CN102670548A - Paroxetine hydrochloride osmotic pump type enteric controlled release tablet - Google Patents
Paroxetine hydrochloride osmotic pump type enteric controlled release tablet Download PDFInfo
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Abstract
The invention provides a novel paroxetine hydrochloride osmotic pump type enteric controlled release tablet. In an osmotic pump type enteric controlled release tablet in an enteric coating, ethyl cellulose and polyvinylpyrrolidone are used as semipermeable membrane formation material, an asymmetric tablet type is preferable, the ageing phenomenon of the semipermeable membrane can be overcome, and the medicine residue is lowered. The invention also provides a method for improving the anti-ageing performance of the paroxetine hydrochloride osmotic pump type enteric controlled release tablet. The method is characterized in that the ethyl cellulose-polyvinylpyrrolidone is adopted to serve as the semipermeable membrane material. In addition, the invention also provides an application of the ethyl cellulose-polyvinylpyrrolidone composite to prepare the paroxetine hydrochloride osmotic pump type enteric controlled release tablet with the anti-ageing performance.
Description
Technical field
The present invention relates to a kind of paroxetine hydrochloride osmotic pump type enteric controlled release tablets, belong to field of pharmaceutical preparations.
Background technology
Paroxetine hydrochloride is a selectivity nervus centralis serotonin reuptake inhibitor, is used to treat depression, obsession, panic disorder or social anxiety disorder.
The ordinary preparation that these article go on the market the earliest, gastrointestinal side effect is serious, and compliance is poor.Therefore, the enteric-coated sustained-release preparation that has abroad gone on the market again and obeyed 1 day.
Because the paroxetine hydrochloride slow releasing preparation is non-constant speed release medicine; The release of medicine and absorption rate also receive the influence of factors such as the interior gastro-intestinal Fluid of patient body, so its blood drug level still has bigger fluctuation, are difficult to control and expectation; Has certain uncertainty; Its useful effect persistent period and side effect size also vary with each individual, and individual variation is big, has uncontrollability.
Osmotic pump type controlled release preparation be with osmotic pressure as release power, be a kind of preparation technique of characteristic with the zero level release dynamics, using the widest is the two-chamber type osmotic pump controlled release tablet, has medicated layer and boosting layer, constitutes coyote hole and power house respectively.Medicated layer is made up of medicine and penetration enhancer and other adjuvants, and the boosting layer is made up of the macromolecular material and the penetration enhancer of one or more swellables.Take back moisture and get into label, make the medicated layer suction softening, and the macromolecular material imbibition of boosting layer produces extruding to coyote hole, and medicine is discharged by small delivery aperture by semipermeable membrane.Keep osmotic pressure constant, can keep moisture to get into the constant airspeed of label, and then make the constant rate of macromolecular material imbibition, keep lasting constant osmotic pressure, it is constant to reach rate of releasing drug.
Paroxetine hydrochloride is suitable for processing the two-chamber type osmotic pump controlled release tablet, and that effective blood drug concentration is held time is long, blood concentration fluctuation is little, side effect is little, individual variation is little, patient dependence is good.
Semipermeable membrane control to drug release in the Oros preparation is quite important.The semipermeable membrane that different materials is formed, different, just relevant with the infiltration coefficient of film to the permeability of water, what the most generally use is cellulose acetate, other also has document to mention like ethyl cellulose etc.Adopt semipermeable membrane material commonly used at present, the osmotic pump type controlled release tablet of cellulose acetate+Polyethylene Glycol, ethyl cellulose+Polyethylene Glycol preparation for example is in a period of time that has just prepared; Its release performance is good, but after storing a period of time, its release performance begins to descend; Storage time is long more, and it is obvious more to descend, and often stipulates the latter half of effect duration at medicine; Release performance obviously descends, and popular saying is for aging.
