CN104814923A - Tamsulosin Hydrochloride sustained-release preparation, preparation method and applications thereof - Google Patents
Tamsulosin Hydrochloride sustained-release preparation, preparation method and applications thereof Download PDFInfo
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- CN104814923A CN104814923A CN201410422665.1A CN201410422665A CN104814923A CN 104814923 A CN104814923 A CN 104814923A CN 201410422665 A CN201410422665 A CN 201410422665A CN 104814923 A CN104814923 A CN 104814923A
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- Prior art keywords
- release
- tamsulosin hydrochloride
- slow
- releasing preparation
- slow releasing
- Prior art date
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- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 title claims abstract description 127
- 238000002360 preparation method Methods 0.000 title claims abstract description 127
- 229960003198 tamsulosin hydrochloride Drugs 0.000 title claims abstract description 125
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- WCOXQTXVACYMLM-UHFFFAOYSA-N 2,3-bis(12-hydroxyoctadecanoyloxy)propyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC(O)CCCCCC)COC(=O)CCCCCCCCCCC(O)CCCCCC WCOXQTXVACYMLM-UHFFFAOYSA-N 0.000 claims description 3
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
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- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 claims description 2
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- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 3
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- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a tamsulosin hydrochloride sustained-release preparation, a preparation method and applications thereof. The preparation comprises, by weight, 5-95% of framework type medicine-containing sustained-release micro-pills, 1-20% of a film control type sustained-release coating film, and 1-10% of a medicine-containing rapid-release layer, wherein the framework type medicine-containing sustained-release micro-pills comprise 0.01-1% of tamsulosin hydrochloride, 5-50% of a sustained-release material, 1-10% of an adhesive, and 5-50% of a pore forming agent, the film control type sustained-release coating film comprises 1-40% of a sustained-release material, 1-5% of a plasticizer, 10-60% of a pore forming agent, and 1-5% of an anti-adhesion agent, and the medicine-containing rapid-release layer comprises 0.01-1% of tamsulosin hydrochloride, 1-95% of a rapid-release material, and 1-10% of an adhesive. The tamsulosin hydrochloride sustained-release preparation has advantages of fast, stable, sustained, and long-lasting effect, low side effect, controllable quality, suitability for mass production and the like.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of tamsulosin hydrochloride slow releasing preparation and preparation method thereof and its application.
Background technology
(structure is such as formula shown in I for tamsulosin hydrochloride, also known as tamsulosin hydrochloride) be a kind of α 1-adrenoceptor inhibitor (blocker) of potent, high selectivity, the clinical dysuria being used for the treatment of benign prostatic hyperplasia (BPH) and prostate hyperplasia and causing.In vitro tests shows, compared with similar drugs terazosin hydrochloride, tamsulosin hydrochloride has curative effect better.But the oral formulations of tamsulosin hydrochloride exists and absorbs rapid, rapid-action, hypotension may be caused and dizzyly wait untoward reaction, therefore clinical many employing tamsulosin hydrochloride slow releasing preparation.
At present, tamsulosin hydrochloride slow releasing preparation comprises skeleton type sustained release preparation and film controlling type slow releasing preparation two kinds.Wherein, skeleton type sustained release preparation adopts erosion type (as hydrophilic gel) macromolecular material, insoluble type macromolecular material and medicament mixed to prepare sustained-release matrix, with Drug controlled release; Film controlling type slow releasing preparation, at the suitable clothing layer of the pan coating of label and piller, makes medicine dissolve or be partly dissolved and disengage under certain condition, to control the slow releasing of medicine.
Slow-release micro-pill is easy to make slow releasing preparation, controlled release preparation or location delivery formulations, and there is the features such as good fluidity, not easily fragmentation, and medicine and gastrointestinal contact area can be improved, promote that drug absorption is complete, improve bioavailability, reduce and even avoid the untoward reaction such as gastric mucosa stimulation.
Tamsulosin hydrochloride slow-release micro-pill is mixed by medicine and blocker, or is first formed often releasing micropill bag by release-controlled film, but these single controlled-release pattern preparations exist the defects such as drug release fluctuation between product batches is large, operation controllability is relatively poor.
Document 1 (the formulation and technology research of tamsulosin hydrochloride sustained-release dropping pill, " Hebei Normal University Journal " (natural science edition), 35th volume the 3rd phase in 2011,279-282 page) disclose a kind of tamsulosin hydrochloride matrix type slow-release pill preparation, said preparation adopts polyethylene glycol 6000 (PEG6000) and Macrogol 4000 (PEG4000) to be immediate release solid dispersal carrier material, tristerin and glyceryl monostearate are sustained-release matrix material, and adopt fusion method to be prepared from.
Document 2 (development of tamsulosin hydrochloride osmotic pump tablet and release factors influencing; " Oceanography Institute Of Zhejiang's journal " (natural science edition), December the 26th volume 4 phase in 2007,435-438 page) disclose a kind of tamsulosin hydrochloride monocompartment osmotic pump-type controlled release tablet, this tablet with hydroxypropyl methylcellulose (HPMC) for hydrophilic gel framework material, employing wet granulation is prepared from, wherein, sodium chloride, clothing film thickness and porogen consumption become the principal element affecting release.
Document 3 (the discussion of tamsulosin hydrochloride formulation and technology; " Journal of Henan University " (medicine), 30th volume the 04th phase in 2011,250-254,263 pages) disclose a kind of tamsulosin hydrochloride hydrogel matrix slow releasing tablet, this tablet with sodium alginate and hydroxypropyl emthylcellulose (HPMC) for framework material.
