CN101584683A - Metolazone slow-release capsule and method for preparing same - Google Patents
Metolazone slow-release capsule and method for preparing same Download PDFInfo
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- CN101584683A CN101584683A CNA2009100120252A CN200910012025A CN101584683A CN 101584683 A CN101584683 A CN 101584683A CN A2009100120252 A CNA2009100120252 A CN A2009100120252A CN 200910012025 A CN200910012025 A CN 200910012025A CN 101584683 A CN101584683 A CN 101584683A
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Abstract
The invention belongs to the technical field of medicaments, and discloses a metolazone slow-release capsule and a method for preparing the same. The preparation comprises an active component of metolazone and a pharmaceutically acceptable carrier component by weight percentage: 1 to 30 percent of metolazone, 10 to 70 percent of auxiliary material with slow-release effect, and the balance of other auxiliary materials. The method comprises the following steps that: (1) matters in a capsule are matrix type particles or pills; (2) the medicine-containing pill is prepared first, and then a slow-release preparation is prepared; and (3) the capsule is the coated slow-release preparation. The metolazone slow-release capsule can ensure that the main medicinal component of metolazone is continuously and regularly released when the metolazone slow-release capsule is orally taken; moreover, the metolazone slow-release capsule has the characteristics of convenient drug administration, persistent curative effect, stable curative effect, little side effect and the like.
Description
Technical field:
The present invention relates to medical technical field, it relates to Metolazone slow-release capsule and preparation method thereof in definite saying.
Background technology:
Metolazone (Metolazone) is non-thiazide diuretic, different with hydrochlorothiazide etc., site of action also acts on proximal convoluted tubule except that Distal convoluted tubule and loop ascending branch far-end, diuretic effect is good, be 10 times of hydrochlorothiazide, the diuresis phase is long, and dose can be kept diuresis 12～24 hours, diuresis does not weaken when renal function goes down yet, the patient that can not use diuretic such as thiazide to companion's renal insufficiency, very effective, this product can be used for patients hypersensitive such as parathiazine class.Clinically, metolazone is mainly used in treatment edema, hypertension.In addition, also have a good action at treatment chronic cardiac insufficiency (heart failure) metolazone, for the invalid intractable congestive heart failure patient of conventional therapy method, oral metolazone 1.25～10mg/ day can obtain significant curative effect according to " lancet " magazine report.
Metolazone was manufactured on Britain and U.S.'s listing early than 1974 by U.S. Pennwalt company, subsequently, in moral, meaning, day, Switzerland and A Ting listing, the name of an article has Zaroxoyn companies such as () Pennnwalt SandozI.S.F, Dulo (Searle company), Normeran (Sanyo), Metenix (Hoechst company) and Oldren (Roemmers company) etc.The listing dosage form is a tablet.Specification is 2.5mg, 5mg or 10mg/ sheet.Be used for the treatment of edema, once a day, 5-10mg.Sometimes can be to 20mg/ day or more heavy dose of.Treatment hypertension once a day, 2.5-5mg uses separately or share with other depressor.
Just because of metolazone has the irreplaceable advantage of other diuretic when treatment edema, hypertension, chronic cardiac insufficiency diseases such as (heart failures), recorded by American Pharmacopeia (23,24,25 editions) always.
Yet there are no Metolazone slow-release capsule in the product that has gone on the market at present, and metolazone is made the feature that slow releasing capsule meets chronopharmacology, can play therapeutical effect preferably disease.
Summary of the invention:
The object of the present invention is to provide a kind of Metolazone slow-release capsule and preparation method thereof, this slow releasing capsule has slow-release function preferably, in in vitro tests, can effectively keep 12 hours, compare with prior dosage form, this medicine slowly discharges to be kept comparatively stable blood concentration and longer release time, has advantages such as toxic and side effects is little and easy to use.
