CN105796522B - Pulsatile release tablets containing fluticasone furoate and Vilantro and preparation method - Google Patents
Pulsatile release tablets containing fluticasone furoate and Vilantro and preparation method Download PDFInfo
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- CN105796522B CN105796522B CN201410841069.7A CN201410841069A CN105796522B CN 105796522 B CN105796522 B CN 105796522B CN 201410841069 A CN201410841069 A CN 201410841069A CN 105796522 B CN105796522 B CN 105796522B
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Abstract
The present invention provides the pulsatile release tablets of a kind of fluticasone furoate and Vilantro, which can reach blood concentration at midnight and early morning, to achieve the purpose that circadian therapy.The pulsatile release tablets include two parts of floating layer and label.Floating layer uses hydrophilic macromolecule and fatty alcohol for auxiliary material, when making it that can be detained regular hour tablet and gastric juice in stomach to contact, floating layer surface hydration, which forms gel, makes volume expansion, when less than gastric juice density, just drift is suspended from gastric content, with the bulk erosion of floating layer, expose label, to make drug be released from label.
Description
Technical field
The invention belongs to medicinal chemistry arts, in particular to a kind of arteries and veins containing fluticasone furoate and Vilantro
Rush controlled release tablet and preparation method.
Background technology
Bronchial asthma be by various kinds of cell (such as eosinophil, mast cell, T lymphocytes, neutrophil leucocyte,
Human airway epithelial cells etc.) and cellular component participation chronic airway inflammation illness.This chronic inflammation leads to airway hyperreactivity
Generation, generally occur within changeable reversible airflow limitation extensively, and cause the panting, is out of breath of recurrent exerbation, uncomfortable in chest or cough
Etc. symptoms, often night and (or) morning breaking-out, most of patients can voluntarily alleviate or through treatment alleviate.
Chronic Obstructive Pulmonary Disease (COPD) is a kind of chronic bronchitis and (or) lung qi with airflow obstruction feature
It is swollen, it can be further development of pulmonary heart disease and the common chronic disease of respiratory failure, it is scorching with the exception of pernicious gas and deleterious particle
Disease reaction is related, and disability rate and case fatality rate are very high, and 40 years old global or more incidence has been up to 9%~10%.The disease clinical manifestation
Symptom has chronic cough, and especially daystart cough is apparent, and there are paroxysmal cough or expectoration at night, may be cured all the life with disease.
BREO ELLIPTA are inhaled glucocorticoid fluticasone furoates (FF) and Vilantro (VI) one time a day
Compound medicine Foradil Aerolizer formoterol fumarate, be used for chronic obstructive pulmonary disease (COPD) and asthma treatment.But the Foradil Aerolizer formoterol fumarate is also
It can not solve to improve pulmonary deposition ratio and reduce the contradiction between patient's maximal inspiratory flow rate.This for suffering from copd patient and
The case where speech is quite unfavorable, and there are patient's poor compliances.Also, the use of the dosage form can be by patient age or physiological status
Influence, the infant weaker to respiratory muscle strength, the patient of the old and the weak and severe asthma attacks patient using having difficulties, because
It is difficult to reach the air-breathing speed of inhalator requirement for this kind of patient's some, some is difficult to learn the proper use of of Foradil Aerolizer formoterol fumarate.
In addition, existing Foradil Aerolizer formoterol fumarate product is there is also cost is high, the disadvantage of operating procedure complexity.
On the other hand, chronic obstructive pulmonary disease (COPD) and asthma are usually broken out in morning and early morning, and daytime is alleviated, and shows
Some conventional tablets cannot be guaranteed blood concentration in morning 3-4 point, although sustained release tablets can keep blood medicine in a long time
Concentration, but blood concentration has Wave crest and wave trough, is easy to cause the generation of preparation toxicity, influences drug safety.
The pulsatile release tablets containing fluticasone furoate and Vilantro that therefore, it is necessary to a kind of, the pulsatile release tablets can be half
Night and early morning reach blood concentration, to achieve the purpose that circadian therapy.
Invention content
The present invention provides the pulsatile release tablets of a kind of fluticasone furoate and Vilantro, which can be half
Night and early morning reach blood concentration, to achieve the purpose that circadian therapy.