Document 4 (investigate by the preparation of tamsulosin hydrochloride slow releasing preparation and vitro release; " Chinese Medicine guide ", the 10th volume 25 phase in 2012,46-48 page) disclose the tamsulosin sustained release sheet be prepared from for framework material with hydroxypropyl emthylcellulose (HPMC).
(centrifugal granulation prepares Effect Factors for Sythetic Technology and the vitro release investigation of tamsulosin hydrochloride sustained-release micro-pill capsules to document 5; " China Dispensary ", the 22nd volume the 13rd phase in 2011,1196-1199 page) disclose and prepare microcrystalline Cellulose Blank Pellets and tamsulosin hydrochloride pastille micropill, then carried out aqueous acrylic resin dispersion coating.
Document 6 (investigate: " Shanghai medicine " by the preparation of tamsulosin hydrochloride sustained-release micro-pill capsules and formulation and technology, 33rd volume the 21st phase in 2012,45-49 page) disclose adopt Sulisi, refined gram should, Opadry II is as coating material, carrying out sustained release coating with spraying solution medicine-feeding method at the bottom of fluid bed, preparing medicine carrying micropill.
Tamsulosin hydrochloride skeleton type sustained release preparation disclosed in aforementioned documents or be single delivery systme or for film control micropill delivery systme, wherein, the fluctuation of skeleton granulation size in single delivery systme, tableting pressure, film control coating of pellets film and drug release hole change etc., all can obviously affect drug release behavior, and then cause low dose of tamsulosin hydrochloride slow releasing preparation to exist batch between the defect such as large, the poor reproducibility of drug release difference, and there is the defects such as initial drug release is not enough in film control micropill delivery systme.For this reason, be bursting to research a kind of rapid-action, repeatability is high, batch between release difference little, release continue tamsulosin hydrochloride slow-release preparation, to improve Drug safety and effectiveness.
Summary of the invention
The object of the present invention is to provide a kind of tamsulosin hydrochloride slow releasing preparation, said preparation is by matrix type pastille slow-release micropill, film controlling type extended release coatings film and pastille release layer composition, wherein, in preparation, the percentage by weight of matrix type pastille slow-release micropill is 5-95%, the percentage by weight of film controlling type extended release coatings film is 1-20%, the percentage by weight of pastille release layer is 1-10%, consisting of of described matrix type pastille slow-release micropill: the tamsulosin hydrochloride containing 0.01-1%, the slow-release material of 5-50%, the binding agent of 1-10% and the porogen of 5-50%, consisting of of described film controlling type extended release coatings film: the slow-release material containing 1-40%, the plasticizer of 1-5%, the porogen of 10-60% and the antiplastering aid of 1-5%, consisting of of described pastille release layer: the tamsulosin hydrochloride containing 0.01-1%, the immediate release material of 1-95% and the binding agent of 1-10%.
In the preferred technical solution of the present invention, in slow releasing preparation, the percentage by weight of matrix type pastille slow-release micropill is 10-90%, is preferably 20-80%.
In the preferred technical solution of the present invention, in slow releasing preparation, the percentage by weight of film controlling type extended release coatings film is 5-15%, is preferably 8-12%.
In the preferred technical solution of the present invention, in slow releasing preparation, the percentage by weight of pastille release layer is 4-8%, is preferably 5-7%.
In the preferred technical solution of the present invention, contained tamsulosin hydrochloride in matrix type pastille slow-release micropill in slow releasing preparation: in pastille release layer, the mass ratio of contained tamsulosin hydrochloride is 60-95:5-40, is preferably 70-90:10-30.
In the preferred technical solution of the present invention, the consisting of of matrix type pastille slow-release micropill in slow releasing preparation: the tamsulosin hydrochloride containing 0.02-0.5%, the slow-release material of 10-35%, the binding agent of 2-8% and the porogen of 10-40%, consisting of of preferred matrix type pastille slow-release micropill: the tamsulosin hydrochloride containing 0.05-0.3%, the slow-release material of 15-30%, the binding agent of 3-6% and the porogen of 15-30%.
In the preferred technical solution of the present invention, the consisting of of film controlling type extended release coatings film in slow releasing preparation: the slow-release material containing 5-35%, the plasticizer of 2-4%, the porogen of 15-50% and the antiplastering aid of 2-4%, consisting of of preferred film controlling type extended release coatings film: the slow-release material containing 10-30%, the plasticizer of 2.5-3.5%, the porogen of 20-40% and the antiplastering aid of 2.5-3.5%.
In the preferred technical solution of the present invention, the consisting of of pastille release layer in slow releasing preparation: the binding agent of the tamsulosin hydrochloride containing 0.05-0.8%, the immediate release material of 5-90% and 2-8%, consisting of of preferred pastille release layer: the binding agent of the tamsulosin hydrochloride containing 0.1-0.6%, the immediate release material of 10-80% and 3-6%.
In the preferred technical solution of the present invention, in slow releasing preparation of the present invention, the content of tamsulosin hydrochloride is 0.1-1.2mg, is preferably 0.2-1.0mg, is more preferably 0.2-0.8mg.
