CN104814923B - A kind of tamsulosin hydrochloride sustained release preparation and preparation method thereof and its application - Google Patents
A kind of tamsulosin hydrochloride sustained release preparation and preparation method thereof and its application Download PDFInfo
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Abstract
The present invention relates to tamsulosin hydrochloride sustained release preparation and preparation method thereof and its application, said preparation is sustained clothing film by matrix type pastille slow-release micropill, film controlling type and pastille release layer is constituted, wherein, the percentage by weight of preparation middle skeleton type pastille slow-release micropill is that the percentage by weight of 5 95%, film controlling type sustained release clothing film is that the 1 20%, percentage by weight of pastille release layer is 1 10%, and the composition of the matrix type pastille slow-release micropill is：Tamsulosin hydrochloride containing 0.01 1%, 5 50% slow-release material, 1 10% adhesive and 5 50% pore-foaming agent, the composition of film controlling type sustained release clothing film is：Slow-release material containing 1 40%, 1 5% plasticizer, 10 60% pore-foaming agent and 1 5% antiplastering aid, the composition of the pastille release layer is：Tamsulosin hydrochloride containing 0.01 1%, 1 95% immediate release material and 1 10% adhesive.Have the advantages that quick, steady, lasting, medicine persistent, side effect are low, quality controllable, be adapted to large-scale production.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of tamsulosin hydrochloride sustained release preparation and preparation method thereof
With its application.
Background technology
Tamsulosin hydrochloride (structure shown in formula I, also known as tamsulosin hydrochloride) is a kind of potent, high selectivity α 1- kidneys
Upper parathyrine acceptor inhibitor (blocking agent), is clinically used for arranging caused by treatment benign prostatic hyperplasis (BPH) and hypertrophy of the prostate
Urinate obstacle.In vitro test shows, compared with similar drugs Terazosin Hydrochloride, and tamsulosin hydrochloride has preferably curative effect.But salt
The oral formulations of sour Tamsulosin, which exist, absorbs rapid, rapid-action, may cause the adverse reactions such as low blood pressure and dizziness, therefore clinical many
Using tamsulosin hydrochloride sustained release preparation.
At present, tamsulosin hydrochloride sustained release preparation includes two kinds of skeleton type sustained release preparation and film controlling type sustained release preparation.Wherein, bone
Frame type sustained release preparation is mixed with slow using erosion type (such as hydrophilic gel) high polymer material, insoluble type high polymer material and medicine
Skeleton is released, with Drug controlled release；Film controlling type sustained release preparation makes medicine exist in the suitable clothing layer of the pan coating of label and piller
Dissolved under certain condition or be partly dissolved and disengage, to control the slow release of medicine.
Sustained release pellet can be easily made sustained release preparation, controlled release preparation or positioning delivery formulations, and with good fluidity, not fragile
Broken the features such as, and the contact area of medicine and intestines and stomach can be improved, promote drug absorption completely, improve bioavilability, reduce
Even avoid the adverse reactions such as stomach lining stimulation.
Tamsulosin hydrochloride sustained release pellet is mixed by medicine with retarding agent, or first will often release micropill coating release-controlled film and
Into, but there is insoluble drug release fluctuation between product batches is big, operation controllability is relatively poor etc. in these single controlled-release pattern preparations
Defect.
Document 1 (the formulation and technology research of tamsulosin hydrochloride sustained-release dropping pill,《Hebei Normal University Journal》(natural science
Version), volume 35 the 3rd phase, the 279-282 pages in 2011) a kind of tamsulosin hydrochloride matrix type slow-release pill preparation is disclosed, the system
Agent uses Macrogol 6000 (PEG6000) and Macrogol 4000 (PEG4000) for immediate release solid dispersible carrier material, firmly
Glycerol and glycerin monostearate are sustained-release matrix material, and are prepared from using fusion method.
Document 2 (development of tamsulosin hydrochloride osmotic pump tablet and drug release factors influencing；《Oceanography Institute Of Zhejiang's journal》
(natural science edition), in December, 2007 volume 26 4 phases, the 435-438 pages) disclose a kind of tamsulosin hydrochloride monocompartment osmotic pump-type
Controlled release tablet, the tablet for hydrophilic gel framework material, is prepared from HPMC (HPMC) using wet granulation,
Wherein, sodium chloride, clothing film thickness and pore-foaming agent consumption turn into the principal element of influence drug release.
(the discussion of tamsulosin hydrochloride formulation and technology of document 3；《Journal of Henan University》(medicine), 2011 volume 30
04 phase, 250-254, page 263) disclose a kind of tamsulosin hydrochloride hydrogel matrix sustained release tablets, the tablet is with sodium alginate
It is framework material with hydroxypropyl methyl cellulose (HPMC).
Document 4 (investigate by the preparation of tamsulosin hydrochloride sustained release preparation and vitro release；《Chinese Medicine guide》, 2012
Volume 10 25 phases, the 46-48 pages) disclose the Tamsulosin being prepared from hydroxypropyl methyl cellulose (HPMC) for framework material
Sustained release tablets.
(centrifugal granulation prepares the Effect Factors for Sythetic Technology and release in vitro of tamsulosin hydrochloride sustained-release micro-pill capsules to document 5
Degree is investigated；《China Dispensary》, volume 22 the 13rd phase, the 1196-1199 pages in 2011) and disclose that to prepare microcrystalline cellulose blank micro-
Ball and tamsulosin hydrochloride pastille micropill, then carried out aqueous acrylic resin dispersion coating.
