CN101439026B - Controlled release preparation containing doxazosin or salt thereof and preparation method thereof - Google Patents
Controlled release preparation containing doxazosin or salt thereof and preparation method thereof Download PDFInfo
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- CN101439026B CN101439026B CN2007101779893A CN200710177989A CN101439026B CN 101439026 B CN101439026 B CN 101439026B CN 2007101779893 A CN2007101779893 A CN 2007101779893A CN 200710177989 A CN200710177989 A CN 200710177989A CN 101439026 B CN101439026 B CN 101439026B
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Abstract
The invention provides a controlled release preparation for doxazosin or salts thereof, wherein, the controlled release preparation comprises a drug containing layer and a boosting layer which have the weight ratio of 1 : 0.5 to 3. The drug containing layer comprises the doxazosin or salts thereof and a carrier, and the carrier is vinylpyrrolidone polymers which occupy 40 percent and 99 percent of the weight of the drug containing layer; the boosting layer at least comprises permeability promoting polymers occupying 10 percent to 80 percent of the weight of the boosting layer, 10 percent to 80 percent water insoluble polymers and 3 percent to 60 percent osmotic pressure accelerators; a controllable speed release drug of the doxazosin or the salts which can be accepted by the doxazosin in pharmacy causes the preparation to achieve the purpose that the doxazosin or the salts which can be accepted by the doxazosin in pharmacy can be released within about 24 h through once drug feeding daily.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly a kind of controlled release preparation that contains active medicine doxazosin or its pharmaceutically acceptable salt and preparation method thereof.
Background technology
Doxazosin (Doxazosin, chemical name: [1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-(1,4-benzodioxan-2-supports carbonyl)] piperazine), be long lasting α
1Receptor antagonist can be controlled the symptom of hypertension and benign prostatic hyperplasia diseases such as (BPH) effectively.Yet when using conventional tablet, thereby, therefore must begin progressively to set up dosage from low dose if directly adopt therapeutic dose to make the blood pressure rapid drawdown cause untoward reaction such as faintness, postural hypotension because of blood drug level raises suddenly.For this reason, pfizer inc has been developed doxazosin GITS (Cardura XL
, can how magnificent
).Studies show that this controlled release form makes the blood drug level tranquilization by accurately controlling rate of releasing drug, has not only improved patient's toleration, and has simplified the dose titration process, demonstrate clinical preferably superiority.
Doxazosin GITS (Cardura XL
, can how magnificent
) be present unique α
1The receptor antagonist controlled release agent.It utilizes osmotic pump principle, makes medicine by set rate constant release, gentle absorption, T
MaxDelay, C
MaxReduce C
MinConstant, thus level and smooth constant time front of blood concentration formed.Its superior pharmacokinetics characteristics have not only reduced the generation of untoward reaction, and can be directly with therapeutic dose 4mg as initial dose, and need not from low dose to begin to adjust, use more conveniently, onset is rapider.Clinical proof, doxazosin GITS is identical with ordinary tablet to the curative effect of hypertension and BPH, and toleration strengthens.Therefore, doxazosin GITS (can how magnificent
) can replace the doxazosin ordinary tablet, as the first-line treatment medicine of these two kinds of diseases.
Listing products C ardura XL
(can how magnificent
) adopt polyoxyethylene (PEO) as pharmaceutical carrier.But with PEO is that the osmotic pump controlled release tablet of main adjuvant has inherent shortcoming: (1) polyoxyethylated absorption speed and hydration rate are all slower, so the time lag of drug release is longer, cause medicine onset rapidly after taking; (2) polyoxyethylated typical glass transformetion range is 65 ℃～67 ℃, so PEO do not have ideal heat stability, and there are the following problems in industrial preparation and storage process for it: solvent seasoning difficulty comparatively in the pelletization.Because baking temperature should not surpass 40 ℃ usually, easily causes Determination of Residual Organic Solvents higher; If want drying more complete, just need relatively long drying time; The storage temperature of tablet is unsuitable too high, and too high laying temperature easily makes polyoxyethylated physicochemical property change, thereby the release behavior of tablet is exerted an influence; In the high speed tabletting process, when using back generation heat to cause temperature to reach 50 ℃ of left and right sides repeatedly, just occur unfavorable phenomenons such as sticking easily, therefore need the temperature of special cooling installation control punch die as punch die.Therefore, press for a kind of better method of searching and solve this problem.
Summary of the invention
The object of the present invention is to provide a kind of osmotic pump type drug-delivery preparation that contains active medicine doxazosin or its salt Carclura, can make medicine enter gastrointestinal tract with the speed of control, said preparation is formed rationally, drug safety, has short time lag, medicine is onset rapidly after taking, and effectively longer duration can reach better controlled-release effect.
Another object of the present invention is to provide the preparation method of the controlled release preparation of a kind of doxazosin or its salt, the salt of doxazosin is generally pharmaceutically acceptable salt, be preferably mesylate, promptly, Carclura, the preparation method of controlled release preparation of the present invention is convenient to produce, and product is easy to store, and can better reach the purpose of sustained release.
Purpose of the present invention is achieved through the following technical solutions:
A kind of controlled release preparation that contains active medicine doxazosin or its salt, comprise that weight ratio is 1: the medicated layer of 0.5-3 and boosting layer, described medicated layer comprises active medicine and carrier, this active medicine is doxazosin or its pharmaceutically acceptable salt that accounts for medicated layer weight 1-60%, and this carrier is the vinylpyrrolidone polymer that accounts for medicated layer weight 40-99%; Described boosting layer comprises the short osmopolymer that accounts for boosting layer weight 10-80%, the insoluble polymer of 10-80% and the osmotic pressure promoter of 3-80% at least.