Summary of the invention:
In order to overcome the defective of prior art; The invention provides and a kind ofly can not receive storage time restriction and remain the novel paroxetine hydrochloride osmotic pump type enteric controlled release tablets of stablizing release performance before the deadline; Comprise paroxetine hydrochloride osmotic pump type controlled release tablet and outer field enteric coating; Between the semipermeable membrane and enteric coating of osmotic pump type controlled release tablet, preferably contain one deck contagion gown.We are surprised to find that through to the scrutinizing and selecting of the semipermeable membrane material of paroxetine hydrochloride osmotic pump type enteric controlled release tablets semipermeable membrane adopts ethyl cellulose and polyvidone to make up as the semipermeable membrane filmogen; Can overcome catabiosis; The two-chamber type paroxetine hydrochloride osmotic pump type enteric controlled release tablets that uses the semipermeable membrane of this kind material to process not only can make drug slow and constant release, prolongs the effective blood drug concentration time; And can make blood drug level more steady; Reduce untoward reaction, and can in its expiration date of drug, keep release performance stable, release is residual little.
Therefore, the object of the invention at first is to provide a kind of and can receive the storage time restriction and remain the paroxetine hydrochloride osmotic pump type enteric controlled release tablets of stable release performance before the deadline.
Form with film the relation between aging in order to investigate film, we have designed the film loss of weight and have tested.The test of film loss of weight is the test of investigating membrane permeability through the mensuration semipermeable membrane through the degree of water logging bubble processing back weight minimizing.Specifically; General semipermeable membrane by the film forming macromolecular material (like cellulose acetate and ethyl cellulose; In water, do not dissolve) and plasticizer (as dissolved Polyethylene Glycol in water or in water insoluble diethyl phthalate) or porogen (for example Polyethylene Glycol, polyvidone; Water-soluble) form, when film in vivo or during external chance water, the solubility composition in the semipermeable membrane (not with bonded plasticizer of film forming macromolecular material or porogen) promptly can dissolve; Make film produce micropore, water promptly gets into label from these micropores (micropore that also has film forming macromolecular material itself) and impels drug release.Its dissolved ratio is directly relevant with the permeability of film, dissolves manyly more, and permeability is good more.If medicine is in put procedure; Plasticizer or porogen and film forming macromolecular material constantly mutually combine; The ratio that causes the solubility composition is descended, and the permeability of film descends, and the speed that water gets into label descends; The rate of release of medicine also decreases, and the result of film loss of weight test this moment is that loss of weight descends.Otherwise if in put procedure, the ratio of solubility composition remains constant, and membrane permeability promptly remains unchanged, and the speed of water entering label is constant, and the rate of release of medicine also remains unchanged, and this moment, the result of film loss of weight test was that loss of weight also remains unchanged.The test of film loss of weight can well reflect permeability and the plasticizer (or porogen) and the bonded degree of film forming macromolecular material of film, that is to say, the test of film loss of weight can directly reflect the degree of aging of film.
The test of film loss of weight shows; The semipermeable membrane of cellulose acetate+Polyethylene Glycol, ethyl cellulose+Polyethylene Glycol combination in put procedure, all exist film forming macromolecular material and Polyethylene Glycol continue mutually combine; Cause the film loss of weight constantly to descend; Membrane permeability constantly descends, and rate of release also constantly descends.Its reason is that mutually combining of Polyethylene Glycol and film forming macromolecular material constantly strengthened in put procedure, and the pore effect that produces through autolysis constantly weakens; The combination of the film of ethyl cellulose+polyvidone, the two does not exist and mutually combines in put procedure, and film loss of weight result of the test is illustrated in the whole put procedure; The ratio of film loss of weight remains constant, and it is constant that membrane permeability also keeps, and rate of release is also constant; Its reason is that polyvidone has only the pore effect in film, and is very little with the interaction of film forming macromolecular material, in put procedure; The solubility composition ratio of stripping from film remains constant, thereby makes the permeability of film keep constant.Whether to sum up, continue to combine with the film forming macromolecular material, by the Substance Properties decision, polyvidone can effectively improve the aging of semipermeable membrane.