The present invention adds suitable pharmaceutically acceptable carrier in tamsulosin hydrochloride preparation, and according to the technology of preparing of slow releasing preparation, [Tang Xing edits " oral sustained-release preparation ", People's Health Publisher, the 1st edition in 2007, " pharmaceutic adjuvant application technology ", China Medical Science Press, 2002, 2nd edition], tamsulosin hydrochloride is made by matrix type pastille slow-release micropill, the slow releasing preparation of film controlling type extended release coatings film and pastille release layer composition, wherein, pastille release layer realizes quick release and the quick acting of tamsulosin hydrochloride, matrix type pastille slow-release micropill and film controlling type extended release coatings film then control the steady long-acting release of tamsulosin hydrochloride, and by controlling coating thickness and/or adding porogen, to control the rate of release of active component, to reduce or to eliminate its untoward reaction, increase safety and the effectiveness of preparation, improve 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, erodible framework material, any one or its combination of insoluble framework material, be preferably pectin, sodium alginate, cellulose derivative is (as methylcellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, microcrystalline Cellulose etc.) or its salt, non-cellulosic polysaccharide is (as chitin, chitosan etc.) or its salt, polyvinyl alcohol, carbopol, Cera Flava, stearic acid, castor wax, octadecanol, Brazil wax, Polyethylene Glycol (is preferably PEG
4000or PEG
6000), acrylic resin, polyethylene, polypropylene, polysiloxanes, alginic acid or its salt, carbopol, modified starch any one or its combination.
In the preferred technical solution of the present invention, in slow releasing preparation of the present invention, the content of tamsulosin hydrochloride is 0.1-1.2mg, is preferably 0.2-1.0mg, is more preferably 0.2-0.8mg.
In the preferred technical solution of the present invention, described film controlling type slow-release material is selected from any one or its combination of Enteric Materials, the insoluble type macromolecular material of water, is preferably any one or its combination of cellulose acetate-phthalate (CAP), Hydroxypropyl Methyl Cellulose Phthalate (HPMCP), polyacrylic resin type enteric material, ethyl cellulose.
In the preferred technical solution of the present invention, described porogen is selected from sucrose, lactose, mannitol, polyvinylpyrrolidone, PEG
4000, PEG
6000, starch, Pulvis Talci, silicon dioxide, micropowder silica gel any one or its combination.
In the preferred technical solution of the present invention, described binding agent is selected from any one or its combination of polyvinylpyrrolidone, hydroxypropyl emthylcellulose or its salt, starch, sucrose, dextrin.
In the preferred technical solution of the present invention, described antiplastering aid is selected from Pulvis Talci, micropowder silica gel, titanium dioxide, magnesium stearate, stearic acid, starch, PEG
4000, PEG
6000, liquid paraffin any one or its combination.
In the preferred technical solution of the present invention, described immediate release material is selected from sucrose, lactose, mannitol, polyvinylpyrrolidone, PEG
4000, PEG
6000any one or its combination.
In the preferred technical solution of the present invention, described Sustained release coating materials is selected from any one or its combination of cellulose derivative, gastric solubility acrylic resin, insoluble microporous membrane coating material, enteric film coating material, is preferably any one or its combination of methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, cellulose acetate, ethyl cellulose (EC), Cellulose Acetate Phthalate, phthalic acid hydroxypropyl methylcellulose, enteric acrylate's resin or its latex aqueous dispersion.
In the preferred technical solution of the present invention, in micropill, add any one or its combination of insoluble framework material, hydrophilic gel framework material, waxiness, porogen, to control the rate of release of active component.
In the preferred technical solution of the present invention, described waxiness is selected from containing C
8-C
30alcohol, acid, ester, salt or amide, be preferably any one or its combination of stearic acid, Cera Flava, castor wax, octadecanol, Brazil wax.
In the preferred technical solution of the present invention, described plasticizer is selected from any one or its combination of dibutyl phthalate, PEG400, Macrogol 600, benzoate, propylene glycol.
In the preferred technical solution of the present invention, skeleton film controlling type slow-release micro-pill: the mass ratio of the coating material of framework film control quick-release and slow-release micropill is 4-8:3-6, is preferably 5-6:4-5.
In the preferred technical solution of the present invention, described tamsulosin hydrochloride slow releasing preparation is selected from any one or its combination of granule, capsule, pill, tablet.
Another object of the present invention is to the preparation method that a kind of tamsulosin hydrochloride slow releasing preparation is provided, comprise the steps:
1) by the tamsulosin hydrochloride of aequum and pharmaceutically acceptable carrier Homogeneous phase mixing, adopt any one of method of extruding and kneading to pellets, centrifugal fluidized granulation method, thermosol squeezing and pressing method, be made into sustained-release matrix micropill;
2) by sustained-release matrix micropill bag by clothing film, be made into skeleton reservoir pellets;
3) by skeleton film controlling type slow release ball bag by pastille release layer, to obtain final product.
In the preferred technical solution of the present invention, bag granulated by the skeleton film controlling type slow release ball of pastille release layer, fill capsule or tabletting, obtained required slow releasing preparation.
In the preferred technical solution of the present invention, the preparation method of matrix sustained-release pellets, the slow-release material of recipe quantity (as hydroxypropyl emthylcellulose etc.) is comprised the steps: to be scattered in water, be heated to 70-90 DEG C (being preferably 80 DEG C), under stirring condition, add the tamsulosin hydrochloride of total amount 60-80% (being preferably 70%), porogen (as lactose) and binding agent (as polyvinylpyrrolidone) is added in obtained slurry, after mix homogeneously, adopt method of extruding and kneading to pellets, centrifugal fluidized granulation method, any one or its combination of thermosol squeezing and pressing method, be made into piller, dry, obtained matrix sustained-release pellets.
