiment 32,39,42,43.
Fig. 8 is the tablets in vitro curve graph of Diclofenac pulse dual-release preparation in embodiment 46,47,48,49, wherein
A, B, C, D respectively correspond embodiment 46,47,48,49.
Fig. 9 is the tablets in vitro curve graph of Diclofenac pulse dual-release preparation in embodiment 52,55,56,57, wherein
A, B, C, D respectively correspond embodiment 52,55,56,57.
Figure 10 is the tablets in vitro curve graph of Diclofenac pulse dual-release preparation in embodiment 60.
Specific embodiment
Below with reference to embodiment and attached drawing, the present invention is described in further detail, but embodiments of the present invention are unlimited
In this.
Drug used in the following embodiment is at least one of Diclofenac and its pharmaceutical salts, and reagent used comes
Source is commercially available.
Embodiment 1: the preparation of drug containing solid dispersions
By drug: stearyl alcohol: polyethylene glycol 2000 is with weight ratio 1:(1~6): (0~0.5) mixing is dispersed using melting
Cooling is prepared drug containing solid dispersions or drug containing solid dispersions is prepared using hot-melt extruded method after uniformly.
Embodiment 2: the preparation of drug containing solid dispersions
By drug: stearic acid: stearyl alcohol is with weight ratio 1:3:0.02 mixing, and cooling is prepared into after being uniformly dispersed using melting
Drug containing solid dispersions are prepared to drug containing solid dispersions or using hot-melt extruded method.
Embodiment 3: the preparation of drug containing solid dispersions
By drug: stearic acid: stearyl alcohol is with weight ratio 1:(1~5): (0~0.5) mixing, after being uniformly dispersed using melting
Cooling is prepared drug containing solid dispersions or drug containing solid dispersions is prepared using hot-melt extruded method.
Embodiment 4: the preparation of drug containing solid dispersions
By drug: polyethylene glycol (4000 or 6000) is with weight ratio 1:(1~6) mixing, it is cold after being uniformly dispersed using melting
But drug containing solid dispersions are prepared；Or drug and polyethylene glycol are dissolved in 80% ethyl alcohol, mixed solution is made, it removes molten
Drug containing solid dispersions are prepared in agent.
Embodiment 5: the preparation of drug containing solid dispersions
By drug (DS): Eudragit RL is with weight ratio 1:(1~7) mixing, it is dissolved in dehydrated alcohol and removes after mixing
Solvent is prepared drug containing solid dispersions or drug containing solid dispersions is prepared using hot-melt extruded method.To different proportion
The release in vitro performance for the drug containing solid dispersions being prepared is detected, the result is shown in Figure 1.As seen from Figure 1, with carrier material
Expect the increase of dosage, sustained drug release effect is gradually obvious.
Embodiment 6: the preparation of drug containing solid dispersions
By drug (DS): Eudragit RL:Eudragit RS is with weight ratio 1:(1~7): (0~4) mixing is dissolved in nothing
Water-ethanol removes solvent after mixing, and drug containing solid dispersions are prepared or drug containing is prepared using hot-melt extruded method and consolidate
Body dispersion.The release in vitro performance for the drug containing solid dispersions that different proportion is prepared is detected, as a result sees Fig. 2.
From Figure 2 it can be seen that burst drug release phenomenon weakens, and slow release effect is more preferable with the reduction of Eudragit RS dosage.
Embodiment 7: the preparation of drug containing solid dispersions
By drug (DS): Eudragit RL: ethyl cellulose is with weight ratio 1:(1~7): (0~5) mixing is dissolved in anhydrous
Ethyl alcohol removes solvent after mixing, and drug containing solid dispersions are prepared；Or drug containing is prepared using hot-melt extruded method and consolidates
Body dispersion.The release in vitro performance for the drug containing solid dispersions that different proportion is prepared is detected, as a result sees Fig. 3.
As seen from Figure 3, it is easy to cause burst release when ethyl cellulose is excessively high, and cannot achieve slow release effect.
Embodiment 8: the preparation of drug containing solid dispersions
By drug: hydroxypropyl methyl cellulose is with weight ratio 1:(1~7) mixing, it is prepared and is contained using hot-melt extruded method
Medicine solid dispersions；Or drug and hydroxypropyl methyl cellulose are dissolved in 80% ethyl alcohol, mixed solution is made, remove solvent system
It is standby to obtain drug containing solid dispersions.