Pulsatile release tablets of the present invention include two parts of floating layer and label.The floating layer is by hydrophily high score
Son, fatty alcohol and lubricant are constituted, and when making it that can be detained regular hour tablet in stomach to contact with gastric juice, float layer surface
Aquation, which forms gel, makes volume expansion, and when less than gastric juice density, just drift is suspended from gastric content, molten with the skeleton of floating layer
Erosion exposes label, to make drug be released from label.
The present invention solves the problems, such as that tablet prepared by general technology can not float and is suspended from gastric content, to obtain
Pulsatile release tablets.Present invention employs diameter 3-6mm slice, thin pieces are prepared as label, excessive can not float of label density is avoided to cause
Can not time lag drug release, the preferred 4-6mm of piece core diameter.The floating layer of the present invention and the weight ratio of label are more than 5 simultaneously:1 (does not calculate
Water and ethyl alcohol), preferably 10:1-5:1, pulsatile release tablets could be obtained；When floating layer and the weight ratio of label are less than 5:When 1, piece
Sub- density, which is crossed serious offense and can not be floated, leads to not time lag drug release.
When preparing piece slug particle, granulation is prepared using the 20-25 mesh of common process, is that be unable to get content uniform
Tablet, present invention employs 60 mesh prepare granulation be the problem that can effectively solve the problem that tablet content is uniform.
Hydrophilic macromolecule of the present invention includes sodium alginate, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose,
Hydroxyethyl cellulose it is one or more；The fatty alcohol includes lauryl alcohol, tetradecyl alchohol, hexadecanol, one kind of octadecyl alcolol or
It is a variety of.
Label of the present invention includes immediate release section, controlled release portion, immediate release section and the additional lubricant of controlled release portion.Wherein
Immediate release section discharges rapidly drug, and drug is made to be rapidly achieved the blood concentration of therapeutically effective amount, controlled release portion Drug controlled release
Rate, it is in 0 grade of high order smooth pattern release profiles to make drug release patterns.
The immediate release section is by main ingredient, filler, disintegrant, adhesive composition.
The controlled release portion is by main ingredient, filler, disintegrant, enteric material composition.
It is fluticasone furoate and Vilantro in the main ingredient,
The filler is one or more compositions of lactose, mannitol, sorbierite, microcrystalline cellulose, starch.
The adhesive is one or more compositions of hydroxypropyl methyl cellulose, povidone k30, second alcohol and water.
The enteric material include be not limited to trade name Eudragit L100, Eudragit L100-55,
The pharmaceutic adjuvant of Eudragit L30-55, KollicoatMAE30DP or KollicoatMAE100P.
The disintegrant is croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinking
One or more compositions of povidone.
The lubricant be magnesium stearate, sodium stearyl fumarate, talcum powder, superfine silica gel powder, hydrogenated vegetable oil one
Kind or a variety of compositions.
The invention further relates to the preparation method of a kind of fluticasone furoate and the pulsatile release tablets of Vilantro, including it is as follows
Step：
(1) preparation of label,
A. the preparation of immediate release section particle：By fluticasone furoate and Vilantro (15：2~7, wt/wt), disintegrant,
Filler is uniformly mixed, and adhesive is sprayed on powder with fluid bed and is pelletized, 40-50 DEG C of drying, with 60 mesh sieves；
B. the preparation of controlled release portion particle：By fluticasone furoate and Vilantro (3：1~2, wt/wt), disintegrant, fill out
It fills agent to be uniformly mixed, enteric material is sprayed on powder with fluid bed and is pelletized, 40-50 DEG C of drying, 60 mesh sieves are uniform；
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die pressure of a diameter of 3-6mm
Label is made in piece；
(2) preparation of floating layer,
By hydrophilic macromolecule and fatty alcohol, mix lubricant is uniformly to obtain the final product；
(3) tabletting
Floating layer powder is wrapped up into label, tabletting to obtain the final product.
Description of the drawings
20 hours release profiles of Vilantro in pulsatile release tablets made from Fig. 1 Examples 1 to 6 and ordinary tablet.
20 hours release profiles of fluticasone furoate in pulsatile release tablets made from Fig. 2 Examples 1 to 6 and ordinary tablet.
Fluticasone furoate is average after Fig. 3 experimental animals take pulsatile release tablets made from Examples 1 to 6 and ordinary tablet
Plasma concentration curve figure.
Fig. 4 experimental animals take pulsatile release tablets made from Examples 1 to 6 and the Vilantro after ordinary tablet is averaged blood
Concentration curve graph.