Contrast test shows; Under the situation of same label; The paroxetine hydrochloride osmotic pump type enteric controlled release tablets that uses common semipermeable membrane material coating and obtain; For example adopt cellulose acetate+Polyethylene Glycol, ethyl cellulose+Polyethylene Glycol as the semipermeable membrane material coating, all have catabiosis to some extent; By comparison, employing ethyl cellulose of the present invention and polyvidone have been eliminated catabiosis as the paroxetine hydrochloride osmotic pump type enteric controlled release tablets of semipermeable membrane filmogen, and stable release performance can be provided in the effect duration of pharmaceutical preparation.
Ethyl cellulose and polyvidone coupling normally as the filmogen of slow-release micro-pill, are not seen the report of the semipermeable membrane that is used for the osmotic pump type controlled release tablet so far.Trace it to its cause, be that the mechanism of two kinds of dosage forms is different, thereby the technical problem that will solve is also different.The release mechanism of slow-release micro-pill is based on diffusion mechanism; Because the particle diameter of slow-release micro-pill is very little; Often comprise hundreds and thousands of micropills in the preparation unit, thereby surface area is very big, the purpose of film control is the film diffusion coefficient that provides suitable; Thereby make drug slow discharge its release characteristics Higuchi equation.The most important point wherein, the film of this moment is not a semipermeable membrane, and not only water can get into, and medicine also can discharge through film.And the said osmotic pump type controlled release tablet of the present invention; Its mechanism is based on the osmotic pressure principle; The technical problem of its solution is how to adopt suitable semipermeable membrane to control moisture to get in the film; And medicine can not discharge from semipermeable membrane, must discharge from the drug release hole of accomplishing fluently in advance, and its release behavior meets zero level and discharges.Because the two mechanism is different; Release characteristics is different; The technical problem that solves is different, adds ethyl cellulose permeability characteristic on the low side, makes those of ordinary skill in the art to recognize: in the osmotic pump type controlled release tablet; Semipermeable membrane can adopt ethyl cellulose and polyvidone as the semipermeable membrane filmogen, and can overcome the semipermeable membrane catabiosis effectively.
Paroxetine hydrochloride osmotic pump type enteric controlled release tablets of the present invention; Paroxetine hydrochloride osmotic pump controlled release tablet in the enteric coating adopts ethyl cellulose and polyvidone as the semipermeable membrane filmogen; The ratio that polyvidone accounts in the semipermeable membrane filmogen is big more; Membrane permeability is big more, discharges fast more; The coating weightening finish is big more, and the film diffusional resistance is big more, discharges slow more.Wherein, for the weight ratio of ethyl cellulose and polyvidone, excessive like the ratio of polyvidone; Then membrane permeability is good excessively causes the release meeting too fast; Otherwise the ratio of polyvidone is too small, and then the too little release of membrane permeability meeting is slow excessively; Or the permeability of semipermeable membrane is too responsive with coating weightening finish variation, makes technology restive.The weight ratio that generally can select the two is 30: 16～20, and preferably the weight ratio of the two is 30: 18.For the coating weightening finish of semipermeable membrane, the too small lepthymenia coating that causes easily that increases weight is inhomogeneous, has the danger of film rupture in the dispose procedure simultaneously; The blocked up technology that causes of the excessive film that increases weight is tediously long, less economical.The weight ratio of general ethyl cellulose/polyvidone is that coating weightening finish in 30: 16～20 o'clock can be chosen as 8%～14%, and the weight ratio of the two is that the coating weightening finish of 30: 18 o'clock preferred semipermeable membranes is 10%～12%.The two can take all factors into consideration the weight ratio of ethyl cellulose/polyvidone and the weightening finish of the coating of semipermeable membrane; As discharge fastly, can suitably reduce the ratio of polyvidone or increase the coating weightening finish, otherwise; As discharge partially slowly, can suitably increase the ratio of polyvidone or reduce the coating weightening finish.