Embodiment 9: the preparation of drug containing solid dispersions
By drug (DS): ethyl cellulose (EC): hydroxypropyl methyl cellulose (HPMC) is with weight ratio 1:(1~10): (0
~5) it mixes, is dissolved in dehydrated alcohol and removes solvent after mixing, drug containing solid dispersions are prepared；Or utilize hot-melt extruded
Drug containing solid dispersions are prepared in method.Its release in vitro performance is detected, as a result sees Fig. 4.From fig. 4, it can be seen that hydroxypropyl
Methylcellulose can promote the release of drug, and dosage is more, the easier dissolution of drug.Thus, it may be preferable to by drug (DS): second
Base cellulose (EC): drug containing solid dispersions are prepared with weight ratio 1:6:0.5 in hydroxypropyl methyl cellulose (HPMC).
Embodiment 10: the preparation of drug containing solid dispersions
By drug (DS): ethyl cellulose (EC): polyethylene glycol (1000 or 2000 or 4000) is with weight ratio 1:6.5:0.2
Mixing, is dissolved in dehydrated alcohol and removes solvent after mixing, drug containing solid dispersions are prepared；Or utilize hot-melt extruded legal system
It is standby to obtain drug containing solid dispersions.
Embodiment 11: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 2 are prepared point
It is granular media 53.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 35.7%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.0%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 5.0h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 40%, 12h
Product dissolution percentage is greater than 80%.Tablets in vitro curve is shown in Fig. 5 A.
Embodiment 12: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 2 are prepared point
It is granular media 53.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 5:5) 35.7%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.0%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 6.3h.
Embodiment 13: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 2 are prepared point
It is granular media 53.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 3:7) 35.7%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.0%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 7.5h.
Embodiment 14: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid dispersion that C14H10Cl2NNaO2 4%, embodiment 2 are prepared
Body 55.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 33.5%, croscarmellose sodium 5.0%, micro mist
Silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 1.6%, Eudragit RS 0.8%, EC T7
0.6%, triethyl citrate 0.3%, talcum powder 0.5% add 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula,
Obtained double releasing pieces core is coated using pan coating method or fluidized bed, coating weight gain rate is 3.0%.The present embodiment
The lag time of pulse dual-release preparation is about 8.5h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 40%,
12h average accumulated dissolves out percentage and is greater than 80%.Tablets in vitro curve is shown in Fig. 5 B.
Embodiment 15: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid dispersion that C14H10Cl2NNaO2 4%, embodiment 2 are prepared
Body 51.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 37.5%, croscarmellose sodium 5.0%, micro mist
Silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6%, talcum powder 0.25% add 90% ethyl alcohol to 100%.It prepares and is coated by above-mentioned formula
Liquid is coated obtained double releasing pieces core using pan coating method or fluidized bed, and coating weight gain rate is 7.0%.This implementation
The lag time of the pulse dual-release preparation of example is about 2.0h.
Embodiment 16: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid dispersion that C14H10Cl2NNaO2 4%, embodiment 2 are prepared
Body 51.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 37.5%, croscarmellose sodium 5.0%, micro mist
Silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 1.0%, Eudragit RS 1.25%, EC T7
0.75%, triethyl citrate 0.6%, talcum powder 0.25% add 90% ethyl alcohol to 100%.It prepares and is coated by above-mentioned formula
Liquid is coated obtained double releasing pieces core using pan coating method or fluidized bed, and coating weight gain rate is 7.9%.This implementation
The lag time of the pulse dual-release preparation of example is about 4.5h.
Embodiment 17: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid dispersion that C14H10Cl2NNaO2 4%, embodiment 2 are prepared
Body 51.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 37.5%, croscarmellose sodium 5.0%, micro mist
Silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 1.0%, Eudragit RS 1.25%, EC T7
0.75%, triethyl citrate 0.6%, talcum powder 0.25% add 90% ethyl alcohol to 100%.It prepares and is coated by above-mentioned formula
Liquid is coated obtained double releasing pieces core using pan coating method or fluidized bed, and coating weight gain rate is 5.1%.This implementation
The lag time of the pulse dual-release preparation of example is about 9.2h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than
40%, 12h average accumulated dissolve out percentage and are greater than 80%.Tablets in vitro curve is shown in Fig. 5 C.