Vinylpyrrolidone polymer of the present invention comprises vinylpyrrolidone homopolymer, nvp copolymer or the mixture of the two.In a preferred embodiment of the invention, the vinylpyrrolidone homopolymer is preferably the vinylpyrrolidone homopolymer, more preferably polyvidone, nvp copolymer are preferably l-vinyl-2-pyrrolidone and vinylacetate with 1: 10 to 10: the 1 polymeric copolyvidone of ratio.
In order to reach better therapeutic effect, its composition of controlled release preparation of the present invention is preferably, and the weight content ratio of medicated layer and boosting layer is 1: 0.5-1.5, more preferably content ratio is 1: 0.8-1.2 most preferably is 1: 1.
In a preferred embodiment, the invention provides a kind of controlled release preparation that contains active medicine doxazosin or its salt, comprise that weight ratio is 1: the medicated layer of 0.5-3 and boosting layer, described medicated layer comprises active medicine and carrier, this active medicine comprises doxazosin or its pharmaceutically acceptable salt, this carrier is a vinylpyrrolidone polymer, and the weight ratio of active medicine and carrier is 1: 1-50; Described boosting layer comprises the short osmopolymer that accounts for boosting layer weight 10-80%, the insoluble polymer of 10-80% and the osmotic pressure promoter of 3-80% at least.
The weight ratio of active component and carrier is preferably 1 in the medicated layer of the present invention: 5-35, more preferably 1: 10-30.
Controlled release preparation of the present invention can be dosage forms such as tablet, capsule, preferred tablet, more preferably controlled release tablet.
In order to reach every performance indications of preparation (for example tablet), and make every best performanceization, above-mentioned medicated layer and boosting layer more preferably contain fluidizer, lubricant and/or coloring agent.
The controlled release preparation of described doxazosin or its salt adopts vinylpyrrolidone polymer as the main adjuvant of medicated layer, and can overcome tradition is controlled releasing penetrant pump shortcoming and the drug release time lag long drawback comparatively responsive to temperature of main function adjuvant with PEO.
Insoluble polymer in the described boosting layer is any one or more than one the mixture in dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, the cross-linking sodium carboxymethyl cellulose.The mixture of one or more in preferred carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, the cross-linking sodium carboxymethyl cellulose.This insoluble polymer does not dissolve in water but has very high rate of water absorption and water absorbing capacity, and volume expands rapidly behind the chance water, thereby the release of medicine is produced motive force.
Short osmopolymer in the described boosting layer is acrylic homopolymer, acrylic copolymer, hydroxypropyl emthylcellulose, vinylpyrrolidone polymer, or the combination in any of mentioned component wherein.
The preferred acrylic copolymer of short osmopolymer of the present invention, it is a carbomer.
Osmotic pressure promoter in the described boosting layer is salt, acids or saccharide, described salt comprises sodium chloride, potassium chloride, magnesium chloride, potassium sulfate, sodium sulfate and/or magnesium sulfate, described acids comprises ascorbic acid or tartaric acid etc., and described saccharide comprises mannitol, sorbitol, xylitol, lactose, glucose, sucrose etc.Wherein preferred osmotic pressure promoter is salt, and preferred especially osmotic pressure promoter is sodium chloride.
The controlled release preparation of described doxazosin or its salt can answer the needs of dosage form to carry out the processing of various dosage forms aspect, for example, the preferred external packets of controlled release tablet is with the thin film of semipermeable materials, this semipermeable membrane is can permeability to the liquid in the gastrointestinal tract as water and other body fluid, and is impermeability for active component doxazosin or its salt.This semipermeable materials comprises cellulosic polymer, Merlon, polyethylene, polyvinyl alcohol, vinylacetate, and it mainly includes but not limited to cellulose acetate, ethyl cellulose, cellulose diacetate, cellulose triacetate and congener.
Its essence of this controlled release preparation is osmotic pump preparation, preferred tablet form of the present invention, on its semipermeable membrane, have at least an access opening connection medicated layer and outside that medicine can be discharged, this hole preferably adopts laser to get through medicated layer from the outside, the size in hole can influence release rate of drugs, the diameter in hole is generally 0.2-1.2mm, preferred 0.4-1.1mm, more preferably 0.6-1.0mm.
The invention provides a kind of bilayer or two compartment osmotic pump type preparation, for example double-deck or two compartment osmotic pump matrix agent enters gastrointestinal absorption in order to release doxazosin or its salt and enters in the body.Vinylpyrrolidone polymer as the carrier of doxazosin or its salt in the medicated layer is about the heavy 40-99% of pastille synusia, its concrete content in medicated layer finally depends on drug release characteristics, 60-99% preferably, be more preferably 70-99%, the vinylpyrrolidone homopolymer is preferably polyvidone among the present invention, molecular weight ranges 1000-3000000, more preferably from about 1300000; Described nvp copolymer is preferably copolyvidone, its be l-vinyl-2-pyrrolidone and vinylacetate with 1: 10 to 10: 1 polymeric copolymer, for example with 7: 3,3; 2,5: 5 and the polymeric copolymer of different proportion such as 3: 7, be more preferably 3: 2.
Boosting layer of the present invention comprises the short osmopolymer that accounts for boosting layer weight 10-80%, the insoluble polymer of 10-80% and the osmotic pressure promoter of 3-60% at least, and wherein, insoluble polymer is 20-60% preferably, is more preferably 20-45%; The short preferred 30-70% of osmopolymer, more preferably 40-60%; Osmotic pressure promoter preferable range is 5-50%, preferably 8-30%.