Specific implementation mode
The formula of the pulsatile release tablets of 1. fluticasone furoate of embodiment and Vilantro and preparation
1. Core formulation (20000)
A. immediate release section prescription：10.0g fluticasone furoates, 2.0g Vilantros, 20.0g low substituted hydroxy-propyl fibers
Element, 200.0g lactose, 2.0g povidone k30.
B. controlled release portion prescription：20.0g fluticasone furoates, 10.0g Vilantros, 30.0g low substituted hydroxy-propyl fibers
Element, 250.0g lactose；40.0g Eudragit L100.
C. lubricant：3.0g magnesium stearate
2. floating layer prescription
800.0g hydroxypropyl methyl celluloses (HPMC), 2200.0g lauryl alcohols, 20.0g magnesium stearates.
3. preparation method：
(1) preparation of label
A. the preparation of immediate release section particle：By fluticasone furoate and Vilantro, low-substituted hydroxypropyl cellulose, lactose
It is uniformly mixed, 2% povidone k30 aqueous solutions is sprayed on powder with fluid bed and are pelletized, 40-50 DEG C of drying, 60 mesh whole grains.
B. the preparation of controlled release portion particle：By fluticasone furoate and Vilantro, replace hydroxypropyl cellulose, lactose mixed
It closes uniformly, 50% ethanol solution of Eudragit L100 is sprayed on powder with fluid bed and is pelletized, dry, 60 mesh whole grains.
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die tabletting of a diameter of 3mm,
Label is made.
(2) preparation of floating layer
By hydroxypropyl methyl cellulose, lauryl alcohol, magnesium stearate is uniformly mixed.
(3) tabletting
Floating layer powder is wrapped up into label, carries out tabletting.
The formula of the pulsatile release tablets of 2. fluticasone furoate of embodiment and Vilantro and preparation
1. Core formulation (20000)
A. immediate release section prescription：20.0g fluticasone furoates, 4.0g Vilantros, 20.0g cross-linked carboxymethyl celluloses
Sodium, 100.0g mannitol, 100.0g microcrystalline celluloses, 3.0g povidone k30.
B. controlled release portion prescription：30.0g fluticasone furoates, 16.0g Vilantros, 40.0g cross-linked carboxymethyl celluloses
Sodium, 100.0g mannitol, 200.0g microcrystalline celluloses, 45.0g KollicoatMAE30DP.
C. lubricant：4.0g magnesium stearate fumaric acid sodiums
2. floating layer prescription
1000.0g sodium alginates, 3200.0g tetradecyl alchohols, 24.0g magnesium stearate fumaric acid sodiums.
3. preparing
(1) preparation of label
A. the preparation of immediate release section particle：By fluticasone furoate and Vilantro, croscarmellose sodium, sweet dew
Alcohol, microcrystalline cellulose are uniformly mixed, 2% povidone k30 aqueous solutions are sprayed on powder with fluid bed and are pelletized, and 40-50 DEG C dry
It is dry, 60 mesh whole grains.
B. the preparation of controlled release portion particle：By fluticasone furoate and Vilantro, croscarmellose sodium, sweet dew
Alcohol, microcrystalline cellulose are uniformly mixed, the aqueous solution of KollicoatMAE30DP are sprayed on powder with fluid bed and is pelletized, and do
It is dry, 60 mesh whole grains.
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die tabletting of a diameter of 3mm,
Label is made.
(2) preparation of floating layer
By sodium alginate, tetradecyl alchohol, magnesium stearate is uniformly mixed.
(3) tabletting
Floating layer powder is wrapped up into label, carries out tabletting.
The formula of the pulsatile release tablets of 3. fluticasone furoate of embodiment and Vilantro and preparation
1. Core formulation (20000)
A. immediate release section prescription：30.0g fluticasone furoates, 10.0g Vilantros, 10.0g sodium carboxymethyl starches,
10.0g low-substituted hydroxypropyl celluloses, 150.0g mannitol, 150.0g lactose, 4.0g hydroxypropyl methyl celluloses.
B. controlled release portion prescription：40.0g fluticasone furoates, 20.0g Vilantros, 44.0g sodium carboxymethyl starches, sweet dew
Alcohol 200g, microcrystalline cellulose 100g, lactose 100g, 50.0g KollicoatMAE100P.