The label of paroxetine hydrochloride osmotic pump type enteric controlled release tablets according to the invention is double-layer tablet, and one deck is a medicated layer, and another layer is the boosting layer, can adopt the adjuvant of two-chamber osmotic pump controlled-release tablet well known in the art to constitute.Wherein, the upper strata medicated layer is made up of medicine, short osmo active substance and other adjuvants; Lower floor's boosting layer is made up of hydrophilic expanded polymer, short osmo active substance and other adjuvants and stain, again in the double-layer tablet outsourcing with semipermeable membrane, and on the upper strata (medicated layer) made a call to an aperture with laser, carry out film coating alternatively.In the above-mentioned adjuvant, short osmo active substance comprises sucrose, glucose, potassium chloride, sodium chloride, sodium sulfate, potassium sulfate, mannitol etc.; Hydrophilic expanded polymer is commonly used has high molecular weight peo (PEO), other hypromellose of high viscosity level (HPMC), carbomer (Carbomer), carmethose (CMC-Na) etc.; Other adjuvants comprise filler, suspending agent, adhesive, lubricant, wetting agent etc.
Paroxetine hydrochloride osmotic pump type enteric controlled release tablets according to the invention, enteric coating adopts enteric coating membrane material well known in the art, comprises enteric filmogen, antiplastering aid, plasticizer, wherein the preferred Youteqi L30D-55 of enteric filmogen.
Paroxetine hydrochloride osmotic pump type enteric controlled release tablets according to the invention between semipermeable membrane and enteric coating, preferably also contains the contagion gown layer, and said contagion gown layer adopts the filmogen that can be used as the contagion gown layer well known in the art, preferred stomach dissolution type coating powder.
The sheet type of paroxetine hydrochloride osmotic pump type enteric controlled release tablets according to the invention; It can be conventional symmetric form; The two sides that is tablet is symmetric (seeing accompanying drawing 1); The outer surface of medicated layer and boosting layer is identical with the angle of the lateral angle of tablet and all less, and for example the most frequently used scrobicula in this area is dashed the sheet type that (being the A type drift among the pharmaceutical machine industry standard JB20022-2004 of the People's Republic of China (PRC)) compacting is come out, and is generally less than 120 °.Or the medicated layer convexity degree asymmetrical type (see accompanying drawing 2) bigger than boosting layer; Preferred asymmetrical type; 130-150 ° of the lateral angle angle of the outer surface of its medicated layer and tablet; For example adopt the most frequently used dark recessed sheet type that (being the Type B drift among the pharmaceutical machine industry standard JB20022-2004 of the People's Republic of China (PRC)) compacting is come out, preferred 135 ° of dashing in this area.The lateral angle of the outer surface of said medicated layer and boosting layer and tablet; Refer to specifically on the tablet longitudinal profile; The collinear angle of the tangent line of the outer surface curve of the outer surface of medicated layer or boosting layer and intersection, tablet side and tablet side (is seen accompanying drawing 3, is respectively θ
1, θ
2).We discover; Asymmetrical type can further reduce the drug release residual quantity in latter stage with respect to symmetric form, and owing to both sides curvature differs greatly; Can distinguish medicated layer and boosting layer in shape; Protruding medicated layer of heaving and smooth boosting layer make tablet in transmission vibrations process, just can make medicated layer up automatically, need not image identification system, greatly reduce the technology cost of laser boring.
As one of preferred embodiment of the present invention, the invention provides a kind of paroxetine hydrochloride osmotic pump type enteric controlled release tablets with ageing resistace, have following prescription:
1, label prescription (in 1000):
Medicated layer:
The boosting layer:
2, semipermeable membrane coating fluid prescription
3, contagion gown coating fluid prescription
4, enteric coating coating fluid prescription
In the above-mentioned prescription, preferred paroxetine hydrochloride (in paroxetine) is 12.5g, 25g.
In the above-mentioned steps, the coating of semipermeable membrane increases weight preferred 8%～14%; The coating weightening finish of contagion gown can be 2.5%～5.0%, and the coating weightening finish of enteric coating can be 8%～10%.