Metolazone slow releasing preparation provided by the invention is made up of active component metolazone and pharmaceutically acceptable carrier, can reduce the untoward reaction of medicine effectively, and blood drug level is more than the treatment effective dose.Said preparation is 12 hours slow release, and the cumulative release amount in the time of 12 hours is at least 60%, and optimum cumulative release amount is at least 70%; The preferred cumulative release amount of preparation in the time of 9 hours is at least 60%, and optimum cumulative release amount is at least 70%.The cumulative release amount of most preferred preparation in the time of 8 hours is at least 60%, and optimum cumulative release amount is at least 70%.Dosage every day of said preparation is 1～10mg.
The present invention is achieved through the following technical solutions:
Said preparation comprises following component by weight percentage:
Metolazone 1%～30%
Play the adjuvant 10%～70% of slow releasing function
Other adjuvant surplus
Metolazone slow-release capsule of the present invention is by filling with wherein slow-releasing granules or with the uniting to use and reach slow releasing function of capsule coating and the two, its content is a kind of of granule, micropill.
The release principle of slow releasing preparation has stripping, diffusion, corrosion to combine with diffusion, stripping etc. usually.Different Metolazone slow-release capsules be can design according to above-mentioned principle, matrix type, film controlling type etc. comprised.
The Metolazone slow-release capsule content is matrix type granule or piller, comprises hydrogel skeleton, waxiness class skeleton, insoluble skeleton; The adjuvant that plays slow releasing function commonly used have hydroxypropyl emthylcellulose, methylcellulose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose,
SR, sodium alginate, agar, tragcanth, chitosan, galactomannan, polyvinyl alcohol, carbopol, Brazil wax, stearyl alcohol, stearic acid, Polyethylene Glycol, castor oil hydrogenated, Cera Flava, polyethylene glycol mono stearate, glyceryl monostearate, triglyceride, the glyceride type of microwax and other fatty acid, polyethylene, polypropylene, polrvinyl chloride, polysiloxanes, ethylene-vinyl acetate copolymer, methacrylic acid-methyl acrylate copolymer, cellulose acetate butyrate, ethyl cellulose, polymethyl methacrylate, carbopol, cyclodextrin.Preparation technology commonly used comprises employing wet method, solvent evaporation technology and fusion technology granulation; Adopt extruding-spheronization, hot melt extruded method, roll into preparation pillers such as ball and centrifugal-fluidization process.
The film controlling type preparation of indication of the present invention is meant that mainly capsule 's content is uniting to use and reaching slow releasing function of film controlling type piller or capsule coating and the two.The adjuvant that plays slow releasing function has esters, polylactic acid, acrylic homopolymer and copolymer and the natural pharmaceutical polymers of cellulose esters, cellulose ethers, cellulose ether.Wherein, described cellulose esters is cellulose acetate and/or cellulose acetate butyrate; Described cellulose ethers is a hydroxypropyl emthylcellulose; The esters of described cellulose ethers is a hydroxypropyl methyl cellulose phthalate; Described acrylic homopolymer and copolymer are one or more of acrylic resin aqueous dispersion; Described natural macromolecular material is crosslinked alginate, chitosan etc.Coating method commonly used has coating pan turnadle pan coating, air suspension fluidized bed coating method, compression coating and crosslinking with radiation coating method.
Other required adjuvant of Metolazone slow-release capsule of the present invention comprises filler, porogen, plasticizer, lubricant, binding agent; Wherein filler adopts a kind of, two or more the compositions in microcrystalline Cellulose, starch, pregelatinized Starch, lactose, mannitol, calcium sulfate, calcium hydrogen phosphate or the dextrin.Porogen adopts sucrose, lactose, mannitol, methylcellulose or sodium lauryl sulphate; Plasticizer adopts glycerol, Oleum Ricini, Polyethylene Glycol triethyl citrate, dibutyl sebacate, diethyl phthalate, acetic acid monoglyceride, tributyl citrate, Oleum Ricini, triacetyl glycerine, cochin oil, oleic acid or their mixture; Binding agent adopts water, and/or the alcoholic solution of hydroxypropyl emthylcellulose, polyvinylpyrrolidone, starch slurry and 50～90%; Lubricant adopts one or more of hard magnesium, Pulvis Talci, Stepanol MG, sodium lauryl sulphate or micropowder silica gel.