C. lubricant：4.0g magnesium stearates, 2.0g talcum powder.
2. floating layer prescription
1000.0g sodium alginates, 200.0g hydroxyethyl celluloses, 5600.0g hexadecanols, 30.0g magnesium stearates.
3. preparing
(1) preparation of label
A. the preparation of immediate release section particle：By fluticasone furoate and Vilantro, sodium carboxymethyl starch, low-substituted hydroxypropyl
Base cellulose, mannitol, microcrystalline cellulose, lactose are uniformly mixed, are sprayed 2% hydroxypropyl methyl cellulose aqueous solution with fluid bed
It is coated on powder and pelletizes, 40-50 DEG C of drying, 60 mesh whole grains.
B. the preparation of controlled release portion particle：By fluticasone furoate and Vilantro, sodium carboxymethyl starch, mannitol is micro-
Crystalline cellulose, lactose are uniformly mixed, 50% ethanol solution of KollicoatMAE100P are sprayed on powder with fluid bed and is made
Grain, dry, 60 mesh whole grains.
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die tabletting of a diameter of 4mm,
Label is made.
(2) preparation of floating layer
By sodium alginate, hydroxyethyl cellulose, hexadecanol, magnesium stearate is uniformly mixed.
(3) tabletting
Floating layer powder is wrapped up into label, carries out tabletting.
The formula of the pulsatile release tablets of 4. fluticasone furoate of embodiment and Vilantro and preparation
1. Core formulation (20000)
A. immediate release section prescription：40.0g fluticasone furoates, 16.0g Vilantros, 15.0g crospovidone, 15.0g
Low-substituted hydroxypropyl cellulose, mannitol 100g, lactose 280g, 4.0g povidone k30.
B. controlled release portion prescription：50.0g fluticasone furoates, 30.0g Vilantros, 15.0g crospovidone, 45.0g
Low-substituted hydroxypropyl cellulose, 200.0g mannitol, 400.0g lactose, 60.0g Eudragit L100-55.
C. lubricant:8.0g magnesium stearate.
2. floating layer prescription
700.0g hydroxypropyl methyl celluloses, 700.0g hydroxyethyl celluloses, 9600.0g octadecyl alcolols, 40.0g stearic acid
Magnesium.
3. preparing
(1) preparation of label
A. the preparation of immediate release section particle：By fluticasone furoate and Vilantro, crospovidone, low substituted hydroxy-propyl
Cellulose, mannitol, lactose are uniformly mixed, 3% povidone k30 aqueous solutions are sprayed on powder with fluid bed and are pelletized, 40-50
DEG C drying, 60 mesh whole grains.
B. the preparation of controlled release portion particle：By fluticasone furoate and Vilantro, crospovidone, low substituted hydroxy-propyl
Cellulose, mannitol, lactose are uniformly mixed, and 50% ethanol solution of Eudragit L100-55 is sprayed on powder with fluid bed
Upper granulation, dry, 60 mesh whole grains.
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die tabletting of a diameter of 5mm,
Label is made.
(2) preparation of floating layer
By hydroxypropyl methyl cellulose, hydroxyethyl cellulose, octadecyl alcolol, magnesium stearate is uniformly mixed.
(3) tabletting
Floating layer powder is wrapped up into label, carries out tabletting.
The formula of the pulsatile release tablets of 5. fluticasone furoate of embodiment and Vilantro and preparation
1. Core formulation (20000)
A. immediate release section prescription：60.0g fluticasone furoates, 20.0g Vilantros, 40.0g low substituted hydroxy-propyl fibers
Element, 50.0g sorbierites, 100.0g lactose, 350.0g microcrystalline celluloses, 4.0g povidone k30.
B. controlled release portion prescription：100.0g fluticasone furoates, 40.0g Vilantros, 70.0g low substituted hydroxy-propyl fibers
Element, 100.0g sorbierites, 200.0g lactose, 300.0g microcrystalline celluloses, 60.0gEudragit L30-55.
C. lubricant：8.0g magnesium stearates, 2.0g superfine silica gel powders.
2. floating layer prescription
1000.0g sodium alginates, 600.0g hydroxyethyl celluloses, 12400.0g octadecyl alcolols, 80.0g magnesium stearates.