Document 6 (investigate by the preparation of tamsulosin hydrochloride sustained-release micro-pill capsules and formulation and technology：《Shanghai medicine》, 2012
Volume 33 the 21st phase, the 45-49 pages) disclose using Sulisi, refined gram of suitable, Opadry II as coating material, use fluid bed
Spray solution medicine-feeding method in bottom carries out sustained release coating, prepares and carries medicine micropill.
Tamsulosin hydrochloride skeleton type sustained release preparation disclosed in aforementioned documents is single delivery systme or is that film control is micro-
Ball delivery systme, wherein, skeleton in single delivery systme granulation size, tableting pressure fluctuation, film control coating of pellets film and release
Medicine hole change etc., can significantly affect insoluble drug release behavior, and then cause between low dose of tamsulosin hydrochloride sustained release preparation is present batch
The defects such as insoluble drug release difference is big, poor reproducibility, and there is the defects such as initial drug release deficiency in film control micropill delivery systme.
Therefore, be bursting to study a kind of rapid-action, reappearance it is high, batch between release difference is small, release is lasting tamsulosin hydrochloride slow-release
Preparation, to improve Drug safety and validity.
The content of the invention
It is an object of the invention to provide a kind of tamsulosin hydrochloride sustained release preparation, said preparation is micro- by matrix type pastille slow-release
Ball, film controlling type sustained release clothing film and pastille release layer composition, wherein, the percentage by weight of preparation middle skeleton type pastille slow-release micropill is
5-95%, the percentage by weight of film controlling type sustained release clothing film are that 1-20%, the percentage by weight of pastille release layer are 1-10%, described
The composition of matrix type pastille slow-release micropill is：The slow-release material of tamsulosin hydrochloride, 5-50% containing 0.01-1%, 1-10%
The pore-foaming agent of adhesive and 5-50%, the composition of film controlling type sustained release clothing film is：Slow-release material, 1-5% containing 1-40%
Plasticizer, 10-60% pore-foaming agent and 1-5% antiplastering aid, the composition of the pastille release layer is：Contain 0.01-1%'s
The adhesive of tamsulosin hydrochloride, 1-95% immediate release material and 1-10%.
In the preferred technical solution of the present invention, the percentage by weight of sustained release preparation middle skeleton type pastille slow-release micropill is 10-
90%, preferably 20-80%.
In the preferred technical solution of the present invention, the percentage by weight of film controlling type sustained release clothing film is 5-15% in sustained release preparation,
Preferably 8-12%.
In the preferred technical solution of the present invention, the percentage by weight of pastille release layer is 4-8% in sustained release preparation, is preferably
5-7%.
In the preferred technical solution of the present invention, contained tamsulosin hydrochloride in sustained release preparation middle skeleton type pastille slow-release micropill：
The mass ratio of contained tamsulosin hydrochloride is 60-95 in pastille release layer：5-40, preferably 70-90：10-30.
In the preferred technical solution of the present invention, the composition of sustained release preparation middle skeleton type pastille slow-release micropill is：Contain 0.02-
0.5% tamsulosin hydrochloride, 10-35% slow-release material, preferably 2-8% adhesive and 10-40% pore-foaming agent, matrix type
The composition of pastille slow-release micropill is：The bonding of the slow-release material, 3-6% of tamsulosin hydrochloride, 15-30% containing 0.05-0.3%
Agent and 15-30% pore-foaming agent.
In the preferred technical solution of the present invention, the composition of film controlling type sustained release clothing film is in sustained release preparation：Contain 5-35%'s
Slow-release material, 2-4% plasticizer, 15-50% pore-foaming agent and 2-4% antiplastering aid, preferably film controlling type are sustained the group of clothing film
Turn into：The plasticizer of slow-release material, 2.5-3.5%, 20-40% pore-foaming agent and 2.5-3.5% containing 10-30% it is anti-stick
Agent.
In the preferred technical solution of the present invention, the composition of pastille release layer is in sustained release preparation：Contain 0.05-0.8%'s
The adhesive of tamsulosin hydrochloride, 5-90% immediate release material and 2-8%, the composition of preferably pastille release layer is：Contain 0.1-
The adhesive of 0.6% tamsulosin hydrochloride, 10-80% immediate release material and 3-6%.
In the preferred technical solution of the present invention, the content of tamsulosin hydrochloride is 0.1-1.2mg in sustained release preparation of the invention,
Preferably 0.2-1.0mg, more preferably 0.2-0.8mg.
The present invention adds suitable pharmaceutically acceptable carrier in tamsulosin hydrochloride preparation, according to the system of sustained release preparation
[Tang Xing is edited standby technology《Oral sustained-release preparation》, People's Health Publisher, 2007, the 1st edition；《Pharmaceutic adjuvant application skill
Art》, China Medical Science Press, second edition in 2002], tamsulosin hydrochloride is made by matrix type pastille slow-release micropill, film
Control type is sustained the sustained release preparation of clothing film and pastille release layer composition, wherein, pastille release layer realizes the fast quick-release of tamsulosin hydrochloride
Put and quick acting, matrix type pastille slow-release micropill and film controlling type sustained release clothing film then control the steady of tamsulosin hydrochloride long-acting to release
Put, and by controlling coating thickness and/or addition pore-foaming agent, to control the rate of release of active component, to reduce or eliminate it
Adverse reaction, increases the security and validity of preparation, improves the compliance of patient medication.