Drug release determination method (2005 editions two appendix xD first methods of Chinese Pharmacopoeia), the device of employing dissolution method (2005 editions two xC second methods of Chinese Pharmacopoeia) is measured the drug release characteristics of preparation of the present invention.
The present invention has selected following 4 kinds of dissolution mediums to simulate intravital gastrointestinal tract environment, to estimate the situation that influences that this preparation medicine release characteristic is subjected to factors such as gastrointestinal peristalsis, pH value and food:
Medium A (SGF, simulated gastric fluid do not contain pepsin): pH1.2
HCl is an amount of
NaCl 0.2％
An amount of 1000ml of water
Medium B (SIF, simulated intestinal fluid do not contain pancreatin): pH6.8
KH2PO4 6.8g
NaOH is an amount of
An amount of 1000ml of water
Medium C (FeSSIF, simulated intestinal fluid, feed state): pH5
Acetic acid 0.144M
NaOH is an amount of
Sodium taurocholate 15mM
Lecithin 4mM
KCl 0.19M
An amount of 1000ml of distilled water
Final medium pH=5
Osmotic pressure (osmolarity)=485-535mOsm; Buffer capacity=75 ± 2mEQ/L/pH medium D (FaSSIF, simulated intestinal fluid, state on an empty stomach): pH6.8
KH
2PO
4 0.029M
NaOH is an amount of
Sodium taurocholate 5mM
Lecithin 1.5mM
KCl 0.22M
An amount of 1000ml of distilled water
Final medium pH=6.8
Osmotic pressure (osmolarity)=280-310mOsm; Buffer capacity=10 ± 2mEQ/L/pH
Above-mentioned medium A is represented standard gastric juice condition; Medium B represents standard intestinal juice condition; Medium C represents the feed state, and medium D represents state on an empty stomach.
Table 1 is metolazone conventional capsule dissolution in vitro in above-mentioned four kinds of media.
Compare with conventional capsule, Metolazone slow-release capsule release in vitro result of the present invention shows that preparation of the present invention discharges medicine lentamente in the medium of four kinds of simulated in vivo environment selecting, and release characteristic is subjected to the influence of medium very little, constant speed discharges medicine equably in clinical use, for the patient provides more steady and persistent curative effect, reduce the generation of untoward reaction.
Advantage of the present invention is: can be widely used in the treatment of single dose metolazone, and therefore obviously improve the compliance and the convenience of administration, be a kind of preparation with clinical meaning.The metolazone oral absorption is rapid, make Atrigel, make its rate of release become apparent absorption rate, can eliminate high peak concentration, reduce fluctuation, can reduce the untoward reaction of medicine, improve the drug level in the tissue, the prolong drug half-life, improve patient's compliance, thereby reduce chemical sproof generation to greatest extent.This prescription can reduce the side effect of metolazone, improves bioavailability, lasting medicine, taking convenience.
Description of drawings:
Fig. 1 is the release in vitro curve of Metolazone slow-release capsule in medium A
Fig. 2 is the release in vitro curve of Metolazone slow-release capsule in medium B
Fig. 3 is the release in vitro curve of Metolazone slow-release capsule in medium C
Fig. 4 is the release in vitro curve of Metolazone slow-release capsule in medium D
The specific embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
Embodiment 1:
Composition weight/1000
Metolazone 10g
Hydroxypropyl emthylcellulose 65g
Lactose 60g
Microcrystalline Cellulose 60g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation method: it is standby to cross 100 mesh sieves behind the Central Plains of will writing out a prescription, the adjuvant pulverize separately; With metolazone and hydroxypropyl emthylcellulose, microcrystalline Cellulose and lactose, cross 100 mesh sieve mix homogeneously, with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, promptly encapsulated.