Medicated layer still to be the boosting layer all can also contain for example micropowder silica gel of fluidizer, lubricant magnesium stearate and the being used for coloring agent inorganic colourant for example of distinguishing the boosting layer for example no matter in the controlled release tablet of the present invention; Also other component be can contain, the hydroaropic substance, diluent, binding agent and the solvent that continue release action for example worked.This class hydroaropic substance can be one or more the mixture in acrylic homopolymer, acrylic copolymer, hypromellose and the congener.Medicated layer also may contain one or more the mixture in the penetration enhancer, for example sodium chloride, lactose, mannitol, glucose, sucrose, fructose.
Coloring agent in above-mentioned medicated layer and the boosting layer comprises inorganic oxide, for example red ferric oxide, yellow ferric oxide, purple ferrum oxide, Black Rouge.
In osmotic pump preparation of the present invention, also can contain:
Plasticizer can be any one or more the mixture in the conventional plasticizer, as phthalate, glyceride, succinate, benzoate, phosphate ester, adipate ester, tartrate, polyethylene glycols.
Opacifier can be a kind of material or multiple mixture, as titanium dioxide, Pulvis Talci, micropowder silica gel.
Porogen may be a kind of material or multiple mixture, as glycerol, propylene glycol, polyvinyl alcohol, water-soluble inorganic salt.
Physicochemical property at this chemical compound of doxazosin, the controlled release preparation of doxazosin provided by the invention or its salt mainly is the controlled release preparation that contains the salt of doxazosin, this salt is preferably mesylate, that is, and and the controlled release tablet that contains Carclura that is preferably provided by the invention.
The present invention also provides a kind of method for preparing the controlled release preparation of doxazosin or its salt, comprising:
At first, the preparation medicated layer is crossed 60 mesh sieves with the vinylpyrrolidone polymer of doxazosin or its salt and 40-99%, and adopts equivalent to progressively increase behind the method mix homogeneously, join in the fluid bed, spray into and be not less than 40% ethanol-water solution, granulate, drying adds magnesium stearate, mixing;
Preparation boosting layer, cross 60 mesh sieves with accounting for the short osmopolymer of boosting layer weight 10-80%, the insoluble polymer of 10-80% and the osmotic pressure promoter of 3-60%, preferred add binding agent, coloring agent and as the mix homogeneously such as micropowder silica gel of fluidizer, add to advance in the fluid bed, spray into the ethanol-water solution that is not less than 40% (preferred 60-95%, more preferably 70-95%), granulate, drying preferably adds magnesium stearate, mix homogeneously again.
Adjuvant in the medicated layer also can comprise magnesium stearate, coloring agent, vinylpyrrolidone polymer carrier, penetration enhancer and/or micropowder silica gel; Adjuvant in the boosting layer also can comprise binding agent, coloring agent and/or fluidizer, and it all can sieve simultaneously, mix with above-mentioned adjuvant;
One deck compression moulding with wherein adds other one deck then, is pressed into double-layer tablet, at the film-coat of label outsourcing with semipermeable materials, and drying, preferably following dry 3 hours at 45 ℃.Make a call to a small delivery aperture with mechanical system or laser, preferably about 0.9mm in the one side of contiguous medicated layer then with suitable diameter.Wrap then with moistureproof film-coat, drying for example is following dry 3 hours at 45 ℃.The purpose of wrapping moistureproof clothing film is to improve the outward appearance of preparation, and colour code is provided simultaneously.
The film-coat of above-mentioned semipermeable materials (abbreviation semipermeable membrane) coating coats with the solution form, its solvent can be one or more the mixture in acetone, water, ethanol, dichloromethane, methanol and the isopropyl alcohol, acetone preferably, for example, the semipermeable membrane clothing generally is cellulose acetate (or other cellulose derivatives) and/or diethyl phthalate to be dissolved in the acetone coated again machine coating.This punching and art for coating are known technology, do not repeat them here.
Adopt vinylpyrrolidone polymer to have wonderful advantage than the polyoxyethylated listing kind of employing as the product of the present invention of label adjuvant preparation:
1) adopting vinylpyrrolidone polymer is that the controlled release tablet that carrier makes has short time lag, and medicine is onset rapidly after taking, and its release characteristic seldom or the influence of unable to take food thing effect; And doxazosin GITS (can how magnificent
) in polyoxyethylated absorption speed and hydration rate all slower, the time lag of drug release is longer, onset rapidly after taking;
2) prior art doxazosin GITS (can how magnificent
) in polyoxyethylated typical glass transformetion range be 65 ℃～67 ℃, do not have ideal heat stability, vinylpyrrolidone polymer among the present invention has better heat stability than polyoxyethylene, the glass transformation temperature of the polyvidone of different molecular weight (Tg) scope is 130 ℃～176 ℃, the glass transformation temperature of 30 POVIDONE K 30 BP/USP-90 (Plasdone K-90) is 174 ℃, the glass transformation temperature of copolyvidone S-630 (Plasdone S-630) is 105 ℃, thereby do not need special working condition and storage requirement, the medicine stability of preparation is good, can reach better controlled release purpose; And doxazosin GITS (can how magnificent
) baking temperature that requires is no more than 40 ℃ usually, causes Determination of Residual Organic Solvents higher; If the higher tablet of ambient temperature very easily makes the polyoxyethylene physicochemical property change in storage is placed, thereby the tablet release behavior is produced inevitable adverse effect; The temperature of the cooling installation control punch die that the tabletting process need is special;
3) the inherent advantage of osmotic pump preparation is that the individual variation of gastrointestinal motility is very little, almost can ignore, and use vinylpyrrolidone polymer to replace PEO can further strengthen the advantage of osmotic pump preparation.
