CN104414993A - Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof - Google Patents
Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof Download PDFInfo
- Publication number
- CN104414993A CN104414993A CN201310366065.3A CN201310366065A CN104414993A CN 104414993 A CN104414993 A CN 104414993A CN 201310366065 A CN201310366065 A CN 201310366065A CN 104414993 A CN104414993 A CN 104414993A
- Authority
- CN
- China
- Prior art keywords
- duloxetine hydrochloride
- preparation
- enteric
- micropill
- coating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a duloxetine hydrochloride enteric micro-pellet capsule. The preparation method comprises following steps: (1) performing air jet pulverization to duloxetine hydrochloride to obtain duloxetine hydrochloride micro-particles; (2) mixing the duloxetine hydrochloride micro-particles with a medicinal excipient and preparing duloxetine hydrochloride micro-pellets through an extrusive granulation technology; (3) wrapping the duloxetine hydrochloride micro-pellets with an isolating layer for reducing mutual influence between main drugs and an enteric coating material; and (4) wrapping the isolating layer on the duloxetine hydrochloride micro-pellets by an enteric coating layer for achieving the enteric effect.
Description
Technical field
The present invention relates to a kind of Duloxetine hydrochloride enteric pellet preparation method, particularly a kind of duloxetine hydrochloride is containing the preparation method of pill core.
Background technology
Duloxetine hydrochloride (Ruloxetine Hydrochloride, trade name Cymbalta) is a kind of selective serotonin and NRI (SSNRI).Its structural formula is as follows:
The pharmacology mechanism of duloxetine hydrochloride is as follows:
The precise mechanism of duloxetine hydrochloride antidepressant and Central Analgesic Effect is not yet clear and definite, but think can be relevant with norepinephrine energy function with its enhancing central nervous system 5-hydroxy tryptamine.Preclinical study result shows, and duloxetine hydrochloride is the potent inhibitor of neuron 5-hydroxy tryptamine and norepinephrine reuptake, relatively weak to the inhibitory action of dopamine reuptake.Results of in vitro studies shows, and duloxetine hydrochloride and Dopaminergic receptors, adrenoreceptor, cholinoceptor, histaminergic receptors, opiate receptor, glutamate receptor, GABA receptor are without obvious affinity.Duloxetine hydrochloride does not suppress monoamine oxidase, MAO.
In August, 2004 and December, the U.S. and European Union ratify duloxetine hydrochloride treatment adult severe depression respectively.This is first indication that duloxetine hydrochloride formally gets permission clinical practice.Two totals comprise random, double blinding, the placebo-controlled study display of 512 routine experimenters, and duloxetine 1 time on the one 60mg treats and can comparatively significantly reduce by placebo for 9 weeks, and namely medication significantly improved depressive symptom after 1 week.Duloxetine hydrochloride treatment also significantly can improve the somatization of patients with depression, comprises insomnia, slow, pain and headache etc., and this typically uses serotonin reuptake inhibitor and treats not obtainable curative effect.It is a serious clinical problem that depressive episode treats the recurrence of the symptom successfully, therefore American Psychiatric association has recommended to maintain antidepressant therapy to reduce the risk of recurrence of patient.In a double blinding, placebo-controlled study, 533 routine severe depression experimenters are after accepting duloxetine 1 time on the one 60mg and treating 12 weeks, and 278 examples meet the patient entering maintenance therapy phase standard and continue to take the duloxetine of same dosage or placebo treatment 6 months more at random.Result shows, and it is significantly longer that duloxetine hydrochloride group patient comparatively accepts placebo to the time that depression shows effect again, and relapse rate is also lower simultaneously.Other double blinding and open research have confirmed long-term efficacy and the safety of duloxetine Cure of depression patient.In studying for a long period of time, what occur in the treatment reported with the later stage in early days shows comparing of adverse events, and long-term treatment does not cause special adverse events.Therefore, duloxetine hydrochloride has good efficacy and saferry.
Although duloxetine hydrochloride has above-mentioned good curative effect, but because of the physics and chemistry character of its uniqueness, particularly its low solubility is only slightly water-soluble and easily degrade in acid, therefore should enteric coated preparation be made, because the slightly water-soluble of medicine obtains preparation be difficult to complete stripping, and principal agent easily interacts with some coating materials in preparation, formation indissoluble or insoluble clothing layer and make principal agent be difficult to stripping, this easily reduces its bioavailability again.