In the preferred technical solution of the present invention, the preparation method of skeleton film controlling type slow-release micro-pill, comprise the steps: 1) slow-release material (as ethyl cellulose) of recipe quantity is made the alcoholic solution of 2-5% (be preferably 3-4%), add porogen, plasticizer, antiplastering aid again, after stirring and evenly mixing, make extended release coatings film coating solution; 2) under 40-60 DEG C of (being preferably 50-55 DEG C) condition, with extended release coatings film coating solution, matrix sustained-release pellets is whitewashed coating, obtained skeleton film controlling type slow-release micro-pill, wherein, the consumption of coating solution is (with dry basis) dry micropill 4-8% (being preferably 5-6%).
In the preferred technical solution of the present invention, the preparation method of slow-release micro-pill, comprise the steps: 1) binding agent (as PVP K30) is added water and makes 3-10% serosity (being preferably 5-8%), add surplus tamsulosin hydrochloride, stir, after Homogeneous phase mixing, make pastille rapid release coating solution; 2) under 40-60 DEG C of (being preferably 50-55 DEG C) condition, by skeleton reservoir pellets pastille rapid release coating solution whitewashing coating, obtained framework film control quick-releasing type slow releasing preparation, to obtain final product.
Another object of the present invention is to the application in the medicine of the dysuria providing tamsulosin hydrochloride slow releasing preparation to cause for the preparation for the treatment of benign prostatic hyperplasia (BPH), prostate hyperplasia.
In order to clearly state protection scope of the present invention, the present invention defines as follows to following term:
Slow-release micro-pill of the present invention is made up of the pastille micropill of skeleton slow release, film controlling type extended release coatings film and pastille rapid release clothing layer.
The present invention detects the vitro release of tamsulosin hydrochloride slow releasing preparation with reference to " Chinese Pharmacopoeia " version in 2010 two annex XD first methods, comprise the steps: with the sodium chloride salt acid solution (simulated gastric fluid) of pH1.2 as medium, rotating speed is 100 revs/min, get filtrate, operate, after 2h, then with pH7.2 phosphate buffer (simulated intestinal fluid) for medium in accordance with the law, get filtrate, operate in accordance with the law.Measure according to high performance liquid chromatography (" Chinese Pharmacopoeia " version in 2010 two annex VD).Chromatographic condition and system suitability condition are: octadecylsilane chemically bonded silica is filler, and 0.18mol/L potassium dihydrogen phosphate-0.2mol/L phosphoric acid solution-acetonitrile (6: 7: 6) is mobile phase, and determined wavelength is 225nm.Number of theoretical plate is not less than 1500 by tamsulosin hydrochloride peak.
Except as otherwise noted, when the present invention relates to the percentage ratio between liquid and liquid, described percentage ratio is volume/volume percentage ratio; When the present invention relates to the percentage ratio between liquid and solid, described percentage ratio is volume/weight percentage ratio; When the present invention relates to the percentage ratio between solid and liquid, described percentage ratio is weight/volume percent; All the other are weight/percentage by weight.
Compared with prior art, tamsulosin hydrochloride slow releasing preparation of the present invention has following Advantageous Effects:
1, tamsulosin hydrochloride slow releasing preparation of the present invention adopts skeleton slow release, triple delivery modes that film-controlled slow-release and rapid release organically combine, and consider drug solubility, the factors such as the release that clinical application needs and release profiles, science has screened slow-release material, binding agent, porogen, plasticizer, the kind of coating material and consumption thereof, and improve porogen consumption in extended release coatings rete, reduce slow-release material consumption, it is made to carry out Drug controlled release with macroporous membrane diffusion barrier prosecutor formula, reach 6-36h held stationary in body, the beneficial effect of lasting release, reduce toxic and side effects and the untoward reaction of medicine, overcome drug release rate fluctuation large, the defects such as homogeneity difference, have fast, steadily, continue, bioavailability is high, drug effect is lasting, side effect is low, quality controllable, drug release rate favorable reproducibility between batch, the advantages such as safety and effectivity.
2, the release amount of medicine in tamsulosin hydrochloride slow releasing preparation rapid release layer 2h of the present invention is greater than 10%, and patient only needs to take slow releasing preparation of the present invention once every day, the therapeutic effect that whole day controls and alleviates the frequent micturition caused by prostate increase can be reached, there is taking convenience, economy, safety, the advantage such as long-acting, add the compliance of patient medication.
3, tamsulosin hydrochloride slow releasing preparation of the present invention had both reached the therapeutic purposes of quick acting, have the advantages that steadily continue long-acting release, overcome again that dosage at the beginning existing for matrix type micropill or reservoir pellets is little, drug release fluctuation is comparatively large, batch between the defect such as poor reproducibility, and reduce the generation of cardiovascular side effects, greatly improve Drug safety, effectiveness.
4, tamsulosin hydrochloride slow releasing preparation of the present invention saves macromolecule coating material consumption, significantly reduces production cost (cost decline 5-15%), and easy and simple to handle, is easy to realize suitability for industrialized production.
Accompanying drawing explanation
The structural representation of Fig. 1 slow-release micro-pill of the present invention.
Principal agent release profiles in the tamsulosin hydrochloride slow releasing preparation that Fig. 2 document 1 (please indicate literature reference) is recorded
The tamsulosin hydrochloride slow releasing preparation 12h release profiles that Fig. 3 embodiment 1 is obtained.
The tamsulosin hydrochloride slow releasing preparation 12h elution profiles that Fig. 4 embodiment 2 is obtained.