The specific embodiment
Embodiment 1
Prescription: (1) medicated layer (every):
Carclura 5.1mg
Polyvidone (Plasdone K90) 30mg
Copolyvidone (Plasdone S630) 70mg
Magnesium stearate 0.5mg
Silicon dioxide 0.6mg
Red ferric oxide 0.02mg
(2) boosting layer (every):
Carboxymethylstach sodium 38mg
Hypromellose (K15M) 10mg
Carbomer (971PNF) 3.7mg
Sodium chloride 28mg
Polyvidone (Plasdone S630) 14mg
Black Rouge 1.0mg
Magnesium stearate 0.5mg
Silicon dioxide 0.4mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose acetate 35g
Diethyl phthalate 1.55g
Acetone 1000ml
Clothing film weight 18mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K90), red ferric oxide and the silicon dioxide mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 95% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer (971PNF), sodium chloride, copolyvidone (S630), Black Rouge and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix homogeneously, spray into 95% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting:
Tabletting: with the above-mentioned A for preparing, B granule, adopt bi-layer tablet press compacting double-layer tablet, sheet directly is 8mm, measures hardness (should reach more than the 8kg), content, related substance, uniformity of dosage units.The label that is up to the standards is standby.
4. coating:
With the above-mentioned double-deck label that is up to the standards, carry out coating with the cellulose acetate coating solution.Product behind the coating descended dry 3 hours at 45 ℃, broke into the aperture of 0.9mm then on the medicated layer surface of tablet with laser-beam drilling machine; Through carrying out coating with moistureproof coating liquid after the assay was approved, coating to coating weightening finish part is about 6.5% of medicine label according to a conventional method, again in 45 ℃ dry 3 hours down, packing, promptly.
Embodiment 2
Prescription: (1) medicated layer (every):
Carclura 5.1mg
Polyvidone (Plasdone K60) 10mg
Copolyvidone (Plasdone S630) 32mg
Magnesium stearate 1.2mg
Silica 1 mg
Red ferric oxide 0.05mg
(2) boosting layer (every):
Carboxymethylstach sodium 24mg
Hypromellose (K100M) 13mg
Carbomer (971PNF) 5.6mg
Sodium chloride 34mg
Polyvidone (Plasdone S630) 25mg
Black Rouge 0.7mg
Magnesium stearate 0.6mg
Silicon dioxide 0.5mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Ethyl cellulose 35g
Diethyl phthalate 1.55g
Acetone 1000ml
Clothing film weight 15mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K60), red ferric oxide and the silicon dioxide mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 90% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, hydroxypropyl emthylcellulose (K100M), carbomer (971PNF), sodium chloride, copolyvidone (S630), Black Rouge and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix homogeneously, spray into 90% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 3
Prescription: (1) medicated layer (every):
Carclura 5.1mg
Polyvidone (Plasdone K120) 5mg
Copolyvidone (Plasdone S630) 18mg
Yellow ferric oxide 1mg
Magnesium stearate 0.8mg
Micropowder silica gel 1.2mg
(2) boosting layer (every):
Carboxymethylstach sodium 16mg
Hypromellose (K100M) 6mg
Carbomer (971PNF) 10mg
Sodium chloride 20mg
Copolyvidone (Plasdone S630) 30mg
Red ferric oxide 0.8mg
Magnesium stearate 0.5mg
Micropowder silica gel 0.6mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Ethyl cellulose 35g
Diethyl phthalate 1.55g
Acetone 1000ml
Clothing film weight 16mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K120), yellow ferric oxide and the micropowder silica gel mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 75% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Recipe quantity is pressed in carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer (971PNF), sodium chloride, copolyvidone (S630), red ferric oxide and the micropowder silica gel of crossing 60 mesh sieves mixed back adding fluid bed, mix homogeneously, spray into 75% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 4
Prescription: (1) medicated layer (every):
Carclura 5.1mg
Polyvidone (Plasdone K90) 26mg
Polyvidone (Plasdone K15) 20mg
Hypromellose (K4M) 59mg
Yellow ferric oxide 0.08mg
Magnesium stearate 0.75mg
Silicon dioxide 0.5mg
(2) boosting layer (every):
Carboxymethylstach sodium 50mg
Cross-linking sodium carboxymethyl cellulose 100mg
Hypromellose (K4M) 35mg
Carbomer (971PNF) 4mg
Sodium chloride 30mg
Copolyvidone (Plasdone S630) 29mg
Black Rouge 1mg
Magnesium stearate 1mg
Silicon dioxide 0.5mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose diacetate 35g
Ethyl phthalate 1.55g
Dichloromethane 1000ml
Clothing film weight 18mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing hypromellose (K4M), polyvidone (K90), polyvidone (Plasdone K15), yellow ferric oxide and the silicon dioxide mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 60% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, carbomer (971PNF), sodium chloride, copolyvidone (S630), Black Rouge and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix homogeneously, spray into 60% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 5
Prescription: (1) medicated layer (every):
Carclura 5.1mg
Polyvidone (Plasdone K90D) 50mg
Hypromellose (K100LV) 55mg
Red ferric oxide 0.05mg
Magnesium stearate 0.75mg
Micropowder silica gel 0.5mg
(2) boosting layer (every):
Cross-linking sodium carboxymethyl cellulose 120mg
Hypromellose (K100LV) 5mg
Carbomer (971PNF) 12mg
Sodium chloride 10mg
Copolyvidone (Plasdone S630) 11mg
Black Rouge 1mg
Magnesium stearate 0.5mg
Micropowder silica gel 0.4mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose acetate 35g
Ethyl phthalate 1.55g
Dichloromethane 1000ml
