CN108066347A - Orally disintegrating tablet medicament composition comprising Tamsulosin and dutasteride - Google Patents

Orally disintegrating tablet medicament composition comprising Tamsulosin and dutasteride Download PDF

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CN108066347A
CN108066347A CN201611022458.2A CN201611022458A CN108066347A CN 108066347 A CN108066347 A CN 108066347A CN 201611022458 A CN201611022458 A CN 201611022458A CN 108066347 A CN108066347 A CN 108066347A
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pill
coating
capsule core
tablet
coating micro
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CN108066347B (en
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衷期群
马俊
刘晓燕
唐振钦
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Shenzhen Wanhe Pharmaceutical Co Ltd
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Shenzhen Wanhe Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
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  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to the Orally disintegrating tablet medicament compositions for including Tamsulosin and dutasteride.It is the tablet formed by tablet forming technique compacting more particularly to a kind of oral disnitegration tablet；The tablet includes the tablet matrix being made of multiple auxiliary materials and two kinds of coating micro-pills being essentially homogeneously scattered in the tablet matrix；Described two coating micro-pills include the capsule core comprising two kinds of different activities ingredients and at least one layer of coating for being covered in the capsule core surface respectively.The invention further relates to the preparation method of the oral disnitegration tablet and its corresponding uses.Excellent technique effect described in description of the invention is presented in oral disnitegration tablet of the present invention.

Description

Orally disintegrating tablet medicament composition comprising Tamsulosin and dutasteride
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of medicament preparation method for being used to treat benign prostatic hyperplasis, More particularly to a kind of method for preparing the medicament comprising Tamsulosin and dutasteride, particularly relate to a kind of prepare tool There is the method for the tamsulosin hydrochloride and dutasteride's Orally disintegrating tablet compositions of excellent pharmacy effect.The Tamsulosin For highly selective α 1A- receptor antagonists, the dutasteride is the selection of the 1- types and 2 type hypotypes of steroids 5- alpha-reductases Property inhibitor.
Background technology
To improve the convenience that drug uses, specific adaptations disease and the medication compliance of particular patients ' crowd, pharmacy are solved Boundary develops a kind of tablet that need to be only placed on and fine particle can be disintegrated on lingual surface and stomach is reached with saliva, this such sheets Agent is commonly referred to as oral disnitegration tablet or oral disintegrating tablet.Such oral disnitegration tablet is taken without chewing, swallowed whole or with water.It is this Patient of the administering mode to child patient, gerontal patient, dysphagia patients and Compliance difference (such as suffer from by psychiatric disorder Person) bring benefit.
The oral disintegrating tablet product technology of preparing listed at present mainly has desivac and pressing.Production prepared by desivac Product disintegration rate is fast, but tablet is almost without hardness, and hygroscopicity is extremely strong, is unfavorable for the production, transport and patient of product It takes；Desivac needs special installation simultaneously, increases production cost, is unfavorable for being widely popularized for the technology.Pressing prepares work Skill is similar to ordinary tablet, and without special installation, while product has certain hardness, but product is usually associated with the increase of hardness Disintegration time extends, in order to obtain shorter disintegration time, and the oral disnitegration tablet for listing pressing production at present is soft Piece (hardness is generally in 1-2kg or so) since tablet hardness is low, easily causes product breakage or fracture, is equally unfavorable for product Production, transport and patient take.In addition, made from pressing tablet exposure in air when hygroscopicity it is strong, this can to production, It packs, store, transporting, using etc. and bringing a series of problems.
The hardness (friability can also reflect the hardness performance of tablet under certain conditions) and disintegration time of oral disnitegration tablet A pair of contradictory body clearly in tablet industry.In order to maintain to prepare, pack, store, transport, use etc. it is a series of during pieces The integrality of agent, it is Orally disintegrating tablet institute to have higher hardness (such as hardness >=3kg, even >=4kg, even >=5kg) It is necessary.With sufficiently fast disintegration time, (such as disintegration time is less than 2min, is, for example, less than 1min, is, for example, less than 45 seconds, example Such as less than 30 seconds) be also Orally disintegrating tablet necessary to.It is improved however as the hardness of tablet, disintegration time can be apparent Extend.
Further, since oral disintegrating tablet, in intraoral disintegration, this due to the disagreeable taste of drug it is possible that can trigger medication not The problem of suitable.Taste discomfort problem present in this oral disintegrating tablet sometimes can be by realizing taste masking purpose by drug coating.
Furthermore in some cases, the positioning of drug discharges or control release is also in need, such as some acid are not Stablizing drug can be discharged by enteric coated positioned so as to fulfill enteral；It is some to need that the drug of release profiles is controlled to pass through bag Extended release coatings discharge so as to fulfill the control of drug.Under the requirement of these positioning releases or control release, Orally disintegrating is prepared Huge challenge can be faced during preparation.
It is therefore, current that there are many attempt drug pellet is made (to realize that the taste masking of active medicine and/or positioning discharge And/or the purpose of control release), the pellet is then mixed into other auxiliary materials and is particularly in the auxiliary material with excellent solubility again The tablet for reaching Orally disintegrating piece performance is pressed into together.Such as the current tamsulosin hydrochloride mouth clinically sold collapse it is slow It is an example to release piece, its main feature is that realizing the positioning release of drug and control release.
Benign prostatic hyperplasis (BPH) is male's gerontal patient's common disease.BPH can cause different degrees of bladder export by Resistance, and cause progressivity frequent micturition and urgent urination due to not smooth and bladder of urinating is quickly full.It is reported that the man in China 60 years old or more Property the elderly in there are about 50% suffer from this disease, and 70 years old or more incidence is up to 88%, if from statistics angle, incidence almost reaches 100%.
BPH drastically influences people’s lives quality, if being not treated in time, may cause sex dysfunction, cause impotence Premature ejaculation；Motility of sperm is influenced, is caused infertile；It causes chronic nephritis or even develops into uremia；Divide in also causing Secrete imbalance, the symptoms such as insomnia and dreamful sleep, weak dizziness, thought slowness, failure of memory；And with the possibility of canceration.This gives Male patient's human body, spirit and economically bring great burden.
Since prostate position, structure are special, surgical operation can only cut off the hyperplasia of coating internal layer, and outer layer does not touch It is dynamic.Moreover, prostate is the switch of control urination, easily occur the frequent micturition even symptom of incontinence after operation on prostate instead, and Prostate still can hyperplasia, can not effect a radical cure.Along with surgical operation therapy has larger wound to human body, so can not be into For the conventional method of Treatment of Benign Prostatic Hyperplasia.
Tamsulosin (Tamsulosin Hydrochloride) is also known as Tamsulosin, clinically dissolves its hydrochloride, Its chemistry is entitled：5- [(2R) -2- [[2- (2- ethoxy phenoxies) ethyl] amino] propyl] -2- methoxybenzenesulphoismide hydrochloric acid Salt, English language Chemical are entitled：5-[(2R)-2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2- Methoxybenzene-sulfonamide hydrochloride, No. CAS：106463-17-6；The molecule of tamsulosin hydrochloride Formula：C20H28N2O5SHCl, molecular weight：444.97；It is clinical there are 1 asymmetric carbon atom in tamsulosin hydrochloride molecular structure The drug used is its R configuration, and chemical structural formula is as follows：
Tamsulosin hydrochloride is a kind of New-type long-acting α -1 adrenoceptor antagonists.The selective good, curative effect of the medical instrument Soon, the characteristics of few side effects, clinically it is widely used in benign prostatic hyperplasis and its related indication treatment.
Tamsulosin hydrochloride preparation is introduced to the market earliest by Japanese Yamanouchi (being afterwards Astellas), is in early days spansule Agent, the interior filling slow-releasing granules of capsule shells.At present in American market sale still for this Duracaps, trade nameYet with tamsulosin hydrochloride for benign prostatic hyperplasis and its related indication treatment, patient is mostly old age People, capsule are inconvenient for this kind of crowd swallowing aspect.For this purpose, be converted into can be with for Yuan Yan manufacturers Astellas The tamsulosin hydrochloride mouth for being directly disintegrated in mouth not by water and being swallowed with saliva collapses sustained release tablets, trade nameJapanese entitled Ha Le Na ー Le D Ingot, every 0.1mg or 0.2mg, it is thisJapan listing and Its package insert is well known, in Japan listingPackage insert on, describe thisSalt The drug release patterns that sour Tamsulosin mouth collapses sustained release tablets fit like a glove with the Duracaps sold previously.It is this The preparation process that tamsulosin hydrochloride mouth collapses sustained release tablets has for example been documented in CN1473035B (Chinese Patent Application No. 02802886.4) in, such as described in embodiment 1 wherein.The tamsulosin hydrochloride mouth, which collapses sustained release tablets, substantially to be included Following steps are prepared：1) it is tamsulosin hydrochloride is coated to microcrystalline cellulose blank capsule core surface；2) coating piller is used Ethyl cellulose release-controlled film wraps up；3) controlled release piller enteric coating material is wrapped up；4) with the water-soluble sugar alcohol such as mannitol, adhesive Solution or the suspension wet method together with enteric pellet prepare particle；5) by particle and mix lubricant tabletting according to a conventional method again； 6) carried out (when using high formability carbohydrate as adhesive such as maltose) under set point of temperature and damp condition warm and humid Balance Treatment (such as 25 DEG C of temperature, 75% humidification process of relative humidity about 20 it is small when, then with 30 DEG C of temperature, relative humidity 40% When heating about 3 is small).In the above-mentioned methods, step (1) is needed with substantial amounts of organic solvent such as methanol, and this technique is not It is environmental-friendly.In addition, step (5) gained tablet hardness requirement is very low, then carried out by step (6) at warm and humid balance It manages to improve tablet hardness, but this warm and humid Balance Treatment needs to spend the time of nearly one day, not only greatly reduces life Produce efficiency.In addition, in above-mentioned steps 4) in, using water-soluble high-molecular substance such as polyvinylpyrrolidone as bonding During agent or when using low melting point carbohydrate such as sucrose as adhesive, step 6) is not to carry out warm and humid Balance Treatment, and It is to make tablet experience such as 90~150 DEG C of high-temperature process 10~20 minutes, then is allowed to cool and is returned to room temperature environment, with this high temperature It handles to improve tablet hardness.It is adjusted due to needing extremely accurate temperature and humidity during warm and humid Balance Treatment tablet, high temperature Using very high temperature when handling tablet, this can all greatly increase the inoperable property of technique, and pass through this warm and humid balance Thus it is still uncertain that whether processing or high-temperature processing technology can bring other problems to tablet.Therefore, this field is still Expectation has new method to prepare the Orally disintegrating tablet with excellent pharmaceutical property.
In addition, dutasteride is 5 alpha reductase inhibitor of 2nd generation, it is that the first is also unique a kind of while inhibition I at present The drug of 5 alpha-reductase of type and II type, is researched and developed by Ge Lansu companies, and on October 10th, 2002 is by U.S.'s food and drug pipe Reason office (FDA) approval lists in the U.S., trade name Avodart, the trade name Avolve in European market, is capsule, 0.5mg/, daily 1 of adult, the course for the treatment of is usually 6 months.
Dutasteride is a kind of 4-Azasteroids compound of synthesis, entitled (5 α, 17 the β)-N- { 2,5- bis- of chemistry (trifluoromethyl) phenyl } -3- oxo -4- azepine androstane -1- alkene -17- formamides ((5 α, 17 β)-N- { 2,5-bis (trifluoromethyl) phenyl } -3-oxo-4-azaandrost-1-ene-17-carboxamide), molecular formula is C27H30F6N2O2, molecular weight 528.5, structural formula is as follows：
Dutasteride is a kind of white to pale powder, 242 ° to 250 DEG C of fusing point.It is dissolved in ethyl alcohol (44mg/mL), Methanol (64mg/mL) and polyethylene glycol 400 (3mg/mL), but it is not soluble in water.Dutasteride's absolute bioavailability is about 60% (floating in the scope of 40%-94%).10% to 15% is reduced with the maximum plasma concentration that food is taken simultaneously, is not had Significant difference clinically is consequently adapted to after meal or bfore meals.Clinical research shows that dutasteride can improve BPH diseases for a long time Shape reduces the generation of acute urinary retention, improves the quality of life of patient.
Meanwhile dutasteride also plays an important role of to reduce prostate canceration risk.Dutasteride can effectively reduce blood Middle prostate specific antigen (PSA) concentration, and high concentration PSA is the strong signal of prostate canceration.By taking dutasteride, The generation that many males can become to avoid prostate cancer, so as to reduce medical treatment cost and occur over the course for the treatment of various Adverse reaction.
The commercial dosage forms of dutasteride are soft capsule for oral use, and every capsule includes the dutasteride of 0.5mg active ingredients, Half-life period is 5 weeks.Although long half time, experiment display will not cause savings to be poisoned.
The tamsulosin hydrochloride and dutasteride's compound preparation released by Ge Lansu companies are in American market with trade name It is sold for the hard capsule of JALYN, every JALYN capsule includes：(1) opaque dark yellow of dutasteride's ellipse is soft Capsule (containing 0.5mg dutasterides and is dissolved in the mixture of BHT and octanoic acid/single-, two- glyceride of certain herbaceous plants with big flowers acid)；(2) it is white To off-white color tamsulosin hydrochloride piller, hydrochloric Tamsulosin 0.4mg, auxiliary material include methacrylic acid copolymer dispersion, Celluloasun Microcrystallisatum, talcum powder, triethyl citrate.
Due to containing dutasteride's soft capsule and substantial amounts of Tamsulosin piller, both materials in JALYN capsules The very differents such as size, mobility, when the two is carried out encapsulated, equipment requirement is very high.It is soft additionally, due to dutasteride Capsule is the soft capsule that content is oiliness, and preparation process is cumbersome.Furthermore JALYN target users are old man Property patient, capsule swallow inconvenience.
Therefore, this field is still expected to have new method to prepare the compound preparation comprising dutasteride and Tamsulosin.
The content of the invention
It is an object of the invention to provide a kind of new methods to prepare the Orally disintegrating tablet with excellent pharmaceutical property. Expect that one or more advantageous effects can be presented in this method, such as gained oral disintegrating tablet solution can realize the taste masking of active medicine And/or positioning discharges and/or controls the purpose of discharging, tablet hardness and disintegrating property are good, production efficiency is high, process operability The advantageous effect of the one or more aspects such as strong.And/or to expect that this oral disnitegration tablet can solve existing comprising dutasteride With the compound preparation of Tamsulosin existing for the above problem.
It is once a day administered in view of dutasteride's regular pharmaceutics can be realized, and Tamsulosin preferably uses enteric coated preparations Or sustained release preparation administration, therefore, the present inventor uses for reference the thinking of existing Tamsulosin Orally disintegrating sustained release tablets, by dutasteride Oral disnitegration tablet is prepared into together with both Tamsulosins, is realized and is simplified preparation process, reduce production equipment requirement, make compound system The agent gerontal patient that is more convenient for such as takes at the purposes of one or more aspects.It has been unexpectedly discovered that using the method for the present invention, By dutasteride and Tamsulosin, according to it, each desired release mode is respectively prepared piller, then by both pillers with it is other Auxiliary material mixing is pressed into oral disnitegration tablet, and expected drug release effect is not only presented in this oral disnitegration tablet, and tablet has There is excellent pharmacy performance.It finds and is accomplished the present invention is based on this.
For this purpose, first aspect present invention provides a kind of oral disnitegration tablet, it is the piece formed by tablet forming technique compacting Agent；The tablet includes the tablet matrix being made of multiple auxiliary materials and be essentially homogeneously scattered in the tablet matrix two Kind coating micro-pill；Described two coating micro-pills include the capsule core comprising two kinds of different activities ingredients and are covered in the capsule core respectively At least one layer of coating on surface.
In the present invention, term " pellet " is also referred to as particle.
It is well known that oral disnitegration tablet or for oral disintegrating tablet, appearance sheet is as conventional tablet form.The piece of the present invention Agent inside disperses, inlays there are two types of pellet, each pellet includes many pellets, it will therefore be appreciated that term " tablet of the present invention Matrix " refers to the part in addition to pellet in tablet.Formed should " tablet matrix " part material, refer to except the pellet it Outer all materials assign whole material shape piece agent forms and pellet structure will not be destroyed during tablet making technology.
The work of the oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the first coating micro-pill Property ingredient is Tamsulosin or its pharmaceutical salts.In one embodiment, the active ingredient of the first coating micro-pill is smooth Suo Luoxin or its pharmaceutical salts, the coating are one layer of sustained-release coating layer.In one embodiment, the first coating micro-pill is described Active ingredient is Tamsulosin or its pharmaceutical salts, and the coating is one layer of enteric coating layer.In one embodiment, the first is wrapped The active ingredient of clothing pellet is Tamsulosin or its pharmaceutical salts, described to include two layers, is sustained release respectively from inside to outside Clothing layer and enteric coating layer.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the work of second of coating micro-pill Property ingredient is dutasteride or its pharmaceutical salts.In one embodiment, the active ingredient degree of being of second of coating micro-pill His male amine or its pharmaceutical salts, the coating are thin film clothing layer.In one embodiment, second coating micro-pill is described Active ingredient is dutasteride or its pharmaceutical salts, and the coating is one layer of enteric coating layer.In one embodiment, second of bag The active ingredient of clothing pellet is dutasteride or its pharmaceutical salts, and the coating is one layer of sustained-release coating layer.In an embodiment party In case, the active ingredient of second of coating micro-pill is dutasteride or its pharmaceutical salts, described to include two layers, from introversion Outer is sustained-release coating layer and enteric coating layer respectively.
It is that Tamsulosin or its pharmaceutical salts and Du Ta are male respectively comprising two kinds of active components in the oral disnitegration tablet of the present invention Different coating micro-pills is respectively prepared in amine or its pharmaceutical salts, both active ingredients, for convenience, they is referred to as One pellet and the second pellet, between them first and second simply for description is facilitated for the sake of, have no precedence point.
The present invention is adding appropriate salt into the oral disnitegration tablet for inlay pellet to the outstanding contributions of the prior art in discovery Class can significantly improve the physical strength and disintegrating property of tablet.Hereafter some embodiments are confirmed including more the present invention The above-mentioned technique effect that oral disnitegration tablet obtained by the pellet of layer clothing layer is presented.The present inventor is in the experiment of supplement, it was found that Pellet used only has one layer of clothing layer (i.e. referring to these embodiments still when these realities when preparing oral disintegrating tablet with reference to these embodiments Apply that example is related to two layers or whens multiple coatings saves one or more layers coating therein and only wraps one layer of coating) when the mouth that is obtained collapse Above-mentioned beneficial technique effect can be also presented in piece.
In addition, in order to obtain the slow release effect for it is expected release profiles, such as a kind of drug therein or two kinds of medicines are obtained It is interior substantially in first order extended release or the releasing effect of Zero order controlled releasing when either 12 is small when object is when 4 is small, 8 is small, tune can be passed through The measures such as the thickness of sustained-release coating layer of a kind of whole drug or two kinds of drugs realize that this is easy to implement in pharmaceutical arts 's.