The tamsulosin hydrochloride slow releasing preparation 24h release profiles that Fig. 5 embodiment 3 is obtained.
The tamsulosin hydrochloride slow releasing preparation 24h elution profiles that Fig. 6 embodiment 4 is obtained.
The hydrochloric acid smooth Lip river matrix type micropill 12h release profiles that Fig. 7 embodiment 1 is obtained.
The tamsulosin hydrochloride skeleton reservoir pellets 12h elution profiles that Fig. 8 embodiment 1 is obtained.
The commercially available tamsulosin hydrochloride sustained-release capsule of Fig. 9 (Harnal) 12h elution profiles.
Detailed description of the invention
Illustrate the present invention below with reference to embodiment, embodiments of the invention are only for illustration of technical scheme of the present invention, and non-limiting essence of the present invention.
embodiment 1the preparation of tamsulosin hydrochloride sustained-release capsule
1) composition of matrix type slow-release micro-pill:
Wherein, hydroxypropyl emthylcellulose is slow-release material, and lactose is as porogen, and PVP K30 (PVPk30) is binding agent, forms skeleton micropore after porogen dissolves in Digestive system, and active component is slowly steadily release from micropore.
2) composition of film-controlled slow-release clothing film
3) composition of pastille release layer
The preparation method of the present embodiment tamsulosin hydrochloride slow releasing preparation, comprises the steps:
1) hydroxypropyl emthylcellulose of aequum is dispersed in purified water, is heated to about 80 DEG C, under stirring condition, adds the tamsulosin hydrochloride of recipe quantity, until form slurry; In hot slurry, add lactose, PVP K30 alcohol-water solution again, be uniformly mixed 20 minutes, adopt method of extruding and kneading to pellets, its extruder is squeezed into
, the extrudate of long 2-6mm, round as a ball one-tenth piller, 40 DEG C of dryings, obtain matrix type slow-release micro-pill;
2) ethyl cellulose of aequum is dissolved in dehydrated alcohol, add porogen (polyethylene glycol 6000), plasticizer (propylene glycol), antiplastering aid (Pulvis Talci) again, after stirring and evenly mixing, place more than 15 hours, be made into extended release coatings film coating solution; Under 55 DEG C of conditions, by matrix type slow-release micro-pill extended release coatings film coating solution whitewashing coating, after micropill weightening finish 5%, obtained skeleton reservoir pellets;
3) PVP K30 of aequum is dissolved in purified water, then adds surplus tamsulosin hydrochloride, stir, after making it be dissolved in serosity, make pastille release layer coating solution; Under 55 DEG C of conditions, by skeleton reservoir pellets pastille release layer coating solution whitewashing coating, dry, make framework film control quick-releasing type slow-release micro-pill;
4) be filled in empty hard capsule by framework film control quick-releasing type slow-release micro-pill, obtained unit dose is the tamsulosin hydrochloride sustained-release capsule of 4mg.
embodiment 2the preparation (12h slow releasing preparation) of tamsulosin hydrochloride sustained-release capsule
1) composition of matrix type pastille slow-release micropill:
2) composition of film controlling type extended release coatings film
3) composition of pastille release layer
The preparation method of the present embodiment tamsulosin hydrochloride sustained-release capsule is with embodiment 1.
embodiment 3the preparation (24h slow releasing preparation) of tamsulosin hydrochloride slow releasing tablet
1) composition of matrix type pastille slow-release label:
Wherein, hydroxypropyl emthylcellulose is slow-release material, and lactose is as porogen, and PVP K30 (PVPk30) is binding agent, forms skeleton micropore after porogen dissolves in Digestive system, and active component is slowly steadily release from micropore.
2) composition of film controlling type extended release coatings film
3) composition of pastille release layer
The preparation method of the present embodiment tamsulosin hydrochloride slow releasing preparation, comprises the steps:
1) hydroxypropyl emthylcellulose of aequum is dispersed in pure water, is heated to about 80 DEG C, under stirring condition, adds the tamsulosin hydrochloride of recipe quantity, until form slurry; In hot slurry, add the alcohol-water solution of lactose, PVP K30 again, be uniformly mixed 20 minutes, adopt method of extruding and kneading to pellets, be squeezed into
0.6-0.9mm, the extrudate of long 2-6mm, round as a ball one-tenth piller, 40 DEG C of dryings, granulate, add magnesium stearate mixing, tabletting, obtains matrix sustained release tablet core;
2) ethyl cellulose of aequum is dissolved in dehydrated alcohol, add porogen (polyethylene glycol 6000), plasticizer (propylene glycol), antiplastering aid (Pulvis Talci) again, after stirring and evenly mixing, place more than 15 hours, be made into extended release coatings film coating solution; Under 55 DEG C of conditions, by matrix sustained release tablet core extended release coatings film coating solution whitewashing coating, after label weightening finish 6%, obtained framework film control matrix core;
3) PVP K30 of aequum is dissolved in purified water, then adds surplus tamsulosin hydrochloride, stir, after making it be dissolved in serosity, make pastille release layer coating solution; Under 55 DEG C of conditions, by framework film control matrix core pastille release layer coating solution whitewashing coating, dry, make framework film control quick-releasing type slow releasing tablet.
embodiment 4the preparation (24h slow releasing preparation) of tamsulosin hydrochloride slow release
1) matrix type pastille slow-release label composition:
Wherein, microcrystalline Cellulose is slow-release material, and sucrose is as porogen, PVP K30 (PVPk30) is binding agent, micropowder silica gel, as lubricant, forms skeleton micropore after porogen dissolves in Digestive system, and active component is slowly steadily release from micropore.