Clothing film weight 14mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing hypromellose (K100LV), polyvidone (K90D), red ferric oxide and the micropowder silica gel mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 90% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Recipe quantity is pressed in cross-linking sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, carbomer (971PNF), sodium chloride, copolyvidone (S630), Black Rouge and the micropowder silica gel of crossing 60 mesh sieves mixed back adding fluid bed, mix homogeneously, spray into 90% alcohol-water solution of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 6
Prescription: (1) medicated layer (every):
Carclura 5.1mg
Polyvidone (Plasdone K30) 85mg
Copolyvidone (Plasdone S630) 155mg
Yellow ferric oxide 0.05mg
Magnesium stearate 0.5mg
Micropowder silica gel 0.5mg
(2) boosting layer (every):
Carboxymethyl starch sodium 20mg
Low-substituted hydroxypropyl cellulose 80mg
Carbomer (971PNF) 25mg
Sodium chloride 37mg
Copolyvidone (Plasdone S630) 38mg
Red ferric oxide 0.95mg
Magnesium stearate 0.48mg
Micropowder silica gel 0.8mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose diacetate 35g
Triethyl citrate 1.55g
Acetone 1000ml
Clothing film weight 19mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K30), yellow ferric oxide and the micropowder silica gel mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 50% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Recipe quantity is pressed in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, carbomer (971PNF), sodium chloride, copolyvidone (S630), red ferric oxide and the micropowder silica gel of crossing 60 mesh sieves mixed back adding fluid bed, mix homogeneously, spray into 50% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 7
Prescription: (1) medicated layer (every):
Carclura 10.2mg
Polyvidone (Plasdone K90) 50mg
Copolyvidone (Plasdone S630) 70mg
Red ferric oxide 0.025mg
Magnesium stearate 0.5mg
Silicon dioxide 0.7mg
(2) boosting layer (every):
Carboxymethylstach sodium 40.2mg
Hypromellose (K15M) 27.6mg
Carbomer (971PNF) 10.4mg
Sodium chloride 30.4mg
Copolyvidone (Plasdone S630) 29.5mg
Black Rouge 1.2mg
Magnesium stearate 0.7mg
Silicon dioxide 0.6mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose acetate 45g
Diethyl phthalate 2.21g
Acetone 1400ml
Clothing film weight 20mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K90), red ferric oxide and the silicon dioxide mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 95% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer (971PNF), sodium chloride, copolyvidone (S630), Black Rouge and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix homogeneously, spray into 95% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 8
Prescription: (1) medicated layer (every):
Carclura 10.2mg
Polyvidone (Plasdone K120) 30mg
Copolyvidone (Plasdone S630) 15mg
Red ferric oxide 0.05mg
Magnesium stearate 0.75mg
Micropowder silica gel 0.5mg
(2) boosting layer (every):
Carboxymethyl starch sodium 25mg
Hypromellose (K15M) 55mg
Sodium chloride 30mg
Copolyvidone (Plasdone S630) 30mg
Black Rouge 0.95mg
Magnesium stearate 0.48mg
Micropowder silica gel 0.5mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose triacetate 45g
Polyethylene glycol 1500 2.21g
Acetone 1400ml
Clothing film weight 24mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K120), red ferric oxide and the micropowder silica gel mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 75% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Recipe quantity is pressed in carboxymethyl starch sodium, hydroxypropyl emthylcellulose, sodium chloride, copolyvidone (S630), Black Rouge and the micropowder silica gel of crossing 60 mesh sieves mixed back adding fluid bed, spray into 75% alcoholic solution of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 9
Prescription: (1) medicated layer (every):
Carclura 10.2mg
Polyvidone (Plasdone K90D) 30mg
Copolyvidone (Plasdone S630) 15mg
Yellow ferric oxide 0.05mg
Magnesium stearate 0.75mg
Silicon dioxide 0.5mg
(2) boosting layer (every):
Carboxymethyl starch sodium 23mg
Carbomer (971PNF) 80mg
Sodium chloride 8mg
Copolyvidone (Plasdone S630) 7mg
Red ferric oxide 0.95mg
Magnesium stearate 0.48mg
Silicon dioxide 0.5mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose diacetate 45g
Polyethylene Glycol 2.21g
Ethanol 1400ml
Clothing film weight 16mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K90D), yellow ferric oxide and the silicon dioxide mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 90% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, carbomer, sodium chloride, copolyvidone (S630), red ferric oxide and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix, spray into 90% alcohol-water solution, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 10
Prescription: (1) medicated layer (every):
Carclura 10.2mg
Polyvidone (Plasdone K-60) 20mg
Copolyvidone (Plasdone S630) 61mg
(2) boosting layer (every):
Carboxymethylstach sodium 45mg
Hypromellose (K100M) 50mg
Carbomer (971PNF) 18mg
Sodium chloride 45mg
Copolyvidone (Plasdone S630) 45mg
Red ferric oxide 0.95mg
Silicon dioxide 0.8mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose acetate 45g
Ethyl phthalate 2.21g
Methanol 1400ml
Clothing film weight 20mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing the copolyvidone (S630), polyvidone (K60) mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 95% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures), standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, hypromellose, carbomer, sodium chloride, copolyvidone (S630), red ferric oxide and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix homogeneously, spray into 95% ethanol water of recipe quantity, granulation (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures), standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 11