Duloxetine hydrochloride raw material is acicular crystal, is insoluble in aqueous medium, and when oral administration in capsule or tablet form, not micronized duloxetine hydrochloride is not easy to dissolve and dispersion, thus can not absorb rapidly in vivo.
Through retrieval, EP0693282A, CN1106191C, disclose the preparation method of duloxetine enteric coated tiny pill capsule, and what the method related to is that duloxetine hydrochloride micropill prepared by blank pill pericardium clothing; Blank pill pericardium clothing after what CN1759829A related to is duloxetine makes solid dispersal liquid solution.And what the present invention relates to is by duloxetine hydrochloride micronization and pharmaceutically acceptable mixed with excipients, makes enteric coated micropill through extruding round as a ball making again containing the pill heart.
Summary of the invention
Therefore, the object of the invention is to overcome above-mentioned defect, a kind of preparation method of Duloxetine hydrochloride enteric pellet capsule is provided.
The object of the invention is to realize by the following technical solutions.
The invention provides a kind of preparation method of Duloxetine hydrochloride enteric pellet capsule, the method comprises the following steps:
(1) mode of comminution by gas stream is adopted to obtain duloxetine hydrochloride microgranule duloxetine hydrochloride raw material;
(2) duloxetine hydrochloride microgranule will be obtained to mix with pharmaceutical excipient, and adopt extruder grain technology to make duloxetine hydrochloride micro-containing pill core ball.
(3) the duloxetine hydrochloride coating of pellets sealing coat will made, influences each other in order to reduce principal agent and enteric coating material in formulation process.
(4) on the micropill surface of the coating sealing coat made, parcel enteric coating layer, possesses enteric effect to make micropill.
(5) No. 3 gelatine capsules are loaded by after the micropill cooling after coating.
About medicated core, wherein, duloxetine hydrochloride feed particles particle size distribution D90 is less than 200 microns.Described D90 is less than 200 microns and refers to: the diameter of 90% microgranule is less than 200 microns, and wherein, 90% is exponential quantity.
Preferably, described in step (1), the D90 of duloxetine hydrochloride microgranule is less than 100 microns, more preferably, is less than 40 microns, further preferably, is less than 25 microns, most preferably, is less than 15 microns.
According to preparation method provided by the invention, wherein, described step (1) comprising: duloxetine hydrochloride raw material is obtained duloxetine hydrochloride microgranule through comminution by gas stream mode.
According to preparation method provided by the invention, pharmaceutical composition described in step (2) is the form of the micropill containing duloxetine hydrochloride.
Pharmaceutical composition described in per unit, namely the duloxetine hydrochloride enough producing about 12 ~ 24 hours treatment actuating quantitys is comprised in every capsules, as as described in per unit, pharmaceutical composition micropill contains the duloxetine hydrochloride of 10 ~ 60mg, preferably, and the duloxetine hydrochloride containing 20 ~ 30mg.
According to preparation method provided by the invention, wherein, pharmaceutical excipient described in step (2) is the general designation of nontoxic pharmaceutically useful carrier and/or auxiliary agent, requires to have the acceptable compatibility and harmless with other components in duloxetine hydrochloride micropill.Described pharmaceutical excipient be preferentially selected from diluent, disintegrating agent, wetting agent and lubricant one or more.
The diluent added or wetting agent contribute to dispersion and the stripping of duloxetine hydrochloride when medicine is taken in.Therefore, preferably, described pharmaceutical excipient contains diluent and/or wetting agent.
According to preparation method provided by the invention, wherein, the pharmaceutical excipient described in step (2) can comprise one or more diluent.Described diluent requires to have suitable mobility, and suitable diluent comprises lactose, Lactis Anhydrous, spray-dried lactose, starch, sucrose, mannitol, Sorbitol, glucose and monohydrate thereof, microcrystalline Cellulose, alkali calcium phosphate or polyvinylpyrrolidone.Microcrystalline Cellulose comprises microcrystalline Cellulose PH101, microcrystalline Cellulose PH201 or its mixture.
When described pharmaceutical excipient comprises diluent, the Optimum of diluent is account for described micropill weight 5 ~ 99%, is preferably 10 ~ 65wt%.
According to preparation method provided by the invention, wherein, the pharmaceutical excipient described in step (2) can comprise one or more wetting agent as pharmaceutical excipient.Suitable wetting agent comprises tween 80, oleic acid, glyceryl monostearate, dehydrated sorbitol mono-fatty acid ester, sorbitan monolaurate, Emulphor FM, Polysorbate 80, Tween 20, enuatrol, sucrose fatty acid ester or sodium lauryl sulphate, poloxamer 188.One or more can be selected.Be preferably sodium lauryl sulphate.The Optimum of wetting agent is account for described pharmaceutical composition weight 0.25 ~ 5%, is preferably 1 ~ 5wt%.