3. preparing
(1) preparation of label
A. the preparation of immediate release section particle：By fluticasone furoate and Vilantro, low-substituted hydroxypropyl cellulose, sorb
Alcohol, lactose, microcrystalline cellulose are uniformly mixed, 4% povidone k30 aqueous solutions are sprayed on powder with fluid bed and are pelletized, 40-50
DEG C drying, 60 mesh whole grains.
B. the preparation of controlled release portion particle：By fluticasone furoate and Vilantro, low-substituted hydroxypropyl cellulose, sweet dew
Alcohol, lactose, microcrystalline cellulose are uniformly mixed, the aqueous solution of Eudragit L30-55 are sprayed on powder with fluid bed and is made
Grain, dry, 60 mesh whole grains.
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die tabletting of a diameter of 6mm,
Label is made.
(2) preparation of floating layer
By sodium alginate, hydroxyethyl cellulose, octadecyl alcolol, magnesium stearate is uniformly mixed.
(3) tabletting
Floating layer powder is wrapped up into label, carries out tabletting.
The preparation of 6. ordinary recipe piece of embodiment
1. prescription (20000)
30.0g fluticasone furoates, 12.0g Vilantros, 50.0g low-substituted hydroxypropyl celluloses, 580.0g lactose,
2950.0g microcrystalline celluloses, 50.0g PVP K30s, 21.5g magnesium stearates.
2. preparing：By fluticasone furoate and Vilantro, disintegrant, filler is uniformly mixed, and will be controlled with fluid bed
5% povidone aqueous solution, which is sprayed on powder, pelletizes, dry, and 25 mesh whole grains, addition mix lubricant is uniform, tabletting.
The different granulating process comparative studies of embodiment 7
Pulsatile release tablets are prepared with the prescription and technique of embodiment 1, wherein whole grain is respectively with 25 mesh whole grains, 60 mesh whole grain systems
Standby pulsatile release tablets uniformity of dosage units result is as follows：
| The preparation process whole grain of label | Uniformity of dosage units |
| 25 mesh whole grains | It is unqualified |
| 60 mesh whole grains | Meet regulation |
8 floating layer of embodiment：Label=3.9：The formula and preparation method of the pulsatile release tablets of 1 (w/w)
1. Core formulation (20000)
A. immediate release section prescription：60.0g fluticasone furoates, 20.0g Vilantros (3：1), 40.0g low substituted hydroxy-propyls
Cellulose, 50.0g sorbierites, 100.0g lactose, 350.0g microcrystalline celluloses, 4.0g povidone k30.
B. controlled release portion prescription：100.0g fluticasone furoates, 40.0g Vilantros (5：2), 70.0g low-substituted hydroxypropyls
Base cellulose, 100.0g sorbierites, 200.0g lactose, 300.0g microcrystalline celluloses, 60.0gEudragit L30-55.
C. lubricant：8.0g magnesium stearates, 2.0g superfine silica gel powders.
2. floating layer prescription
1000.0g sodium alginates, 200.0g hydroxyethyl celluloses, 4000.0g octadecyl alcolols, 44.0g magnesium stearates.
3. preparing
(1) preparation of label
A. the preparation of immediate release section particle：By fluticasone furoate and Vilantro, low-substituted hydroxypropyl cellulose, sorb
Alcohol, lactose, microcrystalline cellulose are uniformly mixed, 4% povidone k30 aqueous solutions are sprayed on powder with fluid bed and are pelletized, 40-50
DEG C drying, 60 mesh whole grains.
B. the preparation of controlled release portion particle：By fluticasone furoate and Vilantro, low-substituted hydroxypropyl cellulose, sweet dew
Alcohol, lactose, microcrystalline cellulose are uniformly mixed, the aqueous solution of Eudragit L30-55 are sprayed on powder with fluid bed and is made
Grain, dry, 60 mesh whole grains.
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die tabletting of a diameter of 6mm,
Label is made.
(2) preparation of floating layer
By sodium alginate, hydroxyethyl cellulose, octadecyl alcolol, magnesium stearate is uniformly mixed.
(3) tabletting
Floating layer powder is wrapped up into label, carries out tabletting.
9 tablet of embodiment floats result
The tablet of embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment 5, embodiment 8 is put into 37 DEG C
In the simulated gastric fluid of 0.1NHCL, float test is carried out.As a result as follows：
As a result show that slice, thin piece prepared by the invention has in simulated gastric fluid when the ratio of floating layer and label is more than 5
Floating acts on.