Prescription: (1) medicated layer (every):
Carclura 10.2mg
Hypromellose (K15M) 20mg
Hypromellose (K100LV) 50mg
Copolyvidone (Plasdone S630) 90mg
Magnesium stearate 0.5mg
Silica 1 mg
Red ferric oxide 0.025mg
(2) boosting layer (every):
Carboxymethylstach sodium 40mg
Hypromellose (K15M) 15.4mg
Carbomer (971PNF) 18.8mg
Sodium chloride 17.1mg
Copolyvidone (Plasdone S630) 17.7mg
Red ferric oxide 0.5mg
Magnesium stearate 0.5mg
Silicon dioxide 0.4mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose acetate 45g
Diethyl phthalate 2.21g
Acetone 1400ml
Clothing film weight 16mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), hypromellose (K15M), hypromellose (K100LV), red ferric oxide and the silicon dioxide mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 95% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, hypromellose (K15M), carbomer, sodium chloride, copolyvidone (S630), red ferric oxide and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix homogeneously, spray into 95% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 12
Prescription: (1) medicated layer (every):
Carclura 10.2mg
Polyvidone (Plasdone K90) 63mg
Copolyvidone (Plasdone S630) 84mg
Yellow ferric oxide 0.05mg
Magnesium stearate 0.75mg
Micropowder silica gel 0.5mg
(2) boosting layer (every):
Carboxymethyl starch sodium 60.3mg
Hypromellose (K15M) 20.1mg
Carbomer (971PNF) 28.5mg
Sodium chloride 30mg
Copolyvidone (Plasdone S630) 31mg
Red ferric oxide 0.95mg
Magnesium stearate 0.48mg
Micropowder silica gel 0.5mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose diacetate 45g
Polyethylene Glycol 2.21g
Ethanol 1400ml
Clothing film weight 16mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the Carclura of recipe quantity with after crossing copolyvidone (S630), polyvidone (K90), yellow ferric oxide and the micropowder silica gel mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 75% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Recipe quantity is pressed in carboxymethyl starch sodium, hypromellose (K15M), carbomer, sodium chloride, copolyvidone (S630), red ferric oxide and the micropowder silica gel of crossing 60 mesh sieves mixed back adding fluid bed, mix homogeneously, spray into 75% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 13
Prescription: (1) medicated layer (every):
Hydrochloric acid doxazosin 4.3mg
Polyvidone (Plasdone K90) 30mg
Copolyvidone (Plasdone S630) 60mg
Magnesium stearate 0.75mg
Silicon dioxide 0.6mg
Red ferric oxide 0.02mg
(2) boosting layer (every):
Carboxymethylstach sodium 42mg
Hypromellose (K15M) 10mg
Carbomer (971PNF) 4mg
Sodium chloride 25mg
Polyvidone (Plasdone S630) 14mg
Black Rouge 1.0mg
Magnesium stearate 0.5mg
Silicon dioxide 0.4mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose acetate 35g
Diethyl phthalate 1.55g
Acetone 1000ml
Clothing film weight 18mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the hydrochloric acid doxazosin of recipe quantity with after crossing copolyvidone (S630), polyvidone (K90), red ferric oxide and the silicon dioxide mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 95% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer (971PNF), sodium chloride, copolyvidone (S630), Black Rouge and the silicon dioxide of crossing 60 mesh sieves are pressed recipe quantity mix back adding fluid bed, mix homogeneously, spray into 95% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 14
Prescription: (1) medicated layer (every):
Hydrochloric acid doxazosin 8.6mg
Polyvidone (Plasdone K120) 30mg
Copolyvidone (Plasdone S630) 15mg
Red ferric oxide 0.025mg
Magnesium stearate 0.75mg
Micropowder silica gel 0.5mg
(2) boosting layer (every):
Carboxymethyl starch sodium 45mg
Hypromellose (K15M) 55mg
Sodium chloride 31mg
Copolyvidone (Plasdone S630) 30mg
Black Rouge 0.95mg
Magnesium stearate 0.48mg
Micropowder silica gel 0.5mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose triacetate 45g
Polyethylene glycol 1500 2.21g
Acetone 1400ml
Clothing film weight 24mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology:
1. the particulate preparation of medicated layer:
With the hydrochloric acid doxazosin of recipe quantity with after crossing copolyvidone (S630), polyvidone (K120), red ferric oxide and the micropowder silica gel mix homogeneously of 60 mesh sieves, add fluid bed, spray into about 75% alcoholic solution granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Add magnesium stearate then, standby (being designated as the A granule).
2. the particulate preparation of boosting layer:
Recipe quantity is pressed in carboxymethyl starch sodium, hydroxypropyl emthylcellulose, sodium chloride, copolyvidone (S630), Black Rouge and the micropowder silica gel of crossing 60 mesh sieves mixed back adding fluid bed, mix homogeneously, spray into 75% ethanol water of recipe quantity, granulate (30 ℃ of bed temperatures, 40 ℃ of inlet temperatures).Subsequently, add magnesium stearate, standby (being designated as the B granule).
3. tabletting and 4. coatings: all with embodiment 1.
Embodiment 15
Prescription: (1) medicated layer (every):
Doxazosin 4mg
Polyvidone (Plasdone K90) 35mg
Copolyvidone (Plasdone S630) 72mg
Magnesium stearate 0.5mg
Silicon dioxide 0.6mg
Red ferric oxide 0.02mg
(2) boosting layer (every):
Carboxymethylstach sodium 40mg
Hypromellose (K15M) 10mg
Carbomer (971PNF) 3.7mg
Sodium chloride 30mg
Polyvidone (Plasdone S630) 12mg
Black Rouge 1.0mg
Magnesium stearate 0.5mg
Silicon dioxide 0.4mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose acetate 35g
Diethyl phthalate 1.55g
Acetone 1000ml
Clothing film weight 18mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 25.5g in riotous profusion
Water 150ml
Preparation technology: with reference to embodiment 14.