According to preparation method provided by the invention, wherein, the pharmaceutical excipient described in step (2) can comprise one or more disintegrating agents.Suitable disintegrating agent comprises starch, sodium starch glycollate, cellulose, alginate, the corn starch of pregelatinized, crosslinked polyvidone or natural gum, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose.
Preferred polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, can select one or more as disintegrating agent.The Optimum of disintegrating agent is account for described micropill weight 0.2 ~ 30%, is preferably 0.2 ~ 10%.
According to preparation method provided by the invention, wherein, can not lubricant be comprised in pharmaceutical excipient described in step (2), also can comprise one or more lubricants.Suitable lubricant comprises stearic acid, stearate (such as, magnesium stearate, calcium stearate and sodium stearate), hydrogenated vegetable oil (such as Sterotex), Pulvis Talci, wax, Stearowet, boric acid, sodium benzoate, sodium acetate, fumaric acid sodium, sodium chloride, DL-LEUCINE, Polyethylene Glycol (such as, Macrogol 4000 and polyethylene glycol 6000), enuatrol, sodium lauryl sulphate or Stepanol MG.The Optimum of wetting agent is the 0.75 ~ 15wt% accounting for described micropill weight, is preferably 1 ~ 5%.
Pulvis Talci is preferred lubricant, and Optimum is account for described micropill gross weight 0.1 ~ 10%, is preferably 0.2 ~ 8%.
According to preparation method provided by the invention, wherein, the extruder grain described in step (2) needs to prepare soft material, and its solution used comprises water, ethanol water, and when using ethanol water, preferred alcohol accounting is 10-50%, is preferably 10 ~ 30%.
According to preparation method provided by the invention, wherein, the extruder grain described in step (2), suitable rotating speed of extruding is 20-60 rev/min, is preferably 25-50 rev/min; Suitable centrifugal round as a ball rotating speed 500-900 rev/min, is preferably 600-800 rev/min; The suitable centrifugal round as a ball time is 3-10 minute, is preferably 5-7 minute.The micropill made is less than 3% at 60 DEG C of drying control moisture, and micropill diameter is 0.3 ~ 0.8mm, and particle size distribution is 80 ~ 90%.
According to preparation method provided by the invention, wherein, described pastille micropill is prepared according to following formula in step (2):
The duloxetine hydrochloride microgranule of 25 ~ 52wt%;
The diluent of 10 ~ 65wt%, described diluent is preferably lactose, sucrose, microcrystalline Cellulose PH101, pregelatinized Starch or its mixture of two or three;
The disintegrating agent of 0.2 ~ 10wt%, described disintegrating agent is preferably polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose or its mixture;
Preferably, also comprise the wetting agent of 1 ~ 5wt% in this formula, described wetting agent is preferably sodium lauryl sulphate.
Preferably, also comprise the lubricant of 0.2 ~ 8wt% in this formula, described lubricant is preferably Pulvis Talci.
Preferably, in described ethanol water, the weight fraction of ethanol is 10 ~ 30%.
According to preparation method provided by the invention, wherein, described step (2) comprising: mixed with lactose, sucrose, microcrystalline Cellulose PH101, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, sodium lauryl sulphate, Pulvis Talci by described duloxetine hydrochloride microgranule, then add ethanol-aqueous solution to be uniformly mixed and to make suitable soft material, put into extruder, extrude become strip-shaped materials with 0.8mm mould and suitable rotating speed of extruding; Then put into centrifugal spheronizator, material cuts by the cutterhead of high speed rotating, roll and make the larger rounding piller of density.The pastille micropill made is dry a period of time at suitable temperature, makes it moisture and is less than 3%.Dry piller sieves, and selects diameter to be 0.3-0.8mm piller.
According to preparation method provided by the invention, wherein, described step (3) sealing coat comprises: water-soluable gel material: be selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone wherein a kind of or its mixture, preferred hydroxypropyl methylcellulose; Plasticizer: be selected from Fructus Citri Limoniae triethylenetetraminehexaacetic acid fat, citric acid tri butyl ester, glycerol triacetate, tributyl 2-acetylcitrate, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglycerides, hydroxypropyl methylcellulose or Polyethylene Glycol one or more, optimization citric acid three second fat; Antiplastering aid: Pulvis Talci, the one of micropowder silica gel or its mixture can be selected from, preferably talc powder.Opacifier can be selected from titanium dioxide or iron oxide red, iron oxide yellow.