Embodiment 2:
Composition weight/1000
Metolazone 10g
Polyoxyethylene 100g
Microcrystalline Cellulose 85g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation method: it is standby to cross 100 mesh sieves behind the Central Plains of will writing out a prescription, the adjuvant pulverize separately; Metolazone and polyoxyethylene, microcrystalline Cellulose are crossed 100 mesh sieve mix homogeneously, and with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, promptly encapsulated.
Embodiment 3:
Composition weight/1000
Metolazone 10g
Sodium alginate 90g
Lactose 50g
Microcrystalline Cellulose 45g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation method: it is standby to cross 100 mesh sieves behind the Central Plains of will writing out a prescription, the adjuvant pulverize separately; Take by weighing metolazone and sodium alginate, microcrystalline Cellulose and the lactose of recipe quantity, cross 100 mesh sieve mix homogeneously, with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, promptly encapsulated.
Embodiment 4:
Composition weight/1000
Metolazone 10g
Lactose 55g
Microcrystalline Cellulose 100g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation method: it is standby to cross 100 mesh sieves behind the Central Plains of will writing out a prescription, the adjuvant pulverize separately; The metolazone that takes by weighing recipe quantity with
SR, microcrystalline Cellulose and lactose are crossed 100 mesh sieve mix homogeneously, and with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, promptly encapsulated.
Embodiment 5:
Composition weight/1000
Metolazone 10g
Ethyl cellulose 30g
Lactose 105g
Microcrystalline Cellulose 50g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation method: it is standby to cross 100 mesh sieves behind the Central Plains of will writing out a prescription, the adjuvant pulverize separately; Take by weighing metolazone and ethyl cellulose, microcrystalline Cellulose and the lactose of recipe quantity, cross 100 mesh sieve mix homogeneously, with an amount of 90% alcohol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, promptly encapsulated.
Embodiment 6:
Composition weight/1000
Metolazone 10g
Polyoxyethylene 145g
Microcrystalline Cellulose 40g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation technology is with embodiment 2.
Embodiment 7:
Composition weight/1000
Metolazone 10g
Sodium alginate 35g
Hydroxypropyl emthylcellulose 50g
Lactose 50g
Microcrystalline Cellulose 50g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation method: it is standby to cross 100 mesh sieves behind the Central Plains of will writing out a prescription, the adjuvant pulverize separately; Take by weighing metolazone and sodium alginate, hydroxypropyl emthylcellulose, microcrystalline Cellulose and the lactose of recipe quantity, cross 100 mesh sieve mix homogeneously, with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, promptly encapsulated.
Embodiment 8:
Composition weight/1000
Metolazone 10g
Hydroxypropyl emthylcellulose 20g
Lactose 55g
Microcrystalline Cellulose 100g
Magnesium stearate 5g
90% ethanol is an amount of
Preparation method: it is standby to cross 100 mesh sieves behind the Central Plains of will writing out a prescription, the adjuvant pulverize separately; The metolazone that takes by weighing recipe quantity with
SR, hydroxypropyl emthylcellulose, microcrystalline Cellulose and lactose are crossed 100 mesh sieve mix homogeneously, and with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, promptly encapsulated.
Embodiment 9:
Composition weight/1000
Metolazone 10g
Glyceryl monostearate 50g
Microcrystalline Cellulose 140g
Preparation method: adopt and extrude spheronization.Earlier glyceryl monostearate is dispersed in the hot water, is heated to 80 ℃, add metolazone while stirring, until forming slurry.Hot slurry and microcrystalline Cellulose are mixed, be added to then in the extruder, obtain extrudate.Roll in finisher,pill and obtain piller, drying is sieved, and cut-off is 1.2mm～1.8mm person directly, incapsulates, promptly.