Above-mentioned embodiment further preferred, paroxetine hydrochloride osmotic pump type enteric controlled release tablets of the present invention has following semipermeable membrane coating fluid prescription:
The coating weightening finish of preferred semipermeable membrane is 10%～12%.
The preparation technology of paroxetine hydrochloride osmotic pump type enteric controlled release tablets according to the invention; Can carry out concrete operations according to osmotic pump type controlled release tablet in the formulation art and enteric coated known technology; For example mix, granulation, tabletting, coating etc., idiographic flow comprise preparation osmotic pump type controlled release tablet label, semipermeable membrane coating, heat treatment, play drug release hole, wrap contagion gown, step such as enteric coated.
Preferred for preparation technology is following:
1, label preparation technology:
Label is a double-layer tablet, and one deck is a medicated layer, and another layer is the boosting layer.
Preparation technology is following:
Medicated layer:
(1) paroxetine hydrochloride sieves with other medicated layer adjuvants;
(2) paroxetine hydrochloride that takes by weighing recipe quantity and other medicated layer adjuvant mix homogeneously (except the lubricant);
(3) add adhesive/wetting agent system soft material;
(4) granulation of sieving, drying, granulate sieves;
(5) mix lubricant of adding recipe quantity is even.
Promptly get the medicated layer granule.
The boosting layer:
(1) osmo active substance that takes by weighing recipe quantity and other adjuvants, mix homogeneously (except the lubricant);
(2) add adhesive/wetting agent system soft material;
(3) granulation of sieving, drying, granulate sieves;
(4) mix lubricant of adding recipe quantity is even.
Promptly get boosting layer granule.
Two parts granule is pressed into double-layer tablet.
2, semipermeable membrane coating solution preparation technology
Take by weighing the 30 POVIDONE K 30 BP/USP 30 and the ethyl cellulose (N-100) of recipe quantity, stirring and dissolving is complete in the adding solvent, promptly gets.
3, semipermeable membrane coating: label is put coating in the coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.
4, heat treatment is removed the solvent in the semipermeable membrane.
5, laser boring: use laser-beam drilling machine with tablet from medicated layer one side perforating, aperture 0.3～0.7mm.
6, contagion gown coating solution preparation technology: take by weighing recipe quantity stomach dissolution type coating powder and add in the water of recipe quantity, stir, promptly get.
7, bag contagion gown: the tablet of laser boring is placed the coating pan coating.
8, enteric coating coating solution preparation technology: the triethyl citrate, Pulvis Talci that take by weighing recipe quantity are sheared (10000rpm shears 3min) evenly with cutter in water, and the Youteqi L30D-55 of recipe quantity is added in the above-mentioned solution, and stirring promptly gets.
9, enteric coated: the tablet that will wrap contagion gown places the coating pan coating.
In the above-mentioned steps, the coating of semipermeable membrane increases weight at 8%-14%, and preferred 10%～12%; The coating weightening finish of contagion gown can be 2.5%～5.0%, and the coating weightening finish of enteric coating can be 8%～10%.
In the above-mentioned steps; During the compacting double-layer tablet; Last low punch can all use the conventional scrobicula in this area to dash; Be pressed into the two sides and be the symmetric form label of conventional profile, for example adopt this area conventional pressing tablet the most frequently used scrobicula dash i.e. A type drift among People's Republic of China's pharmaceutical machine industry standard JB20022-2004; Preferably adopt dark recessed dashing to process the asymmetrical type label respectively with the scrobicula punching press; This moment, the medicated layer drift was dark recessed dashing; For example can adopt this area conventional pressing tablet the most frequently used dark recessed dashing, i.e. Type B drift among People's Republic of China's pharmaceutical machine industry standard JB20022-2004; Boosting layer drift is that scrobicula is dashed; For example adopt this area conventional pressing tablet the most frequently used scrobicula dash; Be the A type drift among the pharmaceutical machine industry standard JB20022-2004 of the People's Republic of China (PRC), the sheet type of extrusion is the bigger asymmetrical type of label medicated layer protrusion angle.