2) composition of film controlling type extended release coatings film
3) composition of pastille release layer
The preparation method of the present embodiment tamsulosin hydrochloride slow releasing preparation is with embodiment 3.
embodiment 5the drug release in vitro degree research of obtained micropill in embodiment 1
Adopt vitro release detection method of the present invention, according to testing conditions listed by table 1, the vitro release of matrix type micropill obtained in comparative study embodiment 1, skeleton reservoir pellets, framework film control fast release micropill, the results are shown in Table l, Fig. 3, Fig. 7-Fig. 8.
The drug release rate comparative study result of the different releasing theory of table 1 embodiment 1
From table 1, Fig. 3, Fig. 7-Fig. 8, framework film control fast release micropill of the present invention, at simulated gastric fluid 2h, can discharge the tamsulosin hydrochloride of 25%, and skeleton reservoir pellets only discharges 9%, and the release of matrix type micropill is up to 32%; And the release of its 12h is respectively 98%, 96%, 80%.
As can be seen here, matrix type micropill is at the release of 2h higher (32%), but its 12h release lower (80%), be difficult to meet the demands such as clinical application effectiveness, steadily release; Skeleton reservoir pellets 12h release reaches 96%, but its 2h release too low (only 9%), be difficult to the requirement meeting clinical quick acting; Framework film control fast release micropill of the present invention have rapid-action, steady release, bioavailability high, safe and effective, be convenient to the advantages such as clinical and patient's use.
embodiment 6the drug release in vitro degree research of obtained slow release label in embodiment 3
Adopt vitro release detection method of the present invention, according to testing conditions listed by table 2, the vitro release of matrix type label obtained in comparative study embodiment 3, framework film control matrix core, framework film control fast-release tablet, the results are shown in Table 2.
The drug release rate comparative study result of the different releasing theory of table 2 embodiment 3
From table 2, framework film control fast release micropill of the present invention, at simulated gastric fluid 2h, can discharge the tamsulosin hydrochloride of 22%, and skeleton reservoir pellets only discharges 7%, and the release of matrix type micropill is up to 30%; And the release of its 12h is respectively 92%, 86%, 76%.
As can be seen here, matrix type micropill is at the release of 2h higher (30%), but its 12h release lower (76%), is difficult to meet the demand that clinical application steadily discharges; Skeleton reservoir pellets 12h release reaches 86%, but its 2h release too low (only 7%), be difficult to the requirement meeting clinical quick acting; Framework film control fast release micropill of the present invention have rapid-action, steady release, bioavailability high, safe and effective, be convenient to the advantages such as clinical and patient's use.
embodiment 7the vitro release research of tamsulosin hydrochloride slow releasing preparation
With commercially available tamsulosin hydrochloride slow releasing preparation (Harnal) for contrast, adopt vitro release detection method of the present invention, the vitro release of the tamsulosin hydrochloride slow releasing preparation that comparative study embodiment 1-embodiment 4 is obtained, the results are shown in Figure 3-Fig. 9.
From Fig. 3-Fig. 9, the release of matrix type tamsulosin hydrochloride slow releasing preparation is very fast, is difficult to the requirement meeting steadily release; The release of skeleton film controlling type tamsulosin hydrochloride slow releasing preparation is too slow, cannot reach the object of quick acting; Framework film control quick-releasing type tamsulosin hydrochloride slow releasing preparation of the present invention has that rapid-action, steady release, bioavailability are high, safety and effectivity, be convenient to the advantages such as clinical and patient's use.
embodiment 8the stability study of tamsulosin hydrochloride slow releasing preparation
With commercially available tamsulosin hydrochloride slow releasing preparation (Harnal) for contrast, adopt following method, compare the stability of tamsulosin hydrochloride slow releasing preparation prepared by embodiment of the present invention 1-4, result is as follows:
1) through 4500LX illumination 10 days, the related substance of tamsulosin hydrochloride slow releasing preparation prepared by embodiment of the present invention 1-4, release, content have no significant change;
2) through 40 DEG C, 60 DEG C high temperature 10 days, the character of tamsulosin hydrochloride slow releasing preparation prepared by embodiment of the present invention 1-4, related substance, release, content have no significant change;
3) high humidity 10 days, the character of tamsulosin hydrochloride slow releasing preparation prepared by embodiment of the present invention 1-4, related substance, release, changes of contents are little, and character slightly affects;
4) under relative humidity 75%, 40 DEG C of conditions, 0, l, 2, in the accelerated test in March, the appearance luster of tamsulosin hydrochloride slow releasing preparation, related substance, content, release, all conform with the regulations, and batch between release repeatability very good.
Visible, slow releasing preparation of the present invention is highly stable.
Claims (26)
1. a tamsulosin hydrochloride slow releasing preparation, said preparation is by matrix type pastille slow-release micropill, film controlling type extended release coatings film and pastille release layer composition, wherein, in preparation, the percentage by weight of matrix type pastille slow-release micropill is 5-95%, the percentage by weight of film controlling type extended release coatings film is 1-20%, the percentage by weight of pastille release layer is 1-10%, consisting of of described matrix type pastille slow-release micropill: the tamsulosin hydrochloride containing 0.01-1%, the slow-release material of 5-50%, the binding agent of 1-10% and the porogen of 5-50%, consisting of of described film controlling type extended release coatings film: the slow-release material containing 1-40%, the plasticizer of 1-5%, the porogen of 10-60% and the antiplastering aid of 1-5%, consisting of of described pastille release layer: the tamsulosin hydrochloride containing 0.01-1%, the immediate release material of 1-95% and the binding agent of 1-10%.