Embodiment 10:
Component
Celphere 300g (commercially available)
Metolazone 10g
Hypromellose (E5) 24g
Sodium lauryl sulphate 0.2g
Eudrugit?NE?30D 70g
Triethyl citrate 3.2g
Pulvis Talci 9g
Preparation method: with 24 gram hydroxypropyl emthylcelluloses in 800ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.The preparation of sustained release coating liquid adds 0.2 gram sodium lauryl sulphate, 3.2g triethyl citrate, 9 gram Pulvis Talci in the 100mL water, stirs 2 hours, makes evenly, and above-mentioned suspension is slowly poured among the 70 gram Eudragit NE 30D, adds water to 250mL, stirs evenly.Filter through 80 mesh sieves.In the coating process, continue to stir.Exsiccant celphere 300 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 10 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating with sustained release coating liquid, 40 ℃ of dryings 24 hours, white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 11:
Component
Celphere 300g (commercially available)
Metolazone 10g
PVP?K30 20g
Sodium lauryl sulphate 0.2g
Eudrugit?NE?30D 70g
Dibutyl sebacate 8g
Pulvis Talci 9g
Preparation method: with 20 gram PVP K30 in 800ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.The preparation of sustained release coating liquid adds 0.2 gram sodium lauryl sulphate, 8 gram dibutyl sebacates, 9 gram Pulvis Talci in the 100mL water, stirs 2 hours, makes evenly, and above-mentioned suspension is slowly poured among the 70 gram Eudragit NE 30D, adds water to 250mL, stirs evenly.Filter through 80 mesh sieves.In the coating process, continue to stir.Exsiccant celphere 150 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 10 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating with sustained release coating liquid, 40 ℃ of dryings 24 hours, white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 12:
Component
Celphere 300g (commercially available)
Metolazone 10g
Hypromellose (E5) 15g
Sodium lauryl sulphate 0.21g
Surelease 60g
PEG4000 2.0g
Pulvis Talci 10g
Preparation method: with 15 gram hydroxypropyl emthylcelluloses in 500ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.0.21 gram sodium lauryl sulphate, 2.0 gram PEG4000,10 gram Pulvis Talci are added in the 100mL water, stirred 2 hours, make evenly, above-mentioned suspension is slowly poured in Surelease 60 grams, add water to 250mL, stir evenly.Filter through 80 mesh sieves.In the coating process, continue to stir.Exsiccant celphere 300 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 10 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating with sustained release coating liquid, 40 ℃ of dryings 24 hours, white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 13:
Component
Celphere 300g (commercially available)
Metolazone 10g
Hypromellose (E5) 16g
Sodium lauryl sulphate 0.22g
Eudragit?RS?30D 55g
Eudragit?RL?30D 5g
PEG6000 1.35g
Pulvis Talci 10.5g
Preparation method: with 16 gram hydroxypropyl emthylcelluloses in 800ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.1.35 gram polyethylene glycol 6000s are dissolved in (heating hydrotropy) adding 0.22 gram sodium lauryl sulphate, 10.5 gram Pulvis Talci in the 100mL water, stirred 2 hours, make evenly.Above-mentioned suspension is slowly poured among 60 gram Eudragit RS 30D and the Eudragit RL30D (10: 1), added water to 250mL and stir evenly.Filter through 80 orders.In the coating process, continue to stir.Exsiccant celphere 300 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 10 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating with controlled release coat liquid, 40 ℃ of dryings 24 hours, white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 14:
Component
Celphere 300g (commercially available)
Metolazone 10g
Hypromellose (E5) 16g
Sodium lauryl sulphate 0.22g
Eudragit?RS?30D 75g
Eudragit?RL?30D 5g
PEG6000 1.35g
Pulvis Talci 10.5g