Embodiment 18: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 5.2%, embodiment 10 are prepared point
It is granular media 50.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 37.3%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6%, talcum powder 0.25% add 90% ethyl alcohol to 100%.It prepares and is coated by above-mentioned formula
Liquid is coated obtained double releasing pieces core using pan coating method or fluidized bed, and coating weight gain rate is 8.1%.This implementation
The lag time of the pulse dual-release preparation of example is about 4.9h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than
40%, 12h average accumulated dissolve out percentage and are greater than 80%.Tablets in vitro curve is shown in Fig. 5 D.
Embodiment 19: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 2 are prepared point
It is granular media 53.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 35.7%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed in addition to superfine silica gel powder, addition starch slurry (20.0wt%) is made soft in right amount
Material, wet granulation are added superfine silica gel powder after dry and mix, and tabletting obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.8%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 5.2h.
Embodiment 20: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 2 are prepared point
It is granular media 53.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 35.7%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed in addition to superfine silica gel powder, it is suitable that sodium carboxymethylcellulose (5.0wt%) is added
Softwood is made in amount, and wet granulation is added superfine silica gel powder after dry and mixes, and tabletting obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.2%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 5.5h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 40%, 12h
Product dissolution percentage is greater than 80%.Tablets in vitro curve is shown in Fig. 6 A.
Embodiment 21: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 5.2%, embodiment 9 are prepared point
It is granular media 50.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 37.3%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 1.13%, Eudragit RS 1.13%, EC
T7 0.75%, triethyl citrate 0.6%, talcum powder 0.5% add 90% ethyl alcohol to 100%.It prepares and wraps by above-mentioned formula
Clothing liquid is coated obtained double releasing pieces core using pan coating method or fluidized bed, and coating weight gain rate is 7.6%.This reality
The lag time for applying the pulse dual-release preparation of example is about 2.0h.
Embodiment 22: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 2 are prepared point
It is granular media 53.0%, microcrystalline cellulose-pregelatinized starch (weight ratio 7:3) 35.7%, croscarmellose sodium 5.0%, micro-
Powder silica gel 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 7.8%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.7h。
Embodiment 23: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 9 are prepared point
Granular media 53.0%, microcrystalline cellulose-lactose (weight ratio 5:5) 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder
2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 7.7%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.5h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 50%, 12h average accumulated dissolution percentage be greater than
85%.Tablets in vitro curve is shown in Fig. 6 B.
Embodiment 24: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 9 are prepared point
Granular media 53.0%, microcrystalline cellulose-lactose (weight ratio 7:3) 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder
2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 7.6%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.3h。
Embodiment 25: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 9 are prepared point
Granular media 53.0%, microcrystalline cellulose 31.7%, croscarmellose sodium 10.0%, talcum powder 1.5%.By aforementioned proportion group
Divide and be uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 7.3%.The lag time of the pulse dual-release preparation of the present embodiment is about
2.8h。
Embodiment 26: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, magnesium stearate 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 7.7%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.0h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 60%, 12h average accumulated dissolution percentage be greater than
90%.Tablets in vitro curve is shown in Fig. 6 C.
Embodiment 27: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.2%, embodiment 10 are prepared point
Granular media 58.0%, microcrystalline cellulose 28.8%, croscarmellose sodium 5.0%, talcum powder 5.0%.By aforementioned proportion group
Divide and be uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.3%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.5h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 6 D.
Embodiment 28: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.2%, embodiment 9 are prepared point
Granular media 58.0%, microcrystalline cellulose 27.8%, croscarmellose sodium 5.0%, superfine silica gel powder-magnesium stearate-talcum powder
(weight ratio 1:1:1) 6.0%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.6%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.7h.
Embodiment 29: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.2%, embodiment 9 are prepared point
Granular media 58.0%, microcrystalline cellulose 30.8%, croscarmellose sodium 5.0%, superfine silica gel powder-magnesium stearate-talcum powder
(weight ratio 5:3:2) 3.0%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.4%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.6h.