2. tamsulosin hydrochloride slow releasing preparation according to claim 1, in described slow releasing preparation, the percentage by weight of matrix type pastille slow-release micropill is 10-90%, is preferably 20-80%.
3. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-2, in described slow releasing preparation, the percentage by weight of film controlling type extended release coatings film is 5-15%, is preferably 8-12%.
4. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-3, in slow releasing preparation, the percentage by weight of pastille release layer is 4-8%, is preferably 5-7%.
5. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-4, contained tamsulosin hydrochloride in matrix type pastille slow-release micropill in described slow releasing preparation: in pastille release layer, the mass ratio of contained tamsulosin hydrochloride is 60-95:5-40, is preferably 70-90:10-30.
6. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-5, the consisting of of matrix type pastille slow-release micropill in described slow releasing preparation: the tamsulosin hydrochloride containing 0.02-0.5%, the slow-release material of 10-35%, the binding agent of 2-8% and the porogen of 10-40%, consisting of of preferred matrix type pastille slow-release micropill: the tamsulosin hydrochloride containing 0.05-0.3%, the slow-release material of 15-30%, the binding agent of 3-6% and the porogen of 15-30%.
7. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-6, the consisting of of film controlling type extended release coatings film in described slow releasing preparation: the slow-release material containing 5-35%, the plasticizer of 2-4%, the porogen of 15-50% and the antiplastering aid of 2-4%, consisting of of preferred film controlling type extended release coatings film: the slow-release material containing 10-30%, the plasticizer of 2.5-3.5%, the porogen of 20-40% and the antiplastering aid of 2.5-3.5%.
8. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-7, the consisting of of pastille release layer in described slow releasing preparation: the binding agent of the tamsulosin hydrochloride containing 0.05-0.8%, the immediate release material of 5-90% and 2-8%, consisting of of preferred pastille release layer: the binding agent of the tamsulosin hydrochloride containing 0.1-0.6%, the immediate release material of 10-80% and 3-6%.
9. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-8, in described slow releasing preparation, the content of tamsulosin hydrochloride is 0.1-1.2mg, is preferably 0.2-1.0mg, is more preferably 0.2-0.8mg.
10. the tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-9, described matrix type slow-release material is selected from hydrophilic gels framework material, erodible framework material, any one or its combination of insoluble framework material, be preferably pectin, sodium alginate, cellulose derivative is (as methylcellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, microcrystalline Cellulose etc.) or its salt, non-cellulosic polysaccharide is (as chitin, chitosan etc.) or its salt, polyvinyl alcohol, carbopol, Cera Flava, stearic acid, Polyethylene Glycol, castor wax, octadecanol, Brazil wax, acrylic resin, polyethylene, polypropylene, polysiloxanes, alginic acid or its salt, carbopol, any one or its combination of modified starch.
11. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-10, in described slow releasing preparation, the content of tamsulosin hydrochloride is 0.1-1.2mg, is preferably 0.2-1.0mg, is more preferably 0.2-0.8mg.
12. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-11, described film controlling type slow-release material is selected from any one or its combination of Enteric Materials, the insoluble type macromolecular material of water, is preferably any one or its combination of cellulose acetate-phthalate (CAP), Hydroxypropyl Methyl Cellulose Phthalate (HPMCP), polyacrylic resin type enteric material, ethyl cellulose.
13. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-12, described porogen is selected from any one or its combination of sucrose, lactose, mannitol, polyvinylpyrrolidone, Macrogol 4000, starch, Pulvis Talci, silicon dioxide, polyethylene glycol 6000, micropowder silica gel.
14. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-13, described binding agent is selected from any one or its combination of polyvinylpyrrolidone, hydroxypropyl emthylcellulose or its salt, starch, sucrose, dextrin.
15. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-14, described antiplastering aid is selected from any one or its combination of Pulvis Talci, micropowder silica gel, titanium dioxide, magnesium stearate, stearic acid, starch, poly-diethanol 4000, poly-diethanol 6000, liquid paraffin.
16. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-15, described immediate release material is selected from any one or its combination of sucrose, lactose, mannitol, polyvinylpyrrolidone, poly-diethanol 4000, poly-diethanol 6000.
17. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-16, described Sustained release coating materials is selected from any one or its combination of cellulose derivative, gastric solubility acrylic resin, insoluble microporous membrane coating material, enteric film coating material, is preferably any one or its combination of methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, cellulose acetate, ethyl cellulose (EC), Cellulose Acetate Phthalate, phthalic acid hydroxypropyl methylcellulose, enteric acrylate's resin or its latex aqueous dispersion.
18. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-17, described plasticizer is selected from any one or its combination of dibutyl phthalate, PEG400, Macrogol 600, benzoate, propylene glycol.
19. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-18, skeleton film controlling type slow-release micro-pill: the mass ratio of the coating material of framework film control quick-release and slow-release micropill is 4-8:3-6, is preferably 5-6:4-5.
20. tamsulosin hydrochloride slow releasing preparation according to any one of claim 1-19, described tamsulosin hydrochloride slow releasing preparation is selected from any one or its combination of granule, capsule, pill, tablet.