Sealing coat
According to preparation method provided by the invention, wherein, described step (3) is mixed with aqueous solution when described sealing coat adopts during hydroxypropyl methylcellulose, hydroxypropyl methylcellulose consumption is for containing pill core 2-10%, be preferably 3 ~ 6%, namely sealing coat hypromellose feeds intake by containing 3 ~ 6% of pill core weight.
According to preparation method provided by the invention, wherein, described step (3) is when described sealing coat adopts Fructus Citri Limoniae triethylenetetraminehexaacetic acid fat, and its consumption is the 0%-20% of hydroxypropyl methylcellulose weight fraction, is preferably 5 ~ 15%.
According to preparation method provided by the invention, wherein, described step (3) is when described sealing coat adopts Pulvis Talci, and its consumption is the 30%-60% of hydroxypropyl methylcellulose weight fraction, is preferably 35 ~ 55%.
According to preparation method provided by the invention, wherein, described step (3) is when described sealing coat adopts titanium dioxide, and its consumption is the 0.5%-2.5% of pastille micropill weight fraction, is preferably 1 ~ 2%.
According to preparation method provided by the invention, wherein, described sealing coat is prepared according to following formula in described step (3):
According to preparation method provided by the invention, wherein, described step (3) comprising: slowly added under electric stirring by described water-soluable gel material and fill in the container of purified water, after stirring and dissolving, after slowly dropping plasticizer is uniformly dispersed, slowly add antiplastering aid, opacifier, continue stirring 45 minutes, filter and obtain sealing coat coating solution with 60 eye mesh screens; Then duloxetine hydrochloride micropill fluid bed is carried out sealing coat coating, coating completes fluidized drying 5-10 minute.
Enteric coating layer
According to preparation method provided by the invention, wherein, described step (4) enteric material can be selected to comprise: cellulose esters and derivant (cellulose acetate phthalate thereof, hydroxypropyl acetic acid amber primary acid ester, phthalic acid hydroxypropyl methylcellulose), polyvinyl acetate phthalate, the EUDRAGIT L100 of pH-sensitive and Lac, the enteric material that can commercially obtain be Rohm drugmaker produce with Eudragit (L100, S100, L30D) methacrylic acid copolymer of trademark Soynatto, the Cellacefate(cellulose acetate phthalate that Eastman chemical company produces), FMC Corp. produce Aquateric(cellulose acetate phthalate aqueous dispersion) and Shin EtsuK.K. produce Aqoat(hydroxypropyl acetic acid amber primary acid ester aqueous dispersion), preferred Eudragit L100-55 aqueous dispersion, plasticizer can be selected from one or more in citric acid three second fat, citric acid tri butyl ester, glycerol triacetate, tributyl 2-acetylcitrate, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglycerides, hydroxypropyl methylcellulose or Polyethylene Glycol, optimization citric acid three second fat, defoamer: depending on concrete condition in technical process, not necessarily will add, generally use dimethicone in prescription.
According to preparation method provided by the invention, wherein, described enteric coating layer is prepared according to following formula in described step (4):
According to preparation method provided by the invention, wherein, described step (4) comprising: slowly added under electric stirring by described enteric material (aqueous dispersion) and fill in the container of purified water, stir and be uniformly dispersed for 5 minutes, slowly drip appropriate 4% (w/v) sodium hydroxide, neutralization part Youteqi carboxyl, under electric stirring, reacts 30 minutes.Slow dropping plasticizer makes it to be uniformly dispersed, and slowly adds antiplastering aid, continues stirring 45 minutes, filters and obtain enteric coating liquid with 60 eye mesh screens; Then duloxetine hydrochloride contagion gown micropill fluid bed is carried out enteric coating coating, coating completes at 45 DEG C of fluidized drying 10-20 minute.45 DEG C of oven ageings 2 hours, obtain enteric coating micropill.
According to preparation method provided by the invention, wherein, described step (5) refers to: after the cooling of enteric coating micropill, loaded No. 3 gelatine capsule weights, namely this obtain duloxetine hydrochloride enteric coated-pellet capsule.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 is the process chart of one embodiment of the invention;
Fig. 2 is the Dissolution profiles figure of the duloxetine hydrochloride enteric coated-pellet capsule that preparation method of the present invention obtains.Note: in figure, time showing is that Duloxetine hydrochloride enteric pellet capsule is successively as the total time of carrying out release experiment in hydrochloric acid solution and phosphate buffered solution.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further described in detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
embodiment 1
The present embodiment is for illustration of the preparation method of duloxetine hydrochloride micropill in the present invention.