In addition; The present invention also provides a kind of method of improving paroxetine hydrochloride osmotic pump type enteric controlled release tablets ageing resistace; It is characterized in that adopting the semipermeable membrane material of ethyl cellulose-polyvidone compositions as osmotic pump controlled release tablet, wherein the weight ratio of ethyl cellulose/polyvidone is 30: 16～20, and the coating weightening finish is 8%～14%; Preferably the weight ratio of the two is 30: 18, and the coating weightening finish of semipermeable membrane is 10%～12%.
In addition; The present invention also provides ethyl cellulose-polyvidone compositions to be used to prepare the purposes of the paroxetine hydrochloride osmotic pump type enteric controlled release tablets with ageing resistace; It is characterized in that adopting the semipermeable membrane material of ethyl cellulose-polyvidone compositions as osmotic pump controlled release tablet, the weight ratio of ethyl cellulose/polyvidone is 30: 16～20 in the compositions, and the coating weightening finish is 8%～14%; Preferably the weight ratio of the two is 30: 18, and the coating weightening finish of semipermeable membrane is 10%～12%.
Description of drawings
The common symmetric form osmotic pump controlled release tablet of Fig. 1
Fig. 2 asymmetrical type osmotic pump controlled release tablet
The two chambers of Fig. 3 asymmetrical type osmotic pump tablet longitudinal profile sketch map
The specific embodiment:
Embodiment 1
One, prescription
1, label prescription (in 1000, specification: 25mg is in paroxetine):
Medicated layer:
The boosting layer:
2, semipermeable membrane coating fluid prescription
Two, detailed preparation technology
1, paroxetine hydrochloride label preparation technology:
Label is a double-layer tablet, and one deck is a medicated layer, and another layer is the boosting layer.
Preparation technology is following:
Medicated layer:
(1) paroxetine hydrochloride is crossed 100 mesh sieves, sodium lauryl sulphate was pulverized 100 mesh sieves, and sodium chloride, sucrose were pulverized 80 mesh sieves;
(2) take by weighing paroxetine hydrochloride, sucrose, sodium chloride, sodium lauryl sulphate, sodium carboxymethyl cellulose, the 30 POVIDONE K 30 BP/USP 30 of recipe quantity, put mix homogeneously in the wet granulator;
(3) with 70% alcoholic solution system soft material of 8% 30 POVIDONE K 30 BP/USP 30;
(4) cross 24 mesh sieves and granulate, 40 ℃ of dryings are crossed 24 mesh sieve granulate;
(5) the magnesium stearate mix homogeneously of adding recipe quantity.
Promptly get the medicated layer granule.
The boosting layer:
(1) sodium chloride was pulverized 80 mesh sieves;
(2) take by weighing hypromellose K4M, microcrystalline Cellulose, sodium chloride, 30 POVIDONE K 30 BP/USP 30, the iron oxide red of recipe quantity, put mix homogeneously in the wet granulator;
(3) with 70% alcoholic solution system soft material of 8% 30 POVIDONE K 30 BP/USP 30;
(4) cross 24 mesh sieves and granulate, 40 ℃ of dryings are crossed 24 mesh sieve granulate;
(5) the magnesium stearate mix homogeneously of adding recipe quantity.
Promptly get boosting layer granule.
Two parts granule is struck out double-layer tablet with the 8mm circle; The medicated layer drift is dark recessed dash (being the Type B drift among the pharmaceutical machine industry standard JB20022-2004 of the People's Republic of China (PRC)); Boosting layer drift is that scrobicula is dashed (being the A type drift among the pharmaceutical machine industry standard JB20022-2004 of the People's Republic of China (PRC)), and the outer surface of the label medicated layer that presses and the angle of the lateral angle of tablet are 135 °.