Embodiment 16
Prescription: (1) medicated layer (every):
Doxazosin 8mg
Polyvidone (Plasdone K120) 28mg
Copolyvidone (Plasdone S630) 18mg
Red ferric oxide 0.05mg
Magnesium stearate 0.75mg
Micropowder silica gel 0.5mg
(2) boosting layer (every):
Carboxymethyl starch sodium 30mg
Hypromellose (K15M) 53mg
Sodium chloride 28mg
Copolyvidone (Plasdone S630) 25mg
Black Rouge 0.95mg
Magnesium stearate 0.48mg
Micropowder silica gel 0.5mg
(3) the semipermeable membrane coating solution is formed (per 1000 with)
Cellulose triacetate 45g
Polyethylene glycol 1500 2.21g
Acetone 1400ml
Clothing film weight 24mg
(4) moistureproof coating liquid is formed (per 1000 with)
Color blue white (CM-0018) 35.7g in riotous profusion
Water 210ml
Preparation technology: with reference to embodiment 14.
Embodiment 17
Under the dissolution medium condition of different pH, tablet of the present invention and commercially available product are carried out the release test.
(1) hydrochloric acid solution (pH=1.2);
(2) acetic acid-sodium-acetate buffer (pH=4.5);
(3) the mimic simulated intestinal fluid (pH6.8) that does not contain pancreatin;
(4) water.
Method of testing: according to drug release determination method (2005 editions two appendix X D of Chinese Pharmacopoeia, first method), adopting the device of dissolution method (2005 editions two appendix X C of Chinese Pharmacopoeia, second method), is solvent with above-mentioned dissolution medium 900ml respectively, rotating speed is that per minute 75 changes, and operation in accordance with the law is 2,4,6,8,10, got solution 10ml in 12 and 16 hours respectively, centrifugal (8000rpm, 15min), and the instant dissolution medium that in process container, replenishes uniform temp, equal volume; Get supernatant,, measure trap respectively at the wavelength place of 245nm according to spectrophotography (2005 editions two appendix IV A of Chinese Pharmacopoeia); Other gets the about 10mg of Carclura reference substance, and accurate the title decides, and puts in the 50ml measuring bottle, adds methanol 20ml, and supersound process makes dissolving, is diluted to scale with methanol, shakes up; Precision is measured above-mentioned solution 10ml, puts in the 100ml measuring bottle, and with the dissolution medium solvent, as stock solution, be solvent with corresponding dissolution medium respectively, by following dilution process, get a certain amount of stock solution and add proper amount of solvent, be diluted to certain density Carclura reference substance solution:
Contrast solution dilution process Carclura concentration (μ g/ml)
1# gets stock solution 1.0ml solubilizer to 50ml 0.4
2# gets stock solution 1.0ml solubilizer to 25ml 0.8
3# gets stock solution 2.0ml solubilizer to 25ml 1.6
4# gets stock solution 5.0ml solubilizer to 25ml 4.0
5# gets stock solution 6.0ml solubilizer to 25ml 4.8
6# gets stock solution 8.0ml solubilizer to 25ml 6.4
7# gets stock solution 10.0ml solubilizer to 25ml 8.0
Get contrast solution 1# respectively, 2#, 3#, 4#, 5#, 6# and 7# measure trap with method, the drawing standard curve.Calculate every burst size according to standard curve at different time.The results are shown in Table 1
Table 1 is from film-making and commercially available release data in hydrochloric acid solution (pH=1.2)
| Time (h) | From film-making (n=6) | Commercially available (n=6) |
| 4 | 22.7％ | 20.3％ |
| 8 | 58.5％ | 58.6％ |
| 12 | 85.1％ | 87.4％ |
| 16 | 98.8％ | 96.0％ |
Table 2 self-control controlled release tablet release data (n=6) in different release medium
| Release medium | Release (%) | ||||
| 4h | 8h | 12h | 16h | ||
| ?4mg | pH1.2 pH4.5 | 22.7 20.0 | 58.5 56.7 | 85.1 82.3 | 98.8 96.4 |
| PH6.8 water | 18.2 16.5 | 54.4 52.8 | 80.5 78.9 | 95.7 93.7 | |
| ?8mg | PH1.2 pH4.5 pH6.8 water | 23.4 19.5 18.5 21.8 | 59.2 57.5 56.4 57.3 | 83.7 81.3 79.5 85.7 | 100.4 98.3 96.8 97.9 |
Table 1 result of the test shows the preparation of method preparation provided by the invention and commercial preparation (can how magnificent
) release all meet state quality standard and require (every burst size of this product should must not should be mutually respectively more than 30%, 35～75% and 80% of labelled amount) at 4,8,16 hours.Compare with commercially available product, the self-control sample is rapid-action, and final release is more complete.
Table 2 is the result prove, the release behavior of controlled release tablet product of the present invention under different pH condition illustrates product of the present invention, and it is not subjected to pH value to influence effect stability in the intravital release of people.
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any change, the modification of being done under spirit of the present invention and the principle, substitute mode that substitutes, makes up, simplifies, all should be equivalence of not deviating from is included within protection scope of the present invention.