Preparation method: with 16 gram hydroxypropyl emthylcelluloses in 800ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.1.35 gram polyethylene glycol 6000s are dissolved in (heating hydrotropy) adding 0.22 gram sodium lauryl sulphate, 10.5 gram Pulvis Talci in the 100mL water, stirred 2 hours, make evenly.Above-mentioned suspension is slowly poured among 80 gram Eudragit RS 30D and the Eudragit RL30D (19: 1), added water to 250mL and stir evenly.Filter through 80 orders.In the coating process, continue to stir.Exsiccant celphere 300 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 100 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating, 40 ℃ of dryings 24 hours with controlled release coat liquid.Get white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 15:
Celphere 300g (commercially available)
Metolazone 10g
Hypromellose (E5) 16g
Tween80 1.15g
Cellulose acetate 20g
Pulvis Talci 10.0g
Preparation method: with 16 gram hydroxypropyl emthylcelluloses in 800ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.The 20g cellulose acetate is dissolved in the 400ml dehydrated alcohol, adds 1.15 gram Tween80 and 10.0 gram Pulvis Talci more successively, stirred 2 hours, make evenly, filter through 80 orders.In the coating process, continue to stir.Exsiccant celphere 300 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 10 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating, 40 ℃ of dryings 24 hours with controlled release coat liquid.Get white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 16:
Celphere 300g (commercially available)
Metolazone 10g
Hypromellose (E5) 16g
Tween80 1.2g
Ethyl cellulose 15g
Pulvis Talci 10.5g
Preparation method: with 16 gram hydroxypropyl emthylcelluloses in 800ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.The 15g ethyl cellulose is dissolved in the 400ml dehydrated alcohol, adds 1.2 gram Tween80 and 10.5 gram Pulvis Talci more successively, stirred 2 hours, make evenly, filter through 80 orders.In the coating process, continue to stir.Exsiccant celphere 300 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 10 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating, 40 ℃ of dryings 24 hours with controlled release coat liquid.Get white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 17:
Celphere 300g (commercially available)
Metolazone 10g
Hypromellose (E5) 16g
Tween80 1.5g
Ethyl cellulose 10g
Acrylic resin RS100 5g
Pulvis Talci 12.0g
Preparation method: with 16 gram hydroxypropyl emthylcelluloses in 800ml room temperature distilled water magnetic agitation 2-8 hour, after treating to dissolve fully, 100 mesh sieves filtered.15g ethyl cellulose, 5g acrylic resin RS100 are dissolved in the 400ml dehydrated alcohol, add 1.5 gram Tween80 and 12.0 gram Pulvis Talci more successively, stirred 2 hours, make evenly, filter through 80 orders.In the coating process, continue to stir.Exsiccant celphere 300 grams are spraying under the atomized adhesive, evenly slowly are sprinkled into metolazone 10 grams, and room temperature is dried.Binding agent with 50ml continues spray coating, and room temperature is dried.Get 24-20 purpose 300 gram and contain pill core, continue spray coating, 40 ℃ of dryings 24 hours with controlled release coat liquid.Get white spherical piller.The slow-release pill of gained incapsulated promptly get Metolazone slow-release capsule of the present invention.
Embodiment 18:
The capsule prescription
Metolazone 10g
Lactose 100g
Microcrystalline Cellulose 80g
Magnesium stearate 10g
90% ethanol is an amount of
Coating fluid prescription
PEG6000 1.5g
Sodium lauryl sulphate 0.2g
Eudrugit?NE?30D 70g
Dibutyl sebacate 8g
Pulvis Talci 9g
Preparation method: it is standby to cross 100 mesh sieves behind will write out a prescription earlier Central Plains, the adjuvant pulverize separately; With metolazone and microcrystalline Cellulose and lactose, cross 100 mesh sieve mix homogeneously again, with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, encapsulated.1.5 gram polyethylene glycol 6000s are dissolved in (heating hydrotropy) adding 0.2 gram sodium lauryl sulphate, 9 gram Pulvis Talci, 8g dibutyl sebacate in the 100mL water, stirred 2 hours, make evenly.Above-mentioned suspension is slowly poured among the 70 gram Eudrugit NE 30D, added water to 250mL and stir evenly.Filter through 80 orders.In the coating process, continue to stir.Get the above-mentioned metolazone capsule that makes, continue spray coating, 40 ℃ of dryings 24 hours with controlled release coat liquid.Promptly get Metolazone slow-release capsule of the present invention.