2, semipermeable membrane coating solution preparation technology
Take by weighing the 30 POVIDONE K 30 BP/USP 30 and the ethyl cellulose (N-100) of recipe quantity, stirring and dissolving is complete in the adding ethanol, promptly gets.
3, semipermeable membrane coating: label is put coating in the multi-functional coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.
Coating is to increasing weight about 8.0%.
4, heat treatment: 40 ℃ of dryings 16 hours.
5, laser boring: use laser-beam drilling machine with tablet from medicated layer one side perforating, aperture 0.3～0.7mm.
Three, release degree and Determination on content and result
[drug release determination] got these article, according to drug release determination method (two appendix XD second methods of Chinese Pharmacopoeia version in 2005), adopts dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) second subtraction unit; TRIS buffer (pH 7.5) 1000ml with 50mmol/L is a release medium, and rotating speed is that per minute 150 changes, operation in accordance with the law; When 2 hours, 5 hours and 8 hours, get solution 10ml respectively, filter; And instant release medium of in process container, replenishing uniform temp, equal volume, precision is measured subsequent filtrate 20 μ l, according to chromatographic condition under the assay item; Inject chromatograph of liquid, the record chromatogram; It is an amount of that precision takes by weighing the paroxetine hydrochloride reference substance in addition; Add the small amount of methanol hydrotropy; And with release medium quantitatively dilution process contain among every 1ml paroxetine 12.5 μ g (specification: 12.5mg) or 25 μ g (specification: solution 25mg), as reference substance solution, measure with method.Respectively by the burst size of external standard method with every different time in buffer of calculated by peak area.Every of these article should should be below 30% of labelled amount respectively mutually 2 hours, 5 hours burst sizes during with 8 hours, more than 50～70% and 80%, all should be up to specification.
[assay] measured according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability use octyl silane group silica gel to be filler; So that phosphate buffer (water-phosphoric acid-triethylamine (100: 0.6: 0.3))-acetonitrile (7: 3) is a mobile phase; The detection wavelength is 295nm; Flow velocity: 2.0ml/min; Number of theoretical plate calculates by the paroxetine hydrochloride peak should be not less than 750.
Algoscopy is got 10 of these article, and every difference is operated as follows: these article are put in the mortar ground, all be transferred in the 50ml measuring bottle, it is an amount of to add methanol; The ultrasonic paroxetine that makes dissolves, and adds methanol and is diluted to scale, shakes up; Filter, precision is measured subsequent filtrate 2ml, puts in the 10ml measuring bottle; Add methanol and be diluted to scale, shake up, as need testing solution.Precision is measured 10 μ l, injects chromatograph of liquid, the record chromatogram.It is an amount of that other gets the paroxetine hydrochloride reference substance, accurate claim fixed, add dissolve with methanol and dilution process contain approximately among every 1ml paroxetine 50 μ g (specification: 12.5mg) or 100 μ g (specification: solution 25mg), measure with method.With every content of calculated by peak area, get 10 meansigma methods by external standard method, promptly get.
Release degree and assay result such as table 1:
Table 1 embodiment 1 release degree and assay result
The result shows that the paroxetine hydrochloride osmotic pump type controlled release tablet release performance of embodiment 1 is good, and long-term placement does not have catabiosis basically.
Four, film loss of weight experiment:
Experimental technique: semipermeable membrane is peeled off from label, removed residual label powder in the above, weigh; Put into the stripping rotor that contains the 500ml distilled water, 37 ℃, press two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution determination, first method (changeing the basket method) operation; Rotating speed is that per minute 50 changes, respectively at 1h, and the 2h sampling; 50 ℃ of oven dry are put and are chilled to room temperature, weigh.Calculate the loss of weight ratio.
Computing formula: film loss of weight percentage ratio (%)=(1-W
T/ W
0) * 100%
W
T: the film weight after the different sampling time point oven dry; W
0: the initial weight of film, the result sees the following form 2:
Film loss of weight result after the long-term placement of table 2 room temperature
The experiment of film loss of weight shows that along with the prolongation of standing time, the semipermeable membrane loss of weight that adopts ethyl cellulose and polyvidone to process keeps constant basically, explains that the stability of film and permeability keep constant basically.