Embodiment 1 illustrates the concrete preparation technology of duloxetine hydrochloride micropill in the present invention, and the final form of described duloxetine hydrochloride micropill is Capsule form.
(1) prepare containing pill core: adopt SHK series wet granulator, feed intake by 1000 amounts, concrete preparation technology is as follows:
Duloxetine hydrochloride microgranule is mixed with sodium lauryl sulphate, sucrose, for subsequent use as component A after crossing 60 mesh sieves; By mixing such as microcrystalline Cellulose PH101, lactose, polyvinylpolypyrrolidone, hydroxypropyl cellulose, Pulvis Talci; cross 60 mesh sieves for subsequent use as B component; component A and B component are placed in wet granulator and are uniformly mixed 5 minutes; then ethanol-aqueous solution is used to make soft material; strip-shaped materials is squeezed in extruding granulator, then round as a ball in centrifugal spheronizator, prepare micropill; 60 DEG C of dryings 4 hours, screening 0.3-0.8mm duloxetine hydrochloride micropill.
(2) sealing coat coating preparation: adopt fluidized-bed coating machine to carry out sealing coat coating to step (1) preparation containing pill core, technique is as follows:
Slowly being added under electric stirring by water-soluable gel material fills in the container of purified water, after stirring and dissolving, after slowly dropping plasticizer is uniformly dispersed, slowly add antiplastering aid, opacifier, continue stirring 45 minutes, filter and obtain sealing coat coating solution with 60 eye mesh screens; Then duloxetine hydrochloride micropill fluid bed is carried out sealing coat coating under suitable coating parameter, coating completes at 45 DEG C of fluidized drying 10-20 minute, obtains contagion gown micropill.
(3) enteric layer coating preparation: adopt fluidized-bed coating machine to prepare contagion gown micropill to step (2) and carry out enteric layers coating, technique is as follows:
Slowly being added under electric stirring by enteric material (aqueous dispersion) fills in the container of purified water, stir and be uniformly dispersed for 2 minutes, slowly drip 4% sodium hydroxide, stir after 30 minutes, after slowly dropping plasticizer is uniformly dispersed, slowly add antiplastering aid, continue stirring 45 minutes, filter and obtain enteric layer coating solution with 60 eye mesh screens; Then duloxetine hydrochloride contagion gown micropill fluid bed is carried out enteric coating coating, coating completes fluidized drying 5-10 minute.40 DEG C of curing ovens 2 hours, obtain enteric coating micropill.
The duloxetine hydrochloride pellet capsule formula that embodiment 2 ~ 15 provides, i.e. principal agent and each supplementary product consumption in simple grain capsule, and comprise coating.
embodiment 2
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 3
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 4
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 5
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 6
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 7
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 8
embodiment 9
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 10
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 11
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 12
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 13
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 14
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
embodiment 15
In the present embodiment, simple grain capsule contains 30mg duloxetine hydrochloride, below lists principal agent and each supplementary product consumption in simple grain duloxetine hydrochloride enteric coated capsule, and wherein duloxetine hydrochloride adopts the duloxetine hydrochloride microgranule prepared by step (1):
dissolution Rate Testing
(Chinese Pharmacopoeia 2010 editions two annex XC second methods 2) are adopted to measure.
1. raw material: the duloxetine hydrochloride enteric coated capsule (commodity are called Cymbalta) of the duloxetine hydrochloride enteric coated capsule that embodiment obtains and purchased from American Li Lai company.