In the preferred technical solution of the present invention, described matrix type slow-release material is selected from hydrophilic gels framework material, molten
Any or its combination, preferably pectin, sodium alginate, cellulose derivative of corrosion framework material, insoluble framework material
(such as methylcellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, HPMC, microcrystalline cellulose
Deng) or its salt, non-cellulosic polysaccharide (such as chitin, chitosan) or its salt, polyvinyl alcohol, carbopol, beeswax, stearic acid,
Castor wax, octadecanol, Brazil wax, polyethylene glycol (are preferably PEG4000Or PEG6000), it is acrylic resin, polyethylene, poly-
Propylene, polysiloxanes, alginic acid or its salt, carbopol, any or its combination of modified starch.
In the preferred technical solution of the present invention, the content of tamsulosin hydrochloride is 0.1-1.2mg in sustained release preparation of the invention,
Preferably 0.2-1.0mg, more preferably 0.2-0.8mg.
In the preferred technical solution of the present invention, it is high that described film controlling type slow-release material is selected from the insoluble type of Enteric Materials, water
Any or its combination, preferably cellulose acetate-phthalate (CAP), phthalic acid hypromellose of molecular material
Plain ester (HPMCP), polyacrylic resin type enteric material, any or its combination of ethyl cellulose.
In the preferred technical solution of the present invention, described pore-foaming agent is selected from sucrose, lactose, mannitol, polyvinylpyrrolidine
Ketone, PEG4000、PEG6000, starch, talcum powder, silica, superfine silica gel powder any or its combination.
In the preferred technical solution of the present invention, described adhesive is selected from polyvinylpyrrolidone, hydroxypropyl methyl fiber
Element or its salt, starch, sucrose, any or its combination of dextrin.
In the preferred technical solution of the present invention, described antiplastering aid is selected from talcum powder, superfine silica gel powder, titanium dioxide, tristearin
Sour magnesium, stearic acid, starch, PEG4000、PEG6000, atoleine any or its combination.
In the preferred technical solution of the present invention, described immediate release material is selected from sucrose, lactose, mannitol, polyvinyl pyrrole
Alkanone, PEG4000、PEG6000It is any or its combination.
In the preferred technical solution of the present invention, described Sustained release coating materials are selected from cellulose derivative, gastric solubility third
Olefin(e) acid resin, insoluble microporous membrane coating material, any or its combination, preferably methyl of enteric film coating material
Cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, ethyl cellulose (EC), phthalic acid acetic acid are fine
Tie up any of element, phthalic acid HPMC, enteric acrylate's resin or its latex aqueous dispersion or its combination.
In the preferred technical solution of the present invention, added in micropill insoluble framework material, hydrophilic gel framework material,
Any or its combination of wax, pore-foaming agent, to control the rate of release of active component.
In the preferred technical solution of the present invention, the wax, which is selected from, contains C8-C30Alcohol, acid, ester, salt or acid amides, be preferably
Stearic acid, beeswax, castor wax, octadecanol, any or its combination of Brazil wax.
In the preferred technical solution of the present invention, described plasticizer be selected from dibutyl phthalate, polyethylene glycol 400,
Macrogol 600, benzoic ether, any or its combination of propane diols.
In the preferred technical solution of the present invention, skeleton film controlling type sustained release pellet：Framework film rate controlling releases the coating of sustained release pellet
The mass ratio of material is 4-8：3-6, preferably 5-6：4-5.
In the preferred technical solution of the present invention, described tamsulosin hydrochloride sustained release preparation is selected from granule, capsule, ball
Agent, any or its combination of tablet.
Another object of the present invention is to provide a kind of preparation method of tamsulosin hydrochloride sustained release preparation, including following steps
Suddenly：
1) the desired amount of tamsulosin hydrochloride is uniformly mixed with pharmaceutically acceptable carrier, using extruding-round as a ball pelletization
Method, Centrifugal fluidized pellet method, thermosol extrusion it is any, be made into sustained-release matrix micropill；
2) sustained-release matrix micropill is coated with clothing film, is made into skeleton reservoir pellets；
3) by skeleton film controlling type sustained release ball coating pastille release layer, produce.
In the preferred technical solution of the present invention, the skeleton film controlling type for being coated with pastille release layer is sustained ball granulation, dress capsule
Or tabletting, required sustained release preparation is made.
In the preferred technical solution of the present invention, the preparation method of matrix sustained-release pellets comprises the steps：By recipe quantity
Slow-release material (such as hydroxypropyl methyl cellulose) is dispersed in water, and is heated to 70-90 DEG C (being preferably 80 DEG C), stirring condition
Under, add the tamsulosin hydrochloride of total amount 60-80% (being preferably 70%), added in obtained slurry pore-foaming agent (such as lactose) and
Adhesive (such as polyvinylpyrrolidone), after being well mixed, using extruding-round as a ball pelletization method, Centrifugal fluidized pellet method, thermosol
Any or its combination of extrusion, is made into piller, dries, matrix sustained-release pellets are made.
In the preferred technical solution of the present invention, the preparation method of skeleton film controlling type sustained release pellet comprises the steps：1) will
2-5% (be preferably 3-4%) ethanol solution is made in the slow-release material (such as ethyl cellulose) of recipe quantity, add pore-foaming agent,
Plasticizer, antiplastering aid, after stirring and evenly mixing, are made sustained release clothing film coating liquid；2) under the conditions of 40-60 DEG C (being preferably 50-55 DEG C),
Matrix sustained-release pellets are whitewashed with sustained release clothing film coating liquid and are coated, skeleton film controlling type sustained release pellet is made, wherein, the use of coating solution
Measure as (in terms of dry) dry micropill 4-8% (being preferably 5-6%).