Embodiment 30: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 9 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 3.0%, microcrystalline cellulose 32.7%, croscarmellose sodium 5.0%, micro mist silicon
Glue 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 8.4%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.5h。
Embodiment 31: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 5.0%, microcrystalline cellulose 30.7%, croscarmellose sodium 5.0%, micro mist silicon
Glue 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 8.0%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.5h。
Embodiment 32: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 5.0%, microcrystalline cellulose 30.7%, croscarmellose sodium 5.0%, micro mist silicon
Glue 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, phthalic acid
Diethylester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to institute
Double releasing pieces core obtained is coated, and coating weight gain rate is 8.3%.The lag time of the pulse dual-release preparation of the present embodiment
About 4.2h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 60%, 12h average accumulated dissolution percentage it is big
In 90%.Tablets in vitro curve is shown in Fig. 7 A.
Embodiment 33: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 5.0%, microcrystalline cellulose 30.7%, croscarmellose sodium 5.0%, micro mist silicon
Glue 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.3% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 5.8%.The lag time of the pulse dual-release preparation of the present embodiment is about
1.1h。
Embodiment 34: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 5.0%, microcrystalline cellulose 30.7%, croscarmellose sodium 5.0%, micro mist silicon
Glue 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 6.5%.The lag time of the pulse dual-release preparation of the present embodiment is about
2.4h。
Embodiment 35: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 5.0%, microcrystalline cellulose 30.7%, croscarmellose sodium 5.0%, micro mist silicon
Glue 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 4.9%.The lag time of the pulse dual-release preparation of the present embodiment is about
1.7h。
Embodiment 36: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 9 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 5.0%, microcrystalline cellulose 30.7%, croscarmellose sodium 5.0%, micro mist silicon
Glue 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 3.0%, EC T7 1.0%, triethyl citrate
0.8%, add 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core is coated, and coating weight gain rate is 4.8%.The lag time of the pulse dual-release preparation of the present embodiment is about
1.9h。
Embodiment 37: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 9 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 6.0%, microcrystalline cellulose 28.7%, croscarmellose sodium 5.0%, talcum powder
3.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 8.5%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.7h。
Embodiment 38: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 9 are prepared point
Granular media 53.0%, hydroxypropyl cellulose 9.0%, microcrystalline cellulose 26.2%, croscarmellose sodium 5.0%, stearic acid
Magnesium 3.0%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 8.8%.The lag time of the pulse dual-release preparation of the present embodiment is about
4.0h。
Embodiment 39: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed in addition to superfine silica gel powder, and hydroxypropyl methyl cellulose (8.0wt%) is added and is made softwood in right amount, wet granulation,
Superfine silica gel powder is added after drying to mix, tabletting obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.3%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.9h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 7 B.
Embodiment 40: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): EC T7 3%, triethyl citrate 0.6%, adds 90% ethyl alcohol extremely
100%.Coating solution is prepared by above-mentioned formula, obtained double releasing pieces core is coated using pan coating method or fluidized bed,
Coating weight gain rate is 6.8%.The lag time of the pulse dual-release preparation of the present embodiment is about 4.3h.
Embodiment 41: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.1%, EC T7 0.9%, triethyl citrate
0.6%, add 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core is coated, and coating weight gain rate is 6.9%.The lag time of the pulse dual-release preparation of the present embodiment is about
1.3h。
Embodiment 42: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 7.3%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.1h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 60%, 12h average accumulated dissolution percentage be greater than
90%.Tablets in vitro curve is shown in Fig. 7 C.
Embodiment 43: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, crospovidone 5.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is mixed
Uniformly, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 2.25%, EC T7 0.75%, lemon triethylenetetraminehexaacetic acid
Ester 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained
Double releasing pieces core be coated, coating weight gain rate be 7.8%.The lag time of the pulse dual-release preparation of the present embodiment is about
3.1h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 60%, 12h average accumulated dissolution percentage be greater than
90%.Tablets in vitro curve is shown in Fig. 7 D.
Embodiment 44: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 4.5%, embodiment 10 are prepared point
Granular media 48.0%, microcrystalline cellulose 40.0%, crospovidone 5.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is mixed
Uniformly, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit L100 3.0%, triethyl citrate 0.45%, adds
90% ethyl alcohol is to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained double releasing pieces
Core is coated, and coating weight gain rate is 15%.The lag time of the pulse dual-release preparation of the present embodiment is about 2.2h.
Embodiment 45: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 4.5%, embodiment 10 are prepared point
Granular media 48.0%, microcrystalline cellulose 40.0%, crospovidone 5.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is mixed
Uniformly, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit S100 3.0%, triethyl citrate 0.45%, adds
90% ethyl alcohol is to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to obtained double releasing pieces
Core is coated, and coating weight gain rate is 25%.The lag time of the pulse dual-release preparation of the present embodiment is about 2.9h.