The work of the oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the first coating micro-pill Property ingredient is tamsulosin hydrochloride, and the active ingredient of second of coating micro-pill is dutasteride.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the weight of the first coating micro-pill Amount accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.In the present invention In Examples below 1-6, the appropriate ratio for changing coating micro-pill and sugar/sugar alcohol makes the first coating micro-pill amount account for Orally disintegrating When for example, about 5%, about 10%, about 15%, about 20%, about 25% in the range of the 5~25% of piece total weight, final gained oral disintegrating tablet Hardness, content uniformity, friability, hydroscopicity, disintegration time, dissolution rate, stability approached with these embodiment results, Without significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the weight of second of coating micro-pill Amount accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.In the present invention In Examples below 1-6, the appropriate ratio for changing coating micro-pill and sugar/sugar alcohol makes second of coating micro-pill amount account for Orally disintegrating When for example, about 5%, about 10%, about 15%, about 20%, about 25% in the range of the 5~25% of piece total weight, final gained oral disintegrating tablet Hardness, content uniformity, friability, hydroscopicity, disintegration time, dissolution rate, stability approached with these embodiment results, Without significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the active ingredient hydrochloric acid Tan Suoluo Pungent weight accounts for the 0.1~10% of the first coating micro-pill total weight, such as 0.1~5%.In Examples below of the present invention It is appropriate to change active ingredient and microcrystalline cellulose (or sucrose etc.) ratio to prepare the capsule core of different content and make activity in 1-6 The weight of ingredient tamsulosin hydrochloride accounts for the 0.1~10% such as 0.1~5% of the first the coating micro-pill total weight obtained below In the range of for example, about 0.1%, about 0.5%, about 1%, about 2%, about 5%, about 10% when, the hardness of final gained oral disintegrating tablet contains Amount uniformity, friability, hydroscopicity, disintegration time, dissolution rate, stability are approached with these embodiment results, without apparent area Not.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the active ingredient dutasteride Weight accounts for the 0.1~10% of second of coating micro-pill total weight, such as 0.1~5%.In Examples below 1-6 of the present invention In, it is appropriate to change active ingredient and microcrystalline cellulose (or sucrose etc.) ratio to prepare the capsule core of different content and make active ingredient The weight of dutasteride accounts for example in the range of the 0.1~10% such as 0.1~5% of second of the coating micro-pill total weight obtained below When such as from about 0.1%, about 0.5%, about 1%, about 2%, about 5%, about 10%, the hardness of final gained oral disintegrating tablet, content uniformity, Friability, hydroscopicity, disintegration time, dissolution rate, stability are approached with these embodiment results, no significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the first coating micro-pill is flat Equal grain size is 50~350 μm, such as 50~300 μm, such as 100~250 μm.In Examples below 1-6 of the present invention, suitably change Become capsule core size using obtain the average grain diameter of the first coating micro-pill as about 50 μm of 50~300 μ ms such as average grain diameter, about At 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm, hardness, content uniformity, the friability of final gained oral disintegrating tablet Degree, hydroscopicity, disintegration time, dissolution rate, stability are approached with these embodiment results, no significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein second of coating micro-pill is flat Equal grain size is 50~350 μm, such as 50~300 μm, such as 100~250 μm.In Examples below 1-6 of the present invention, suitably change Become capsule core size using obtain the average grain diameter of second of coating micro-pill as about 50 μm of 50~300 μ ms such as average grain diameter, about At 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm, hardness, content uniformity, the friability of final gained oral disintegrating tablet Degree, hydroscopicity, disintegration time, dissolution rate, stability are approached with these embodiment results, no significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein, the smooth rope of active ingredient hydrochloric acid Rosin is essentially homogeneously coated to be essentially homogeneously scattered in the capsule core in the capsule core surface or the active ingredient In, and then the pellet core is coated to obtain the first coating micro-pill.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein, the active ingredient dutasteride It is essentially homogeneously coated to be essentially homogeneously scattered in the capsule core in the capsule core surface or the active ingredient, And then the pellet core is coated to obtain second of coating micro-pill.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of the first coating micro-pill Core material is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, breast Sugar or lactose ball.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of second of coating micro-pill Core material is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, breast Sugar or lactose ball.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the first described coating micro-pill and/ Or the capsule core of second of coating micro-pill is microcrystalline cellulose capsule core or sucrose ball.It has been found that the selection of capsule core material not shadow The implementation of the present invention is rung, such as in Examples below 1-6 of the present invention, when will be as the microcrystalline cellulose of capsule core in initial step When element is changed to sucrose ball or sucrose, every physicochemical property and embodiment 1-6 tablets and the indifference of gained oral disnitegration tablet.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of the first coating micro-pill Core is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is essentially homogeneously coated in the capsule core surface.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of second of coating micro-pill Core is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously coated in the capsule core surface.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of the first coating micro-pill Core is microcrystalline cellulose capsule core, after the active ingredient hydrochloric acid Tamsulosin with adhesive by being compounded into solution or suspension, It is essentially homogeneously coated in the capsule core surface.In one embodiment, in the solvent for preparing the solution or suspension Do not include organic solvent.In one embodiment, the solvent for preparing the solution or suspension is water.According to the present invention first The oral disnitegration tablet of aspect any embodiment, wherein the capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, institute It is essentially homogeneously coated in the capsule core after active ingredient dutasteride is stated by being compounded into solution or suspension with adhesive Surface.In one embodiment, preparing does not include organic solvent in the solvent of the solution or suspension.In an embodiment party In case, the solvent for preparing the solution or suspension is water.It has been unexpectedly discovered that ought be using water in above process When preparing the solvent of binder solution or suspension, than it in using organic solvent methanol or methanol-water mixtures as molten The situation of agent, obtained pellet core have significantly better active component content uniformity.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of the first coating micro-pill Core is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is distributed substantially uniformly through inside the capsule core.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of second of coating micro-pill Core is microcrystalline cellulose capsule core, and the active ingredient dutasteride is distributed substantially uniformly through inside the capsule core.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein the ball of the first coating micro-pill Core is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is distributed substantially uniformly through inside the capsule core；Institute It states active ingredient hydrochloric acid Tamsulosin and adds the solution containing adhesive or suspension after mixing with microcrystalline cellulose to stir It mixes comminution granulation or capsule core is made in fluidized bed prilling method；Alternatively, addition contains active ingredient hydrochloric acid Tan Suoluo into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in pungent and adhesive solution or suspension.In one embodiment, Preparing does not include organic solvent in the solvent of the solution or suspension.In one embodiment, the solution or mixed is prepared The solvent of suspension is water.The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein second of coating The capsule core of pellet is microcrystalline cellulose capsule core, and the active ingredient dutasteride is distributed substantially uniformly through in the capsule core Portion；The active ingredient dutasteride adds the solution containing adhesive or suspension with microcrystalline cellulose to stir after mixing It mixes comminution granulation or capsule core is made in fluidized bed prilling method；Alternatively, into microcrystalline cellulose addition containing active ingredient dutasteride and Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of adhesive.In one embodiment, prepare Do not include organic solvent in the solvent of the solution or suspension.In one embodiment, the solution or suspension are prepared Solvent be water.It has been unexpectedly discovered that ought the use of water be in above process to prepare binder solution or suspension During solvent, than it in using the situation of organic solvent methanol or methanol-water mixtures as solvent, obtained pellet core has There is significantly better active component content uniformity.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein being used to prepare described two capsule cores It is polymer substance that described adhesive is each independent, is, for example, water-soluble high-molecular substance, such as fine selected from hydroxypropyl methyl Dimension element, hydroxypropyl cellulose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol, and combinations thereof.Certainly, above-mentioned macromolecule Substance can also be as the adhesive of other steps.It is well known that the dosage of such adhesive can be according to art technology The experience of personnel and the introduction of textbook are easily adjusted, such as the weight of adhesive can be the 1~10% of capsule core weight, example Weight such as adhesive can be the 1~7.5% of capsule core weight, for example, adhesive weight can be capsule core weight 1~ 5%.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein described two coating micro-pill surfaces At least one layer coating is each independently selected from：Film-coating, enteric coating, clothing soluble in the stomach, extended release coatings, controlled release clothing and combinations thereof.For appointing A kind of coating micro-pill, when it uses multiple coatings, clothing layer order can determine due to different purposes.For example, it is desired in stomach In do not dissolve but when needing the requirement slowly discharged in intestinal juice, can be first in pellet core surface bundled slow-releasing clothing layer, then Wrap up one layer of enteric coating layer again outside sustained-release coating layer.In another example when need cover adverse drug taste need again in gastro-intestinal Fluid In slowly discharge requirement when, can be in pellet core surface bundled slow-releasing clothing layer, you can realize this purpose.
Film-coating is well known to those skilled in the art.Illustrative film-coating filmogen is such as, but not limited to hydroxypropyl Methylcellulose, hydroxypropyl cellulose, methyl hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyethylene glycol Deng.
Enteric coating is well known to those skilled in the art.Illustrative enteric coating filmogen is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly L, S type.
Clothing soluble in the stomach is well known to those skilled in the art.Illustrative clothing filmogen soluble in the stomach is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly E types.
Extended release coatings and controlled release clothing are well known to those skilled in the art.Illustrative extended release coatings and controlled release clothing filmogen are most To be typically ethyl cellulose.
Some additives are added in coating material to adapt to specifically coating requirement, this is those skilled in the art according to warp Test what can easily be determined.Such as plasticizer, colorant and screening agent etc. can be added in coating solution.
For the present invention when being coated to any one or two kinds of coating micro-pill surfaces, the solvent in coating solution can be had Machine is molten or water either its mixed liquor.In one embodiment, organic solvent is not included in the solvent in coating solution.One In a embodiment, the solvent in coating solution is water.
It is it is known in the art that typically that capsule core and its coating, which are prepared, with the preparation method for obtaining coating micro-pill of the present invention Using the granulation of fluidized bed principle, art for coating, such as the preparation method for the sustained-release microparticle being recorded in CN1473035B. It is well known that the amount of the clothing layer in capsule core surface package, it can be according to the experience of those skilled in the art and the religion of textbook It leads and is easily adjusted, such as the weight of clothing layer can be the 1~20% of capsule core weight, such as the weight of clothing layer can be capsule core weight The 1~15% of amount, such as the weight of clothing layer can be the 1~10% of capsule core weight.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein prepare it is described any one or two During kind of coating micro-pill, using only water without using organic solvent as preparation binder solution or the solvent of coating solution.Although CN1473035B introductions present invention discover that are had using methanol and the mixed solvent of a small amount of water using water without organic solvent There is better processing performance.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the auxiliary material of the tablet matrix Excipient including being selected from following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, maltose, trehalose, sorbierite, malt Sugar alcohol, xylitol, erythrite, glucose, and combinations thereof.It is preferable to use above-mentioned one or more sugar for particularly this excipient And/or the combination of sugar alcohol.It is well known that tablet is too small to increase film-making difficulty；But because saliva amount is few, the meeting when tablet is excessive Influence disintegration effect and mouthfeel.Typically, for every active ingredient below 30mg tablet, by oral disnitegration tablet Piece is controlled again in 60~600mg, particularly 75~500mg, and particularly 100~500mg is than more preferably.Therefore, in this hair In a bright embodiment, the piece of oral disnitegration tablet of the present invention is 60~600mg again, particularly 75~500mg, particularly 100~500mg.Since the main material in oral disnitegration tablet is excipient, dosage of the excipient in oral disnitegration tablet It can be added as the amount of balancing patch weight, such as to be similar to " amount for adding to tablet weight ", " in right amount, add to tablet full weight Amount ", " appropriate, the mg " etc. that piece made to weigh ... or other similar form of presentation, meaning are equal to above-mentioned " as balancing patch The amount addition of weight (reaching ... mg) ".
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the auxiliary material of the tablet matrix Including adhesive.In one embodiment, adhesive used is identical when described adhesive can be with preparing coating micro-pill. In one embodiment, described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol.Especially it is possible to it is making , will be a certain or several part or all of in the sugar or sugar alcohol as excipient during standby tablet, solution is prepared with water to make For adhesive, with binder solution wet granular after then coating micro-pill is mixed with excipient.Forming the tablet matrix Preparation process in the dosage of adhesive added can be easy according to the experience of those skilled in the art and the introduction of textbook Ground adjusts, such as the weight of the adhesive can be the 1~20% of Orally disintegrating sheet weight, such as the weight of the adhesive can be with It is the 2~15% of Orally disintegrating sheet weight, such as the weight of the adhesive can be the 3~12% of Orally disintegrating sheet weight. In Examples below 1-6 of the present invention, the adhesive for forming the tablet matrix is changed to using hydroxypropyl cellulose, hydroxypropyl methyl It is obtained whens cellulose, sorbierite or xylitol etc., and when the adhesive additive amount is 3~12% scope of oral disintegrating tablet weight The hardness of oral disintegrating tablet, content uniformity, friability, hydroscopicity, disintegration time, dissolution rate, stability with these embodiments As a result approach, no significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the bonding of the tablet matrix Agent is selected from following one or more：Maltose, trehalose, D-sorbite, maltitol, glucose, xylitol, red moss Alcohol, mannitol, sucrose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copolyvidone or poly- second Enol.No matter it has been found that using which kind of above-mentioned adhesive, appropriate salt is added into the matrix of oral disintegrating tablet using the method for the present invention Class can be directly compressed into the tablet of desired hardness and with excellent disintegrating property, and is not required to during this film-making It will first with low-pressure tabletting and then again humidified-dry or high temperature-cooling treatment as prior art.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the auxiliary material of the tablet matrix It may also include disintegrant.Typical disintegrant is such as, but not limited to：Cornstarch, carboxymethylcellulose calcium, pregelatinized starch, crosslinking Polyvinylpyrrolidone, sodium starch glycollate, croscarmellose sodium crospovidone, low substitution degree hydroxy-propyl fiber Element etc..The dosage of the disintegrant added in the preparation process for forming the tablet matrix can be according to those skilled in the art's The introduction of experience and textbook is easily adjusted, such as the weight of the disintegrant can be the 1~20% of Orally disintegrating sheet weight, Such as the weight of the disintegrant can be the 1~15% of Orally disintegrating sheet weight, such as the weight of the disintegrant can be oral cavity It is disintegrated the 2~10% of sheet weight.In the Examples below 1-6 of the present invention, the 2~10% of Orally disintegrating sheet weight is suitably added It is obtained when above-mentioned disintegrant cornstarch, carboxymethylcellulose calcium, crosslinked polyvinylpyrrolidone or sodium starch glycollate The hardness of oral disintegrating tablet, content uniformity, friability, hydroscopicity, disintegration time, dissolution rate, stability with these embodiments As a result approach, no significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the auxiliary material of the tablet matrix It may also include the additives such as sweetener, colorant.The sweetener that is added in the preparation process for forming the tablet matrix, coloring The dosage of the additives such as agent can be easily adjusted according to the experience of those skilled in the art and the introduction of textbook, such as the sweet tea The weight of the additives such as taste agent, colorant can be the 0.1~5% of Orally disintegrating sheet weight independently, such as the sweet taste The weight of the additives such as agent, colorant can be the 0.2~2.5% of Orally disintegrating sheet weight independently, such as the sweet taste The weight of the additives such as agent, colorant can be the 0.5~2% of Orally disintegrating sheet weight independently.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the auxiliary material of the tablet matrix It further includes selected from following salt：Sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid hydrogen two Potassium, and combinations thereof.The present inventor it has been unexpectedly discovered that when into tablet matrix add appropriate amount above-mentioned salt when, The tablet with excellent hardness and friability index can be not only directly obtained by wet granule compression tablet method without carrying out Prolonged humiture Balance Treatment or excessive temperature processing, and this hardness and friability index have excellent stabilization Property, more valuable, on the premise of with excellent hardness and friability index, Tablets have excellent disintegrative Energy.Present invention determine that the dosage of the salt added in the preparation process for forming the tablet matrix, particularly, the salt Weight can be the 1~15% of Orally disintegrating sheet weight, for example, the salt weight can be Orally disintegrating sheet weight 2~ 10%, such as the weight of the salt can be the 2.5~10% of Orally disintegrating sheet weight.In Examples below 1-6 of the present invention, Add above-mentioned each salt and weight be adjusted in 2~10% scope of Orally disintegrating sheet weight, obtained oral disintegrating tablet it is hard Degree, content uniformity, friability, hydroscopicity, disintegration time, dissolution rate, stability are approached with these embodiment results, without bright Aobvious difference.When finding the effect of above-mentioned salt in Tablets, it is (such as organic that the present inventor attempts to use instead other salts Salt such as sodium citrate, such as calcium salt such as calcium sulfate, calcium carbonate and calcium monohydrogen phosphate) when find that they cannot obtain such as this hair Bright salt mentioned above improves tablet strength and does not influence the effect of disintegration.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the auxiliary material of the tablet matrix It may also include lubricant.Lubricant containing convention amount is for tablet appearance and prevents that sticking from being beneficial.Workable lubrication Agent is selected from：Magnesium stearate, calcium stearate, sucrose fatty ester, polyethylene glycol, talcum powder, stearic acid etc. and combinations thereof.It is being formed The dosage of the lubricant added in the preparation process of the tablet matrix can be according to the experience of those skilled in the art and religion section The introduction of book is easily adjusted, such as the weight of the lubricant can be the 0.5~10% of Orally disintegrating sheet weight, such as the profit The weight of lubrication prescription can be the 0.5~5% of Orally disintegrating sheet weight, such as the weight of the lubricant can be oral disnitegration tablet weight The 0.5~2% of amount.In Examples below 1-6 of the present invention, it is Orally disintegrating sheet weight to add above-mentioned each lubricant and weight During 0.5~2% scope, the hardness of obtained oral disintegrating tablet, content uniformity, friability, hydroscopicity, disintegration time, dissolution rate, Stability is approached with these embodiment results, no significant difference.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, wherein forming the auxiliary material of the tablet matrix Including：Excipient, adhesive, salt, lubricant.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is the method by including the following steps It is prepared：Two kinds of coating micro-pills made from the difference are mixed with excipient, it is mixed to this using fluidized bed granulation process Close sprayed into material binder solution make wet granular and drying (well known to medicament manufacturing field technical staff, typically, The dry moisture caused in material is less than 5%, especially less than 4%, especially less than 3%), into gained dry particle Lubricant is added, is uniformly mixed, tabletting.In one embodiment, when it is present, the salt can by with excipient The mode mixed together with coating micro-pill is added.In one embodiment, when it is present, the salt can pass through addition Mode into binder solution is added.In one embodiment, when it is present, the salt is in addition lubricant What the stage added in the form of a powder.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is the method by including the following steps It is prepared：Binder solution is sprayed into using fluidized bed granulation process into excipient to carry out making wet granular and drying (medicament It is typically, dry so that the moisture in material is less than 5%, especially less than well known to manufacturing field technical staff 4%, especially less than 3%), into gained dry particle, two kinds of coating micro-pills and lubricant, mixing are equal made from addition difference It is even, tabletting.In one embodiment, when it is present, the salt can be by preparing particle after being mixed with excipient Mode is added.In one embodiment, when it is present, the salt can be by way of being added in binder solution Addition.In one embodiment, when it is present, the salt was added in the form of a powder in the stage of addition lubricant 's.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 The then regulation under " 0921 disintegration time limited inspection technique " and " oral disintegrating tablet " item therein, the disintegration time limited that replication is 6,6 It was all disintegrated in 60 seconds and passes through sieve；Particularly 6 were all disintegrated in 45 seconds and pass through sieve；Particularly 6 It was all disintegrated in 30 seconds and passes through sieve.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 The then friability of the method measure tablet under " 0923 tablet friability inspection technique " item, no fracture, cracking and the piece crushed, and Less loss weight is less than 3%, is, for example, less than 2%, is, for example, less than 1.5%, is, for example, less than 1%.Above-mentioned " less loss weight " usually also may be used Referred to as " wear intensity ".
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention, according to United States Pharmacopeia USP35-NF30 editions "< 1217>The method of TABLET BREAKING FORCE " measures the hardness of tablet, value in the range of 3~6kg, such as 4~ In the range of 6kg.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention measures its hydroscopicity according to following method, Hydroscopicity (is, for example, less than 15%, is, for example, less than 12.5%, be, for example, less than 10%) less than 20%：Take 5.0~5.5g's of total weight Tablet, precise weighing；Make it flat auxiliary and expose to the open air 25 DEG C of temperature, 75% condition of relative humidity assign 24 it is small when, precise weighing；It presses Following formula calculates hydroscopicity：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%.
Since the first active medicine tamsulosin hydrochloride of the present invention preferably makes it slowly be discharged in intestines, It is preferred to wrap up enteric slow release clothing.Therefore：
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 Then the 3rd method of " 0931 dissolution rate with drug release determination method ", using acid medium (water and with salt acid for adjusting pH value 1.2) 250ml as Dissolution medium carries out Dissolution Rate Testing, and 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate is less than 20% in 15 minutes, example Such as less than 15%；
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 Then the 3rd method of " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium phosphate soln of 0.02mol/L is used in combination Phosphoric acid is adjusted to pH6.8) 250ml for dissolution medium carry out Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution Degree reach 30% measure after present dissolution test starts 0.25~4 it is small when during, particularly 0.5~3 it is small when during；
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 Then the 3rd method of " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium phosphate soln of 0.02mol/L is used in combination Phosphoric acid is adjusted to pH6.8) 250ml for dissolution medium carry out Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution Degree reach 50% measure after present dissolution test starts 0.5~8 it is small when during, particularly 0.75~6 it is small when during；
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 Then the 3rd method of " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium phosphate soln of 0.02mol/L is used in combination Phosphoric acid is adjusted to pH6.8) 250ml for dissolution medium carry out Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution Degree reach 80% measure after present dissolution test starts 1~12 it is small when during, particularly 1.5~9 it is small when during；And/or
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 Then the 3rd method of " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium phosphate soln of 0.02mol/L is used in combination Phosphoric acid is adjusted to pH6.8) 250ml for dissolution medium carry out Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution Degree reach 30% measure after present dissolution test starts 0.25~4 it is small when during when small (particularly 0.5~3 during), salt Sour Tamsulosin dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when during (particularly 0.75~ 6 it is small when during), tamsulosin hydrochloride dissolution rate reach 80% measure after present dissolution test starts 1~12 it is small when during When small (particularly 1.5~10 during).
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is contacted in the material with the tablet matrix Preceding the first coating micro-pill (i.e. tamsulosin hydrochloride coating micro-pill, after each layer coating is completed, carry out it is subsequent State before non-coated operating procedure), according to Chinese Pharmacopoeia version in 2015 four general rules " 0931 dissolution rate and drug release determinations 3rd method of method ", using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml to be molten Go out medium and carry out Dissolution Rate Testing, 50 revs/min of rotating speed, the tamsulosin hydrochloride in the neutral dissolution medium of pH value 6.8 Dissolution rate is shown as 30%, 50%, 80% each time point, the dissolution rate of the first coating micro-pill and the salt of oral disnitegration tablet The absolute value of the difference of sour Tamsulosin dissolution rate is in the range of 0-15%, particularly in the range of 0-12.5%.During above three Between put tamsulosin hydrochloride dissolution rate difference between the first coating micro-pill and oral disnitegration tablet, can claim respectively in the present invention For tamsulosin hydrochloride 30% dissolution it is poor, 50% dissolution it is poor, 80% dissolve out it is poor or be referred to as 3 points of dissolutions it is poor ( It is so that this 30% dissolution is poor, 50% dissolution is poor, the order of the poor three of 80% dissolution when mentioning them simultaneously in invention context It lists).This 3 points dissolution differences can be used for reflecting that the tamsulosin hydrochloride between coating micro-pill and its final tablet is molten Out-degree behavioral difference reflects the influence to pellet tamsulosin hydrochloride dissolved corrosion in coating micro-pill subsequent technique processing procedure.
Since second of active medicine dutasteride of the present invention should not discharge in the oral cavity, preferably make its It discharges in stomach or in intestines, is more preferably discharged in intestines, therefore, the coating of second of coating micro-pill enables to dutasteride not Discharge in the oral cavity either second of coating micro-pill coating enable to dutasteride discharge under one's belt or second bag The coating of clothing pellet enables to dutasteride to be discharged in intestines.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is logical according to Chinese Pharmacopoeia version four in 2015 Then the 3rd method of " 0931 dissolution rate and drug release determination method ", using water 250ml as dissolution medium, 50 revs/min of rotating speed, at 15 points Dutasteride's dissolution rate is less than 20% in clock, is, for example, less than 15%.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention is contacted in the material with the tablet matrix (i.e. coating micro-pill is after each layer coating is completed, before subsequent non-coated operating procedure is carried out for the preceding coating micro-pill State), according to the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time point, the dissolution rate and oral disnitegration tablet of coating micro-pill Dissolution rate absolute value of the difference in the range of 0-15%, particularly in the range of 0-12.5%.Above-mentioned time point coating micro-pill Dissolution rate difference between oral disnitegration tablet can be referred to as dutasteride 50% and dissolve out difference in the present invention.This dissolution is poor It is different to can be used for reflecting dutasteride's dissolution rate behavioral difference between coating micro-pill and its final tablet, reflect coating micro-pill To the influence of dutasteride's dissolved corrosion in pellet in subsequent technique processing procedure.
The oral disnitegration tablet of any embodiment according to a first aspect of the present invention substantially shines what is included the following steps What method was prepared：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described activity Ingredient is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made； Make second active ingredient is essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially It is homogeneously dispersed in the capsule core, then gained pellet core is coated, second of coating micro-pill is made；
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting.[ In one example, the auxiliary material for forming the tablet matrix includes excipient, salt, adhesive, lubricant etc.]
The oral disnitegration tablet of any embodiment, wherein step ii according to a first aspect of the present invention) it is held according to following operation Row：
Iia) described two coating micro-pills with excipient are mixed, are sprayed using fluidized bed granulation process into the mixed material Enter binder solution to carry out making wet granular and drying, lubricant is added into gained dry particle, be uniformly mixed, tabletting；Wherein, The salt can be added by way of being mixed together with excipient with coating micro-pill or the salt can pass through The mode being added in binder solution is added or the salt was added in the form of a powder in the stage of addition lubricant Add.
The oral disnitegration tablet of any embodiment, wherein step ii according to a first aspect of the present invention) it is held according to following operation Row：
Iib) spray into binder solution into excipient using fluidized bed granulation process to carry out making wet granular and drying, to institute It obtains and two kinds of coating micro-pills and lubricant is added in dry particle, be uniformly mixed, tabletting；Wherein, the salt can by with The mode that particle is prepared after excipient mixing is added or the salt can be by way of being added in binder solution Addition or the salt were added in the form of a powder in the stage of addition lubricant.