Embodiment 19:
The capsule prescription
Metolazone 10g
Lactose 100g
Microcrystalline Cellulose 80g
Magnesium stearate 10g
90% ethanol is an amount of
Coating fluid prescription
Eudragit?RS?30D 75g
Eudragit?RL?30D 5g
PEG6000 1.5g
Sodium lauryl sulphate 0.2g
Dibutyl sebacate 8g
Pulvis Talci 9g
Preparation method: it is standby to cross 100 mesh sieves behind will write out a prescription earlier Central Plains, the adjuvant pulverize separately; With metolazone and microcrystalline Cellulose and lactose, cross 100 mesh sieve mix homogeneously again, with an amount of 90% ethanol system soft material, 20 mesh sieves are granulated, 60 ± 5 ℃ of dryings of wet granular, 20 mesh sieve granulate; Add magnesium stearate, mixing, encapsulated.1.5 gram polyethylene glycol 6000s are dissolved in (heating hydrotropy) adding 0.2 gram sodium lauryl sulphate, 9 gram Pulvis Talci, 8g dibutyl sebacate in the 100mL water, stirred 2 hours, make evenly.Above-mentioned suspension slowly poured into above-mentioned suspension is slowly poured among 80 gram Eudragit RS 30D and the Eudragit RL 30D (19: 1), add water to 250mL and stir evenly.Filter through 80 orders.In the coating process, continue to stir.Get the above-mentioned metolazone capsule that makes, continue spray coating, 40 ℃ of dryings 24 hours with controlled release coat liquid.Promptly get Metolazone slow-release capsule of the present invention.
Claims (8)
1, a kind of Metolazone slow-release capsule is characterized in that being made up of active component metolazone and pharmaceutically acceptable carrier, and said preparation comprises following component by weight percentage:
Metolazone 1%～30%
Play the adjuvant 10%～70% of slow releasing function
Other adjuvant surplus.
2, Metolazone slow-release capsule according to claim 1 is characterized in that: described Metolazone slow-release capsule is that a kind of in matrix type granule or piller, the film controlling type piller incapsulates acquisition or plain particles or piller and incapsulate the back coating and obtain.
3, Metolazone slow-release capsule according to claim 2 is characterized in that: described matrix type granule or piller comprise granule or piller that hydrogel skeleton, waxiness class skeleton, insoluble skeleton are made; Described film controlling type piller consists of celphere, medicated layer, confining bed, sustained-release coating layer from inside to outside.
4, according to claim 1 or 2 or 3 described Metolazone slow-release capsules; it is characterized in that: when content is matrix type granule or piller, the adjuvant that plays slow releasing function have hydroxypropyl emthylcellulose, methylcellulose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose,
SR, sodium alginate, agar, tragcanth, chitosan, galactomannan, polyvinyl alcohol, carbopol, Brazil wax, stearyl alcohol, stearic acid, Polyethylene Glycol, castor oil hydrogenated, Cera Flava, polyethylene glycol mono stearate, glyceryl monostearate, triglyceride, the glyceride type of microwax and other fatty acid, polyethylene, polypropylene, polrvinyl chloride, polysiloxanes, ethylene-vinyl acetate copolymer, methacrylic acid-methyl acrylate copolymer, cellulose acetate butyrate, ethyl cellulose, polymethyl methacrylate, carbopol, in the cyclodextrin one or more; When content was the film controlling type piller, the adjuvant that plays slow releasing function had esters, polylactic acid, acrylic homopolymer and the copolymer of cellulose esters, cellulose ethers, cellulose ether and in the natural pharmaceutical polymers one or more.
5, Metolazone slow-release capsule according to claim 4 is characterized in that: wherein, described cellulose esters is cellulose acetate and/or cellulose acetate butyrate; Described cellulose ethers is a hydroxypropyl emthylcellulose; The esters of described cellulose ethers is a hydroxypropyl methyl cellulose phthalate; Described acrylic homopolymer and copolymer are one or more of acrylic resin aqueous dispersion; Described natural macromolecular material comprises crosslinked alginate, chitosan.