Embodiment 46: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 4.5%, embodiment 10 are prepared point
Granular media 48.0%, microcrystalline cellulose 40.0%, crospovidone 5.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is mixed
Uniformly, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit L100 1.5%, Eudragit S100 1.5%, lemon
Lemon triethylenetetraminehexaacetic acid ester 0.45% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidisation
Bed is coated obtained double releasing pieces core, and coating weight gain rate is 30%.The pulse dual-release preparation of the present embodiment is released
Medicine time lag is about 3.2h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 60%, 12h average accumulated dissolution hundred
Rate is divided to be greater than 90%.Tablets in vitro curve is shown in Fig. 8 A.
Embodiment 47: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 4.5%, embodiment 10 are prepared point
Granular media 48.0%, microcrystalline cellulose 40.0%, crospovidone 5.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is mixed
Uniformly, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): hydroxypropyl methylcellulose phthalate 3.0%, citric acid three
Ethyl ester 0.45% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating method or fluidized bed to institute
Double releasing pieces core obtained is coated, and coating weight gain rate is 25%.The lag time of the pulse dual-release preparation of the present embodiment
About 2.6h.Up to when lag, drug 1h average accumulated dissolution percentage be greater than 60%, 12h average accumulated dissolution percentage it is big
In 90%.Tablets in vitro curve is shown in Fig. 8 B.
Embodiment 48: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, sodium carboxymethyl starch 5.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is mixed
It closes uniformly, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.2%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.9h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 8 C.
Embodiment 49: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, low-substituted hydroxypropyl cellulose 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.7%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.8h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 8 D.
Embodiment 50: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 37.7%, croscarmellose sodium-low-substituted hydroxypropyl cellulose (weight ratio 8:2)
3.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.4%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 4.1h.
Embodiment 51: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 30.7%, croscarmellose sodium-low-substituted hydroxypropyl cellulose (weight ratio 5:5)
10.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.1%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.9h.
Embodiment 52: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 28.7%, croscarmellose sodium-low-substituted hydroxypropyl cellulose-crospovidone
(weight ratio 1:1:1) 12.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double release
Film releasing core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.9%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.8h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 9 A.
Embodiment 53: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 25.7%, croscarmellose sodium-low-substituted hydroxypropyl cellulose-carboxymethyl starch
Sodium (weight ratio 1:1:1) 15.0%, superfine silica gel powder 2.5%.Aforementioned proportion component is uniformly mixed, direct powder compression obtains double
Discharge label.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.3%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 4.0h.
Embodiment 54: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 16%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 7.5h.
Embodiment 55: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 9.5%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 4.5h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 9 B.
Embodiment 56: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that Diclofenac Potassium 3.5%, embodiment 10 are prepared point
Granular media 55.0%, microcrystalline cellulose 34%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion group
Divide and be uniformly mixed, direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.0%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.7h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 9 C.
Embodiment 57: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 5.8%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 2.0h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Fig. 9 D.
Embodiment 58: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 1.0%, Eudragit RS 1.25%, EC T7
0.75%, triethyl citrate 0.6%, magnesium stearate 0.25% add 90% ethyl alcohol to 100%.It prepares and wraps by above-mentioned formula
Clothing liquid is coated obtained double releasing pieces core using pan coating method or fluidized bed, and coating weight gain rate is 8.0%.This reality
The lag time for applying the pulse dual-release preparation of example is about 3.3h.
Embodiment 59: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.2%, embodiment 10 are prepared point
Granular media 58.0%, microcrystalline cellulose 31.3%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.9% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.8%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 5.5h.
Embodiment 60: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed in addition to superfine silica gel powder, starch slurry (20.0wt%) is added, softwood is made in right amount, wet granulation is added after dry
Superfine silica gel powder mixes, and tabletting obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 7.4%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.3h.Up to when lag, it is averagely tired that drug in 1h average accumulated dissolution percentage is greater than 60%, 12h
Product dissolution percentage is greater than 90%.Tablets in vitro curve is shown in Figure 10.