Above-mentioned iia) and iib) two kinds of modes for mixing coating micro-pill with excipient, the present inventor carry out respectively Verification, it is found that the oral disnitegration tablet properties obtained by both hybrid modes are no difference, particularly excellent in imparting tablet The aspect of performance such as different physical strength and quick disintegration effect are no difference.In addition, the present invention, which has been verified that, passes through system Salt is incorporated into the performance of gained tablet in the particulate matter comprising excipient by grain technique；Further, the present inventor is also mending It is demonstrated in the experiment filled and adds in final stage of the salt before tabletting, that is, adding the stage of lubricant in the form of a powder Addition, it has been found that, salt is added to intragranular mode gained tablet properties and had no by this addition manner with above-mentioned Difference.
Further, second aspect of the present invention provides a kind of method for preparing oral disnitegration tablet, and this method passes through tabletting Technique suppresses oral disnitegration tablet；The tablet includes the tablet matrix being made of multiple auxiliary materials and is essentially homogeneously scattered in Two kinds of coating micro-pills in the tablet matrix；Described two coating micro-pills include the capsule core for including two kinds of different activities ingredients respectively And it is covered at least one layer of coating on the capsule core surface.
The method of any embodiment according to a second aspect of the present invention, includes the following steps：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described activity Ingredient is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made； Make second active ingredient is essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially It is homogeneously dispersed in the capsule core, then gained pellet core is coated, second of coating micro-pill is made；
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting.[ In one example, the auxiliary material for forming the tablet matrix includes excipient, salt, adhesive, lubricant etc.]
The method of any embodiment, wherein step ii according to a second aspect of the present invention) it is performed according to following operation：
Iia) described two coating micro-pills with excipient are mixed, are sprayed using fluidized bed granulation process into the mixed material Enter binder solution to carry out making wet granular and drying, lubricant is added into gained dry particle, be uniformly mixed, tabletting；Or
Iib) spray into binder solution into excipient using fluidized bed granulation process to carry out making wet granular and drying, to institute It obtains and two kinds of coating micro-pills and lubricant is added in dry particle, be uniformly mixed, tabletting.
The active ingredient of the method for any embodiment according to a second aspect of the present invention, wherein the first coating micro-pill It is Tamsulosin or its pharmaceutical salts.In one embodiment, the active ingredient of the first coating micro-pill is Tamsulosin Or its pharmaceutical salts, the coating are one layer of sustained-release coating layer.In one embodiment, the first coating micro-pill it is described activity into It is Tamsulosin or its pharmaceutical salts to divide, and the coating is one layer of enteric coating layer.In one embodiment, the first coating micro-pill The active ingredient be Tamsulosin or its pharmaceutical salts, it is described to include two layers, be respectively from inside to outside sustained-release coating layer and Enteric coating layer.
The method of any embodiment according to a second aspect of the present invention, wherein the active ingredient of second of coating micro-pill It is dutasteride or its pharmaceutical salts.In one embodiment, the active ingredient of second of coating micro-pill is dutasteride Or its pharmaceutical salts, the coating are thin film clothing layer.In one embodiment, the activity of second coating micro-pill into It is dutasteride or its pharmaceutical salts to divide, and the coating is one layer of enteric coating layer.In one embodiment, second of coating micro-pill The active ingredient be dutasteride or its pharmaceutical salts, the coating is one layer of sustained-release coating layer.In one embodiment, The active ingredient of two kinds of coating micro-pills is dutasteride or its pharmaceutical salts, described to include two layers, is distinguished from inside to outside It is sustained-release coating layer and enteric coating layer.
Active ingredient in the method for any embodiment according to a second aspect of the present invention, wherein the first coating micro-pill is Tamsulosin hydrochloride, the active ingredient in second of coating micro-pill is dutasteride.
The method of any embodiment according to a second aspect of the present invention, wherein the weight of the first coating micro-pill accounts for this The 5~50% of oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.
The method of any embodiment according to a second aspect of the present invention, wherein the weight of second of coating micro-pill accounts for this The 5~50% of oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.
The method of any embodiment according to a second aspect of the present invention, wherein the weight of the active ingredient hydrochloric acid Tamsulosin Amount accounts for the 0.1~10% of the first coating micro-pill total weight, such as 0.1~5%.
The method of any embodiment according to a second aspect of the present invention, wherein the weight of the active ingredient dutasteride accounts for The 0.1~10% of second of coating micro-pill total weight, such as 0.1~5%.
The method of any embodiment according to a second aspect of the present invention, wherein the average grain diameter of the first coating micro-pill For 50~350 μm, such as 50~300 μm, such as 100~250 μm.
The method of any embodiment according to a second aspect of the present invention, wherein the average grain diameter of second of coating micro-pill For 50~350 μm, such as 50~300 μm, such as 100~250 μm.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core material of the first coating micro-pill Selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, lactose or breast Sugar ball.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core material of second of coating micro-pill Selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, lactose or breast Sugar ball.
The method of any embodiment according to a second aspect of the present invention, wherein the first described coating micro-pill and/or second The capsule core of kind coating micro-pill is microcrystalline cellulose capsule core or sucrose ball.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are essentially homogeneously coated in the capsule core surface.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are essentially homogeneously coated in the capsule core surface.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, after the active ingredient hydrochloric acid Tamsulosin with adhesive by being compounded into solution or suspension, substantially It is equably coated in the capsule core surface.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, after the active ingredient dutasteride with adhesive by being compounded into solution or suspension, substantially uniformly Ground is coated in the capsule core surface.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are distributed substantially uniformly through inside the capsule core.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are distributed substantially uniformly through inside the capsule core.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are distributed substantially uniformly through inside the capsule core；The activity Ingredient tamsulosin hydrochloride adds the solution containing adhesive or suspension with stirring-granulating after mixing with microcrystalline cellulose Capsule core is made in method or fluidized bed prilling method；Alternatively, addition containing active ingredient hydrochloric acid Tamsulosin and is glued into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of mixture.
The method of any embodiment according to a second aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are distributed substantially uniformly through inside the capsule core；The active ingredient Dutasteride adds the solution containing adhesive or suspension with stirring-granulating method or fluidisation after mixing with microcrystalline cellulose Capsule core is made in bed comminution granulation；Alternatively, into microcrystalline cellulose add the solution containing active ingredient dutasteride and adhesive or Capsule core is made with stirring-granulating method or fluidized bed prilling method in suspension.
The method of any embodiment according to a second aspect of the present invention, wherein being used to prepare the described viscous of described two capsule cores It is polymer substance that mixture is each independent, is, for example, water-soluble high-molecular substance, such as selected from hydroxypropyl methyl cellulose, hydroxyl Propyl cellulose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol, and combinations thereof.Certainly, above-mentioned polymer substance also may be used Using the adhesive as other steps.
The method of any embodiment according to a second aspect of the present invention, wherein at least one layer of bag on the coating micro-pill surface Clothing is selected from：Film-coating, enteric coating, clothing soluble in the stomach, extended release coatings, controlled release clothing and combinations thereof.When using multiple coatings, clothing layer order can With because being determined during different purposes.For example, it is desired to when not dissolving under one's belt but needing the requirement slowly discharged in intestinal juice, it can be with First in pellet core surface bundled slow-releasing clothing layer, one layer of enteric coating layer is then wrapped up again outside sustained-release coating layer.In another example when need It, can be in pellet core surface bundled slow-releasing covering adverse drug taste needs the requirement slowly discharged in gastro-intestinal Fluid again when Clothing layer, you can realize this purpose.
Film-coating is well known to those skilled in the art.Illustrative film-coating filmogen is such as, but not limited to hydroxypropyl Methylcellulose, hydroxypropyl cellulose, methyl hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyethylene glycol Deng.
Enteric coating is well known to those skilled in the art.Illustrative enteric coating filmogen is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly L, S type.
Clothing soluble in the stomach is well known to those skilled in the art.Illustrative clothing filmogen soluble in the stomach is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly E types.
Extended release coatings and controlled release clothing are well known to those skilled in the art.Illustrative extended release coatings and controlled release clothing filmogen are most To be typically ethyl cellulose.
Some additives are added in coating material to adapt to specifically coating requirement, this is those skilled in the art according to warp Test what can easily be determined.Such as plasticizer, colorant and screening agent etc. can be added in coating solution.
It is it is known in the art that typically that capsule core and its coating, which are prepared, with the preparation method for obtaining coating micro-pill of the present invention Using the granulation of fluidized bed principle, art for coating, such as the preparation method for the sustained-release microparticle being recorded in CN1473035B. It is well known that the amount of the clothing layer in capsule core surface package, it can be according to the experience of those skilled in the art and the religion of textbook It leads and is easily adjusted, such as the weight of clothing layer can be the 1~20% of capsule core weight, such as the weight of clothing layer can be capsule core weight The 1~15% of amount, such as the weight of clothing layer can be the 1~10% of capsule core weight.
The method of any embodiment according to a second aspect of the present invention wherein when preparing the coating micro-pill, is used only Water and without using organic solvent as the solvent for preparing binder solution or coating solution.Although CN1473035B introductions use first The mixed solvent of alcohol and a small amount of water, however present invention discover that there is better processing performance without organic solvent using water.
The method of any embodiment according to a second aspect of the present invention, wherein forming the auxiliary material of the tablet matrix includes choosing From the excipient of following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, maltose, trehalose, sorbierite, maltitol, wood Sugar alcohol, erythrite, glucose, and combinations thereof.It is preferable to use above-mentioned one or more sugar and/or sugar alcohols for particularly this excipient Combination.
The method of any embodiment according to a second aspect of the present invention, wherein the auxiliary material for forming the tablet matrix includes gluing Mixture.In one embodiment, adhesive used is identical when described adhesive can be with preparing coating micro-pill.At one In embodiment, described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol.Especially it is possible to preparing tablet When, it will be a certain or several part or all of in the sugar or sugar alcohol as excipient, solution is prepared using as bonding by the use of water Agent, with binder solution wet granular after then coating micro-pill is mixed with excipient.
The method of any embodiment according to a second aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include disintegrant.Typical disintegrant is such as, but not limited to：Cornstarch, carboxymethylcellulose calcium, pregelatinized starch, crosslinked polyethylene Pyrrolidones, sodium starch glycollate, croscarmellose sodium crospovidone, low degree of substitution hydroxypropyl cellulose etc..
The method of any embodiment according to a second aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include the additives such as sweetener, colorant.
The method of any embodiment according to a second aspect of the present invention, wherein the auxiliary material for forming the tablet matrix further includes Selected from following salt：Sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and its Combination.
The method of any embodiment according to a second aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include lubricant.Lubricant containing convention amount is for tablet appearance and prevents that sticking from being beneficial.Workable lubricant is selected from： Magnesium stearate, calcium stearate, sucrose fatty ester, polyethylene glycol, talcum powder, stearic acid etc. and combinations thereof.
The method of any embodiment according to a second aspect of the present invention, wherein forming the auxiliary material of the tablet matrix includes： Excipient, adhesive, salt, lubricant.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet are by including the following steps Method be prepared：Two kinds of coating micro-pills made from the difference with excipient are mixed, use fluidized bed granulation process Binder solution is sprayed into the mixed material to carry out making wet granular and drying, is added lubricant into gained dry particle, is mixed Close uniform, tabletting.In one embodiment, when it is present, the salt can be by micro- with coating together with excipient The mode of ball mixing is added.In one embodiment, when it is present, the salt can be by being added to binder solution In mode add.In one embodiment, when it is present, the salt is the stage in addition lubricant with powder Form addition.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet are by including the following steps Method be prepared：Binder solution is sprayed into using fluidized bed granulation process into excipient to carry out making wet granular and do Dry, into gained dry particle, two kinds of coating micro-pills and lubricant made from addition difference, are uniformly mixed, tabletting.In a reality It applies in scheme, when it is present, the salt can be added by way of preparing particle after being mixed with excipient.In a reality It applies in scheme, when it is present, the salt can be added by way of being added in binder solution.In an embodiment party In case, when it is present, the salt was added in the form of a powder in the stage of addition lubricant.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 Regulation under four general rules " 0921 disintegration time limited inspection technique " and " oral disintegrating tablet " item therein, the disintegration time limited that replication is 6, 6 were all disintegrated in 60 seconds and pass through sieve；Particularly 6 were all disintegrated in 45 seconds and pass through sieve；Particularly 6 Piece was all disintegrated in 30 seconds and passes through sieve.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 Method under four general rule " 0923 tablet friability inspection technique " items measures the friability of tablet, no fracture, cracking and crushing Piece, and less loss weight is less than 3%, is, for example, less than 2%, is, for example, less than 1.5%, is, for example, less than 1%.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine United States Pharmacopeia USP35- NF30 editions "<1217>The method of TABLET BREAKING FORCE " measures the hardness of tablet, and value is in the range of 3~6kg, example Such as in the range of 4~6kg.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet measure its suction according to following method Wet rate, hydroscopicity (are, for example, less than 15%, are, for example, less than 12.5%, be, for example, less than 10%) less than 20%：Take total weight 5.0~ 5.5g tablet, precise weighing；Make it flat auxiliary and expose to the open air 25 DEG C of temperature, 75% condition of relative humidity assign 24 it is small when, it is accurate It weighs；Hydroscopicity is calculated as follows：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with acid medium (water and with salt acid for adjusting pH value 1.2) 250ml carries out Dissolution Rate Testing for dissolution medium, and 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate is less than in 15 minutes 20%, it is, for example, less than 15%.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when during, particularly 0.5~3 small period Between.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when during, particularly 0.75~6 small period Between.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 80% measure after present dissolution test starts 1~12 it is small when during, particularly 1.5~9 it is small when during.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when during (particularly 0.5~3 small period Between), tamsulosin hydrochloride dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when during (particularly 0.75~6 it is small when during), tamsulosin hydrochloride dissolution rate reach 80% it is measure after present dissolution test starts 1~12 small When during when small (particularly 1.5~10 during).
The method of any embodiment according to a second aspect of the present invention, the institute before being contacted with the material of the tablet matrix State the first coating micro-pill (i.e. tamsulosin hydrochloride coating micro-pill, after each layer coating is completed, carry out it is subsequent non-coated State before operating procedure), according to the of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate with drug release determination method " Three methods, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium Carry out Dissolution Rate Testing, 50 revs/min of rotating speed, the tamsulosin hydrochloride dissolution rate in the neutral dissolution medium of pH value 6.8 It is shown as 30%, 50%, 80% each time point, the dissolution rate of the first coating micro-pill and the smooth rope of the hydrochloric acid of oral disnitegration tablet The absolute value of the difference of Rosin dissolution rate is in the range of 0-15%, particularly in the range of 0-12.5%.
The method of any embodiment according to a second aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", using water 250ml as dissolution medium, 50 revs/min of rotating speed, Dutasteride's dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%.
The method of any embodiment according to a second aspect of the present invention, the institute before being contacted with the material of the tablet matrix Coating micro-pill (i.e. coating micro-pill is after each layer coating is completed, the state before subsequent non-coated operating procedure is carried out) is stated, According to the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time point, the dissolution rate and oral disnitegration tablet of coating micro-pill Dissolution rate absolute value of the difference in the range of 0-15%, particularly in the range of 0-12.5%.
Further, third aspect present invention provides a kind of to oral disnitegration tablet raising hardness and improvement disintegrating property Method, this method suppress oral disnitegration tablet by tablet forming technique；The tablet include the tablet matrix being made of multiple auxiliary materials and Two kinds of coating micro-pills being essentially homogeneously scattered in the tablet matrix；Described two coating micro-pills include including two kinds respectively The capsule core of different activities ingredient and at least one layer of coating for being covered in the capsule core surface, it is described to be formed in the auxiliary material of tablet matrix Including salt.
The method of any embodiment according to a third aspect of the present invention, wherein the salt is selected from：Sodium chloride, chlorination Potassium, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.
The method of any embodiment according to a third aspect of the present invention prepares the method for the oral disnitegration tablet including as follows Step：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described activity Ingredient is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made； Make second active ingredient is essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially It is homogeneously dispersed in the capsule core, then gained pellet core is coated, second of coating micro-pill is made；
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting.
The method of any embodiment, wherein step ii according to a third aspect of the present invention) it is performed according to following operation：
Iia) described two coating micro-pills with excipient are mixed, are sprayed using fluidized bed granulation process into the mixed material Enter binder solution to carry out making wet granular and drying, lubricant is added into gained dry particle, be uniformly mixed, tabletting；Or
Iib) spray into binder solution into excipient using fluidized bed granulation process to carry out making wet granular and drying, to institute It obtains and two kinds of coating micro-pills and lubricant is added in dry particle, be uniformly mixed, tabletting.
The active ingredient of the method for any embodiment according to a third aspect of the present invention, wherein the first coating micro-pill It is Tamsulosin or its pharmaceutical salts.In one embodiment, the active ingredient of the first coating micro-pill is Tamsulosin Or its pharmaceutical salts, the coating are one layer of sustained-release coating layer.In one embodiment, the first coating micro-pill it is described activity into It is Tamsulosin or its pharmaceutical salts to divide, and the coating is one layer of enteric coating layer.In one embodiment, the first coating micro-pill The active ingredient be Tamsulosin or its pharmaceutical salts, it is described to include two layers, be respectively from inside to outside sustained-release coating layer and Enteric coating layer.
The method of any embodiment according to a third aspect of the present invention, wherein the active ingredient of second of coating micro-pill It is dutasteride or its pharmaceutical salts.In one embodiment, the active ingredient of second of coating micro-pill is dutasteride Or its pharmaceutical salts, the coating are thin film clothing layer.In one embodiment, the activity of second coating micro-pill into It is dutasteride or its pharmaceutical salts to divide, and the coating is one layer of enteric coating layer.In one embodiment, second of coating micro-pill The active ingredient be dutasteride or its pharmaceutical salts, the coating is one layer of sustained-release coating layer.In one embodiment, The active ingredient of two kinds of coating micro-pills is dutasteride or its pharmaceutical salts, described to include two layers, is distinguished from inside to outside It is sustained-release coating layer and enteric coating layer.
Active ingredient in the method for any embodiment according to a third aspect of the present invention, wherein the first coating micro-pill is Tamsulosin hydrochloride, the active ingredient in second of coating micro-pill is dutasteride.
The method of any embodiment according to a third aspect of the present invention, wherein the weight of the first coating micro-pill accounts for this The 5~50% of oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.
The method of any embodiment according to a third aspect of the present invention, wherein the weight of second of coating micro-pill accounts for this The 5~50% of oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.
The method of any embodiment according to a third aspect of the present invention, wherein the weight of the active ingredient hydrochloric acid Tamsulosin Amount accounts for the 0.1~10% of the first coating micro-pill total weight, such as 0.1~5%.
The method of any embodiment according to a third aspect of the present invention, wherein the weight of the active ingredient dutasteride accounts for The 0.1~10% of second of coating micro-pill total weight, such as 0.1~5%.
The method of any embodiment according to a third aspect of the present invention, wherein the average grain diameter of the first coating micro-pill For 50~350 μm, such as 50~300 μm, such as 100~250 μm.
The method of any embodiment according to a third aspect of the present invention, wherein the average grain diameter of second of coating micro-pill For 50~350 μm, such as 50~300 μm, such as 100~250 μm.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core material of the first coating micro-pill Selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, lactose or breast Sugar ball.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core material of second of coating micro-pill Selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, lactose or breast Sugar ball.
The method of any embodiment according to a third aspect of the present invention, wherein the first described coating micro-pill and/or second The capsule core of kind coating micro-pill is microcrystalline cellulose capsule core or sucrose ball.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are essentially homogeneously coated in the capsule core surface.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are essentially homogeneously coated in the capsule core surface.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, after the active ingredient hydrochloric acid Tamsulosin with adhesive by being compounded into solution or suspension, substantially It is equably coated in the capsule core surface.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, after the active ingredient dutasteride with adhesive by being compounded into solution or suspension, substantially uniformly Ground is coated in the capsule core surface.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are distributed substantially uniformly through inside the capsule core.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are distributed substantially uniformly through inside the capsule core.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are distributed substantially uniformly through inside the capsule core；The activity Ingredient tamsulosin hydrochloride adds the solution containing adhesive or suspension with stirring-granulating after mixing with microcrystalline cellulose Capsule core is made in method or fluidized bed prilling method；Alternatively, addition containing active ingredient hydrochloric acid Tamsulosin and is glued into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of mixture.
The method of any embodiment according to a third aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are distributed substantially uniformly through inside the capsule core；The active ingredient Dutasteride adds the solution containing adhesive or suspension with stirring-granulating method or fluidisation after mixing with microcrystalline cellulose Capsule core is made in bed comminution granulation；Alternatively, into microcrystalline cellulose add the solution containing active ingredient dutasteride and adhesive or Capsule core is made with stirring-granulating method or fluidized bed prilling method in suspension.
The method of any embodiment according to a third aspect of the present invention, wherein being used to prepare the described viscous of described two capsule cores It is polymer substance that mixture is each independent, such as selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidine Ketone, copolyvidone or polyvinyl alcohol, and combinations thereof.Certainly, above-mentioned polymer substance can also be as the adhesive of other steps.
The method of any embodiment according to a third aspect of the present invention, wherein at least one layer of bag on the coating micro-pill surface Clothing is selected from：Film-coating, enteric coating, clothing soluble in the stomach, extended release coatings, controlled release clothing and combinations thereof.When using multiple coatings, clothing layer order can With because being determined during different purposes.For example, it is desired to when not dissolving under one's belt but needing the requirement slowly discharged in intestinal juice, it can be with First in pellet core surface bundled slow-releasing clothing layer, one layer of enteric coating layer is then wrapped up again outside sustained-release coating layer.In another example when need It, can be in pellet core surface bundled slow-releasing covering adverse drug taste needs the requirement slowly discharged in gastro-intestinal Fluid again when Clothing layer, you can realize this purpose.
Film-coating is well known to those skilled in the art.Illustrative film-coating filmogen is such as, but not limited to hydroxypropyl Methylcellulose, hydroxypropyl cellulose, methyl hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyethylene glycol Deng.
Enteric coating is well known to those skilled in the art.Illustrative enteric coating filmogen is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly L, S type.
Clothing soluble in the stomach is well known to those skilled in the art.Illustrative clothing filmogen soluble in the stomach is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly E types.
Extended release coatings and controlled release clothing are well known to those skilled in the art.Illustrative extended release coatings and controlled release clothing filmogen are most To be typically ethyl cellulose.
Some additives are added in coating material to adapt to specifically coating requirement, this is those skilled in the art according to warp Test what can easily be determined.Such as plasticizer, colorant and screening agent etc. can be added in coating solution.