In the preferred technical solution of the present invention, the preparation method of sustained release pellet comprises the steps：1) by adhesive (such as
PVP K30) adding water is made 3-10% slurries (being preferably 5-8%), and surplus tamsulosin hydrochloride is added, is stirred,
After even mixing, pastille quick-release coating solution is made；2) under the conditions of 40-60 DEG C (being preferably 50-55 DEG C), by skeleton reservoir pellets
Whitewashed and be coated with pastille quick-release coating solution, framework film control quick-releasing type sustained release preparation is made, produces.
Another object of the present invention is to provide tamsulosin hydrochloride sustained release preparation be used for prepare treat benign prostatic hyperplasis
(BPH), the application in the medicine of urination disorder caused by hypertrophy of the prostate.
In order to clearly state protection scope of the present invention, the present invention is defined as follows to following terms：
Pastille micropill, film controlling type sustained release clothing film and pastille quick-release clothing layer that sustained release pellet of the present invention is sustained by skeleton
Composition.
Reference of the present invention《Chinese Pharmacopoeia》Two methods of the annex XD first detection tamsulosin hydrochloride sustained release preparations of version in 2010
Vitro release, comprises the steps：With pH1.2 sodium chloride salt acid solution (simulated gastric fluid) be medium, rotating speed be 100 turns/
Minute, filtrate is taken, is operated in accordance with the law, filtrate is taken, in accordance with the law for medium after 2h, then with pH7.2 phosphate buffers (simulated intestinal fluid)
Operation.According to high performance liquid chromatography (《Chinese Pharmacopoeia》The two annex VD of version in 2010) determine.Chromatographic condition and system suitability
Experimental condition is：Octadecylsilane chemically bonded silica is filler, 0.18mol/L potassium dihydrogen phosphate -0.2mol/L phosphoric acid
Solution-acetonitrile (6: 7: 6) is mobile phase, and Detection wavelength is 225nm.Number of theoretical plate is not less than 1500 based on tamsulosin hydrochloride peak.
Unless otherwise indicated, the present invention relates to during the percentage between liquid and liquid, described percentage is volume/body
Product percentage；The present invention relates to during the percentage between liquid and solid, the percentage is volume/weight percentage；This hair
It is bright be related between solid and liquid percentage when, the percentage be weight/volume percent；Remaining is w/w hundred
Divide ratio.
Compared with prior art, tamsulosin hydrochloride sustained release preparation of the invention has following advantageous effects：
1st, tamsulosin hydrochloride sustained release preparation of the invention is using the triple of skeleton sustained release, film-controlled slow-release and quick-release combination
Delivery mode, and consider the factors such as drug solubility, the release that clinical application needs and release profiles, science is screened
Slow-release material, adhesive, pore-foaming agent, plasticizer, the species of coating material and its consumption, and improve pore-foaming agent in extended release coatings film layer
Consumption, reduces slow-release material consumption, it is carried out Drug controlled release with macroporous membrane diffusion barrier prosecutor formula, reaches that internal 6-36h is protected
Maintain an equal level beneficial effect that is steady, persistently discharging, reduces toxic side effect and the adverse reaction of medicine, overcomes drug release rate fluctuation
Greatly, the defect such as homogeneity difference, with quick, steady, lasting, bioavilability height, medicine persistent, side effect be low, quality
It is controllable, batch between drug release rate favorable reproducibility, safety and effectivity the advantages of.
2nd, the release amount of medicine in tamsulosin hydrochloride sustained release preparation rapid release layer 2h of the invention is more than 10%, and patient
Only need to take sustained release preparation of the invention once daily, you can reach whole day control and alleviate the frequent micturition caused by prostate increase
Therapeutic effect, has the advantages that convenient to take, economical, safe, long-acting, adds the compliance of patient medication.
3rd, tamsulosin hydrochloride sustained release preparation of the invention had both reached the therapeutic purposes of quick acting, long-acting with steadily continuing
The characteristics of release, overcome that matrix type micropill or dosage at the beginning present in reservoir pellets are small, insoluble drug release fluctuation is larger again,
The defect such as poor reproducibility between batch, and the generation of cardiovascular side effects is reduced, it is greatly enhanced Drug safety, validity.
4th, tamsulosin hydrochloride sustained release preparation of the invention saves macromolecule coating material consumption, significantly reduces and is produced into
This (cost declines 5-15%), and it is easy to operate, it is easy to accomplish industrialized production.
Brief description of the drawings
The structural representation of Fig. 1 sustained release pellets of the present invention.
Main ingredient release profiles in the tamsulosin hydrochloride sustained release preparation that Fig. 2 documents 1 (please indicate literature reference) are recorded
Tamsulosin hydrochloride sustained release preparation 12h release profiles made from Fig. 3 embodiments 1.
Tamsulosin hydrochloride sustained release preparation 12h elution profiles made from Fig. 4 embodiments 2.
Tamsulosin hydrochloride sustained release preparation 24h release profiles made from Fig. 5 embodiments 3.
Tamsulosin hydrochloride sustained release preparation 24h elution profiles made from Fig. 6 embodiments 4.
The smooth Lip river matrix type micropill 12h release profiles of hydrochloric acid made from Fig. 7 embodiments 1.