Embodiment 61: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.8%, embodiment 10 are prepared point
Granular media 53.0%, microcrystalline cellulose 35.7%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed in addition to superfine silica gel powder, sodium carboxymethylcellulose (5.0wt%) is added, softwood is made in right amount, wet granulation is done
Superfine silica gel powder is added after dry to mix, tabletting obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 0.45%, Eudragit RS 1.8%, EC T7
0.75%, triethyl citrate 0.6% adds 90% ethyl alcohol to 100%.Coating solution is prepared by above-mentioned formula, using pan coating
Method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 8.6%.The double releases of the pulse of the present embodiment
The lag time of preparation is about 3.9h.
Embodiment 62: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.2%, embodiment 10 are prepared point
Granular media 58.0%, microcrystalline cellulose 31.3%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium be coated formula of liquid (g/mL): Eudragit RL 30D 50.0%, triethyl citrate 1.5%,
Glycerin monostearate 0.75%, Tween 80 0.3%, add water to 100%.By above-mentioned formula by Tween 80, triethyl citrate
After being dispersed in water with glycerin monostearate, it is sieved after mixing with Eudragit RL 30D dispersion, using pot
Coating method or fluidized bed are coated obtained double releasing pieces core, and coating weight gain rate is 3.1%.The pulse of the present embodiment is double
The lag time of delivery formulations is about 9.1h.
Embodiment 63: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.2%, embodiment 10 are prepared point
Granular media 58.0%, microcrystalline cellulose 31.3%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium be coated formula of liquid (g/mL): Eudragit RL 30D 50.0%, triethyl citrate 1.5%,
Talcum powder 7.5%, adds water to 100%.After talcum powder, triethyl citrate are dispersed in water by above-mentioned formula, with
Eudragit RL 30D dispersion is sieved after mixing, using pan coating method or fluidized bed to obtained double releasing pieces core
It is coated, coating weight gain rate is 3.0%.The lag time of the pulse dual-release preparation of the present embodiment is about 12.5h.
Embodiment 64: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that C14H10Cl2NNaO2 3.2%, embodiment 10 are prepared point
Granular media 58.0%, microcrystalline cellulose 31.3%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 30D 16.7%, Eudragit RS 30D
33.3%, triethyl citrate 1.5%, talcum powder 7.5%, add water to 100%.By above-mentioned formula by talcum powder, citric acid three
It after ethyl ester is dispersed in water, is sieved after mixing with Eudragit dispersion, using pan coating method or fluidized bed to institute
Double releasing pieces core obtained is coated, and coating weight gain rate is 3.1%.The lag time of the pulse dual-release preparation of the present embodiment
About 10.7h.
Embodiment 65: the preparation of pulse dual-release preparation
Double releasing pieces core formula (mass fraction): the drug containing solid that Diclofenac Potassium 4.5%, embodiment 10 are prepared point
Granular media 45.0%, microcrystalline cellulose 43.0%, croscarmellose sodium 5.0%, superfine silica gel powder 2.5%.By aforementioned proportion
Component is uniformly mixed, and direct powder compression obtains double releasing pieces core.
Based calcium is coated formula of liquid (g/mL): Eudragit RL 30D 20.0%, Eudragit RS 30D
30.0%, triethyl citrate 1.5%, talcum powder 7.5%, add water to 100%.By above-mentioned formula by talcum powder, citric acid three
It after ethyl ester is dispersed in water, is sieved after mixing with Eudragit dispersion, using pan coating method or fluidized bed to institute
Double releasing pieces core obtained is coated, and coating weight gain rate is 3.0%.The lag time of the pulse dual-release preparation of the present embodiment
About 9.8h.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510249751.1A CN104856971B (en) | 2015-05-15 | 2015-05-15 | A kind of pulse dual-release preparation and the preparation method and application thereof |
Applications Claiming Priority (1)
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| CN1650847A (en) * | 2004-02-04 | 2005-08-10 | 上海医药工业研究院 | A kind of albuterol time-controlled pulse sustained-release oral preparation and preparation method thereof |
| CN101094661A (en) * | 2004-11-04 | 2007-12-26 | 阿斯利康(瑞典)有限公司 | Modified release tablet formulations for proton pump inhibitors |
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| CN1650847A (en) * | 2004-02-04 | 2005-08-10 | 上海医药工业研究院 | A kind of albuterol time-controlled pulse sustained-release oral preparation and preparation method thereof |
| CN101094661A (en) * | 2004-11-04 | 2007-12-26 | 阿斯利康(瑞典)有限公司 | Modified release tablet formulations for proton pump inhibitors |
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