It is it is known in the art that typically that capsule core and its coating, which are prepared, with the preparation method for obtaining coating micro-pill of the present invention Using the granulation of fluidized bed principle, art for coating, such as the preparation method for the sustained-release microparticle being recorded in CN1473035B. It is well known that the amount of the clothing layer in capsule core surface package, it can be according to the experience of those skilled in the art and the religion of textbook It leads and is easily adjusted, such as the weight of clothing layer can be the 1~20% of capsule core weight, such as the weight of clothing layer can be capsule core weight The 1~15% of amount, such as the weight of clothing layer can be the 1~10% of capsule core weight.
The method of any embodiment according to a third aspect of the present invention wherein when preparing the coating micro-pill, is used only Water and without using organic solvent as the solvent for preparing binder solution or coating solution.Although CN1473035B introductions use first The mixed solvent of alcohol and a small amount of water, however present invention discover that there is better processing performance without organic solvent using water.
The method of any embodiment according to a third aspect of the present invention, wherein forming the auxiliary material of the tablet matrix includes choosing From the excipient of following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, maltose, trehalose, sorbierite, maltitol, wood Sugar alcohol, erythrite, glucose, and combinations thereof.It is preferable to use above-mentioned one or more sugar and/or sugar alcohols for particularly this excipient Combination.
The method of any embodiment according to a third aspect of the present invention, wherein the auxiliary material for forming the tablet matrix includes gluing Mixture.In one embodiment, adhesive used is identical when described adhesive can be with preparing coating micro-pill.At one In embodiment, described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol.Especially it is possible to preparing tablet When, it will be a certain or several part or all of in the sugar or sugar alcohol as excipient, solution is prepared using as bonding by the use of water Agent, with binder solution wet granular after then coating micro-pill is mixed with excipient.
The method of any embodiment according to a third aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include disintegrant.Typical disintegrant is such as, but not limited to：Cornstarch, carboxymethylcellulose calcium, pregelatinized starch, crosslinked polyethylene Pyrrolidones, sodium starch glycollate, croscarmellose sodium crospovidone, low degree of substitution hydroxypropyl cellulose etc..
The method of any embodiment according to a third aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include the additives such as sweetener, colorant.
The method of any embodiment according to a third aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include lubricant.Lubricant containing convention amount is for tablet appearance and prevents that sticking from being beneficial.Workable lubricant is selected from： Magnesium stearate, calcium stearate, sucrose fatty ester, polyethylene glycol, talcum powder, stearic acid etc. and combinations thereof.
The method of any embodiment according to a third aspect of the present invention, wherein forming the auxiliary material of the tablet matrix includes： Excipient, adhesive, salt, lubricant.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet are by including the following steps Method be prepared：Two kinds of coating micro-pills made from the difference with excipient are mixed, use fluidized bed granulation process Binder solution is sprayed into the mixed material to carry out making wet granular and drying, is added lubricant into gained dry particle, is mixed Close uniform, tabletting.In one embodiment, when it is present, the salt can be by micro- with coating together with excipient The mode of ball mixing is added.In one embodiment, when it is present, the salt can be by being added to binder solution In mode add.In one embodiment, when it is present, the salt is the stage in addition lubricant with powder Form addition.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet are by including the following steps Method be prepared：Binder solution is sprayed into using fluidized bed granulation process into excipient to carry out making wet granular and do Dry, into gained dry particle, two kinds of coating micro-pills and lubricant made from addition difference, are uniformly mixed, tabletting.In a reality It applies in scheme, when it is present, the salt can be added by way of preparing particle after being mixed with excipient.In a reality It applies in scheme, when it is present, the salt can be added by way of being added in binder solution.In an embodiment party In case, when it is present, the salt was added in the form of a powder in the stage of addition lubricant.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 Regulation under four general rules " 0921 disintegration time limited inspection technique " and " oral disintegrating tablet " item therein, the disintegration time limited that replication is 6, 6 were all disintegrated in 60 seconds and pass through sieve；Particularly 6 were all disintegrated in 45 seconds and pass through sieve；Particularly 6 Piece was all disintegrated in 30 seconds and passes through sieve.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 Method under four general rule " 0923 tablet friability inspection technique " items measures the friability of tablet, no fracture, cracking and crushing Piece, and less loss weight is less than 3%, is, for example, less than 2%, is, for example, less than 1.5%, is, for example, less than 1%.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine United States Pharmacopeia USP35- NF30 editions "<1217>The method of TABLET BREAKING FORCE " measures the hardness of tablet, and value is in the range of 3~6kg, example Such as in the range of 4~6kg.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet measure its suction according to following method Wet rate, hydroscopicity (are, for example, less than 15%, are, for example, less than 12.5%, be, for example, less than 10%) less than 20%：Take total weight 5.0~ The tablet of 5.5g, precise weighing；Make it flat auxiliary and expose to the open air 25 DEG C of temperature, 75% condition of relative humidity assign 24 it is small when, it is accurate It weighs；Hydroscopicity is calculated as follows：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with acid medium (water and with salt acid for adjusting pH value 1.2) 250ml carries out Dissolution Rate Testing for dissolution medium, and 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate is less than in 15 minutes 20%, it is, for example, less than 15%.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when during, particularly 0.5~3 small period Between.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when during, particularly 0.75~6 small period Between.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 80% measure after present dissolution test starts 1~12 it is small when during, particularly 1.5~9 it is small when during.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when during (particularly 0.5~3 small period Between), tamsulosin hydrochloride dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when during (particularly 0.75~6 it is small when during), tamsulosin hydrochloride dissolution rate reach 80% it is measure after present dissolution test starts 1~12 small When during when small (particularly 1.5~10 during).
The method of any embodiment according to a third aspect of the present invention, the institute before being contacted with the material of the tablet matrix State the first coating micro-pill (i.e. tamsulosin hydrochloride coating micro-pill, after each layer coating is completed, carry out it is subsequent non-coated State before operating procedure), according to the of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate with drug release determination method " Three methods, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium Carry out Dissolution Rate Testing, 50 revs/min of rotating speed, the tamsulosin hydrochloride dissolution rate in the neutral dissolution medium of pH value 6.8 It is shown as 30%, 50%, 80% each time point, the dissolution rate of the first coating micro-pill and the smooth rope of the hydrochloric acid of oral disnitegration tablet The absolute value of the difference of Rosin dissolution rate is in the range of 0-15%, particularly in the range of 0-12.5%.
The method of any embodiment according to a third aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", using water 250ml as dissolution medium, 50 revs/min of rotating speed, Dutasteride's dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%.
The method of any embodiment according to a third aspect of the present invention, the institute before being contacted with the material of the tablet matrix Coating micro-pill (i.e. coating micro-pill is after each layer coating is completed, the state before subsequent non-coated operating procedure is carried out) is stated, According to the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time point, the dissolution rate and oral disnitegration tablet of coating micro-pill Dissolution rate absolute value of the difference in the range of 0-15%, particularly in the range of 0-12.5%.
Further, fourth aspect present invention provides salt and is preparing the oral cavity with high rigidity and fast disintegration property Purposes in disintegrated tablet, the oral disnitegration tablet are suppressed by tablet forming technique；The oral disnitegration tablet is included by multiple auxiliary materials group Into tablet matrix and two kinds of coating micro-pills being essentially homogeneously scattered in the tablet matrix；Described two coatings are micro- Ball includes the capsule core comprising two kinds of different activities ingredients and at least one layer of coating for being covered in the capsule core surface respectively；The salt Class is added to as auxiliary material in the tablet matrix.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the salt is selected from：Sodium chloride, chlorination Potassium, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.
The purposes of any embodiment according to a fourth aspect of the present invention prepares the method for the oral disnitegration tablet including as follows Step：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described activity Ingredient is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made； Make second active ingredient is essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially It is homogeneously dispersed in the capsule core, then gained pellet core is coated, second of coating micro-pill is made；
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting.
The purposes of any embodiment, wherein step ii according to a fourth aspect of the present invention) it is performed according to following operation：
Iia) described two coating micro-pills with excipient are mixed, are sprayed using fluidized bed granulation process into the mixed material Enter binder solution to carry out making wet granular and drying, lubricant is added into gained dry particle, be uniformly mixed, tabletting；Wherein, The salt can be added by way of being mixed together with excipient with coating micro-pill or the salt can pass through The mode being added in binder solution is added or the salt was added in the form of a powder in the stage of addition lubricant Add.
The purposes of any embodiment, wherein step ii according to a fourth aspect of the present invention) it is performed according to following operation：
Iib) spray into binder solution into excipient using fluidized bed granulation process to carry out making wet granular and drying, to institute It obtains and two kinds of coating micro-pills and lubricant is added in dry particle, be uniformly mixed, tabletting；Wherein, the salt can by with The mode that particle is prepared after excipient mixing is added or the salt can be by way of being added in binder solution Addition or the salt were added in the form of a powder in the stage of addition lubricant.
The active ingredient of the purposes of any embodiment according to a fourth aspect of the present invention, wherein the first coating micro-pill It is Tamsulosin or its pharmaceutical salts.In one embodiment, the active ingredient of the first coating micro-pill is Tamsulosin Or its pharmaceutical salts, the coating are one layer of sustained-release coating layer.In one embodiment, the first coating micro-pill it is described activity into It is Tamsulosin or its pharmaceutical salts to divide, and the coating is one layer of enteric coating layer.In one embodiment, the first coating micro-pill The active ingredient be Tamsulosin or its pharmaceutical salts, it is described to include two layers, be respectively from inside to outside sustained-release coating layer and Enteric coating layer.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the active ingredient of second of coating micro-pill It is dutasteride or its pharmaceutical salts.In one embodiment, the active ingredient of second of coating micro-pill is dutasteride Or its pharmaceutical salts, the coating are thin film clothing layer.In one embodiment, the activity of second coating micro-pill into It is dutasteride or its pharmaceutical salts to divide, and the coating is one layer of enteric coating layer.In one embodiment, second of coating micro-pill The active ingredient be dutasteride or its pharmaceutical salts, the coating is one layer of sustained-release coating layer.In one embodiment, The active ingredient of two kinds of coating micro-pills is dutasteride or its pharmaceutical salts, described to include two layers, is distinguished from inside to outside It is sustained-release coating layer and enteric coating layer.
Active ingredient in the purposes of any embodiment according to a fourth aspect of the present invention, wherein the first coating micro-pill is Tamsulosin hydrochloride, the active ingredient in second of coating micro-pill is dutasteride.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the weight of the first coating micro-pill accounts for this The 5~50% of oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the weight of second of coating micro-pill accounts for this The 5~50% of oral disnitegration tablet total weight, such as 5~40%, such as 5~30%, such as 5~25%.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the weight of the active ingredient hydrochloric acid Tamsulosin Amount accounts for the 0.1~10% of the first coating micro-pill total weight, such as 0.1~5%.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the weight of the active ingredient dutasteride accounts for The 0.1~10% of second of coating micro-pill total weight, such as 0.1~5%.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the average grain diameter of the first coating micro-pill For 50~350 μm, such as 50~300 μm, such as 100~250 μm.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the average grain diameter of second of coating micro-pill For 50~350 μm, such as 50~300 μm, such as 100~250 μm.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core material of the first coating micro-pill Selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, lactose or breast Sugar ball.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core material of second of coating micro-pill Selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sucrose or sucrose ball, starch or starch ball, lactose or breast Sugar ball.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the first described coating micro-pill and/or second The capsule core of kind coating micro-pill is microcrystalline cellulose capsule core or sucrose ball.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are essentially homogeneously coated in the capsule core surface.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are essentially homogeneously coated in the capsule core surface.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, after the active ingredient hydrochloric acid Tamsulosin with adhesive by being compounded into solution or suspension, substantially It is equably coated in the capsule core surface.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, after the active ingredient dutasteride with adhesive by being compounded into solution or suspension, substantially uniformly Ground is coated in the capsule core surface.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are distributed substantially uniformly through inside the capsule core.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are distributed substantially uniformly through inside the capsule core.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of the first coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient hydrochloric acid Tamsulosin are distributed substantially uniformly through inside the capsule core；The activity Ingredient tamsulosin hydrochloride adds the solution containing adhesive or suspension with stirring-granulating after mixing with microcrystalline cellulose Capsule core is made in method or fluidized bed prilling method；Alternatively, addition containing active ingredient hydrochloric acid Tamsulosin and is glued into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of mixture.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the capsule core of second of coating micro-pill is micro- Crystalline cellulose capsule core, the active ingredient dutasteride are distributed substantially uniformly through inside the capsule core；The active ingredient Dutasteride adds the solution containing adhesive or suspension with stirring-granulating method or fluidisation after mixing with microcrystalline cellulose Capsule core is made in bed comminution granulation；Alternatively, into microcrystalline cellulose add the solution containing active ingredient dutasteride and adhesive or Capsule core is made with stirring-granulating method or fluidized bed prilling method in suspension.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein being used to prepare the described viscous of described two capsule cores It is polymer substance that mixture is each independent, is, for example, water-soluble high-molecular substance, such as selected from hydroxypropyl methyl cellulose, hydroxyl Propyl cellulose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol, and combinations thereof.Certainly, above-mentioned polymer substance also may be used Using the adhesive as other steps.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein at least one layer of bag on the coating micro-pill surface Clothing is selected from：Film-coating, enteric coating, clothing soluble in the stomach, extended release coatings, controlled release clothing and combinations thereof.When using multiple coatings, clothing layer order can With because being determined during different purposes.For example, it is desired to when not dissolving under one's belt but needing the requirement slowly discharged in intestinal juice, it can be with First in pellet core surface bundled slow-releasing clothing layer, one layer of enteric coating layer is then wrapped up again outside sustained-release coating layer.In another example when need It, can be in pellet core surface bundled slow-releasing covering adverse drug taste needs the requirement slowly discharged in gastro-intestinal Fluid again when Clothing layer, you can realize this purpose.
Film-coating is well known to those skilled in the art.Illustrative film-coating filmogen is such as, but not limited to hydroxypropyl Methylcellulose, hydroxypropyl cellulose, methyl hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyethylene glycol Deng.
Enteric coating is well known to those skilled in the art.Illustrative enteric coating filmogen is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly L, S type.
Clothing soluble in the stomach is well known to those skilled in the art.Illustrative clothing filmogen soluble in the stomach is such as, but not limited to acrylic acid With the Eudragit of methacrylate copolymer particularly E types.
Extended release coatings and controlled release clothing are well known to those skilled in the art.Illustrative extended release coatings and controlled release clothing filmogen are most To be typically ethyl cellulose.
Some additives are added in coating material to adapt to specifically coating requirement, this is those skilled in the art according to warp Test what can easily be determined.Such as plasticizer, colorant and screening agent etc. can be added in coating solution.
It is it is known in the art that typically that capsule core and its coating, which are prepared, with the preparation method for obtaining coating micro-pill of the present invention Using the granulation of fluidized bed principle, art for coating, such as the preparation method for the sustained-release microparticle being recorded in CN1473035B. It is well known that the amount of the clothing layer in capsule core surface package, it can be according to the experience of those skilled in the art and the religion of textbook It leads and is easily adjusted, such as the weight of clothing layer can be the 1~20% of capsule core weight, such as the weight of clothing layer can be capsule core weight The 1~15% of amount, such as the weight of clothing layer can be the 1~10% of capsule core weight.
The purposes of any embodiment according to a fourth aspect of the present invention wherein when preparing the coating micro-pill, is used only Water and without using organic solvent as the solvent for preparing binder solution or coating solution.Although CN1473035B introductions use first The mixed solvent of alcohol and a small amount of water, however present invention discover that there is better processing performance without organic solvent using water.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein forming the auxiliary material of the tablet matrix includes choosing From the excipient of following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, maltose, trehalose, sorbierite, maltitol, wood Sugar alcohol, erythrite, glucose, and combinations thereof.It is preferable to use above-mentioned one or more sugar and/or sugar alcohols for particularly this excipient Combination.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein the auxiliary material for forming the tablet matrix includes gluing Mixture.In one embodiment, adhesive used is identical when described adhesive can be with preparing coating micro-pill.At one In embodiment, described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol.Especially it is possible to preparing tablet When, it will be a certain or several part or all of in the sugar or sugar alcohol as excipient, solution is prepared using as bonding by the use of water Agent, with binder solution wet granular after then coating micro-pill is mixed with excipient.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include disintegrant.Typical disintegrant is such as, but not limited to：Cornstarch, carboxymethylcellulose calcium, pregelatinized starch, crosslinked polyethylene Pyrrolidones, sodium starch glycollate, croscarmellose sodium crospovidone, low degree of substitution hydroxypropyl cellulose etc..
The purposes of any embodiment according to a fourth aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include the additives such as sweetener, colorant.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein forming the auxiliary material of the tablet matrix can also wrap Include lubricant.Lubricant containing convention amount is for tablet appearance and prevents that sticking from being beneficial.Workable lubricant is selected from： Magnesium stearate, calcium stearate, sucrose fatty ester, polyethylene glycol, talcum powder, stearic acid etc. and combinations thereof.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein forming the auxiliary material of the tablet matrix includes： Excipient, adhesive, salt, lubricant.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 Regulation under four general rules " 0921 disintegration time limited inspection technique " and " oral disintegrating tablet " item therein, the disintegration time limited that replication is 6, 6 were all disintegrated in 60 seconds and pass through sieve；Particularly 6 were all disintegrated in 45 seconds and pass through sieve；Particularly 6 Piece was all disintegrated in 30 seconds and passes through sieve.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 Method under four general rule " 0923 tablet friability inspection technique " items measures the friability of tablet, no fracture, cracking and crushing Piece, and less loss weight is less than 3%, is, for example, less than 2%, is, for example, less than 1.5%, is, for example, less than 1%.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine United States Pharmacopeia USP35- NF30 editions "<1217>The method of TABLET BREAKING FORCE " measures the hardness of tablet, and value is in the range of 3~6kg, example Such as in the range of 4~6kg.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet measure its suction according to following method Wet rate, hydroscopicity (are, for example, less than 15%, are, for example, less than 12.5%, be, for example, less than 10%) less than 20%：Take total weight 5.0~ The tablet of 5.5g, precise weighing；Make it flat auxiliary and expose to the open air 25 DEG C of temperature, 75% condition of relative humidity assign 24 it is small when, it is accurate It weighs；Hydroscopicity is calculated as follows：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with acid medium (water and with salt acid for adjusting pH value 1.2) 250ml carries out Dissolution Rate Testing for dissolution medium, and 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate is less than in 15 minutes 20%, it is, for example, less than 15%.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when during, particularly 0.5~3 small period Between.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when during, particularly 0.75~6 small period Between.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 80% measure after present dissolution test starts 1~12 it is small when during, particularly 1.5~9 it is small when during.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", with neutral medium, (disodium hydrogen phosphate of 0.02mol/L is molten Liquid is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, hydrochloric acid Tan Suoluo for dissolution medium Pungent dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when during (particularly 0.5~3 small period Between), tamsulosin hydrochloride dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when during (particularly 0.75~6 it is small when during), tamsulosin hydrochloride dissolution rate reach 80% it is measure after present dissolution test starts 1~12 small When during when small (particularly 1.5~10 during).
The purposes of any embodiment according to a fourth aspect of the present invention, the institute before being contacted with the material of the tablet matrix State the first coating micro-pill (i.e. tamsulosin hydrochloride coating micro-pill, after each layer coating is completed, carry out it is subsequent non-coated State before operating procedure), according to the of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate with drug release determination method " Three methods, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium Carry out Dissolution Rate Testing, 50 revs/min of rotating speed, the tamsulosin hydrochloride dissolution rate in the neutral dissolution medium of pH value 6.8 It is shown as 30%, 50%, 80% each time point, the dissolution rate of the first coating micro-pill and the smooth rope of the hydrochloric acid of oral disnitegration tablet The absolute value of the difference of Rosin dissolution rate is in the range of 0-15%, particularly in the range of 0-12.5%.
The purposes of any embodiment according to a fourth aspect of the present invention, the oral disnitegration tablet shine Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method ", using water 250ml as dissolution medium, 50 revs/min of rotating speed, Dutasteride's dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%.
The purposes of any embodiment according to a fourth aspect of the present invention, the institute before being contacted with the material of the tablet matrix Coating micro-pill (i.e. coating micro-pill is after each layer coating is completed, the state before subsequent non-coated operating procedure is carried out) is stated, According to the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time point, the dissolution rate and oral disnitegration tablet of coating micro-pill Dissolution rate absolute value of the difference in the range of 0-15%, particularly in the range of 0-12.5%.
In the step of above-mentioned preparation method of the invention, although the specific steps of its description are in some details or language The step of in description with described in the preparation example of following detailed description part, is otherwise varied, however, people in the art The detailed disclosure of member's full text according to the present invention can summarize approach described above step completely.
Any embodiment of the either side of the present invention can be combined with the other any embodiments of the present invention, As long as they are not in contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can fit For the technical characteristic in the other any embodiments of the present invention, as long as they are not in contradiction.
The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary When offering expressed meaning and the inconsistent present invention, the statement of the present invention is subject to.In addition, the various terms that use of the present invention and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention Subject to the meaning stated.
It should be noted that the present invention " the one layer of sustained-release coating layer " or " one layer of enteric coating layer " that refers to, refer to only one Kind clothing layer, such as only sustained-release coating layer or only enteric coating layer.It is well known that in medicament art for coating, package A kind of clothing layer, which is typically required, is continuously or intermittently coated material, particularly in the case of intermittent coating, A kind of such clothing layer can be made of multilayer, that is, sprayed one layer of coating solution and be dried at once, then continuing to one layer of sprinkling Coating solution is simultaneously dried at once, is so coated repeatedly until such a clothing layer reaches desired effect.
In the present invention, oral disnitegration tablet is prepared by adding salt in the tablet matrix outside pellet, tablet can It is wet-dry without undergoing adding for cumbersome and bad control as CN1473035B to be directly compressed into the hardness of needs Dry or heating-cooling technique, tablet obtained have excellent intensity and disintegrating property, and with excellent stability. In fact, the present inventor in experiments it is found that, preparing oral disnitegration tablet to embodiment 9 with reference to CN1473035B embodiments 1 When, into the degree of 5~5.5kg of hardness rather than the degree of about 1~2kg is pressed into directly by tablet press in tabletting, obtained Tablet whether carry out humidifying-drying or heating-cooling processing, cannot meet tablet friability and/or disintegrating property Requirement, be specifically that the tablet so obtained disintegration time in the case where not humidified-dry or heating-cooling is handled is equal More than 2.5min, and the corresponding embodiment with reference to CN1473035B humidify-dry or heating-cooling processing after, tablet Friability can not be met the requirements, and each batch of piece for whetheing there is fracture, cracking or crushing, less loss weight is in 3.4~6.1% scopes It is interior.Therefore, in any embodiment of either side of the present invention, tabletting is carried out in the mixed material that will include coating micro-pill When, apply the pressure that can make tablet up to 3~7kg (such as up to 3.5~6.5kg, such as up to 4~6kg) hardness on tablet press machine Hybrid particles are tabletted.