2. test procedure:
Get this product, drug release determination method (Chinese Pharmacopoeia 2010 editions two annex XD second method methods 2), adopt the device of dissolution method (Chinese Pharmacopoeia 2005 editions two annex XC first methods), first with hydrochloric acid solution (8.5 → 1000) 1000ml for dissolution medium, rotating speed is 100 turns per minute, operates in accordance with the law.Through sampling in 120 minutes, filter with 0.45 μm of microporous filter membrane, get subsequent filtrate as test sample I; [sodium phosphate (Na is got immediately with pH6.8 buffer solution
3pO
412H
2o) 19.01g and hydrochloric acid 6.375ml, add water to 1000ml, being 6.8 ± 0.05 with 5ml/L hydrochloric acid or 5mol/L sodium hydroxide adjust pH] 1000ml is dissolution medium, rotating speed is constant, continue to operate in accordance with the law, through sampling in 10,20,30,45,60,90,120 minutes, filter with 0.45 μm of microporous filter membrane, get subsequent filtrate as test sample II.Another precision takes duloxetine hydrochloride reference substance and is about 14mg, puts in 25ml measuring bottle, adds 0.5ml dissolve with methanol, is diluted to scale, shakes up with pH6.8 buffer solution.Precision measures 2ml to 25ml(60mg) or 50ml(30mg) in measuring bottle, add pH6.8 buffer solution and be diluted to scale, shake up, as the reference substance solution II for buffer dissolution medium.Precision measures reference substance II 5ml, puts in 50ml measuring bottle, adds pH6.8 buffer solution and is diluted to scale, shake up, as the reference substance solution I for sour dissolution medium.Measure according to content assaying method, get need testing solution I, II and each 10 μ l injection liquid chromatographies of reference substance solution I, II respectively, record chromatogram.As aobvious duloxetine and α-Nai phenol peak in need testing solution I, every burst size in sour dissolution medium is calculated with 2.06 times of sums of duloxetine peak area and α-Nai phenol peak-to-peak area by external standard method, every burst size in sour dissolution medium must not be greater than 10% of labelled amount, and in need testing solution II, duloxetine content presses external standard method with the burst size of calculated by peak area every in buffer dissolution medium.
Table 1 dissolution determination result
Note: A: self-control sample Cumulative release amount (%)
B: formerly grind control sample Cumulative release amount (%)
As can be seen from Table 1, adopt the duloxetine hydrochloride pellet capsule that preparation method of the present invention obtains, its stripping curve, suitable with abroad.Stripping curve as shown in Figure 2 for the duloxetine hydrochloride enteric coated capsule (being designated as external capsule) of the duloxetine hydrochloride pellet capsule (being designated as Microdot Capsule) that embodiment 5 provides and Lilly Co., Eli..
Claims (15)
1. a preparation method for Duloxetine hydrochloride enteric pellet capsule, the method comprises the following steps:
(1) mode of comminution by gas stream is adopted to obtain duloxetine hydrochloride microgranule duloxetine hydrochloride raw material;
(2) the duloxetine hydrochloride microgranule obtained is mixed with pharmaceutical excipient, adopt extruder grain technology to make duloxetine hydrochloride micropill;
(3) the duloxetine hydrochloride coating of pellets sealing coat will made, to reduce influencing each other of principal agent and enteric coating material in formulation process;
(4) on the micropill surface of the coating sealing coat made, parcel enteric coating layer possesses enteric effect to make micropill;
(5) No. 3 gelatine capsules are loaded by after the micropill cooling after coating.
2. preparation method according to claim 1, wherein, described in step (1), duloxetine hydrochloride Particle Distribution D90 is less than 200 microns.Described D90 is less than 200 microns and refers to: the diameter of 90% microgranule is less than 200 microns, and wherein, 90% is exponential quantity;
Preferably, the D90 of described duloxetine hydrochloride microgranule is less than 100 microns, more preferably, is less than 40 microns, further preferably, is less than 25 microns, most preferably, is less than 15 microns.
3. preparation method according to claim 1, wherein, described in step (2), duloxetine hydrochloride micropill is the form of pellet, and its final dosage form is the form of capsule;
Preferably, every described duloxetine hydrochloride pellet capsule contains the duloxetine hydrochloride microgranule of 10 ~ 60mg, more preferably, and the duloxetine hydrochloride microgranule containing 20 ~ 30mg.
4. preparation method according to claim 1, wherein, described in step (2), pharmaceutical excipient is selected from one or more in diluent, disintegrating agent, wetting agent and lubricant.
5. preparation method according to claim 1, wherein, in step (2), prepare described duloxetine hydrochloride micropill according to following formula:
The duloxetine hydrochloride microgranule of 25 ~ 52wt%;
The diluent of 10 ~ 65wt%, described diluent is preferably lactose, sucrose, microcrystalline Cellulose PH101 or its mixture;
The disintegrating agent of 0.2 ~ 10wt%, described disintegrating agent is preferably polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose;
The wetting agent of 1 ~ 5wt%, described wetting agent is sodium lauryl sulphate, poloxamer 188, is preferably sodium lauryl sulphate;
Preferably, also comprise the lubricant of 0.2 ~ 8wt% in this formula, described lubricant is preferably Pulvis Talci.