Tamsulosin hydrochloride skeleton reservoir pellets 12h elution profiles made from Fig. 8 embodiments 1.
The commercially available tamsulosin hydrochloride sustained-release capsules of Fig. 9 (Harnal) 12h elution profiles.
Embodiment
The present invention is illustrated below with reference to embodiment, embodiments of the invention are merely to illustrate the technical side of the present invention
Case, and non-limiting essence of the invention.
Embodiment 1The preparation of tamsulosin hydrochloride sustained-release capsule
1) composition of matrix type sustained release pellet：
Wherein, hydroxypropyl methyl cellulose is slow-release material, and lactose is used as pore-foaming agent, PVP K30
(PVPk30) it is adhesive, formation skeleton micropore after pore-foaming agent dissolves in digestive juice, active component is slow steady from micropore
Release.
2) composition of film-controlled slow-release clothing film
3) composition of pastille release layer
The preparation method of the present embodiment tamsulosin hydrochloride sustained release preparation, comprises the steps：
1) the desired amount of hydroxypropyl methyl cellulose is dispersed in purified water, is heated to about 80 DEG C, under stirring condition, plus
Enter the tamsulosin hydrochloride of recipe quantity, until forming slurry；Lactose, PVP K30 alcohol water are added in hot slurry again
Solution, stirring mixing 20 minutes, using extruding-round as a ball pelletization method, its extruder is squeezed into, long 2-6mm's
Extrudate, round as a ball into piller, 40 DEG C of dryings produce matrix type sustained release pellet；
2) the desired amount of ethyl cellulose is dissolved in absolute ethyl alcohol, adds pore-foaming agent (Macrogol 6000), increasing
Agent (propane diols), antiplastering aid (talcum powder) are moulded, after stirring and evenly mixing, is placed more than 15 hours, sustained release clothing film coating liquid is made into；
Under the conditions of 55 DEG C, matrix type sustained release pellet is coated with the liquid whitewashing of sustained release clothing film coating, after after micropill weightening 5%, bone is made
Frame reservoir pellets；
3) the desired amount of PVP K30 is dissolved in purified water, adds surplus tamsulosin hydrochloride, stirred,
It is dissolved in after slurries, pastille release layer coating solution is made；Under the conditions of 55 DEG C, by skeleton reservoir pellets pastille release layer
Coating solution whitewashing is coated, and dries, framework film control quick-releasing type sustained release pellet is made；
4) framework film control quick-releasing type sustained release pellet is filled in empty hard capsule, the hydrochloric acid that unit dose is 4mg is made
Tamsulosin sustained release capsule.
Embodiment 2The preparation (12h sustained release preparations) of tamsulosin hydrochloride sustained-release capsule
1) composition of matrix type pastille slow-release micropill：
2) film controlling type is sustained the composition of clothing film
3) composition of pastille release layer
The preparation method be the same as Example 1 of the present embodiment tamsulosin hydrochloride sustained-release capsule.
Embodiment 3The preparation (24h sustained release preparations) of tamsulosin hydrochloride sustained-release tablet
1) composition of matrix type pastille slow-release label：
Wherein, hydroxypropyl methyl cellulose is slow-release material, and lactose is used as pore-foaming agent, PVP K30
(PVPk30) it is adhesive, formation skeleton micropore after pore-foaming agent dissolves in digestive juice, active component is slow steady from micropore
Release.
2) film controlling type is sustained the composition of clothing film
3) composition of pastille release layer
The preparation method of the present embodiment tamsulosin hydrochloride sustained release preparation, comprises the steps：
1) the desired amount of hydroxypropyl methyl cellulose is dispersed in pure water, is heated to about 80 DEG C, under stirring condition, addition
The tamsulosin hydrochloride of recipe quantity, until forming slurry；Lactose, the alcohol water of PVP K30 are added in hot slurry again
Solution, stirring mixing 20 minutes, using extruding-round as a ball pelletization method, is squeezed into0.6-0.9mm, long 2-6mm extrudate,
It is round as a ball into piller, 40 DEG C of dryings, whole grain adds magnesium stearate and mixed, tabletting produces matrix sustained release tablet core；
2) the desired amount of ethyl cellulose is dissolved in absolute ethyl alcohol, adds pore-foaming agent (Macrogol 6000), increasing
Agent (propane diols), antiplastering aid (talcum powder) are moulded, after stirring and evenly mixing, is placed more than 15 hours, sustained release clothing film coating liquid is made into；
Under the conditions of 55 DEG C, matrix sustained release tablet core is coated with the liquid whitewashing of sustained release clothing film coating, after after label weightening 6%, bone is made
Frame film controlling type label；
3) the desired amount of PVP K30 is dissolved in purified water, adds surplus tamsulosin hydrochloride, stirred,
It is dissolved in after slurries, pastille release layer coating solution is made；Under the conditions of 55 DEG C, by framework film control matrix core pastille release layer
Coating solution whitewashing is coated, and dries, framework film control quick-releasing type sustained release tablets are made.
Embodiment 4The preparation (24h sustained release preparations) of tamsulosin hydrochloride sustained release
1) matrix type pastille slow-release label is constituted：
Wherein, microcrystalline cellulose is slow-release material, and sucrose is as pore-foaming agent, PVP K30 (PVPk30)
Adhesive, superfine silica gel powder is as lubricant, and pore-foaming agent forms skeleton micropore after being dissolved in digestive juice, and active component is from micropore
Slow steady release.