Tamsulosin belongs to treatment benign prostate hyperplasia (BPH) medication, is blocked for 1 adrenocepters of selectivity α Agent, main function mechanism are the α 1A adrenocepters selectively blocked in prostate, and relax prostate smooth musculature cells, from And the symptoms such as dysuria caused by improving benign prostate hyperplasia.Presently commercially available Tamsulosin is mainly hydrochloric acid Tan Suoluo Pungent spansule, trade name " Harnal ", be a kind of hard shell capsules, content be off-white color spheric granules, clinical common dose It is to be grown up once a day, one (0.2mg) every time, oral meal；Can suitably it be increased and decreased according to the difference of age, symptom.Hydrochloric acid is smooth It in terms of the pharmacokinetics of Suo Luoxin spansule, absorbs, be distributed, eliminate：When this product adult once takes orally 0.2mg, 6.8 is small When after blood concentration peak, half-life period for 10.0 it is small when, AUC0~∞ is almost equal with ordinary preparation, therefore is biological The undiminished sustained release preparation of availability.Continuous oral, blood concentration can reach stable state on day 4.
Dutasteride is the Specific competition inhibitor of 5α-reductase I types and II type isodynamic enzymes, can be with 5α-reductase shape Into stable multienzyme complex.The internal and external degree of dissociation testing result carried out to the multienzyme complex is shown：The complex dissociation It spends extremely low.Dutasteride is not combined with human androgenic receptor.Dutasteride inhibits conversion of the testosterone to protona (DHT).Make For androgen, DHT plays a role during prostate progenesis and then increase.Testosterone is converted into through 5α-reductase DHT, 5α-reductase have two kinds of isodynamic enzymes of I types and II types.II type isodynamic enzymes are mainly distributed on germinal tissue, and I type isodynamic enzymes pair Conversion of the testosterone in skin and liver also has effect.
The present invention, not only can be straight by wet granule compression tablet method by adding a small amount of inorganic salts into oral disnitegration tablet Excellent hardness and the tablet of friability index must be had without carrying out prolonged humiture Balance Treatment or pole by obtaining High-temperature processing, and this hardness and friability index have excellent stability, it is more valuable, with excellent hard On the premise of degree and friability index, Tablets have excellent disintegrating property.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general And/or specific description.Although to realize the present invention many materials used in purpose and operating method be it is known in the art that But the present invention is still described in detail as far as possible herein.Following embodiment further illustrates the present invention rather than limits this hair It is bright.
In the present invention, the active component content uniformity of pellet core can be characterized using sized particles content ratio. The sized particles content ratio is measured according to following manner：The standard medicine sieve of two kinds of sieve meshes of selection, they enable to obtained Pellet core there are 28~38% can sieve (this some particles is known as small particles) by the medicine of small mesh number, having 28~38% cannot (this some particles is known as big particle) is sieved by the medicine of big mesh number, has 28~38% to be trapped within (this part between two medicine sieves Particle during particle is known as), which is subjected to gradation sizing with two medicine sieves, measures the drug of granule subdivision respectively The medicament contg (can be denoted as Q2) of content (can be denoted as Q1) and big particle fraction calculates the ratio of this Q2 and Q1, is big granule Sub- content ratio.This sized particles content is better than the active component content uniformity that pellet core is represented closer to 1, this is right In its subsequent treatment process be very useful, and help to ensure that obtain with excellent content uniformity tablet.
The evaluation method of oral disnitegration tablet：
The assay of active ingredient：For measuring the content of active ingredient hydrochloric acid Tamsulosin in various materials, use HPLC methods measure, HPLC conditions：C18 chromatographic columns, column length 250mm, internal diameter 4.6mm, filler particle size 5um, mobile phase：Methanol/water =70/30, ultraviolet detection and wavelength are 254nm, with external standard method with peak area quantification.For measuring active ingredient in various materials The content of dutasteride is measured, HPLC conditions using HPLC methods：Chromatographic column：C18 chromatographic columns (250mm × 4.6mm, 5 μm), with Methanol：Water (80：20) it is mobile phase；Flow velocity：1.0mL/min；Column temperature：25℃；Detection wavelength：220nm, sample size：20μL.Such as Fruit is to be related to other active ingredients, then can refer to and above-mentioned be suitably modified to be suitable for this in addition on the basis of the HPLC methods Drug.
Stability is disposed：By oral disnitegration tablet simulation listing pack under the conditions of, at a temperature of putting 40 DEG C place 5 Measure relevant parameter (0 month value generally equal to piece at 0 month by the moon (this process can be described as stability disposal in the present invention) The value that agent measures after being made) and relevant parameter at May, relevant parameter 0 month and value in May are compared, to evaluate mouth The stability of cavity disintegrating tablet.
Content uniformity：This is the routine for judging content difference of the low dose of solid pharmaceutical preparation in different agents unit Method, the method with reference to described in CN1473035B, active ingredient in different tablets is characterized with coefficient of variation CV% in the present invention Uniformity.Generally CV% it is the smaller the better and less than 3.5% be it is satisfactory, and CV% be more than 3.5% when think not It can receive.The tamsulosin hydrochloride in tablet and the CV% values of dutasteride can be measured respectively.
Friability：According to the method (100 under Chinese Pharmacopoeia four general rules of version in 2015 " 0923 tablet friability inspection technique " item Turn) measure the friability of tablet, no fracture, cracking and the piece crushed, and less loss weight (usually also referred to as " wear intensity ") When being, for example, less than 1% less than specified value, it is generally recognized that qualified.Usually, oral disnitegration tablet less loss after being disposed through stability Weight, which can increase, (if there is opposite situation, then typically exhibits that tablet hardness dramatically increases and disintegration time can prolong significantly It is long)；With less loss weight in May and the difference divided by 0 month less loss weight of 0 month less loss weight, increase percentage as less loss weight, it should Percentage is better closer to 0.This less loss weight, which increases percentage, to reflect tablet in stability in a manner of quantization The situation of change of hardness after disposal.
Hardness：According to United States Pharmacopeia USP35-NF30 editions "<1217>The method of TABLET BREAKING FORCE " measures piece The hardness of agent is represented with the average for measuring 6 gained, it is generally recognized that has its hardness of the tablet of excellent hardness value in 4~6kg models In enclosing.
Hydroscopicity：Take the tablet of 5.0~5.5g of total weight, precise weighing；Make it flat auxiliary and expose to the open air in 25 DEG C of temperature, relatively 75% condition of humidity assign 24 it is small when, precise weighing；Hydroscopicity is calculated as follows：Hydroscopicity=[(piece weight-suction after moisture absorption processing Wet process anter weight) ÷ moisture absorptions processing anter weight] × 100%.Oral disnitegration tablet causes its moisture absorption due to its auxiliary material characteristic used Rate usually all can be very high, can be less than 20% especially less than 15% degree, is very excellent, on sale at present mouth The wettability that cavity disintegrating tablet is measured by the above method usually can all reach more than 20% even more than 30%.
Disintegration time：According to Chinese Pharmacopoeia four general rules of version in 2015 " 0921 disintegration time limited inspection technique " and therein " mouth collapses Regulation under piece " item, the disintegration time that replication is 6 calculate disintegration time of its average value as this batch of tablet, at 6 On the premise of being all disintegrated and pass through sieve, disintegration time is just meaningful.
The dissolution rate of tamsulosin hydrochloride：Measure the dissolving out capability of tablet and its intermediate material.Using Chinese Pharmacopoeia 2015 3rd method of year four general rules of version " 0931 dissolution rate and drug release determination method " measures tamsulosin hydrochloride, and dissolution fluid 250ml turns 50 revs/min of speed, dissolution medium A (neutral medium)：The disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8； Dissolution medium B (acid medium)：Water and with salt acid for adjusting pH value 1.2.By the stipulated time be discharged into dissolution medium activity into The percentage of the amount of contained active ingredient is expressed as dissolution rate in the amount and stripping material divided.Dissolution rate in acid medium：It surveys Dissolution rate when earnest material was dissolved out wherein through 2 hours；Dissolution rate in neutral medium：Start in Dissolution Rate Testing until dissolution Up to extend again after 90% 2 it is small when time range in, continue, monitor material dissolution rate and corresponding time, example wherein at any time Such as its each time point in the dissolution rate of active medicine dissolution display 30%, 50%, 80% can be determined for certain material.This Tamsulosin hydrochloride in invention oral disnitegration tablet or various materials carries out dissolution rate examination in the neutral dissolution medium of pH value 6.8 It tests, determines that drug dissolution respectively reaches for 30%, 50%, 80% time point after present dissolution test starts that measures, respectively Referred to as 30% dissolution point, 50% dissolution point, 80% dissolution point, three are also known as 3 dissolution points (in the context of the present invention simultaneously When mentioning them, listed with the order of this 30% dissolution point, 50% dissolution point, 80% dissolution point three).It is smooth for hydrochloric acid Suo Luoxin, generally speaking, the coating micro-pill before solution is connect with the tablet matrix material are molten in the neutrality of pH value 6.8 The drug dissolution gone out in medium is shown as 30%, 50%, 80% each time point, the dissolution rate and Orally disintegrating of coating micro-pill The absolute value of the difference of the dissolution rate of piece is preferably in the range of 0-15%, particularly preferably in the range of 0-12.5%.Above-mentioned three A time point, the dissolution rate difference between coating micro-pill and oral disnitegration tablet can be referred to as 30% dissolution in the present invention Difference, 50% dissolution it is poor, 80% dissolve out it is poor or be referred to as 3 points of dissolutions it is poor (when in the context of the present invention while mentioning them, It is so that this 30% dissolution is poor, 50% dissolution is poor, the order of the poor three of 80% dissolution is listed).Above-mentioned 3 points of dissolutions difference reflects Coating micro-pill with its after (such as wet granulation, particle drying, mix, tabletting) is handled through subsequent technique gained final finished it Between dissolving out capability difference, this species diversity is more low better.
The dissolution rate of dutasteride：Measure the dissolving out capability of tablet and its intermediate material.Using Chinese Pharmacopoeia version in 2015 3rd method of four general rules " 0931 dissolution rate and drug release determination method " measures dutasteride, dissolution medium water 250ml, rotating speed 50 Rev/min.It measures and counts, dutasteride's dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%.In addition, measure with (i.e. coating micro-pill is carrying out subsequently the coating micro-pill before the material contact of the tablet matrix after each layer coating is completed Non-coated operating procedure before state), according to Chinese Pharmacopoeia version in 2015 four general rules " 0931 dissolution rate and drug release determinations 3rd method of method ", using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml to be molten Go out medium and carry out Dissolution Rate Testing, 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time point, and coating is micro- The absolute value of the difference of the dissolution rate of the dissolution rate of ball and the oral disnitegration tablet being measured in the same method, measures and calculates the absolute value.Usually It is expected in the range of 0-15%, particularly in the range of 0-12.5%.
Embodiment 1：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
(1) tamsulosin hydrochloride 80g, hydroxypropyl methyl cellulose 80g are dissolved in 2000g purified waters.Crystallite is fine The plain particle of dimension (Celphere102, Asahi Chemical Industry, average grain diameter is about 120 μm, more than 95% grain size is in 50-150 μ ms) 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the solution, obtains tamsulosin hydrochloride particle.
In addition, dutasteride 100g, hydroxypropyl methyl cellulose 80g are dissolved in 2000g purified waters.By microcrystalline cellulose Plain particle (Celphere102, Asahi Chemical Industry, average grain diameter is about 120 μm, more than 95% grain size is in 50-150 μ ms) 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the solution, obtains dutasteride's particle.
Above and the fluidized bed pelletizer of the context of the invention, produce for Technology Co., Ltd. of Yingge Granulating Covering Technology Co., Ltd., Chongqing WBF-60 type fluidized bed pelletizers.When being granulated and/or be coated using this fluidized bed pelletizer, according to different material, spraying Speed usually can be controlled in 10~120g/min scopes, and spray air pressure usually can be controlled in the range of 0.5~5kg/cm2, makes Product temperature degree is usually can be controlled in the range of 30~50 DEG C, and suction temperature usually can be controlled in the range of 40~85 DEG C and usually than system Product temperature degree is 10~25 DEG C high；For elements such as different material/equipment, these parameters be those skilled in the art it is common and It can rule of thumb be adjusted by those skilled in the art, they for example coincide substantially with used in CN1473035B, In the application context, when being granulated and/or being coated, if not otherwise indicated, using this equipment and this scope is used Parameter is handled.
(2) then, ethyl cellulose (is ground and can crosses 200 mesh sieves) 530g and hydroxypropyl methyl cellulose 180g is added to In water 20000g, ethyl cellulose is strongly made to be suspended and dissolves HPMC, obtain sustained release coating suspension.By tamsulosin hydrochloride Particle 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the coating solution, is obtained tamsulosin hydrochloride and is delayed Release pellet.
(3) sustained release pellet 4000g is put into fluidized bed pelletizer again, with the lateral spray-on process Aquacoat (U.S. FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm Company system) 667g, the mixed liquor of purified water 6667g be coated, obtain tamsulosin hydrochloride enteric sustained-release pellet (active ingredient 1.135%) content is.
In addition, dutasteride's particle 4000g is put into fluidized bed pelletizer, it is (beautiful with Aquacoat with lateral spray-on process State FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm company systems) 667g, the mixed liquor of purified water 6667g be coated, obtain dutasteride's enteric-coated micro-pill (active component content For 1.386%).
(4) it is tamsulosin hydrochloride enteric solubility sustained release pellet 368g, dutasteride's enteric-coated micro-pill is (male wherein containing him is spent Amine amount is 1.25 times of tamsulosin hydrochloride amount), mannitol 2320g, lactose 640g, sodium chloride 240g is in fluidized bed pelletizer In, it is granulated and is dried with the 40%w/w aqueous solutions of the maltose containing 400g and (continuously sprayed in fluidized bed pelletizer dry Dry processing, it is not necessary to the discontinuous cyclic process of spray-drying is carried out as CN1473035B), obtain particulate matter, moisture Less than 3%.
(5) particulate matter obtained by above step (4) with calcium stearate 32g is uniformly mixed, obtains mixed particle eventually, measure wherein The content of active ingredient for calculate every in include specified amount active ingredient when tablet weight, on rotary pelleting machine with Certain pressure makes tablet hardness, and up to the degree of 5.0~5.5kg, directly by these, mixed particle is pressed into every hydrochloric smooth rope eventually The tablet of Rosin 0.2mg/ dutasterides 0.25mg is to get tamsulosin hydrochloride/dutasteride's oral disnitegration tablet.By gained tablet Commercially available product packaged form is simulated, is packed, you can.
The present embodiment intermediate material property and the physicochemical property of gained oral disnitegration tablet are measured, it is as a result as follows：
The sized particles content ratio of tamsulosin hydrochloride particle obtained by step (1)：1.01, the big granule of dutasteride's particle Sub- content ratio：1.03；
About 153 μm of Tamsulosin enteric sustained-release pellet average grain diameter, the grain size of more than 95% particle exist obtained by step (3) 120-180 μ ms, about 146 μm of dutasteride's enteric-coated micro-pill average grain diameter, the grain size of more than 95% particle are in 120-180 μm of model It encloses；
Hardness：5.3kg；
Content uniformity：Tamsulosin CV%=1.3%, dutasteride CV%=0.9%；
Friability：Without fracture, cracking and the piece crushed, less loss weight 0.36%；
Hydroscopicity：9.2%；
Disintegration time：20 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate 5.5% when acid medium 2 is small；When 3 dissolution points are respectively 1.22 small, 2.57 it is small when, 5.20 it is small when；3 points of dissolution differences are respectively 3.1%, 4.8%, 2.3%.Dutasteride：15 minutes dissolution rates of water 3.5%, neutral medium 50% dissolves out poor 6.3%.
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, it is only 14.1% that less loss weight, which increases percentage,.
Above example 1, if not adding dutasteride's pellet in step (4), (5), gained oral disnitegration tablet with it is above-mentioned The physicochemical property of two component tablets is essentially identical.
Comparative example 1：
Embodiment 1 with reference to CN1473035B is that the dispensing of [0130] to [0133] section and preparation method prepare oral disnitegration tablet, As a result：
The sized particles content ratio of tamsulosin hydrochloride particle：0.89；
Enteric sustained-release pellet average grain diameter about 147m, the grain size of more than 95% particle are in 120-180 μ ms；
Hardness：5.7kg；
Content uniformity：CV%=1.9%；
Friability：Without fracture, cracking and the piece crushed, less loss weight 0.86%；
Hydroscopicity：21.3%；
Disintegration time：25 seconds；
Dissolution rate：Dissolution rate 4.4% when acid medium 2 is small；Three dissolution point be respectively 1.14 it is small when, 2.38 it is small when, 5.65 Hour；3 points of dissolution difference % in the range of 5~10%.
After the disposal of the stability of 5 months：Disintegration time, dissolution rate have no significant change, and hardness and friability are apparent Variation, hardness are reduced to 3.6kg, and it is 126.1% that less loss weight, which increases percentage,.
Comparative example 1a：With reference to more than comparative example 1, if adding in the embodiment of the present invention 1 simultaneously in the operation of [0132] section Dutasteride's enteric-coated micro-pill obtained by step (3) (being wherein 1.25 times of tamsulosin hydrochloride amount containing dutasteride's amount), gained The properties of oral disintegrating tablet and above-mentioned 1 result of comparative example are essentially identical.
Comparative example 2：
The embodiment 2 i.e. dispensing of [0153] section and the preparation method for respectively referring to CN1473035B prepares tamsulosin hydrochloride oral cavity Disintegrated tablet prepares paracetamol oral disnitegration tablet with reference to the dispensing and preparation method of above-mentioned document embodiment 5, implements with reference to above-mentioned document The dispensing and preparation method of example 7 prepare tamsulosin hydrochloride oral disnitegration tablet, are prepared with reference to the dispensing and preparation method of above-mentioned document embodiment 8 Licardipine Hydrochloride oral disnitegration tablet prepares tamsulosin hydrochloride oral cavity and collapses with reference to the dispensing and preparation method of above-mentioned document embodiment 9 Solve piece.
As a result：The sized particles content ratio of various pellet core particles is in the range of 0.85~0.91；
The average grain diameter of coating micro-pill before being mixed with water-soluble sugar or sugar alcohol is in 142~185 μ ms, 95% The grain size of more than particle is in 100-300 μ ms；
The hardness of each oral disnitegration tablet is in the range of 4.5~6.1kg；
The content uniformity CV% of each oral disnitegration tablet is in the range of 1.9~3.2%；
During the friability of each oral disnitegration tablet measures, without fracture, cracking and the piece crushed, less loss weight 0.68~ In the range of 0.95%；
The hydroscopicity of each oral disnitegration tablet is in the range of 22.3~31.6%；
The disintegration time of each oral disnitegration tablet is in the range of 20~40 seconds；
The dissolution rate of each Tamsulosin oral disnitegration tablet：Dissolution rate is in the range of 5.5~10% when acid medium 2 is small； Three dissolution point respectively during when 0.5~3 is small, 0.75~6 it is small when during, 1.5~10 it is small when during；3 points of dissolution differences exist % in the range of 5~15%；The dissolution rate of other each medicines is also in desired scope；
After the disposal of the stability of 5 months：The disintegration time of various tablets, dissolution rate have no significant change, but hardness With friability significant change, each for decreasing value up to 1.3~2.1kg, less loss weight increases percentage 115~184% to hardness In the range of.
Comparative example 2a：With reference to more than comparative example 2, it by active ingredient therein (is not tamsulosin hydrochloride that different, which is only, ) tamsulosin hydrochloride is changed to, as a result various tablets and 2 respective tablets of comparative example are essentially identical, particularly sized particles content Than, hydroscopicity, stability disposal variation etc. it is essentially identical with comparative example 2.With reference to more than comparative example 2, but contain in addition Dutasteride's enteric-coated micro-pill obtained by 1 step of the embodiment of the present invention (3) is added in while medicine pellet (is wherein containing dutasteride's amount Every 1mg in gained tablet), the properties of gained oral disintegrating tablet and above-mentioned 2 result of comparative example are essentially identical.
More than comparative example 1, comparative example 1a, comparative example 2 and comparative example 2a according to the prior art as it can be seen that prepare Orally disintegrating Piece, the different size of particle of pellet core particle wherein active component content difference are more apparent；Although these tablets pass through precompressed A soft tablet is made, then by humidify-drying program or disposed by superhigh temperature for a long time-cooling program obtains There must be the tablet of desired hardness, but the hardness of this tablet and relative friability stability are unsatisfactory.
Comparative example 3：
With reference to the dispensing and preparation method of the embodiment of the present invention 1~8, unlike in the first step to prepare pellet core (such as real Apply tamsulosin hydrochloride particle obtained by 1 step of example (1)) when, wherein 80% water is replaced to use with the methanol of its 1.5 times of weight Methanol+Water (that is, for example, in 1 step of embodiment (1), its 2000g water is replaced to prepare drug-binder solution For water 400g and methanol 2400g), oral disintegrating tablet is then prepared in accordance with the law.
As a result：The sized particles content ratio of tamsulosin hydrochloride particle obtained by step (1), in the range of 0.84~0.91 Oral disintegrating tablets of the content uniformity CV% less than 4% is made and then needs to show when carrying out mixed eventually with lubricant and extends incorporation time (incorporation time is typically 3~4 times of Examples 1 to 8)；Before mixing is to obtain satisfied uniformity of dosage units for a long time herein Put, obtained tablet hardness, friability, hydroscopicity, disintegration time, dissolution rate, stability disposal etc. aspect of performance with Examples 1 to 8 tablet is without significant difference；But it so mixes to bring to technological requirements such as moisture-proof (avoiding moisture absorption) for a long time and choose War.
Comparative example 4：
With reference to the dispensing and preparation method of the embodiment of the present invention 1~8, the difference is that being mixed by coating micro-pill and sugar and/or sugar alcohol Close granulation or when coating micro-pill is mixed with the sugar through granulation and/or sugar alcohol particle, do not add salt, and during tabletting such as this A little embodiments are such, make tablet hardness up to the degree of 5.0~5.5kg on rotary pelleting machine with certain pressure, directly (without It is that first to apply a small pressure in advance as CN1473035B humidified again or heat) by these, mixed particle compacting hydrochloric acid is smooth eventually Rope sieve octyl- dutasteride's oral disnitegration tablet.
As a result：
Tablet hardness is in 4.8~6kg；
The content uniformity CV% of two kinds of active components is in the range of 1~2%；
Friability：There is the piece of fracture, cracking and crushing, less loss weight is in the range of 1.77~2.52%；
Hydroscopicity is in the range of 25.1~32.1%；
Disintegration time is respectively less than 45 seconds；
Dissolution rate and dissolution rate stability and oral disintegrating tablet no significant difference obtained by Examples 1 to 8；Subtract after stability is disposed Weight loss increases percentage up to 200~270%.These are the result shows that salt and first like that without reference to CN1473035B ought not be added A pre- small pressure of applying is humidified again or if heating, and the intensity of gained tablet is excessively poor, receives entirely without decree people.