6. preparation method according to claim 5, wherein, in step (2), prepare described duloxetine hydrochloride micropill according to following formula:
7. preparation method according to claim 1, described step (2) comprising:
Described duloxetine hydrochloride microgranule is mixed with lactose, sucrose, microcrystalline Cellulose PH101, polyvinylpolypyrrolidone, hydroxypropyl cellulose, sodium lauryl sulphate, Pulvis Talci, then add ethanol-aqueous solution to be uniformly mixed and to make suitable soft material, put into extruder, with 0.8mm mould, extrude rotating speed: 25 ~ 50 turns/min extruding becomes strip-shaped materials; Then centrifugal spheronizator is put into the round as a ball 5-7 minute of 600 ~ 800 turns/min.The pastille micropill made is less than 3% at 60 DEG C of drying control moisture, and pastille micropill diameter is that 0.3-0.8mm particle size distribution is at 80-90%.
8. preparation method according to claim 1, described step (2) is mixed with lactose, microcrystalline Cellulose PH101, low-substituted hydroxypropyl methylcellulose etc. by described duloxetine hydrochloride microgranule, then add ethanol water and carry out soft material processed, preferably, in described ethanol-aqueous solution, the weight fraction of ethanol is 10 ~ 30%.
9. preparation method according to claim 1, wherein, step (3) described sealing coat is selected from hydroxypropyl methylcellulose when being hydrophilic gel material, and described hydroxypropyl methylcellulose consumption is that the pastille micropill ball heart weighs 3 ~ 6wt%;
When described sealing coat adopts Fructus Citri Limoniae triethylenetetraminehexaacetic acid fat to be plasticizer, its consumption is 0 ~ 20wt% of hydrophilic gel material consumption, is preferably 5 ~ 15wt%;
When described sealing coat adopts Pulvis Talci to be antiplastering aid, its consumption is 30 ~ 60wt% of hydrophilic gel material consumption, is preferably 35 ~ 55wt%;
When described sealing coat adopts titanium dioxide to be opacifier, its consumption is that pastille micropill weighs 0.5 ~ 2.5wt%, is preferably 1 ~ 2wt%.
10. preparation method according to claim 1, wherein, described step prepares described sealing coat according to following formula in (3):
11. preparation methoies according to claim 1, wherein, described step (3) comprising: slowly added under electric stirring by described water-soluable gel material and fill in the container of purified water, after stirring and dissolving, after slowly dropping plasticizer is uniformly dispersed, slowly add antiplastering aid, opacifier, continue stirring 45 minutes, filter and obtain sealing coat coating solution with 60 eye mesh screens; Then duloxetine hydrochloride micropill fluid bed is carried out sealing coat coating, coating completes at 45 DEG C of fluidized drying 10-20 minute.
12. preparation methoies according to claim 1, wherein, the choosing of step (4) described enteric layers is when especially strange L100-55 are enteric material, and described L100-55 consumption is that contagion gown micropill ball weighs 8 ~ 13wt%;
The choosing of described enteric layers when especially strange L100-55 be enteric material, need use 4%(w/v) in sodium hydrate aqueous solution and part especially strange carboxyl, 4%(w/v) sodium hydrate aqueous solution consumption be especially very L100-5 consumption 20 ~ 50%;
When described enteric layers adopts Fructus Citri Limoniae triethylenetetraminehexaacetic acid fat to be plasticizer, its consumption is the 2%-8wt% of enteric materials consumption;
When described enteric layers adopts Pulvis Talci to be antiplastering aid, its consumption is 10 ~ 50wt% of enteric materials consumption.
13. according to preparation method provided by the invention, and wherein, described step prepares described enteric coating layer according to following formula in (4):
14. according to preparation method provided by the invention, wherein, described step (4) comprising: slowly added under electric stirring by described enteric material (aqueous dispersion) and fill in the container of purified water, stir and be uniformly dispersed for 5 minutes, slowly drip appropriate 4% sodium hydroxide, neutralization part Youteqi carboxyl, under electric stirring, reacts 30 minutes.Slow dropping plasticizer makes it to be uniformly dispersed, and slowly adds antiplastering aid, continues stirring 45 minutes, filters and obtain enteric coating liquid with 60 eye mesh screens; Then duloxetine hydrochloride contagion gown micropill fluid bed is carried out enteric coating coating, coating completes at 45 DEG C of fluidized drying 10-20 minute.45 DEG C of oven ageings 2 hours, obtain enteric coating micropill.