The release profiles of the pulsatile release tablets of 10. fluticasone furoate of embodiment and Vilantro detect
Vitro release is tested：The tablet of embodiment 1-6 is put into stripping rotor, in the HCL that dissolution medium is 0.1mol/L
In solution, under the conditions of 37 DEG C of water-baths, rotating speed 50rpm, after 0.5h, 1.0h, 1.5h, the separately sampled measurement of 2.0h, then
In 100mL pH6.8 phosphate buffers, under the conditions of 37 DEG C of water-baths, rotating speed 50rpm, in 2.5h, 3.0h, 3.5h, 4.0h,
4.5h, 5.0h, 5.5h, 6.0h, 6.5h, 7.0h, 7.5h, 8.0h, 8.5h, 9.0h, 9.5h, 10.0h, 10.5h, 11.0h,
11.5h, 12.0h, 12.5h, 13.0h, 13.5h, 14.0h, 14.5h, 15.0h, 15.5h, 16.0h, 16.5h, 17.0h,
17.5h, 18.0h, 18.5h, 19.0h, 19.5h, 20.0h are measured by sampling.
The pulsatile release tablets for the fluticasone furoate and Vilantro that experiment in vitro detection Examples 1 to 6 prepares
Release profiles, as a result as depicted in figs. 1 and 2, the controlled release tablet of Examples 1 to 5 can pass through " when demurrage " not released the drug
Afterwards, drug is released into meal, reaches the concentration of therapeutically effective amount, then with 0 grade of high order smooth pattern release profiles Drug controlled release rate
Whole release profiles.To achieve the effect that realize being treated when selecting for disease according to chronopharmacology and chronotherapeutics principle.
And ordinary tablet was then just discharged at 0.5 hour, was treated when cannot achieve the effect that select.
11 fluticasone furoate of embodiment and the research of the pulsatile release tablets domesticated dog Internal pharmacokinetics of Vilantro
The in vivo studies of pharmaceutical preparation is to evaluate the most basic and most reliable foundation of the quality of the pharmaceutical preparations.The purpose of pulse preparation
It is to realize that being treated when selecting for disease, i.e. preparation can pass through one not in vivo according to chronopharmacology and chronotherapeutics principle
After " when demurrage " of drug release, drug is disengaged completely rapidly.Pulse using HPLC methods to fluticasone furoate and Vilantro
The physiological disposition of controlled release tablet is studied, and whether has the characteristic of pulsed release to prove preparation described in this patent in vivo.
15 scholar 2.0kg domesticated dogs 36 of weight, every group 6, after fasting 12h, the oral administration under study subject waking state,
Water supply 200ml simultaneously is fed after 6h is administered, and the fluticasone furoate and Vilantro pulse controlled release of embodiment 1 is administered in test group 1
Piece；The fluticasone furoate and Vilantro pulsatile release tablets of embodiment 2 is administered in test group 2；Embodiment 3 is administered in test group 3
Fluticasone furoate and Vilantro pulsatile release tablets；The fluticasone furoate and Vilantro arteries and veins of embodiment 4 is administered in test group 4
Rush controlled release tablet；The fluticasone furoate and Vilantro pulsatile release tablets of embodiment 5 is administered in test group 5；The administration of test group 6 is implemented
The fluticasone furoate and Vilantro pulsatile release tablets of example 6.Remaining needle is buried in domesticated dog foreleg vein, respectively 0,0.5,1.0,
1.5,2.0,2.5,3.0,4.0,6.0,9.0,12.0,20.0h stipulated times took a blood sample, and each 5ml. blood samplings finish, to remaining needle
Interior injection 0.3ml heparin sodium aquas 10IU/mL, anti-hemostasis-coagulation.Blood sample 2500rpm is centrifuged into 10min, detaches and obtains blood plasma and wait for
It surveys.
Test result, experimental animal take the mean blood plasma concentration measurement knot at each time point after pulsatile release tablets and ordinary tablet
Fruit see the table below 1~2.