Embodiment 2：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
(1) tamsulosin hydrochloride 80g, hydroxypropyl methyl cellulose 80g are dissolved in 2000g purified waters.Crystallite is fine The plain particle of dimension (Celphere102, Asahi Chemical Industry, average grain diameter is about 160 μm, more than 95% grain size is in 100-250 μ ms) 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the solution, obtains tamsulosin hydrochloride particle.
In addition, dutasteride 100g, hydroxypropyl methyl cellulose 80g are dissolved in 2000g purified waters.By microcrystalline cellulose Plain particle (Celphere102, Asahi Chemical Industry, average grain diameter is about 120 μm, more than 95% grain size is in 50-150 μ ms) 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the solution, obtains dutasteride's particle.
(2) then, ethyl cellulose (is ground and can crosses 200 mesh sieves) 550g and hydroxypropyl methyl cellulose 160g is added to In water 18000g, ethyl cellulose is strongly made to be suspended and dissolves HPMC, obtain sustained release coating suspension.By tamsulosin hydrochloride Particle 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the coating solution, is obtained tamsulosin hydrochloride and is delayed Release pellet.
(3) sustained release pellet 4000g is put into fluidized bed pelletizer again, with the lateral spray-on process Aquacoat (U.S. FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm Company system) 667g, the mixed liquor of purified water 6667g be coated, obtain tamsulosin hydrochloride enteric sustained-release pellet.
In addition, dutasteride's particle 4000g is put into fluidized bed pelletizer, it is (beautiful with Aquacoat with lateral spray-on process State FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm company systems) 667g, the mixed liquor of purified water 6667g be coated, obtain dutasteride's enteric-coated micro-pill.
(4) (it is that hydrochloric acid is smooth wherein containing dutasteride's amount by enteric solubility sustained release pellet 360g, dutasteride's enteric-coated micro-pill 1.25 times of Suo Luoxin amounts), mannitol 2400g, lactose 640g, potassium chloride 250g in fluidized bed pelletizer, with containing The 30%w/w aqueous solutions of the maltose of 350g are granulated and are dried and (are continuously spray-dried program), obtain particulate matter, and moisture contains Amount is less than 3%.
(5) particulate matter obtained by above step (4) with calcium stearate 30g is uniformly mixed, obtains mixed particle eventually, measure wherein The content of active ingredient for calculate every in include specified amount active ingredient when tablet weight, on rotary pelleting machine with Certain pressure makes tablet hardness, and up to the degree of 5.0~5.5kg, directly by these, mixed particle is pressed into every hydrochloric smooth rope eventually The tablet of Rosin 0.4mg/ dutasterides 0.5mg is to get oral disnitegration tablet.Gained tablet is simulated into commercially available product packaged form, it is close Package fills, you can.
The present embodiment intermediate material property and the physicochemical property of gained oral disnitegration tablet are measured, it is as a result as follows：
The sized particles content ratio of tamsulosin hydrochloride particle obtained by step (1)：0.98, the big granule of dutasteride's particle Sub- content ratio：1.00；
About 235 μm of Tamsulosin enteric sustained-release pellet average grain diameter, the grain size of more than 95% particle exist obtained by step (3) 150-350 μ ms, about 182 μm of dutasteride's enteric-coated micro-pill average grain diameter, the grain size of more than 95% particle are in 130-270 μm of model It encloses；
Hardness：4.8kg；
Content uniformity：Tamsulosin CV%=0.9%, dutasteride CV%=1.2%；
Friability：Without fracture, cracking and the piece crushed, less loss weight 0.38%；
Hydroscopicity：8.6%；
Disintegration time：20 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate 3.2% when acid medium 2 is small；When 3 dissolution points are respectively 1.63 small, 3.65 it is small when, 7.84 it is small when；3 points of dissolution differences are respectively 4.3%, 6.3%, 2.7%.Dutasteride：15 minutes dissolution rates of water 2.7%, neutral medium 50% dissolves out poor 7.7%.
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, it is only 11.6% that less loss weight, which increases percentage,.
Embodiment 3：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
(1) tamsulosin hydrochloride 80g, hydroxypropyl methyl cellulose 80g are dissolved in 2000g purified waters.Crystallite is fine The plain particle of dimension (Celphere102, Asahi Chemical Industry, average grain diameter is about 80 μm, more than 95% grain size is in 50-120 μ ms) 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the solution, obtains tamsulosin hydrochloride particle.
In addition, dutasteride's particle is prepared with reference to 2 step of embodiment (1) method.
(2) then, ethyl cellulose (is ground and can crosses 200 mesh sieves) 600g and hydroxypropyl methyl cellulose 180g is added to In water 20000g, ethyl cellulose is strongly made to be suspended and dissolves HPMC, obtain sustained release coating suspension.By tamsulosin hydrochloride Particle 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the coating solution, is obtained sustained release pellet.
(3) sustained release pellet 4000g is put into fluidized bed pelletizer again, with the lateral spray-on process Aquacoat (U.S. FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm Company system) 667g, the mixed liquor of purified water 6667g be coated, obtain enteric sustained-release pellet.
Dutasteride's enteric-coated micro-pill is prepared with reference to 2 step of embodiment (3) method.
(4) (it is that hydrochloric acid is smooth wherein containing dutasteride's amount by enteric solubility sustained release pellet 360g, dutasteride's enteric-coated micro-pill 1.25 times of Suo Luoxin amounts), mannitol 3000g, sodium dihydrogen phosphate 200g in fluidized bed pelletizer, with the sugarcane containing 300g The 25%w/w aqueous solutions of sugar are granulated and are dried and (are continuously spray-dried program), obtain particulate matter, and moisture is less than 3%.
(5) particulate matter obtained by above step (4) with calcium stearate 30g is uniformly mixed, obtains mixed particle eventually, measure wherein The content of active ingredient for calculate every in include specified amount active ingredient when tablet weight, on rotary pelleting machine with Certain pressure makes tablet hardness, and up to the degree of 5.0~5.5kg, directly by these, mixed particle is pressed into every hydrochloric smooth rope eventually The tablet of Rosin 0.4mg is to get oral disnitegration tablet.Gained tablet is simulated into commercially available product packaged form, is packed, you can.
The present embodiment intermediate material property and the physicochemical property of gained oral disnitegration tablet are measured, it is as a result as follows：
The sized particles content ratio of tamsulosin hydrochloride particle obtained by step (1)：1.02；
About 115 μm of enteric sustained-release pellet average grain diameter, the grain size of more than 95% particle are in 80-170 μm of model obtained by step (3) It encloses；
Hardness：6.1kg；
Content uniformity：Tamsulosin CV%=1.2%, dutasteride CV%=1.5%；
Friability：Without fracture, cracking and the piece crushed, less loss weight 0.24%；
Hydroscopicity：8.1%；
Disintegration time：30 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate 3.7% when acid medium 2 is small；When 3 dissolution points are respectively 1.61 small, 3.60 it is small when, 7.13 it is small when；3 points of dissolution differences are respectively 4.4%, 6.0%, 3.6%.Dutasteride：15 minutes dissolution rates of water 4.3%, neutral medium 50% dissolves out poor 6.4%.
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, it is only 8.4% that less loss weight, which increases percentage,.
Embodiment 4：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
(1) tamsulosin hydrochloride 80g, hydroxypropyl methyl cellulose 80g are dissolved in 2000g purified waters.Crystallite is fine The plain particle of dimension (Celphere102, Asahi Chemical Industry, average grain diameter is about 140 μm, more than 95% grain size is in 100-200 μ ms) 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the solution, obtains tamsulosin hydrochloride particle.
In addition, dutasteride's particle is prepared with reference to 2 step of embodiment (1) method.
(2) then, ethyl cellulose (is ground and can crosses 200 mesh sieves) 550g and hydroxypropyl methyl cellulose 160g is added to In water 20000g, ethyl cellulose is strongly made to be suspended and dissolves HPMC, obtain sustained release coating suspension.By tamsulosin hydrochloride Particle 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the coating solution, is obtained sustained release pellet.
(3) sustained release pellet 4000g is put into fluidized bed pelletizer again, with lateral spray-on process Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm company systems) 667g, purified water The mixed liquor of 10000g is coated, and obtains enteric sustained-release pellet.
Dutasteride's enteric-coated micro-pill is prepared with reference to 2 step of embodiment (3) method.
(4) (it is that hydrochloric acid is smooth wherein containing dutasteride's amount by enteric solubility sustained release pellet 360g, dutasteride's enteric-coated micro-pill 0.8 times of Suo Luoxin amounts), mannitol 3000g, dipotassium hydrogen phosphate 200g in fluidized bed pelletizer, with poly- containing 200g The 20%w/w aqueous solutions of vinylpyrrolidone are granulated and are dried and (are continuously spray-dried program), obtain particulate matter, and moisture contains Amount is less than 3%.
(5) particulate matter obtained by above step (4) with magnesium stearate 30g is uniformly mixed, obtains mixed particle eventually, measure wherein The content of active ingredient for calculate every in include specified amount active ingredient when tablet weight, on rotary pelleting machine with Certain pressure makes tablet hardness, and up to the degree of 5.0~5.5kg, directly by these, mixed particle is pressed into every hydrochloric smooth rope eventually The tablet of Rosin 0.4mg is to get oral disnitegration tablet.Gained tablet is simulated into commercially available product packaged form, is packed, you can.
The present embodiment intermediate material property and the physicochemical property of gained oral disnitegration tablet are measured, it is as a result as follows：
The sized particles content ratio of tamsulosin hydrochloride particle obtained by step (1)：1.01；
About 175 μm of enteric sustained-release pellet average grain diameter, the grain size of more than 95% particle are at 100-220 μm obtained by step (3) Scope；
Hardness：5.6kg；
Content uniformity：Tamsulosin CV%=1.3%, dutasteride CV%=1.0%；
Friability：Without fracture, cracking and the piece crushed, less loss weight 0.44%；
Hydroscopicity：10.2%；
Disintegration time：25 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate 2.6% when acid medium 2 is small；When 3 dissolution points are respectively 1.6 small, 3.7 it is small when, 7.3 it is small when；3 points of dissolution differences are respectively 4.1%, 6.3%, 4.3%.Dutasteride：15 minutes dissolution rates of water 3.1%, neutral medium 50% dissolves out poor 5.2%.
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, it is only 8.7% that less loss weight, which increases percentage,.
Embodiment 5：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
(1) hydroxypropyl methyl cellulose 80g is dissolved in 2000g purified waters.Tamsulosin hydrochloride 20g and crystallite is fine Dimension element 4000g is mixed together, crushes and crosses 200 mesh sieves, which is put into fluidized bed pelletizer, is carried out for HPMC solution Be granulated and dry (being continuously spray-dried program), obtain Tamsulosin particulate matter (average grain diameter is about 260 μm, more than 95% Grain size is in 150-350 μ ms), moisture is less than 3%；
In addition, hydroxypropyl methyl cellulose 80g is dissolved in 2000g purified waters.By dutasteride 25g and microcrystalline cellulose Plain 4000g is mixed together, crushes and crosses 200 mesh sieves, which is put into fluidized bed pelletizer, is made for HPMC solution Grain and drying (being continuously spray-dried program), obtaining dutasteride's particulate matter, (average grain diameter is about 260 μm, more than 95% grain Footpath is in 150-350 μ ms), moisture is less than 3%；
(2) then, ethyl cellulose (is ground and can crosses 200 mesh sieves) 550g and polyvinylpyrrolidone 120g adds to water In 20000g, ethyl cellulose is strongly made to be suspended and dissolves PVP, obtain sustained release coating suspension.By tamsulosin hydrochloride grain Sub- 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the coating solution, is obtained sustained release pellet.
(3) sustained release pellet 4000g is put into fluidized bed pelletizer again, with the lateral spray-on process Aquacoat (U.S. FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm Company system) 667g, the mixed liquor of purified water 6667g be coated, it is (after measured, active to obtain Tamsulosin enteric sustained-release pellet Component content 0.28%).
In addition, dutasteride's particulate matter 4000g obtained by step (1) is put into fluidized bed pelletizer, with lateral spray-on process With Aquacoat (U.S. FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 4000g, Eudragit NE30D (trade name, Rohm company systems) 667g, the mixed liquor of purified water 6667g are coated, and it is micro- to obtain dutasteride's enteric Ball.
(4) (it is salt wherein containing dutasteride's amount by Tamsulosin enteric sustained-release pellet 360g, dutasteride's enteric-coated micro-pill 3 times of sour Tamsulosin amount), mannitol 2400g, sorbierite 500g, disodium hydrogen phosphate 250g in fluidized bed pelletizer, use The 25%w/w aqueous solutions of trehalose containing 300g are granulated and are dried and (are continuously spray-dried program), obtain particulate matter, water Content is divided to be less than 3%.
(5) particulate matter obtained by above step (4) with magnesium stearate 30g is uniformly mixed, obtains mixed particle eventually, measure wherein The content of active ingredient for calculate every in include specified amount active ingredient when tablet weight, on rotary pelleting machine with Certain pressure makes tablet hardness, and up to the degree of 5.0~5.5kg, directly by these, mixed particle is pressed into every hydrochloric smooth rope eventually The tablet of Rosin 0.2mg is to get oral disnitegration tablet.Gained tablet is simulated into commercially available product packaged form, is packed, you can.
The present embodiment intermediate material property and the physicochemical property of gained oral disnitegration tablet are measured, it is as a result as follows：
The sized particles content ratio of tamsulosin hydrochloride particle obtained by step (1)：0.99, the big granule of dutasteride's particle Sub- content is than 0.98；
About 290 μm of enteric sustained-release pellet average grain diameter, the grain size of more than 95% particle are at 250-350 μm obtained by step (3) Scope, about 230 μm of dutasteride's pellet average grain diameter, the grain size of more than 95% particle are in 160-320 μ ms；
Hardness：5.2kg；
Content uniformity：Tamsulosin CV%=1.2%, dutasteride CV%=0.9%；
Friability：Without fracture, cracking and the piece crushed, less loss weight 0.41%；
Hydroscopicity：12.4%；
Disintegration time：41 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate 3.3% when acid medium 2 is small；When 3 dissolution points are respectively 2.26 small, 4.68 it is small when, 8.55 it is small when；3 points of dissolution differences are respectively 4.2%, 5.1%, 4.4%.Dutasteride：15 minutes dissolution rates of water 3.6%, neutral medium 50% dissolves out poor 8.2%.
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, it is only 13.5% that less loss weight, which increases percentage,.
Embodiment 6：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
(1) hydroxypropyl methyl cellulose 160g is dissolved in 2000g purified waters.By tamsulosin hydrochloride 200g and crystallite Cellulose 4000g be mixed together, crush and cross 200 mesh sieves, which is put into fluidized bed pelletizer, for HPMC solution into Row is granulated and drying (being continuously spray-dried program), and obtaining particulate matter, (average grain diameter is about 250 μm, more than 95% grain size exists 150-350 μ ms), moisture is less than 3%；
In addition, hydroxypropyl methyl cellulose 160g is dissolved in 2000g purified waters.By tamsulosin hydrochloride 250g and micro- Crystalline cellulose 4000g is mixed together, crushes and crosses 200 mesh sieves, which is put into fluidized bed pelletizer, for HPMC solution It is granulated and is dried and (be continuously spray-dried program), obtaining particulate matter, (average grain diameter is about 240 μm, more than 95% grain size In 150-350 μ ms), moisture is less than 3%；
(2) then, ethyl cellulose (is ground and can crosses 200 mesh sieves) 500g and hydroxypropyl methyl cellulose 120g is added to In water 20000g, ethyl cellulose is strongly made to be suspended and dissolves HPMC, obtain sustained release coating suspension.By tamsulosin hydrochloride Particle 4000g is put into fluidized bed pelletizer, is coated with lateral spray-on process with the coating solution, is obtained sustained release pellet.
(3) sustained release pellet 4000g is put into fluidized bed pelletizer again, with the lateral spray-on process Aquacoat (U.S. FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 3500g, Eudragit NE30D (trade name, Rohm Company system) 600g, the mixed liquor of purified water 6000g be coated, obtain enteric sustained-release pellet (after measured, active component content 4.2%).
In addition, dutasteride's particulate matter 4000g obtained by step (1) is put into fluidized bed pelletizer, with lateral spray-on process With Aquacoat (U.S. FMC) 2000g, Eudragit L30D55 (trade name, Rohm company systems) 3500g, Eudragit NE30D (trade name, Rohm company systems) 600g, the mixed liquor of purified water 6000g are coated, and it is micro- to obtain dutasteride's enteric Ball.
(4) (wherein it is containing dutasteride's amount by Tamsulosin enteric solubility sustained release pellet 250g, dutasteride's enteric-coated micro-pill 1.5 times of tamsulosin hydrochloride amount), mannitol 2500g, lactose 500g, potassium dihydrogen phosphate 200g in fluidized bed pelletizer, It is granulated and is dried and (be continuously spray-dried program) with the 25%w/w aqueous solutions of the sucrose containing 300g, obtain particulate matter, water Content is divided to be less than 3%.
(5) particulate matter obtained by above step (4) with calcium stearate 35g is uniformly mixed, obtains mixed particle eventually, measure wherein The content of active ingredient for calculate every in include specified amount active ingredient when tablet weight, on rotary pelleting machine with Certain pressure makes tablet hardness, and up to the degree of 5.0~5.5kg, directly by these, mixed particle is pressed into every hydrochloric smooth rope eventually The tablet of Rosin 0.4mg is to get oral disnitegration tablet.Gained tablet is simulated into commercially available product packaged form, is packed, you can.
The present embodiment intermediate material property and the physicochemical property of gained oral disnitegration tablet are measured, it is as a result as follows：
The sized particles content ratio of tamsulosin hydrochloride particle obtained by step (1)：0.98, the big granule of dutasteride's particle Sub- content is than 1.03；
About 290 μm of enteric sustained-release pellet average grain diameter, the grain size of more than 95% particle are at 250-340 μm obtained by step (3) Scope, about 255 μm of dutasteride's pellet average grain diameter, the grain size of more than 95% particle are in 180-330 μ ms；
Hardness：5.5kg；
Content uniformity：Tamsulosin CV%=1.3%, dutasteride CV%=0.7%；
Friability：Without fracture, cracking and the piece crushed, less loss weight 0.53%；
Hydroscopicity：9.1%；
Disintegration time：30 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate 4.3% when acid medium 2 is small；When 3 dissolution points are respectively 2.6 small, 5.7 it is small when, 8.7 it is small when；3 points of dissolution differences are respectively 3.1%, 4.3%, 4.1%.Dutasteride：15 minutes dissolution rates of water 3.1%, neutral medium 50% dissolves out poor 6.7%.
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, it is only 8.8% that less loss weight, which increases percentage,.
It in the experiment of supplement, is changed for above example 1-6, without pellet process processed, but by each system Pellet technique is changed to various solid materials are mixed with sugar/sugar alcohol, salt etc. directly in subsequent step can cross 120 mesh powders Merge granulation, mixed eventually with lubricant, tabletting.Although it turns out that tablet initial hardness so obtained, friability, hydroscopicity, Disintegration time etc. is without significant change, but hardness and friability have significant change, hardness drop after being disposed through the stability of 5 months Low and less loss weight increases percentage up to more than 120%.
Embodiment 7：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
Dispensing and technique substantially respectively refer to Examples 1 to 6, unlike：In step (4), salt is dissolved in bonding Fluidized bed pelletizer is used in agent solution.The physicochemical property of gained oral disnitegration tablet is as follows：
Hardness is in the range of 4~6kg；
The content uniformity CV% of two kinds of active components is in the range of 0.8~2.5%；
Friability：Without fracture, cracking and the piece crushed, less loss weight is in the range of 0.3~0.7%；
Hydroscopicity is respectively less than 12.5%；
Disintegration time is respectively less than 45 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate is respectively less than 15% when acid medium 2 is small；3 dissolution points respectively 0.5~ 3 it is small when during, 0.75~6 it is small when during, 1.5~10 it is small when during；3 points of dissolution differences are in the range of 0-12.5%.It is male to spend him Amine：15 minutes dissolution rates of water are respectively less than 15%, and neutral medium 50% dissolves out difference and is respectively less than 15%；
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, less loss weight increases percentage and is respectively less than 15%.
Embodiment 7a：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
Dispensing and technique substantially respectively refer to Examples 1 to 6, unlike：The not addition salt in step (4), and It is to mix salt in the stage of addition lubricant in the form of a powder to add in.Every physicochemical property of gained oral disnitegration tablet with The tablet of embodiment 7 is essentially identical.
Embodiment 8：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
Dispensing and technique substantially respectively refer to Examples 1 to 6, unlike：In step (4) and step (5), first make tax Shape agent sugar and/or sugar alcohol, salt are uniformly mixed, it in fluidized bed pelletizer is pelletized and dried with binder solution, Gained particulate matter is uniform with enteric solubility sustained release pellet and mix lubricant again, obtains mixed particle eventually, is then pressed according to step (5) Piece.The physicochemical property of gained oral disnitegration tablet is as follows：
The physicochemical property of gained oral disnitegration tablet is as follows：
Hardness is in the range of 4~6kg；
The content uniformity CV% of two kinds of active components is in the range of 0.8~2.5%；
Friability：Without fracture, cracking and the piece crushed, less loss weight is in the range of 0.3~0.6%；
Hydroscopicity is respectively less than 12%；
Disintegration time is respectively less than 40 seconds；
Dissolution rate：Tamsulosin hydrochloride：Dissolution rate is respectively less than 15% when acid medium 2 is small；3 dissolution points respectively 0.5~ 3 it is small when during, 0.75~6 it is small when during, 1.5~10 it is small when during；3 points of dissolution differences are in the range of 0-12.5%.It is male to spend him Amine：15 minutes dissolution rates of water are respectively less than 15%, and neutral medium 50% dissolves out difference and is respectively less than 13%；
After being disposed through the stability of 5 months, tablet：Hardness, friability, hydroscopicity, disintegration time, dissolution rate are without change Change, less loss weight increases percentage and is respectively less than 13%.
In addition, in the present embodiment 8, when being added to salt to be used for wet granulation in binder solution, so obtained by The physicochemical property of tablet and 8 tablet of above-described embodiment are essentially identical.
Embodiment 8a：Prepare tamsulosin hydrochloride-dutasteride's oral disnitegration tablet
Dispensing and technique substantially with reference to embodiment 8, unlike：The addition salt not in the step (4), but by salt It mixes and adds in the stage of addition lubricant in the form of a powder.Every physicochemical property of gained oral disnitegration tablet and embodiment 8 Tablet it is essentially identical.