2) film controlling type is sustained the composition of clothing film
3) composition of pastille release layer
The preparation method be the same as Example 3 of the present embodiment tamsulosin hydrochloride sustained release preparation.
Embodiment 5The drug release in vitro degree research of micropill is made in embodiment 1
Using vitro release detection method of the present invention, according to testing conditions listed by table 1, comparative studies embodiment
Obtained matrix type micropill, skeleton reservoir pellets, the vitro release of framework film control fast release micropill, the results are shown in Table l, figure in 1
3rd, Fig. 7-Fig. 8.
The drug release rate comparative studies result of the different releasing theories of 1 embodiment of table 1
From table 1, Fig. 3, Fig. 7-Fig. 8, framework film control fast release micropill of the invention can discharge in simulated gastric fluid 2h
25% tamsulosin hydrochloride, and skeleton reservoir pellets only discharge 9%, matrix type micropill release up to 32%；And its 12h is released
Degree of putting is respectively 98%, 96%, 80%.
As can be seen here, matrix type micropill is higher (32%) in 2h release, but its 12h release is relatively low (80%), difficult
To meet the demands such as clinical application validity, steady release；Skeleton reservoir pellets 12h releases are up to 96%, but its 2h discharges
Spend too low (only 9%), it is difficult to meet the requirement of clinical quick acting；The present invention framework film control fast release micropill have it is rapid-action,
Steady release, bioavilability be high, safely and effectively, be easy to the advantages of clinical and patient uses.
Embodiment 6The drug release in vitro degree research of sustained release label is made in embodiment 3
Using vitro release detection method of the present invention, according to testing conditions listed by table 2, comparative studies embodiment
Obtained matrix type label, framework film control matrix core, the vitro release of framework film control fast-release tablet, the results are shown in Table 2 in 3.
The drug release rate comparative studies result of the different releasing theories of 2 embodiment of table 3
From table 2, framework film control fast release micropill of the invention can discharge the 22% smooth Lip river of hydrochloric acid in simulated gastric fluid 2h
Newly, and skeleton reservoir pellets only discharge 7%, matrix type micropill release up to 30%；And its 12h release is respectively
92%th, 86%, 76%.
As can be seen here, matrix type micropill is higher (30%) in 2h release, but its 12h release is relatively low (76%), difficult
To meet the demand that clinical application steadily discharges；Skeleton reservoir pellets 12h releases are up to 86%, but its 2h release is too low
(only 7%), it is difficult to meet the requirement of clinical quick acting；The present invention framework film control fast release micropill have it is rapid-action, steadily release
Put, bioavilability is high, safely and effectively, be easy to the advantages of clinical and patient uses.
Embodiment 7The vitro release research of tamsulosin hydrochloride sustained release preparation
It is control with commercially available tamsulosin hydrochloride sustained release preparation (Harnal), using vitro release detection side of the present invention
Method, the vitro release of tamsulosin hydrochloride sustained release preparation, is as a result shown in Fig. 3-Fig. 9 made from comparative studies embodiment 1- embodiments 4.
From Fig. 3-Fig. 9, the release of matrix type tamsulosin hydrochloride sustained release preparation is very fast, it is difficult to which what satisfaction steadily discharged will
Ask；The release of skeleton film controlling type tamsulosin hydrochloride sustained release preparation is too slow, it is impossible to reach the purpose of quick acting；The framework film of the present invention
Control quick-releasing type tamsulosin hydrochloride sustained release preparation has rapid-action, steady release, bioavilability height, safety and effectivity, is easy to clinic
And patient is the advantages of use.
Embodiment 8The stability study of tamsulosin hydrochloride sustained release preparation
It is control with commercially available tamsulosin hydrochloride sustained release preparation (Harnal), using following methods, compares 1-4 of the embodiment of the present invention
The stability of the tamsulosin hydrochloride sustained release preparation of preparation is as a result as follows：
1) through 4500LX illumination 10 days, the relevant material of tamsulosin hydrochloride sustained release preparation prepared by 1-4 of the embodiment of the present invention,
Release, content have no significant change；
2) through 40 DEG C, 60 DEG C of high temperature 10 days, the character of tamsulosin hydrochloride sustained release preparation prepared by 1-4 of the embodiment of the present invention,
Relevant material, release, content have no significant change；
3) high humidity 10 days, the character of tamsulosin hydrochloride sustained release preparation prepared by 1-4 of the embodiment of the present invention, relevant material, are released
Less, character slightly has influence for degree of putting, changes of contents；
4) under the conditions of relative humidity 75%, 40 DEG C, in 0, l, 2, the accelerated test in March, tamsulosin hydrochloride sustained release system
The appearance luster of agent, relevant material, content, release, meet regulation, and release reappearance is very good between batch.
It can be seen that, sustained release preparation of the invention is highly stable.