The fluticasone furoate blood medicine that is averaged that 1. experimental animal of table takes each time point after pulsatile release tablets and ordinary tablet is dense
Degree
| Blood sampling time/experiment group number (ng/ml) | 1 | 2 | 3 | 4 | 5 | 6 |
| 0h | 0 | 0 | 0 | 0 | 0 | 0 |
| 0.5h | 0 | 0 | 0 | 0 | 0 | 65 |
| 1.0h | 0 | 0 | 0 | 0 | 0 | 85 |
| 1.5h | 0 | 0 | 0 | 0 | 0 | 100 |
| 2.0h | 0 | 0 | 12 | 0 | 30 | 115 |
| 2.5h | 0 | 15 | 35 | 22 | 48 | 110 |
| 3.0h | 30 | 35 | 60 | 40 | 80 | 100 |
| 4.0h | 50 | 60 | 85 | 70 | 106 | 90 |
| 6.0h | 80 | 85 | 99 | 92 | 106 | 75 |
| 9.0h | 92 | 95 | 101 | 103 | 106 | 55 |
| 12.0h | 100 | 96 | 101 | 103 | 106 | 40 |
| 20.0h | 100 | 98 | 101 | 103 | 106 | 30 |
2. experimental animal of table takes the Vilantro mean blood plasma concentration at each time point after pulsatile release tablets and ordinary tablet
| Blood sampling time/experiment group number (ng/ml) | 1 | 2 | 3 | 4 | 5 | 6 |
| 0h | 0 | 0 | 0 | 0 | 0 | 0 |
| 0.5h | 0 | 0 | 0 | 0 | 0 | 65 |
| 1.0h | 0 | 0 | 0 | 0 | 0 | 90 |
| 1.5h | 0 | 0 | 0 | 0 | 0 | 100 |
| 2.0h | 0 | 0 | 10 | 0 | 20 | 105 |
| 2.5h | 0 | 12 | 35 | 22 | 50 | 110 |
| 3.0h | 30 | 30 | 60 | 45 | 75 | 100 |
| 4.0h | 60 | 58 | 85 | 70 | 104 | 90 |
| 6.0h | 92 | 90 | 99 | 103 | 106 | 78 |
| 9.0h | 95 | 92 | 101 | 103 | 106 | 53 |
| 12.0h | 95 | 96 | 101 | 103 | 106 | 40 |
| 20.0h | 95 | 98 | 101 | 103 | 106 | 31 |
It is tested by domesticated dog vivo biodistribution availability, it can be seen that compared with ordinary tablet, the drug release time of pulsatile release tablets
After move, ordinary tablet has released the drug when being 0.5, and pulsatile tablets are most short starts to release the drug for 2.0h, internal residence time.Show arteries and veins
There are obvious delay release characteristics, tablets in vitro and body absorption typical " S " type is all presented in vivo for punching.
12 fluticasone propionates of embodiment/effect of the Vilantro pulsatile release tablets to Brown-Norway rats with asthma airway inflammation
Method:By weight (250 ± 20) g, male rat (The Fourth Military Medical University's Experimental Animal Center provides) 70, at random
It is divided into asthma group (A groups), Normal group (B groups), fluticasone propionate/Vilantro pulsatile release tablets treatment group (C groups),
Middle C groups are divided into as 5 groups, per each 10 of group, press embodiment 1 respectively, embodiment 2, embodiment 3, embodiment 4, and embodiment 5 is given
Every group of each l0 of animal of medicine asthma groups (A groups) and Normal group (B groups) is only.A groups rat is white with ovum gallinaceum in the 1st day and the 15th day
There is exaggerated respiration with rat every time, accelerates and the asthma such as movement of nodding, expiratory dyspnea, cough, tumble in albumen (OVA) sensitization
Symptom is to excite successfully, establishes asthmatic model；B groups physiological saline Neulized inhalation and in kind sensitization；C groups are before excitation
Fluticasone propionate/Vilantro pulsatile release tablets are administered to rat oral gavage within 2 hours, other programs are identical as A groups.
As a result：Lung tissue of rats pathological section is prepared, visible A groups bronchium epithelial cell shedding, tube wall inflammation under light microscopic
Disease cellular infiltration, goblet cell hyperplasia, smooth muscle thicken, and the above-mentioned change of C groups is substantially reduced compared with A groups；Compared with A groups, C groups branch
Tracheae pipe thickness, smooth muscle thickness significantly reduce.In excitation process, asthma group rat and blank control group rat exhale
Suction distress syndrome (be short of breath, be livid purple etc.), fluticasone propionate/Vilantro pulsatile release tablets treatment group rat has no breathing
Distress syndrome illustrates that fluticasone propionate/Vilantro pulsatile release tablets have anti-inflammatory effect, and playing one to treating asthma is set for
With.