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention It encloses without being limited thereto.The equivalent substitute or conversion that those skilled in the art are made on the basis of the present invention, in the present invention Protection domain within.Protection scope of the present invention is subject to claims.

Claims (10)

1. a kind of oral disnitegration tablet is the tablet formed by tablet forming technique compacting；The tablet includes being made of multiple auxiliary materials Tablet matrix and two kinds of coating micro-pills being essentially homogeneously scattered in the tablet matrix；Described two coating micro-pills Include the capsule core comprising two kinds of different activities ingredients and at least one layer of coating for being covered in the capsule core surface respectively.
2. oral disnitegration tablet according to claim 1, it is characterised in that any one of following or multinomial：
The active ingredient of the first coating micro-pill is Tamsulosin or its pharmaceutical salts；The activity of the first coating micro-pill Ingredient is Tamsulosin or its pharmaceutical salts, and the coating is one layer of sustained-release coating layer；The active ingredient of the first coating micro-pill It is Tamsulosin or its pharmaceutical salts, the coating is one layer of enteric coating layer；The active ingredient of the first coating micro-pill is smooth Suo Luoxin or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
The active ingredient of second of coating micro-pill is dutasteride or its pharmaceutical salts；The activity of second of coating micro-pill Ingredient is dutasteride or its pharmaceutical salts, and the coating is thin film clothing layer；The active ingredient of second of coating micro-pill It is dutasteride or its pharmaceutical salts, the coating is one layer of enteric coating layer；The active ingredient degree of being of second of coating micro-pill His male amine or its pharmaceutical salts, the coating are one layer of sustained-release coating layer；He is male for the active ingredient degree of being of second of coating micro-pill Amine or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
The active ingredient of the first coating micro-pill is tamsulosin hydrochloride, and the active ingredient of second of coating micro-pill is Dutasteride；
The weight of the first coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, such as 5~ 30%, such as 5~25%；
The weight of second of coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, such as 5~ 30%, such as 5~25%；
The weight of the active ingredient hydrochloric acid Tamsulosin accounts for the 0.1~10% of the first coating micro-pill total weight, such as 0.1~5%；
The weight of the active ingredient dutasteride accounts for the 0.1~10% of second of coating micro-pill total weight, such as 0.1~ 5%；
The average grain diameter of the first coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The average grain diameter of second of coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The active ingredient hydrochloric acid Tamsulosin is essentially homogeneously coated in the capsule core surface or the active ingredient base It is homogeneously dispersed on this in the capsule core, and then the pellet core is coated to obtain the first coating micro-pill；
The active ingredient dutasteride essentially homogeneously it is coated in the capsule core surface or the active ingredient substantially It is homogeneously dispersed in the capsule core, and then the pellet core is coated to obtain second of coating micro-pill；
The capsule core material of the first coating micro-pill is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sugarcane Sugar or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core material of second of coating micro-pill is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sugarcane Sugar or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core of the first described coating micro-pill and/or second of coating micro-pill is microcrystalline cellulose capsule core or sucrose ball；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is evenly coated in the capsule core surface；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is coated in the capsule core surface；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin passes through with gluing It is essentially homogeneously coated in the capsule core surface after mixture is compounded into solution or suspension；Prepare the solution or suspension Solvent in not include organic solvent；The solvent for preparing the solution or suspension is water；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, the active ingredient dutasteride by with adhesive It is essentially homogeneously coated in the capsule core surface after being compounded into solution or suspension；Prepare the molten of the solution or suspension Do not include organic solvent in agent；The solvent for preparing the solution or suspension is water；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；The active ingredient hydrochloric acid Tamsulosin added after mixing with microcrystalline cellulose containing Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of adhesive；Alternatively, add into microcrystalline cellulose Add the solution containing active ingredient hydrochloric acid Tamsulosin and adhesive or suspension with stirring-granulating method or fluidized bed prilling legal system Into capsule core；Preparing does not include organic solvent in the solvent of the solution or suspension；Prepare the solvent of the solution or suspension For water；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；The active ingredient dutasteride is added after mixing with microcrystalline cellulose containing adhesive Capsule core is made with stirring-granulating method or fluidized bed prilling method in solution or suspension；Alternatively, addition contains work into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of property ingredient dutasteride and adhesive；Prepare institute Stating does not include organic solvent in the solvent of solution or suspension；The solvent for preparing the solution or suspension is water；
It is polymer substance that it is each independent, which to be wherein used to prepare the described adhesives of described two capsule cores, is, for example, high water solubility Molecular substance, such as selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copolyvidone or poly- second Enol, and combinations thereof；
At least one layer of coating on described two coating micro-pill surfaces is each independently selected from：It is film-coating, enteric coating, clothing soluble in the stomach, slow Release clothing, controlled release clothing and combinations thereof；
When preparing any one or two kinds of coating micro-pills, using only water without using organic solvent as preparation adhesive The solvent of solution or coating solution；
Forming the auxiliary material of the tablet matrix includes the excipient selected from following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, Maltose, trehalose, sorbierite, maltitol, xylitol, erythrite, glucose, and combinations thereof；
The piece of oral disnitegration tablet is 60~600mg again, particularly 75~500mg, particularly 100~500mg；
Forming the auxiliary material of the tablet matrix includes adhesive；Described adhesive is used when can be with preparing coating micro-pill to glue Mixture is identical；Described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol；
The adhesive for forming the tablet matrix is selected from following one or more：Maltose, trehalose, D-sorbite, wheat Bud sugar alcohol, glucose, xylitol, erythrite, mannitol, sucrose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, poly- second Alkene pyrrolidone, copolyvidone or polyvinyl alcohol；
The auxiliary material for forming the tablet matrix may also include disintegrant.Typical disintegrant is such as, but not limited to：Cornstarch, carboxylic Methylcellulose calcium, pregelatinized starch, crosslinked polyvinylpyrrolidone, sodium starch glycollate, croscarmellose sodium are handed over Join povidone, low degree of substitution hydroxypropyl cellulose etc.；
The auxiliary material for forming the tablet matrix may also include the additives such as sweetener, colorant；
The auxiliary material for forming the tablet matrix is further included selected from following salt：Sodium chloride, potassium chloride, sodium dihydrogen phosphate, phosphoric acid Disodium hydrogen, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof；
The weight of the salt can be the 1~15% of Orally disintegrating sheet weight, such as the weight of the salt can be Orally disintegrating The 2~10% of sheet weight, such as the weight of the salt can be the 2.5~10% of Orally disintegrating sheet weight；
The auxiliary material for forming the tablet matrix may also include lubricant, and workable lubricant is selected from：Magnesium stearate, stearic acid Calcium, sucrose fatty ester, polyethylene glycol, talcum powder, stearic acid etc. and combinations thereof；
Forming the auxiliary material of the tablet matrix includes：Excipient, adhesive, salt, lubricant.
3. oral disnitegration tablet according to claim 1, it is characterised in that any one of following or multinomial：
It is prepared by a method comprising the following steps to obtain：By two kinds of coating micro-pills and excipient made from the difference Mixing, sprays into binder solution into the mixed material using fluidized bed granulation process and carries out making wet granular and drying (medicament system It makes well known to field technology personnel, typically, the dry moisture caused in material is less than 5%, especially less than 4%, Especially less than 3%), lubricant is added into gained dry particle, be uniformly mixed, tabletting；When it is present, the salt can To be added by way of being mixed together with excipient with coating micro-pill；When it is present, the salt can be by being added to Mode in binder solution is added；When it is present, the salt was added in the form of a powder in the stage of addition lubricant Add；
It is prepared by a method comprising the following steps to obtain：Bonding is sprayed into excipient using fluidized bed granulation process Agent solution carries out making wet granular and drying is (typically, dry so that in material well known to medicament manufacturing field technical staff Moisture is less than 5%, especially less than 4%, especially less than 3%), into gained dry particle two made from addition difference Kind coating micro-pill and lubricant are uniformly mixed, tabletting；When it is present, the salt can be by making after being mixed with excipient The mode of standby particle is added；When it is present, the salt can be added by way of being added in binder solution；When depositing When, the salt be addition lubricant stage add in the form of a powder.
4. oral disnitegration tablet according to claim 1, it is characterised in that any one of following or multinomial：
It is according to the rule under Chinese Pharmacopoeia four general rules of version in 2015 " 0921 disintegration time limited inspection technique " and " oral disintegrating tablet " item therein Fixed, the disintegration time limited that replication is 6,6 were all disintegrated in 60 seconds and pass through sieve；Particularly 6 in 45 seconds All it is disintegrated and passes through sieve；Particularly 6 were all disintegrated in 30 seconds and pass through sieve；
It measures the crisp of tablet according to the method under Chinese Pharmacopoeia four general rules of version in 2015 " 0923 tablet friability inspection technique " item Broken degree, no fracture, cracking and the piece crushed, and less loss weight is less than 3%, is, for example, less than 2%, is, for example, less than 1.5%, such as Less than 1%；
Its according to United States Pharmacopeia USP35-NF30 editions "<1217>The method of TABLET BREAKING FORCE " measures the hard of tablet Degree, value is in the range of 3~6kg, such as in the range of 4~6kg；
It measures its hydroscopicity according to following method, hydroscopicity be less than 20% (be, for example, less than 15%, be, for example, less than 12.5%, such as Less than 10%)：Take the tablet of 5.0~5.5g of total weight, precise weighing；Make it flat auxiliary and expose to the open air in 25 DEG C of temperature, relative humidity 75% condition assign 24 it is small when, precise weighing；Hydroscopicity is calculated as follows：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%；
It shines the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with acid medium (water and with salt acid for adjusting pH value 1.2) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, in 15 minutes for dissolution medium Tamsulosin hydrochloride dissolution rate is less than 20%, is, for example, less than 15%；
It shines the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when During when period, particularly 0.5~3 are small；
It shines the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 50% measure after present dissolution test starts 0.5~8 it is small when During when period, particularly 0.75~6 are small；
It shines the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach for 80% 1~12 small period measured after present dissolution test starts Between, particularly 1.5~9 it is small when during；；
It shines the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with neutral medium (disodium phosphate soln of 0.02mol/L is simultaneously adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% measure after present dissolution test starts 0.25~4 it is small when Period when small (particularly 0.5~3 during), tamsulosin hydrochloride dissolution rate reach 50% and measure after present dissolution test starts 0.5~8 it is small when during when small (particularly 0.75~6 during), tamsulosin hydrochloride dissolution rate reaches 80% and measures now Dissolution test start after 1~12 it is small when during when small (particularly 1.5~10 during)；
The first coating micro-pill described in before being contacted with the material of the tablet matrix (i.e. tamsulosin hydrochloride coating micro-pill, It is after each layer coating is completed, the state before subsequent non-coated operating procedure is carried out), according to Chinese Pharmacopoeia version four in 2015 3rd method of portion's general rule " 0931 dissolution rate and drug release determination method ", with the neutral medium (disodium phosphate soln of 0.02mol/L And adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, in pH value 6.8 for dissolution medium Tamsulosin hydrochloride dissolution rate in neutral dissolution medium is shown as 30%, 50%, 80% each time point, the first coating The absolute value of the difference of the dissolution rate of pellet and the tamsulosin hydrochloride dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly In the range of 0-12.5%；
It shines the 3rd method of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method ", with water 250ml For dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%；
Before being contacted with the material of the tablet matrix the coating micro-pill (i.e. coating micro-pill after the coating of each layer is completed, Carry out the state before subsequent non-coated operating procedure), according to four general rules of Chinese Pharmacopoeia version in 2015, " 0931 dissolution rate is with releasing 3rd method of degree of putting measuring method ", with neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, and 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time The absolute value of the difference of point, the dissolution rate of coating micro-pill and the dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly in 0- In the range of 12.5%；
What it was substantially prepared according to the method included the following steps：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described active ingredient It is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made；Make Two kinds of active ingredients are essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially uniform Ground is scattered in the capsule core, then gained pellet core is coated, and second of coating micro-pill is made；With
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting；
Wherein step ii) it is performed according to following operation：
Iia) described two coating micro-pills with excipient are mixed, is sprayed into and glued into the mixed material using fluidized bed granulation process Mixture solution carries out making wet granular and drying, and lubricant is added into gained dry particle, is uniformly mixed, tabletting；Wherein, it is described Salt can be added by way of being mixed together with excipient with coating micro-pill or the salt can pass through addition Mode into binder solution is added or the salt was added in the form of a powder in the stage of addition lubricant 's；
Wherein step ii) it is performed according to following operation：
Iib binder solution) is sprayed into excipient using fluidized bed granulation process to carry out making wet granular and drying, is done to gained Two kinds of coating micro-pills and lubricant are added in dry particle, is uniformly mixed, tabletting；Wherein, the salt can by with figuration The mode that particle is prepared after agent mixing is added or the salt can be added by way of being added in binder solution Add or the salt was added in the form of a powder in the stage of addition lubricant.
5. preparing the method for oral disnitegration tablet, this method suppresses oral disnitegration tablet by tablet forming technique；The tablet is included by a variety of The tablet matrix of auxiliary material composition and two kinds of coating micro-pills being essentially homogeneously scattered in the tablet matrix；It is described two Coating micro-pill includes the capsule core comprising two kinds of different activities ingredients and at least one layer of coating for being covered in the capsule core surface respectively.
6. method according to claim 5, it is characterised in that any one of following or multinomial：
It includes the following steps：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described active ingredient It is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made；Make Two kinds of active ingredients are essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially uniform Ground is scattered in the capsule core, then gained pellet core is coated, and second of coating micro-pill is made；With
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting；
Wherein step ii) it is performed according to following operation：
Iia) described two coating micro-pills with excipient are mixed, is sprayed into and glued into the mixed material using fluidized bed granulation process Mixture solution carries out making wet granular and drying, and lubricant is added into gained dry particle, is uniformly mixed, tabletting；Or
Iib binder solution) is sprayed into excipient using fluidized bed granulation process to carry out making wet granular and drying, is done to gained Two kinds of coating micro-pills and lubricant are added in dry particle, is uniformly mixed, tabletting；
The active ingredient of wherein the first coating micro-pill is Tamsulosin or its pharmaceutical salts；The first coating micro-pill it is described Active ingredient is Tamsulosin or its pharmaceutical salts, and the coating is one layer of sustained-release coating layer；The activity of the first coating micro-pill Ingredient is Tamsulosin or its pharmaceutical salts, and the coating is one layer of enteric coating layer；The active ingredient of the first coating micro-pill It is Tamsulosin or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
The active ingredient of wherein second coating micro-pill is dutasteride or its pharmaceutical salts；Second coating micro-pill it is described Active ingredient is dutasteride or its pharmaceutical salts, and the coating is thin film clothing layer；The activity of second of coating micro-pill Ingredient is dutasteride or its pharmaceutical salts, and the coating is one layer of enteric coating layer；The active ingredient of second of coating micro-pill It is dutasteride or its pharmaceutical salts, the coating is one layer of sustained-release coating layer；The active ingredient degree of being of second of coating micro-pill His male amine or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
Active ingredient wherein in the first coating micro-pill is tamsulosin hydrochloride, and the active ingredient in second of coating micro-pill is Dutasteride；
The weight of the first coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, such as 5~ 30%, such as 5~25%；
The weight of wherein described second of coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, example Such as 5~30%, such as 5~25%；
The weight of wherein described active ingredient hydrochloric acid Tamsulosin accounts for the 0.1~10% of the first coating micro-pill total weight, Such as 0.1~5%；
The weight of wherein described active ingredient dutasteride accounts for the 0.1~10% of second of coating micro-pill total weight, such as 0.1~5%；
The average grain diameter of the first wherein described coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The average grain diameter of wherein described second of coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The capsule core material of the first wherein described coating micro-pill be selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its Ball, sucrose or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core material of wherein described second of coating micro-pill be selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its Ball, sucrose or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core of the first wherein described coating micro-pill and/or second of coating micro-pill is microcrystalline cellulose capsule core or sucrose ball；
The capsule core of the first wherein described coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is basic On it is equably coated in the capsule core surface；
The capsule core of wherein described second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is substantially equal It is evenly coated in the capsule core surface；
The capsule core of the first wherein described coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin passes through It is essentially homogeneously coated in the capsule core surface after being compounded into solution or suspension with adhesive；
The capsule core of wherein described second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride passes through with gluing It is essentially homogeneously coated in the capsule core surface after mixture is compounded into solution or suspension；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；The active ingredient hydrochloric acid Tamsulosin added after mixing with microcrystalline cellulose containing Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of adhesive；Alternatively, add into microcrystalline cellulose Add the solution containing active ingredient hydrochloric acid Tamsulosin and adhesive or suspension with stirring-granulating method or fluidized bed prilling legal system Into capsule core；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；The active ingredient dutasteride is added after mixing with microcrystalline cellulose containing adhesive Capsule core is made with stirring-granulating method or fluidized bed prilling method in solution or suspension；Alternatively, addition contains work into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of property ingredient dutasteride and adhesive；
It is polymer substance that it is each independent, which to be used to prepare the described adhesives of described two capsule cores, is, for example, water soluble polymer Substance, for example, selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol, And combinations thereof.Certainly, above-mentioned polymer substance can also be as the adhesive of other steps；
At least one layer of coating on the coating micro-pill surface is selected from：Film-coating, enteric coating, clothing soluble in the stomach, extended release coatings, controlled release clothing and its Combination；
When preparing the coating micro-pill, using only water without using organic solvent as preparing binder solution or coating solution Solvent；
Forming the auxiliary material of the tablet matrix includes the excipient selected from following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, Maltose, trehalose, sorbierite, maltitol, xylitol, erythrite, glucose, and combinations thereof.Particularly this excipient It is preferable to use the combinations of above-mentioned one or more sugar and/or sugar alcohol；
Forming the auxiliary material of the tablet matrix includes adhesive；Described adhesive is used when can be with preparing coating micro-pill to glue Mixture is identical；Described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol；
The auxiliary material for forming the tablet matrix may also include disintegrant.Typical disintegrant is such as, but not limited to：Cornstarch, carboxylic Methylcellulose calcium, pregelatinized starch, crosslinked polyvinylpyrrolidone, sodium starch glycollate, croscarmellose sodium are handed over Join povidone, low degree of substitution hydroxypropyl cellulose etc.；
The auxiliary material for forming the tablet matrix may also include the additives such as sweetener, colorant；
The auxiliary material for forming the tablet matrix is further included selected from following salt：Sodium chloride, potassium chloride, sodium dihydrogen phosphate, phosphoric acid Disodium hydrogen, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof；
The auxiliary material for forming the tablet matrix may also include lubricant；Workable lubricant is selected from：Magnesium stearate, stearic acid Calcium, sucrose fatty ester, polyethylene glycol, talcum powder, stearic acid etc. and combinations thereof；
Forming the auxiliary material of the tablet matrix includes：Excipient, adhesive, salt, lubricant；
The oral disnitegration tablet is prepared by a method comprising the following steps to obtain：By two kinds of coatings made from the difference Pellet is mixed with excipient, and spraying into binder solution into the mixed material using fluidized bed granulation process make wet granular simultaneously It is dry, lubricant is added into gained dry particle, is uniformly mixed, tabletting；When it is present, the salt can by with tax The mode that shape agent mixes together with coating micro-pill is added；When it is present, the salt can be by being added to binder solution In mode add；When it is present, the salt was added in the form of a powder in the stage of addition lubricant；
The oral disnitegration tablet is prepared by a method comprising the following steps to obtain：Using fluidized bed granulation process to figuration It sprays into binder solution in agent to carry out making wet granular and drying, into gained dry particle, two kinds of coatings made from addition difference are micro- Ball and lubricant are uniformly mixed, tabletting；When it is present, the salt can be by preparing particle after being mixed with excipient Mode is added；When it is present, the salt can be added by way of being added in binder solution；When it is present, institute The salt stated was added in the form of a powder in the stage of addition lubricant；
The oral disnitegration tablet is according to Chinese Pharmacopoeia four general rules of version in 2015 " 0921 disintegration time limited inspection technique " and therein " mouth collapses Regulation under piece " item, the disintegration time limited that replication is 6,6 were all disintegrated in 60 seconds and pass through sieve；Particularly 6 It was all disintegrated in 45 seconds and passes through sieve；Particularly 6 were all disintegrated in 30 seconds and pass through sieve；
The oral disnitegration tablet is according to the method under Chinese Pharmacopoeia four general rules of version in 2015 " 0923 tablet friability inspection technique " item The friability of tablet, no fracture, cracking and the piece crushed are measured, and less loss weight is less than 3%, is, for example, less than 2%, for example (,) it is small It is, for example, less than 1% in 1.5%；
The oral disnitegration tablet according to United States Pharmacopeia USP35-NF30 editions "<1217>The method of TABLET BREAKING FORCE " is surveyed The hardness of stator agent, value is in the range of 3~6kg, such as in the range of 4~6kg；
The oral disnitegration tablet measures its hydroscopicity according to following method, and hydroscopicity (is, for example, less than 15%, is, for example, less than less than 20% 12.5%, it is, for example, less than 10%)：Take the tablet of 5.0~5.5g of total weight, precise weighing；Make it flat auxiliary and expose to the open air in temperature 25 DEG C, 75% condition of relative humidity assign 24 it is small when, precise weighing；Hydroscopicity is calculated as follows：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method carries out Dissolution Rate Testing, 50 revs/min of rotating speed using acid medium (water and with salt acid for adjusting pH value 1.2) 250ml as dissolution medium Clock, tamsulosin hydrochloride dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% and measure after present dissolution test starts 0.25~4 it is small when during, particularly 0.5~3 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 50% and measure after present dissolution test starts 0.5~8 it is small when during, particularly 0.75~6 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 80% and measure after present dissolution test starts 1~12 it is small when during, particularly 1.5~9 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% and measure after present dissolution test starts 0.25~4 it is small when during when small (particularly 0.5~3 during), tamsulosin hydrochloride dissolution rate reaches 50% and measures now Dissolution test start after 0.5~8 it is small when during when small (particularly 0.75~6 during), tamsulosin hydrochloride dissolution rate reaches Measure after present dissolution test starts the 1~12 of 80% it is small when during when small (particularly 1.5~10 during)；
The first coating micro-pill described in before being contacted with the material of the tablet matrix (i.e. tamsulosin hydrochloride coating micro-pill, It is after each layer coating is completed, the state before subsequent non-coated operating procedure is carried out), according to Chinese Pharmacopoeia version four in 2015 3rd method of portion's general rule " 0931 dissolution rate and drug release determination method ", with the neutral medium (disodium phosphate soln of 0.02mol/L And adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, in pH value 6.8 for dissolution medium Tamsulosin hydrochloride dissolution rate in neutral dissolution medium is shown as 30%, 50%, 80% each time point, the first coating The absolute value of the difference of the dissolution rate of pellet and the tamsulosin hydrochloride dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly In the range of 0-12.5%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using water 250ml as dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is less than 20% in 15 minutes, such as small In 15%；
Before being contacted with the material of the tablet matrix the coating micro-pill (i.e. coating micro-pill after the coating of each layer is completed, Carry out the state before subsequent non-coated operating procedure), according to four general rules of Chinese Pharmacopoeia version in 2015, " 0931 dissolution rate is with releasing 3rd method of degree of putting measuring method ", with neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, and 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time The absolute value of the difference of point, the dissolution rate of coating micro-pill and the dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly in 0- In the range of 12.5%.