Claims (22)
1. a kind of tamsulosin hydrochloride sustained release preparation, said preparation is sustained clothing film and pastille by matrix type pastille slow-release micropill, film controlling type
Release layer is constituted, wherein, the percentage by weight of preparation middle skeleton type pastille slow-release micropill is 5-95%, film controlling type sustained release clothing film
Percentage by weight is that 1-20%, the percentage by weight of pastille release layer are 1-10%, and matrix type pastille slow-release micropill, film controlling type delay
The total amount for releasing clothing film and pastille release layer is 100%,
The composition of the matrix type pastille slow-release micropill is：The matrix type of tamsulosin hydrochloride, 5-50% containing 0.01-1% delays
The pore-foaming agent of material, 1-10% adhesive and 5-50% is released, the composition of the film controlling type sustained release clothing film is：Contain 1-40%'s
Film controlling type slow-release material, 1-5% plasticizer, 10-60% pore-foaming agent and 1-5% antiplastering aid, the pastille release layer
Constitute and be：The immediate release material and 1-10% adhesive of tamsulosin hydrochloride, 1-95% containing 0.01-1%；
The matrix type slow-release material be selected from pectin, sodium alginate, cellulose derivative or its salt, non-cellulosic polysaccharide or its
Salt, polyvinyl alcohol, carbopol, beeswax, stearic acid, castor wax, octadecanol, Brazil wax, polyethylene glycol, acrylic acid tree
Fat, polyethylene, polypropylene, polysiloxanes, alginic acid or its salt, carbopol, any or its combination, the fibre of modified starch
The plain derivative of dimension is methylcellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, HPMC, micro-
Crystalline cellulose, the non-cellulosic polysaccharide is chitin, chitosan；
The film controlling type slow-release material is selected from cellulose acetate-phthalate (CAP), Hydroxypropyl Methyl Cellulose Phthalate
(HPMCP), any or its combination of polyacrylic resin type enteric material, ethyl cellulose；Described pore-foaming agent is selected from sugarcane
Sugar, lactose, mannitol, polyvinylpyrrolidone, Macrogol 4000, starch, talcum powder, silica, Macrogol 6000,
Any or its combination of superfine silica gel powder；
Described adhesive is selected from times of polyvinylpyrrolidone, hydroxypropyl methyl cellulose or its salt, starch, sucrose, dextrin
A kind of or its combination；
Described antiplastering aid is selected from talcum powder, superfine silica gel powder, titanium dioxide, magnesium stearate, stearic acid, starch, polyethylene glycol
4000th, any or its combination of Macrogol 6000, atoleine；
Described immediate release material is selected from sucrose, lactose, mannitol, polyvinylpyrrolidone, Macrogol 4000, polyethylene glycol
6000 any or its combination；
Described plasticizer is selected from dibutyl phthalate, polyethylene glycol 400, Macrogol 600, benzoic ether, propane diols
It is any or its combination.
2. tamsulosin hydrochloride sustained release preparation according to claim 1, the sustained release preparation middle skeleton type pastille slow-release micropill
Percentage by weight be 10-90%, the percentage by weight of film controlling type sustained release clothing film is 8-12%, sustained release system in the sustained release preparation
The percentage by weight of pastille release layer is 4-8%, matrix type pastille slow-release micropill, film controlling type sustained release clothing film and pastille quick-release in agent
The total amount of layer is 100%.
3. tamsulosin hydrochloride sustained release preparation according to claim 1, the sustained release preparation middle skeleton type pastille slow-release micropill
Percentage by weight be 20-80%, the percentage by weight of film controlling type sustained release clothing film is 5-15%, sustained release system in the sustained release preparation
The percentage by weight of pastille release layer is 5-7%, matrix type pastille slow-release micropill, film controlling type sustained release clothing film and pastille quick-release in agent
The total amount of layer is 100%.
4. the tamsulosin hydrochloride sustained release preparation according to claim 1-3 any one, the sustained release preparation middle skeleton type contains
Contained tamsulosin hydrochloride in medicine sustained release pellet：The mass ratio of contained tamsulosin hydrochloride is 60-95 in pastille release layer：5-40.
5. tamsulosin hydrochloride sustained release preparation according to claim 4, the sustained release preparation middle skeleton type pastille slow-release micropill
In contained tamsulosin hydrochloride：The mass ratio of contained tamsulosin hydrochloride is 70-90 in pastille release layer：10-30.
6. the tamsulosin hydrochloride sustained release preparation according to claim 1-3,5 any one, the sustained release preparation middle skeleton type contains
The composition of medicine sustained release pellet is：The matrix type slow-release material of tamsulosin hydrochloride, 10-50% containing 0.02-1%, 2-10%
The pore-foaming agent of adhesive and 10-50%.
7. tamsulosin hydrochloride sustained release preparation according to claim 6, the sustained release preparation middle skeleton type pastille slow-release micropill
Composition be：The matrix type slow-release material of tamsulosin hydrochloride, 15-50% containing 0.05-1%, 3-10% adhesive and 15-
50% pore-foaming agent.
8. film controlling type is sustained in the tamsulosin hydrochloride sustained release preparation according to claim any one of 1-3, the sustained release preparation
The composition of clothing film is：Film controlling type slow-release material, 2-5% plasticizer, 15-60% pore-foaming agent and 2-5% containing 5-40%
Antiplastering aid.
9. film controlling type is sustained the group of clothing film in tamsulosin hydrochloride sustained release preparation according to claim 8, the sustained release preparation
Turn into：Film controlling type slow-release material, 2.5-5% plasticizer, 20-60% pore-foaming agent and 2.5-5% containing 10-40% it is anti-
Stick.
10. pastille speed in the tamsulosin hydrochloride sustained release preparation according to any one of claim 1-3,5,9, the sustained release preparation
The composition for releasing layer is：The immediate release material and 2-10% adhesive of tamsulosin hydrochloride, 5-95% containing 0.05-1%.
11. the composition of pastille release layer in tamsulosin hydrochloride sustained release preparation according to claim 10, the sustained release preparation
For：The immediate release material and 3-10% adhesive of tamsulosin hydrochloride, 10-95% containing 0.1-1%.