6, Metolazone slow-release capsule according to claim 2, be characterised in that: in the described coating, the adjuvant that plays slow releasing function has esters, polylactic acid, acrylic homopolymer and copolymer and the natural pharmaceutical polymers of cellulose esters, cellulose ethers, cellulose ether.
7, Metolazone slow-release capsule according to claim 6 is characterised in that: described cellulose esters is cellulose acetate and/or cellulose acetate butyrate; Described cellulose ethers is a hydroxypropyl emthylcellulose; The esters of described cellulose ethers is a hydroxypropyl methyl cellulose phthalate; Described acrylic homopolymer and copolymer are one or more of acrylic resin aqueous dispersion; Described natural macromolecular material comprises crosslinked alginate, chitosan.
8, Metolazone slow-release capsule according to claim 1 is characterized in that: described other adjuvant comprises filler, porogen, plasticizer, lubricant, binding agent; Wherein filler adopts a kind of, two or more the compositions in microcrystalline Cellulose, starch, pregelatinized Starch, lactose, mannitol, calcium sulfate, calcium hydrogen phosphate or the dextrin; Porogen adopts sucrose, lactose, mannitol, methylcellulose or sodium lauryl sulphate; Plasticizer adopts glycerol, Oleum Ricini, Polyethylene Glycol, triethyl citrate, dibutyl sebacate, diethyl phthalate, acetic acid monoglyceride, tributyl citrate, Oleum Ricini, triacetyl glycerine, cochin oil, oleic acid or their mixture; Binding agent adopts water, and/or a kind of in the alcoholic solution of hydroxypropyl emthylcellulose, polyvinylpyrrolidone, starch slurry and 50～90%; Lubricant adopts one or more of hard magnesium, Pulvis Talci, Stepanol MG, sodium lauryl sulphate or micropowder silica gel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100120252A CN101584683A (en) | 2009-06-12 | 2009-06-12 | Metolazone slow-release capsule and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100120252A CN101584683A (en) | 2009-06-12 | 2009-06-12 | Metolazone slow-release capsule and method for preparing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101584683A true CN101584683A (en) | 2009-11-25 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100120252A Pending CN101584683A (en) | 2009-06-12 | 2009-06-12 | Metolazone slow-release capsule and method for preparing same |
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| Country | Link |
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| CN (1) | CN101584683A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102557995A (en) * | 2011-12-14 | 2012-07-11 | 天津药物研究院药业有限责任公司 | Method for synthesizing N-ethoxalyl-5-choro-2-methyl-4-sulfanoyl aniline |
| CN104758289A (en) * | 2015-03-09 | 2015-07-08 | 西安力邦制药有限公司 | A compound antihypertensive composition containing metolazone and applications thereof |
| CN112912067A (en) * | 2018-08-31 | 2021-06-04 | 欧普科爱尔兰环球控股有限公司 | Pediatric dosage forms, methods of manufacture and use |
| CN114794309A (en) * | 2022-06-01 | 2022-07-29 | 江苏翼邦生物技术有限公司 | Feed additive containing acidifying agent and preparation method and application thereof |
-
2009
- 2009-06-12 CN CNA2009100120252A patent/CN101584683A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102557995A (en) * | 2011-12-14 | 2012-07-11 | 天津药物研究院药业有限责任公司 | Method for synthesizing N-ethoxalyl-5-choro-2-methyl-4-sulfanoyl aniline |
| CN104758289A (en) * | 2015-03-09 | 2015-07-08 | 西安力邦制药有限公司 | A compound antihypertensive composition containing metolazone and applications thereof |
| CN104758289B (en) * | 2015-03-09 | 2019-05-03 | 西安力邦制药有限公司 | A kind of compound antihypertensive drug combination and its application containing medetofazone |
| CN112912067A (en) * | 2018-08-31 | 2021-06-04 | 欧普科爱尔兰环球控股有限公司 | Pediatric dosage forms, methods of manufacture and use |
| CN114794309A (en) * | 2022-06-01 | 2022-07-29 | 江苏翼邦生物技术有限公司 | Feed additive containing acidifying agent and preparation method and application thereof |
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