7. pair oral disnitegration tablet improves hardness and improves the method for disintegrating property, this method suppresses Orally disintegrating by tablet forming technique Piece；The tablet includes the tablet matrix being made of multiple auxiliary materials and be essentially homogeneously scattered in the tablet matrix two Kind coating micro-pill；Described two coating micro-pills include the capsule core comprising two kinds of different activities ingredients and are covered in the capsule core respectively At least one layer of coating on surface, the auxiliary material for forming tablet matrix include salt.
8. method according to claim 7, it is characterised in that any one of following or multinomial：
The salt is selected from：Sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, And combinations thereof；
The method for preparing the oral disnitegration tablet includes the following steps：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described active ingredient It is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made；Make Two kinds of active ingredients are essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially uniform Ground is scattered in the capsule core, then gained pellet core is coated, and second of coating micro-pill is made；With
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting；
Step ii) it is performed according to following operation：
Iia) described two coating micro-pills with excipient are mixed, is sprayed into and glued into the mixed material using fluidized bed granulation process Mixture solution carries out making wet granular and drying, and lubricant is added into gained dry particle, is uniformly mixed, tabletting；Or
Iib binder solution) is sprayed into excipient using fluidized bed granulation process to carry out making wet granular and drying, is done to gained Two kinds of coating micro-pills and lubricant are added in dry particle, is uniformly mixed, tabletting；
The active ingredient of wherein the first coating micro-pill is Tamsulosin or its pharmaceutical salts；The first coating micro-pill it is described Active ingredient is Tamsulosin or its pharmaceutical salts, and the coating is one layer of sustained-release coating layer；The activity of the first coating micro-pill Ingredient is Tamsulosin or its pharmaceutical salts, and the coating is one layer of enteric coating layer；The active ingredient of the first coating micro-pill It is Tamsulosin or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
The active ingredient of wherein second coating micro-pill is dutasteride or its pharmaceutical salts；Second coating micro-pill it is described Active ingredient is dutasteride or its pharmaceutical salts, and the coating is thin film clothing layer；The activity of second of coating micro-pill Ingredient is dutasteride or its pharmaceutical salts, and the coating is one layer of enteric coating layer；The active ingredient of second of coating micro-pill It is dutasteride or its pharmaceutical salts, the coating is one layer of sustained-release coating layer；The active ingredient degree of being of second of coating micro-pill His male amine or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
Active ingredient wherein in the first coating micro-pill is tamsulosin hydrochloride, and the active ingredient in second of coating micro-pill is Dutasteride；
The weight of the first wherein described coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, example Such as 5~30%, such as 5~25%；
The weight of wherein described second of coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, example Such as 5~30%, such as 5~25%；
The weight of wherein described active ingredient hydrochloric acid Tamsulosin accounts for the 0.1~10% of the first coating micro-pill total weight, Such as 0.1~5%；
The weight of the active ingredient dutasteride accounts for the 0.1~10% of second of coating micro-pill total weight, such as 0.1~ 5%；
The average grain diameter of the first coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The average grain diameter of second of coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The capsule core material of the first coating micro-pill is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sugarcane Sugar or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core material of second of coating micro-pill is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sugarcane Sugar or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core of the first described coating micro-pill and/or second of coating micro-pill is microcrystalline cellulose capsule core or sucrose ball；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is evenly coated in the capsule core surface；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is coated in the capsule core surface；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin passes through with gluing It is essentially homogeneously coated in the capsule core surface after mixture is compounded into solution or suspension；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, the active ingredient dutasteride by with adhesive It is essentially homogeneously coated in the capsule core surface after being compounded into solution or suspension；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；The active ingredient hydrochloric acid Tamsulosin added after mixing with microcrystalline cellulose containing Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of adhesive；Alternatively, add into microcrystalline cellulose Add the solution containing active ingredient hydrochloric acid Tamsulosin and adhesive or suspension with stirring-granulating method or fluidized bed prilling legal system Into capsule core；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；The active ingredient dutasteride is added after mixing with microcrystalline cellulose containing adhesive Capsule core is made with stirring-granulating method or fluidized bed prilling method in solution or suspension；Alternatively, addition contains work into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of property ingredient dutasteride and adhesive；
It is polymer substance that it is each independent, which to be used to prepare the described adhesives of described two capsule cores, such as selected from hydroxypropyl methyl Cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol, and combinations thereof；
At least one layer of coating on the coating micro-pill surface is selected from：Film-coating, enteric coating, clothing soluble in the stomach, extended release coatings, controlled release clothing and its Combination；
When preparing the coating micro-pill, using only water without using organic solvent as preparing binder solution or coating solution Solvent；
Forming the auxiliary material of the tablet matrix includes the excipient selected from following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, Maltose, trehalose, sorbierite, maltitol, xylitol, erythrite, glucose, and combinations thereof.Particularly this excipient It is preferable to use the combinations of above-mentioned one or more sugar and/or sugar alcohol；
Forming the auxiliary material of the tablet matrix includes adhesive；Described adhesive is used when can be with preparing coating micro-pill to glue Mixture is identical；Described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol；
The auxiliary material for forming the tablet matrix may also include disintegrant；Typical disintegrant is such as, but not limited to：Cornstarch, carboxylic Methylcellulose calcium, pregelatinized starch, crosslinked polyvinylpyrrolidone, sodium starch glycollate, croscarmellose sodium are handed over Join povidone, low degree of substitution hydroxypropyl cellulose etc.；
The auxiliary material for forming the tablet matrix may also include the additives such as sweetener, colorant；
The auxiliary material for forming the tablet matrix may also include lubricant.Lubricant containing convention amount is for tablet appearance and prevents Sticking is beneficial；Workable lubricant is selected from：Magnesium stearate, calcium stearate, sucrose fatty ester, polyethylene glycol, talcum Powder, stearic acid etc. and combinations thereof；
Forming the auxiliary material of the tablet matrix includes：Excipient, adhesive, salt, lubricant；
The oral disnitegration tablet is prepared by a method comprising the following steps to obtain：By two kinds of coatings made from the difference Pellet is mixed with excipient, and spraying into binder solution into the mixed material using fluidized bed granulation process make wet granular simultaneously It is dry, lubricant is added into gained dry particle, is uniformly mixed, tabletting；When it is present, the salt can by with tax The mode that shape agent mixes together with coating micro-pill is added；When it is present, the salt can be by being added to binder solution In mode add；When it is present, the salt was added in the form of a powder in the stage of addition lubricant；
The oral disnitegration tablet is prepared by a method comprising the following steps to obtain：Using fluidized bed granulation process to figuration It sprays into binder solution in agent to carry out making wet granular and drying, into gained dry particle, two kinds of coatings made from addition difference are micro- Ball and lubricant are uniformly mixed, tabletting；When it is present, the salt can be by preparing particle after being mixed with excipient Mode is added；When it is present, the salt can be added by way of being added in binder solution；When it is present, institute The salt stated was added in the form of a powder in the stage of addition lubricant；
The oral disnitegration tablet is according to Chinese Pharmacopoeia four general rules of version in 2015 " 0921 disintegration time limited inspection technique " and therein " mouth collapses Regulation under piece " item, the disintegration time limited that replication is 6,6 were all disintegrated in 60 seconds and pass through sieve；Particularly 6 It was all disintegrated in 45 seconds and passes through sieve；Particularly 6 were all disintegrated in 30 seconds and pass through sieve；
The oral disnitegration tablet is according to the method under Chinese Pharmacopoeia four general rules of version in 2015 " 0923 tablet friability inspection technique " item The friability of tablet, no fracture, cracking and the piece crushed are measured, and less loss weight is less than 3%, is, for example, less than 2%, for example (,) it is small It is, for example, less than 1% in 1.5%；
The oral disnitegration tablet according to United States Pharmacopeia USP35-NF30 editions "<1217>The method of TABLET BREAKING FORCE " is surveyed The hardness of stator agent, value is in the range of 3~6kg, such as in the range of 4~6kg；
The oral disnitegration tablet measures its hydroscopicity according to following method, and hydroscopicity (is, for example, less than 15%, is, for example, less than less than 20% 12.5%, it is, for example, less than 10%)：Take the tablet of 5.0~5.5g of total weight, precise weighing；Make it flat auxiliary and expose to the open air in temperature 25 DEG C, 75% condition of relative humidity assign 24 it is small when, precise weighing；Hydroscopicity is calculated as follows：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method carries out Dissolution Rate Testing, 50 revs/min of rotating speed using acid medium (water and with salt acid for adjusting pH value 1.2) 250ml as dissolution medium Clock, tamsulosin hydrochloride dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% and measure after present dissolution test starts 0.25~4 it is small when during, particularly 0.5~3 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 50% and measure after present dissolution test starts 0.5~8 it is small when during, particularly 0.75~6 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 80% and measure after present dissolution test starts 1~12 it is small when during, particularly 1.5~9 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% and measure after present dissolution test starts 0.25~4 it is small when during when small (particularly 0.5~3 during), tamsulosin hydrochloride dissolution rate reaches 50% and measures now Dissolution test start after 0.5~8 it is small when during when small (particularly 0.75~6 during), tamsulosin hydrochloride dissolution rate reaches Measure after present dissolution test starts the 1~12 of 80% it is small when during when small (particularly 1.5~10 during)；
The first coating micro-pill described in before being contacted with the material of the tablet matrix (i.e. tamsulosin hydrochloride coating micro-pill, It is after each layer coating is completed, the state before subsequent non-coated operating procedure is carried out), according to Chinese Pharmacopoeia version four in 2015 3rd method of portion's general rule " 0931 dissolution rate and drug release determination method ", with the neutral medium (disodium phosphate soln of 0.02mol/L And adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, in pH value 6.8 for dissolution medium Tamsulosin hydrochloride dissolution rate in neutral dissolution medium is shown as 30%, 50%, 80% each time point, the first coating The absolute value of the difference of the dissolution rate of pellet and the tamsulosin hydrochloride dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly In the range of 0-12.5%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using water 250ml as dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is less than 20% in 15 minutes, such as small In 15%；
Before being contacted with the material of the tablet matrix the coating micro-pill (i.e. coating micro-pill after the coating of each layer is completed, Carry out the state before subsequent non-coated operating procedure), according to four general rules of Chinese Pharmacopoeia version in 2015, " 0931 dissolution rate is with releasing 3rd method of degree of putting measuring method ", with neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, and 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time The absolute value of the difference of point, the dissolution rate of coating micro-pill and the dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly in 0- In the range of 12.5%.
9. purposes of the salt in the oral disnitegration tablet with high rigidity and fast disintegration property is prepared, the oral disnitegration tablet lead to Cross tablet forming technique compacting；The oral disnitegration tablet includes the tablet matrix being made of multiple auxiliary materials and essentially homogeneously divides Dissipate two kinds of coating micro-pills in the tablet matrix；Described two coating micro-pills are included respectively comprising two kinds of different activities ingredients Capsule core and at least one layer of coating for being covered in the capsule core surface；The salt is added to as auxiliary material in the tablet matrix.
10. purposes according to claim 9, it is characterised in that any one of following or multinomial：
The salt is selected from：Sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, And combinations thereof；
The method for preparing the oral disnitegration tablet includes the following steps：
I) make the first active ingredient is essentially homogeneously coated in the capsule core surface or to make the first described active ingredient It is essentially homogeneously scattered in the capsule core, then gained pellet core is coated, the first coating micro-pill is made；Make Two kinds of active ingredients are essentially homogeneously coated in the capsule core surface or to make the second active ingredient substantially uniform Ground is scattered in the capsule core, then gained pellet core is coated, and second of coating micro-pill is made；With
Ii) described two coating micro-pills are mixed with the auxiliary material of the salt and the formation tablet matrix, tabletting；
Step ii) it is performed according to following operation：
Iia) described two coating micro-pills with excipient are mixed, is sprayed into and glued into the mixed material using fluidized bed granulation process Mixture solution carries out making wet granular and drying, and lubricant is added into gained dry particle, is uniformly mixed, tabletting；Wherein, it is described Salt can be added by way of being mixed together with excipient with coating micro-pill or the salt can pass through addition Mode into binder solution is added or the salt was added in the form of a powder in the stage of addition lubricant 's；
Step ii) it is performed according to following operation：
Iib binder solution) is sprayed into excipient using fluidized bed granulation process to carry out making wet granular and drying, is done to gained Two kinds of coating micro-pills and lubricant are added in dry particle, is uniformly mixed, tabletting；Wherein, the salt can by with figuration The mode that particle is prepared after agent mixing is added or the salt can be added by way of being added in binder solution Add or the salt was added in the form of a powder in the stage of addition lubricant；
The active ingredient of the first coating micro-pill is Tamsulosin or its pharmaceutical salts；The activity of the first coating micro-pill Ingredient is Tamsulosin or its pharmaceutical salts, and the coating is one layer of sustained-release coating layer；The active ingredient of the first coating micro-pill It is Tamsulosin or its pharmaceutical salts, the coating is one layer of enteric coating layer；The active ingredient of the first coating micro-pill is smooth Suo Luoxin or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
The active ingredient of second of coating micro-pill is dutasteride or its pharmaceutical salts；The activity of second of coating micro-pill Ingredient is dutasteride or its pharmaceutical salts, and the coating is thin film clothing layer；The active ingredient of second of coating micro-pill It is dutasteride or its pharmaceutical salts, the coating is one layer of enteric coating layer；The active ingredient degree of being of second of coating micro-pill His male amine or its pharmaceutical salts, the coating are one layer of sustained-release coating layer；He is male for the active ingredient degree of being of second of coating micro-pill Amine or its pharmaceutical salts, it is described to include two layers, it is sustained-release coating layer and enteric coating layer respectively from inside to outside；
Active ingredient in the first coating micro-pill is tamsulosin hydrochloride, the active ingredient degree of being in second of coating micro-pill he Male amine；
The weight of the first coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, such as 5~ 30%, such as 5~25%；
The weight of second of coating micro-pill accounts for the 5~50% of the oral disnitegration tablet total weight, such as 5~40%, such as 5~ 30%, such as 5~25%；
The weight of the active ingredient hydrochloric acid Tamsulosin accounts for the 0.1~10% of the first coating micro-pill total weight, such as 0.1~5%；
The weight of the active ingredient dutasteride accounts for the 0.1~10% of second of coating micro-pill total weight, such as 0.1~ 5%；
The average grain diameter of the first coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The average grain diameter of second of coating micro-pill is 50~350 μm, such as 50~300 μm, such as 100~250 μm；
The capsule core material of the first coating micro-pill is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sugarcane Sugar or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core material of second of coating micro-pill is selected from cellulose or derivatives thereof (such as microcrystalline cellulose) or its ball, sugarcane Sugar or sucrose ball, starch or starch ball, lactose or lactose ball；
The capsule core of the first described coating micro-pill and/or second of coating micro-pill is microcrystalline cellulose capsule core or sucrose ball；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is evenly coated in the capsule core surface；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is coated in the capsule core surface；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin passes through with gluing It is essentially homogeneously coated in the capsule core surface after mixture is compounded into solution or suspension；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, the active ingredient dutasteride by with adhesive It is essentially homogeneously coated in the capsule core surface after being compounded into solution or suspension；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；
The capsule core of the first coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient hydrochloric acid Tamsulosin is substantially equal It is distributed in evenly inside the capsule core；The active ingredient hydrochloric acid Tamsulosin added after mixing with microcrystalline cellulose containing Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of adhesive；Alternatively, add into microcrystalline cellulose Add the solution containing active ingredient hydrochloric acid Tamsulosin and adhesive or suspension with stirring-granulating method or fluidized bed prilling legal system Into capsule core；
The capsule core of second of coating micro-pill is microcrystalline cellulose capsule core, and the active ingredient dutasteride is essentially homogeneously It is distributed in inside the capsule core；The active ingredient dutasteride is added after mixing with microcrystalline cellulose containing adhesive Capsule core is made with stirring-granulating method or fluidized bed prilling method in solution or suspension；Alternatively, addition contains work into microcrystalline cellulose Capsule core is made with stirring-granulating method or fluidized bed prilling method in the solution or suspension of property ingredient dutasteride and adhesive；
It is polymer substance that it is each independent, which to be used to prepare the described adhesives of described two capsule cores, is, for example, water soluble polymer Substance, for example, selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copolyvidone or polyvinyl alcohol, And combinations thereof.Certainly, above-mentioned polymer substance can also be as the adhesive of other steps；
At least one layer of coating on the coating micro-pill surface is selected from：Film-coating, enteric coating, clothing soluble in the stomach, extended release coatings, controlled release clothing and its Combination；
When preparing the coating micro-pill, using only water without using organic solvent as preparing binder solution or coating solution Solvent；
Forming the auxiliary material of the tablet matrix includes the excipient selected from following (sugar and/or sugar alcohol)：Mannitol, lactose, sucrose, Maltose, trehalose, sorbierite, maltitol, xylitol, erythrite, glucose, and combinations thereof；
Forming the auxiliary material of the tablet matrix includes adhesive；Described adhesive is used when can be with preparing coating micro-pill to glue Mixture is identical；Described adhesive can be identical with the above-mentioned sugar as excipient or sugar alcohol；
The auxiliary material for forming the tablet matrix may also include disintegrant, and typical disintegrant is such as, but not limited to：Cornstarch, carboxylic Methylcellulose calcium, pregelatinized starch, crosslinked polyvinylpyrrolidone, sodium starch glycollate, croscarmellose sodium are handed over Join povidone, low degree of substitution hydroxypropyl cellulose etc.；
The auxiliary material for forming the tablet matrix may also include the additives such as sweetener, colorant；
The auxiliary material for forming the tablet matrix may also include lubricant；Workable lubricant is selected from：Magnesium stearate, stearic acid Calcium, sucrose fatty ester, polyethylene glycol, talcum powder, stearic acid etc. and combinations thereof；
Forming the auxiliary material of the tablet matrix includes：Excipient, adhesive, salt, lubricant；
The oral disnitegration tablet is according to Chinese Pharmacopoeia four general rules of version in 2015 " 0921 disintegration time limited inspection technique " and therein " mouth collapses Regulation under piece " item, the disintegration time limited that replication is 6,6 were all disintegrated in 60 seconds and pass through sieve；Particularly 6 It was all disintegrated in 45 seconds and passes through sieve；Particularly 6 were all disintegrated in 30 seconds and pass through sieve；
The oral disnitegration tablet is according to the method under Chinese Pharmacopoeia four general rules of version in 2015 " 0923 tablet friability inspection technique " item The friability of tablet, no fracture, cracking and the piece crushed are measured, and less loss weight is less than 3%, is, for example, less than 2%, for example (,) it is small It is, for example, less than 1% in 1.5%；
The oral disnitegration tablet according to United States Pharmacopeia USP35-NF30 editions "<1217>The method of TABLET BREAKING FORCE " is surveyed The hardness of stator agent, value is in the range of 3~6kg, such as in the range of 4~6kg；
The oral disnitegration tablet measures its hydroscopicity according to following method, and hydroscopicity (is, for example, less than 15%, is, for example, less than less than 20% 12.5%, it is, for example, less than 10%)：Take the tablet of 5.0~5.5g of total weight, precise weighing；Make it flat auxiliary and expose to the open air in temperature 25 DEG C, 75% condition of relative humidity assign 24 it is small when, precise weighing；Hydroscopicity is calculated as follows：
Hydroscopicity=[(piece weight-moisture absorption processing anter weight after moisture absorption processing) ÷ moisture absorptions processing anter weight] × 100%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method carries out Dissolution Rate Testing, 50 revs/min of rotating speed using acid medium (water and with salt acid for adjusting pH value 1.2) 250ml as dissolution medium Clock, tamsulosin hydrochloride dissolution rate is less than 20% in 15 minutes, is, for example, less than 15%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% and measure after present dissolution test starts 0.25~4 it is small when during, particularly 0.5~3 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 50% and measure after present dissolution test starts 0.5~8 it is small when during, particularly 0.75~6 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 80% and measure after present dissolution test starts 1~12 it is small when during, particularly 1.5~9 it is small when during；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml as dissolution medium into Row Dissolution Rate Testing, 50 revs/min of rotating speed, tamsulosin hydrochloride dissolution rate reach 30% and measure after present dissolution test starts 0.25~4 it is small when during when small (particularly 0.5~3 during), tamsulosin hydrochloride dissolution rate reaches 50% and measures now Dissolution test start after 0.5~8 it is small when during when small (particularly 0.75~6 during), tamsulosin hydrochloride dissolution rate reaches Measure after present dissolution test starts the 1~12 of 80% it is small when during when small (particularly 1.5~10 during)；
The first coating micro-pill described in before being contacted with the material of the tablet matrix (i.e. tamsulosin hydrochloride coating micro-pill, It is after each layer coating is completed, the state before subsequent non-coated operating procedure is carried out), according to Chinese Pharmacopoeia version four in 2015 3rd method of portion's general rule " 0931 dissolution rate and drug release determination method ", with the neutral medium (disodium phosphate soln of 0.02mol/L And adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing, 50 revs/min of rotating speed, in pH value 6.8 for dissolution medium Tamsulosin hydrochloride dissolution rate in neutral dissolution medium is shown as 30%, 50%, 80% each time point, the first coating The absolute value of the difference of the dissolution rate of pellet and the tamsulosin hydrochloride dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly In the range of 0-12.5%；
The oral disnitegration tablet is according to the 3rd of four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method " the Method, using water 250ml as dissolution medium, 50 revs/min of rotating speed, dutasteride's dissolution rate is less than 20% in 15 minutes, such as small In 15%；
Before being contacted with the material of the tablet matrix the coating micro-pill (i.e. coating micro-pill after the coating of each layer is completed, Carry out the state before subsequent non-coated operating procedure), according to four general rules of Chinese Pharmacopoeia version in 2015, " 0931 dissolution rate is with releasing 3rd method of degree of putting measuring method ", with neutral medium the disodium phosphate soln of 0.02mol/L (and adjusted with phosphoric acid to pH6.8) 250ml carries out Dissolution Rate Testing for dissolution medium, and 50 revs/min of rotating speed, dutasteride's dissolution rate is shown as 50% time The absolute value of the difference of point, the dissolution rate of coating micro-pill and the dissolution rate of oral disnitegration tablet is in the range of 0-15%, particularly in 0- In the range of 12.5%.
CN201611022458.2A 2016-11-16 2016-11-16 Orally disintegrating tablet pharmaceutical composition comprising tamsulosin and dutasteride Active CN108066347B (en)

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