21. 1 kinds of methods preparing tamsulosin hydrochloride slow releasing preparation described in any one of claim 1-20, comprise the steps:
1) by the tamsulosin hydrochloride of aequum and pharmaceutically acceptable carrier Homogeneous phase mixing, adopt any one of method of extruding and kneading to pellets, centrifugal fluidized granulation method, thermosol squeezing and pressing method, be made into sustained-release matrix micropill;
2) by sustained-release matrix micropill bag by clothing film, be made into skeleton reservoir pellets;
3) by skeleton film controlling type slow release ball bag by pastille release layer, obtained framework film control quick-releasing type slow-release micro-pill.
22. methods according to claim 21, granulate framework film control quick-releasing type slow-release micro-pill, fill capsule or tabletting, obtained required slow releasing preparation.
23. methods according to any one of claim 21-22, wherein, the preparation method of matrix sustained-release pellets comprises the steps: the slow-release material of recipe quantity (as hydroxypropyl emthylcellulose etc.) to be scattered in water, be heated to 70-90 DEG C (being preferably 80 DEG C), under stirring condition, add the tamsulosin hydrochloride of total amount 60-80% (being preferably 70%), porogen (as lactose) and binding agent (as polyvinylpyrrolidone) is added in obtained slurry, after mix homogeneously, adopt method of extruding and kneading to pellets, centrifugal fluidized granulation method, any one or its combination of thermosol squeezing and pressing method, be made into piller, dry, obtained matrix sustained-release pellets.
24. methods according to any one of claim 21-23, wherein, the preparation method of skeleton film controlling type slow-release micro-pill, comprise the steps: 1) slow-release material (as ethyl cellulose) of recipe quantity is made the alcoholic solution of 2-5% (be preferably 3-4%), add porogen, plasticizer, antiplastering aid again, after stirring and evenly mixing, make extended release coatings film coating solution; 2) under 40-60 DEG C of (being preferably 50-55 DEG C) condition, with extended release coatings film coating solution, matrix sustained-release pellets is whitewashed coating, obtained skeleton film controlling type slow-release micro-pill, wherein, the consumption of coating solution is (with dry basis) dry micropill 4-8% (being preferably 5-6%).
25. methods according to any one of claim 21-22, wherein, the preparation method of framework film control quick-releasing type slow-release micro-pill, comprise the steps: 1) binding agent (as PVP K30) is added water and makes 3-10% serosity (being preferably 5-8%), add surplus tamsulosin hydrochloride, stir, after Homogeneous phase mixing, make pastille rapid release coating solution; 2) under 40-60 DEG C of (being preferably 50-55 DEG C) condition, by skeleton reservoir pellets pastille rapid release coating solution whitewashing coating, obtained framework film control quick-releasing type slow releasing preparation, to obtain final product.
Application in the medicine of the dysuria that the tamsulosin hydrochloride slow releasing preparation that the tamsulosin hydrochloride slow releasing preparation described in 26. any one of claim 1-20 or any one of claim 21-25 prepare gained causes for the preparation for the treatment of benign prostatic hyperplasia (BPH), prostate hyperplasia.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105165763A (en) * | 2015-08-06 | 2015-12-23 | 广西柳州昊邦日化有限公司 | Method for manufacturing mosquito sucking mat for mosquito sucking device |
| CN107519147A (en) * | 2016-06-21 | 2017-12-29 | 广州医药研究总院有限公司 | Desmethylvenlafaxine slow-release pill and preparation method thereof |
| CN108096220A (en) * | 2017-12-11 | 2018-06-01 | 苏州中化药品工业有限公司 | A kind of sustained-release preparation of tamsulosin hydrochloride and preparation method thereof |
| CN109319913A (en) * | 2018-10-11 | 2019-02-12 | 仲恺农业工程学院 | Slow-release potassium hydrogen persulfate preparation and preparation method thereof |
| CN114099500A (en) * | 2020-08-26 | 2022-03-01 | 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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| CN103520164A (en) * | 2013-10-30 | 2014-01-22 | 程刚 | Ticagrelor sustained-release preparation |
| CN103585112A (en) * | 2012-08-14 | 2014-02-19 | 齐鲁制药有限公司 | Tamsulosin enteric coated sustained-release pellet and preparation method thereof |
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| CN103585112A (en) * | 2012-08-14 | 2014-02-19 | 齐鲁制药有限公司 | Tamsulosin enteric coated sustained-release pellet and preparation method thereof |
| CN103520164A (en) * | 2013-10-30 | 2014-01-22 | 程刚 | Ticagrelor sustained-release preparation |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105165763A (en) * | 2015-08-06 | 2015-12-23 | 广西柳州昊邦日化有限公司 | Method for manufacturing mosquito sucking mat for mosquito sucking device |
| CN107519147A (en) * | 2016-06-21 | 2017-12-29 | 广州医药研究总院有限公司 | Desmethylvenlafaxine slow-release pill and preparation method thereof |
| CN108096220A (en) * | 2017-12-11 | 2018-06-01 | 苏州中化药品工业有限公司 | A kind of sustained-release preparation of tamsulosin hydrochloride 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 |
| CN109319913A (en) * | 2018-10-11 | 2019-02-12 | 仲恺农业工程学院 | Slow-release potassium hydrogen persulfate preparation and preparation method thereof |
| CN114099500A (en) * | 2020-08-26 | 2022-03-01 | 上海博志研新药物技术有限公司 | Edaravone sustained-release pharmaceutical composition, preparation method and application |
| CN114099500B (en) * | 2020-08-26 | 2023-09-22 | 上海云晟研新生物科技有限公司 | Edaravone sustained-release pharmaceutical composition, preparation method and application |
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