15. according to preparation method provided by the invention, and wherein, described step (5) refers to: after the cooling of enteric coating micropill, loaded No. 3 gelatine capsule weights, namely this obtain duloxetine hydrochloride enteric coated-pellet capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310366065.3A CN104414993A (en) | 2013-08-20 | 2013-08-20 | Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310366065.3A CN104414993A (en) | 2013-08-20 | 2013-08-20 | Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104414993A true CN104414993A (en) | 2015-03-18 |
Family
ID=52965820
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310366065.3A Pending CN104414993A (en) | 2013-08-20 | 2013-08-20 | Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104414993A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116617189A (en) * | 2023-07-26 | 2023-08-22 | 四川尚锐生物医药有限公司 | Duloxetine hydrochloride sustained-release capsule and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101939004A (en) * | 2008-01-25 | 2011-01-05 | 阿尔法制药有限公司 | Delayed release pharmaceutical composition of duloxetine |
| KR20120021483A (en) * | 2010-08-03 | 2012-03-09 | 근화제약주식회사 | Pharmaceutical composition containing antidepressant |
| CN102908331A (en) * | 2011-08-01 | 2013-02-06 | 浙江九洲药物科技有限公司 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
-
2013
- 2013-08-20 CN CN201310366065.3A patent/CN104414993A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101939004A (en) * | 2008-01-25 | 2011-01-05 | 阿尔法制药有限公司 | Delayed release pharmaceutical composition of duloxetine |
| KR20120021483A (en) * | 2010-08-03 | 2012-03-09 | 근화제약주식회사 | Pharmaceutical composition containing antidepressant |
| CN102908331A (en) * | 2011-08-01 | 2013-02-06 | 浙江九洲药物科技有限公司 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116617189A (en) * | 2023-07-26 | 2023-08-22 | 四川尚锐生物医药有限公司 | Duloxetine hydrochloride sustained-release capsule and preparation method thereof |
| CN116617189B (en) * | 2023-07-26 | 2023-09-26 | 四川尚锐生物医药有限公司 | Duloxetine hydrochloride sustained-release capsule and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101094675A (en) | Formulations of [1,4]diazepino[6,7,1-ij]quinoline derivatives | |
| JPH10502629A (en) | Pharmaceutical compositions for controlled release of moguisteine in suspension | |
| EP1967211A1 (en) | Method of producing solid preparation disintegrating in the oral cavity | |
| CN1886119A (en) | Pantoprazole multiparticulate formulations | |
| JP5956475B2 (en) | Orally disintegrating tablets containing bitter mask granules | |
| CN111012756B (en) | Dabigatran etexilate pharmaceutical composition and preparation method thereof | |
| CN104013592A (en) | Memantine hydrochloride slow-release pill and preparation method thereof | |
| CN103356489B (en) | Proton pump inhibitor enteric coated pellet and preparation and preparation method thereof | |
| US20180055778A1 (en) | Extended-release topiramate capsules | |
| EP2533766B1 (en) | Pharmaceutical mini-tablets for sustained release of flecainide acetate | |
| CN104814923B (en) | A kind of tamsulosin hydrochloride sustained release preparation and preparation method thereof and its application | |
| CN103520129B (en) | Montelukast sodium pulse release preparation | |
| WO2008083561A1 (en) | Oral pharmaceutical composition of glycyrrhizin or its salts and the preparation method thereof | |
| WO2012159237A1 (en) | Quick release-sustained release composition of compound methoxyphenamine | |
| CN109157527B (en) | Irbesartan capsule and preparation method thereof | |
| CN104414993A (en) | Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof | |
| CN109200032A (en) | High drug load venlafaxine hydrochloride sustained-release pellet composition and spansule and preparation method | |
| CN112386578B (en) | Montelukast sodium chewable tablet and preparation method thereof | |
| KR100857061B1 (en) | Tablet containing vaccinium myrtillus extract and preparing method thereof | |
| US10881615B2 (en) | Pharmaceutical composition comprising dabigatran etexilate, and preparation method, solid preparation and use thereof | |
| CN104225596A (en) | Pharmaceutical composition for treating gastritis and gastric ulcers | |
| CN104274444B (en) | Oral double pellet pharmaceutical compositions of dabigatran etcxilate or its salt | |
| CN102552107B (en) | Two-phase release preparation containing zolpidem or salt of zolpidem and preparation method thereof | |
| CN114533744A (en) | Ticagrelor-aspirin compound pellet preparation and preparation method thereof | |
| CN107625733B (en) | Clarithromycin granules capable of being swallowed without water and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150318 |