Claims (8)
1. controlled release tablet that contains doxazosin or its salt, it is characterized in that: this controlled release tablet comprises that weight ratio is 1: the medicated layer of 0.5-3 and boosting layer, described medicated layer comprises active medicine and carrier, this active medicine is doxazosin or its pharmaceutically acceptable salt that accounts for medicated layer weight 1-60%, and this carrier is the vinylpyrrolidone polymer that accounts for medicated layer weight 40-99%; Described boosting layer comprises the short osmopolymer that accounts for boosting layer weight 10-80%, the insoluble polymer of 10-80% and the osmotic pressure promoter of 3-80% at least; Described short osmopolymer is any one or its mixture in acrylic polymer, hydroxypropyl emthylcellulose, vinylpyrrolidone homopolymer, the nvp copolymer, and described acrylic polymer is a carbomer; Described insoluble polymer is any one or its mixture in dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, the cross-linking sodium carboxymethyl cellulose; The external packets of described controlled release tablet is with the thin film of semipermeable materials, and has at least an access opening to connect medicated layer and outside medicine can be discharged on the thin film of this semipermeable materials.
2. doxazosin or its salt controlled release tablet of containing according to claim 1, it is characterized in that: described vinylpyrrolidone polymer is the vinylpyrrolidone homopolymer, this vinylpyrrolidone homopolymer is a polyvidone.
3. the controlled release tablet that contains doxazosin or its salt according to claim 1, it is characterized in that: described vinylpyrrolidone polymer is a nvp copolymer, and this nvp copolymer is that l-vinyl-2-pyrrolidone and vinylacetate were with 1: 10 to 10: the 1 polymeric copolyvidone of ratio.
4. the controlled release tablet that contains doxazosin or its salt according to claim 1, it is the osmotic pump type controlled release tablet that contains active medicine, it is characterized in that: also contain fluidizer, lubricant and/or coloring agent in the described medicated layer.
5. the controlled release tablet that contains doxazosin or its salt as claimed in claim 1, wherein, described osmotic pressure promoter is salt, acids and/or saccharide, this salt is sodium chloride, potassium chloride, magnesium chloride, potassium sulfate, sodium sulfate and/or magnesium sulfate, this acids is ascorbic acid and/or tartaric acid, and this saccharide is mannitol, sorbitol, xylitol, lactose, glucose and/or sucrose.
6. the controlled release tablet that contains doxazosin or its salt as claimed in claim 1, wherein, this semipermeable materials is any one or its mixture in cellulose acetate, ethyl cellulose, cellulose propionate, cellulose diacetate, cellulose triacetate, Merlon, polyethylene, polyvinyl alcohol, the vinylacetate.
7. the preparation method of the controlled release tablet of each described doxazosin or its salt among claim 1-3 and the 5-6, wherein this preparation method comprises:
(1) preparation medicated layer, active medicine and carrier are crossed 60 mesh sieves, this active medicine is doxazosin or its pharmaceutically acceptable salt that accounts for medicated layer weight 1-60%, this carrier is the vinylpyrrolidone polymer that accounts for medicated layer weight 40-99%, again with active medicine and carrier mix homogeneously, spray into concentration and be not less than 40% alcoholic solution, granulate;
(2) preparation boosting layer will comprise that the adjuvant of short osmopolymer, insoluble polymer and penetration enhancer is crossed 60 mesh sieves, then it be mixed, and spray into concentration and be not less than 40% alcoholic solution and granulate;
(3) with above-mentioned medicated layer compression moulding, add the boosting lamination then and make medicated core, this medicated core is for comprising the double-decker of one deck medicated layer and one deck boosting layer at least;
(4) at the thin film of described medicated core external packets with semipermeable materials, drying, and make a call to a small delivery aperture with mechanical system or laser with suitable diameter in the one side of contiguous medicated layer.
8. the preparation method of the controlled release tablet of doxazosin as claimed in claim 7 or its salt, wherein this semipermeable materials is any one or its mixture in cellulose acetate, ethyl cellulose, cellulose propionate, cellulose diacetate, cellulose triacetate, Merlon, polyethylene, polyvinyl alcohol, the vinylacetate.
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| CN101856337B (en) * | 2010-05-28 | 2012-10-03 | 中国科学院上海药物研究所 | Novel penetration and controlled-release medicament delivery system and preparation method thereof |
| CN103877061B (en) * | 2014-03-18 | 2016-03-30 | 合肥华方医药科技有限公司 | Doxazosin-mesylate controlled-releasing tablet preparation and preparation method thereof |
| CN106727406B (en) * | 2017-01-04 | 2018-01-19 | 北京汇诚瑞祥医药技术有限公司 | A kind of controlled release composition containing Doxazosin and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4837111A (en) * | 1988-03-21 | 1989-06-06 | Alza Corporation | Dosage form for dispensing drug for human therapy |
| CN1402632A (en) * | 1999-12-23 | 2003-03-12 | 辉瑞产品公司 | Hydrogel-driven drug dosage form |
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2007
- 2007-11-23 CN CN2007101779893A patent/CN101439026B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4837111A (en) * | 1988-03-21 | 1989-06-06 | Alza Corporation | Dosage form for dispensing drug for human therapy |
| CN1402632A (en) * | 1999-12-23 | 2003-03-12 | 辉瑞产品公司 | Hydrogel-driven drug dosage form |
Non-Patent Citations (1)
| Title |
|---|
| 甘勇.难溶性药物格列吡嗪渗透泵型控释片及释药机理的研究.《中国优秀博硕士论文全文数据库（博士）医药卫生科技辑2004年第01期》.2004,第30页第10行至最后一行及第31页图2-5,参见论文第32页第5行至最后一行，表2-7及图2-7，第33页第1-7行，表2-8及图2-8. * |
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