Finally, it should be noted that above example only helps skilled in the art to understand the essence of the present invention, not
As limiting the scope of the invention.
Claims (5)
1. the pulsatile release tablets of a kind of fluticasone furoate and Vilantro, which is characterized in that the pulsatile release tablets can be at midnight
Blood concentration is reached with early morning；
The pulsatile release tablets include two parts of floating layer and label,
The floating layer is made of hydrophilic macromolecule, fatty alcohol auxiliary material and lubricant,
The label is made of the lubricant added outside immediate release section and controlled release portion and immediate release section and controlled release portion；
The immediate release section is made of main ingredient, filler, disintegrant, adhesive；
The controlled release portion is made of main ingredient, filler, disintegrant, enteric material；
Lubricant is added outside the immediate release section and controlled release portion；
The ratio of fluticasone furoate and Vilantro is 5 in the main ingredient：1~3 (wt/wt).
2. pulsatile release tablets according to claim 1, which is characterized in that
The hydrophilic macromolecule includes sodium alginate, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxy ethyl fiber
Plain is one or more,
The fatty alcohol includes lauryl alcohol, tetradecyl alchohol, hexadecanol, octadecyl alcolol it is one or more.
3. pulsatile release tablets according to claim 2, which is characterized in that
The filler is one or more compositions of lactose, mannitol, sorbierite, microcrystalline cellulose, starch；
The adhesive is one or more compositions of hydroxypropyl methyl cellulose, povidone k30, second alcohol and water；
The enteric material include but not limited to trade name EudragitL100, EudragitL100-55,
The pharmaceutic adjuvant of EudragitL30-55, KollicoatMAE30DP or KollicoatMAE100P；
The disintegrant is that croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crosslinking are poly-
Tie up one or more compositions of ketone；
The lubricant be magnesium stearate, sodium stearyl fumarate, talcum powder, superfine silica gel powder, hydrogenated vegetable oil one kind or
A variety of compositions.
4. a kind of preparation method of any pulsatile release tablets of claim 1-3, includes the following steps,
(1) preparation of label,
A. the preparation of immediate release section particle：Fluticasone furoate and Vilantro, disintegrant, filler are uniformly mixed, with stream
Adhesive is sprayed on powder by change bed pelletizes, 40-50 DEG C of drying, 60 mesh sieves；
B. the preparation of controlled release portion particle：Fluticasone furoate and Vilantro, disintegrant, filler are uniformly mixed, with stream
Enteric material is sprayed on powder by change bed pelletizes, 40-50 DEG C of drying, 60 mesh sieves；
C. immediate release section particle, controlled release portion particle and mix lubricant is uniform, with the punch die tabletting of a diameter of 3-6mm, i.e.,
Label is made；
(2) preparation of floating layer,
Uniformly by hydrophilic macromolecule and fatty alcohol, mix lubricant to obtain the final product；
(3) tabletting,
Floating layer powder is wrapped up into label, tabletting to obtain the final product.
5. preparation method according to claim 4, fluticasone furoate and the mass ratio of Vilantro are in wherein step a
15：2~7, fluticasone furoate and the mass ratio of Vilantro are 3 in stepb：1~2.
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| CN201410841069.7A CN105796522B (en) | 2014-12-30 | 2014-12-30 | Pulsatile release tablets containing fluticasone furoate and Vilantro and preparation method |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103933049A (en) * | 2014-04-02 | 2014-07-23 | 上海新亚药业有限公司 | Vilanterol trifluoromethanesulfonate-containing pharmaceutical preparation |
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| CN103933049A (en) * | 2014-04-02 | 2014-07-23 | 上海新亚药业有限公司 | Vilanterol trifluoromethanesulfonate-containing pharmaceutical preparation |
Non-Patent Citations (3)
| Title |
|---|
| New Trends in Asthma Treatment;David El-Qutob;《Clinical Research in Pulmonology》;20141010;第2卷(第2期) * |
| 糠酸氟替卡松、三氟甲磺酸维兰特罗及其联合制剂治疗慢性阻塞性肺疾病研究进展;梁丽等;《世界临床药物》;20111231;第32卷(第7期);第392-395页 * |
| 长效β2-激动剂与吸入性皮质类固醇激素;Bijl-Hofland ID等;《国外医学内科学分册》;20020831;第29卷(第8期);第359页 * |
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