12. salt in the tamsulosin hydrochloride sustained release preparation according to any one of claim 1-3,5,9,11, the sustained release preparation
The content of sour Tamsulosin is 0.1-1.2mg.
13. the content of tamsulosin hydrochloride in tamsulosin hydrochloride sustained release preparation according to claim 12, the sustained release preparation
For 0.2-1.0mg.
14. the content of tamsulosin hydrochloride in tamsulosin hydrochloride sustained release preparation according to claim 12, the sustained release preparation
For 0.2-0.8mg.
15. the tamsulosin hydrochloride sustained release preparation according to claim 1-3,5,9,11, any one of 13-14, described hydrochloric acid
Tamsulosin sustained release preparation be selected from granule, capsule, pill, tablet it is any.
16. a kind of method for preparing any one of the claim 1-15 tamsulosin hydrochloride sustained release preparations, comprises the steps：
1) the desired amount of tamsulosin hydrochloride is uniformly mixed with matrix type slow-release material, adhesive and pore-foaming agent, using extruding-rolling
Circle pelletization method, Centrifugal fluidized pellet method, thermosol extrusion it is any, be made into matrix type pastille slow-release micropill；
2) by matrix type pastille slow-release micropill coating film controlling type sustained release clothing film, it is made into skeleton film controlling type sustained release pellet；
3) by skeleton film controlling type sustained release ball coating pastille release layer, framework film control quick-releasing type sustained release pellet is made.
17. method according to claim 16, the granulation of framework film control quick-releasing type sustained release pellet, dress capsule or tabletting are made
Required sustained release preparation.
18. the method according to claim any one of 16-17, wherein, the preparation method bag of matrix type pastille slow-release micropill
Include following step：The matrix type slow-release material of recipe quantity is dispersed in water, is heated under 70-90 DEG C, stirring condition, is added total
60-80% tamsulosin hydrochloride is measured, pore-foaming agent and adhesive are added in obtained slurry, after being well mixed, using extruding-rolling
Circle pelletization method, Centrifugal fluidized pellet method, any or its combination of thermosol extrusion, are made into piller, dry, bone is made
Frame type pastille slow-release micropill.
19. method according to claim 18, wherein, the preparation method of matrix type pastille slow-release micropill includes following steps
Suddenly：The matrix type slow-release material of recipe quantity is dispersed in water, 80 DEG C, under stirring condition are heated to, the salt of total amount 70% is added
Sour Tamsulosin, adds pore-foaming agent and adhesive in obtained slurry, after being well mixed, using extruding-round as a ball pelletization method, from
The heart-fluidisation makes any or its combination of ball method, thermosol extrusion, is made into piller, dries, matrix type pastille slow-release is made
Micropill.
20. the method according to claim 16-17,19 any one, wherein, the preparation side of skeleton film controlling type sustained release pellet
Method, comprises the steps：1) 2-5% ethanol solution is made in the film controlling type slow-release material of recipe quantity, adds pore-foaming agent, increasing
Agent, antiplastering aid are moulded, after stirring and evenly mixing, sustained release clothing film coating liquid is made；2) under the conditions of 40-60 DEG C, with sustained release clothing film coating liquid
Matrix type pastille slow-release micropill is whitewashed and is coated, skeleton film controlling type sustained release pellet is made, wherein, the consumption of coating solution is with dry
It is calculated as dry micropill 4-8%.
21. method according to claim 20, wherein, the preparation method of skeleton film controlling type sustained release pellet, including following steps
Suddenly：1) 3-4% ethanol solution is made in the film controlling type slow-release material of recipe quantity, adds pore-foaming agent, plasticizer, antiplastering aid,
After stirring and evenly mixing, sustained release clothing film coating liquid is made；2) under the conditions of 50-55 DEG C, with sustained release clothing film coating liquid to matrix type pastille
Sustained release pellet whitewashing is coated, and skeleton film controlling type sustained release pellet is made, wherein, the consumption of coating solution is to be calculated as dry micropill with dry
5-6%.
22. any one of tamsulosin hydrochloride sustained release preparation or claim 16-21 described in claim any one of 1-15 method
Tamsulosin hydrochloride sustained release preparation obtained by preparation is used to prepare the caused urination barrier for the treatment of benign prostatic hyperplasis, hypertrophy of the prostate
Application in the medicine hindered.
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| CN201410422665.1A CN104814923B (en) | 2014-08-21 | 2014-08-21 | A kind of tamsulosin hydrochloride sustained release preparation and preparation method thereof and its application |
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| CN107519147B (en) * | 2016-06-21 | 2021-12-21 | 广州医药研究总院有限公司 | Desvenlafaxine sustained-release pellet and preparation method thereof |
| CN108096220B (en) * | 2017-12-11 | 2021-03-30 | 苏州中化药品工业有限公司 | Tamsulosin hydrochloride sustained-release preparation and preparation method thereof |
| CN109319913B (en) * | 2018-10-11 | 2022-07-01 | 仲恺农业工程学院 | Slow-release potassium hydrogen persulfate preparation and preparation method thereof |
| WO2022042644A1 (en) * | 2020-08-26 | 2022-03-03 | 上海博志研新药物技术有限公司 | Edaravone sustained-release pharmaceutical composition, preparation method, and application |
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| CN103520164B (en) * | 2013-10-30 | 2015-01-28 | 程刚 | Ticagrelor sustained-release preparation |
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