Embodiment 2
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane coating fluid prescription:
Two, detailed preparation technology
1, paroxetine hydrochloride label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology
Take by weighing the 30 POVIDONE K 30 BP/USP 30 and the ethyl cellulose (N-100) of recipe quantity, stirring and dissolving is complete in the adding ethanol, promptly gets.
3, semipermeable membrane coating: label is put coating in the multi-functional coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.
The coating weightening finish is respectively 10.0%, 12.0%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
Three, release degree and assay result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release degree and assay result such as table 3:
Table 3 embodiment 2 release degree and assay result
The result shows, the paroxetine hydrochloride osmotic pump controlled release tablet of embodiment 2, and under 30: 18 ratio, release performance is all good down for the coating weightening finish from 10.0%～12.0%, and long-term placement does not have catabiosis basically.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the result sees the following form 4:
Film loss of weight result after the long-term placement of table 4 room temperature
The experiment of film loss of weight shows that along with the prolongation of standing time, the semipermeable membrane loss of weight that adopts ethyl cellulose and polyvidone to process keeps constant basically, explains that the stability of film and permeability keep constant basically.
Embodiment 3
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane coating fluid prescription
Two, detailed preparation technology
1, paroxetine hydrochloride label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology
Take by weighing the 30 POVIDONE K 30 BP/USP 30 and the ethyl cellulose (N-100) of recipe quantity, stirring and dissolving is complete in the adding ethanol, promptly gets.
3, semipermeable membrane coating: label is put coating in the multi-functional coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.
The coating weightening finish is respectively 12.0%, 14.0%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
Three, release degree and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release degree and assay result such as table 5:
Table 5 embodiment 3 release degree and assay result
The result shows, the paroxetine hydrochloride osmotic pump controlled release tablet of embodiment 3, and under 30: 20 ratio, release performance is all good down for the coating weightening finish from 12.0%～14.0%, and long-term placement does not have catabiosis basically.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the result sees the following form 6:
Film loss of weight result after the long-term placement of table 6 room temperature
The experiment of film loss of weight shows that along with the prolongation of standing time, the semipermeable membrane loss of weight that adopts ethyl cellulose and polyvidone to process keeps constant basically, explains that the stability of film and permeability keep constant basically.
Embodiment 4
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane coating fluid prescription: with embodiment 2
Two, detailed preparation technology
1, paroxetine hydrochloride label preparation technology: with embodiment 2, when difference only was to suppress double-layer tablet, drift all was that scrobicula is dashed, and was pressed into conventional symmetric form label.
2, semipermeable membrane coating solution preparation technology: with embodiment 2
3, semipermeable membrane coating: technology: with embodiment 2, the coating weightening finish is 11.0%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
Three, release degree and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release degree and assay result such as table 7
Table 7 embodiment 4 release degree and assay result
The result shows that label is the paroxetine hydrochloride osmotic pump controlled release tablet of conventional symmetric form, compares with asymmetrical type among the embodiment 2; Has the aging-resistant advantage equally; Only be that the release degree is lower slightly, residual quantity is bigger when discharging end point 8h, but cumulative release also remains on more than 90%.
Four, film loss of weight experiment:
Experimental technique is with embodiment 1, and the result sees the following form 8:
Film loss of weight result after the long-term placement of table 8 room temperature
The experiment of film loss of weight shows that along with the prolongation of standing time, the semipermeable membrane loss of weight that adopts ethyl cellulose and polyvidone to process keeps constant basically, explains that the stability of film and permeability keep constant basically.
Embodiment 5 cellulose acetate+Polyethylene Glycol is done semipermeable membrane material (comparative example 1)
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane coating fluid prescription
Two, detailed preparation technology
1, paroxetine hydrochloride label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology
The Macrogol 4000 that takes by weighing recipe quantity is soluble in water, and cellulose acetate is disperseed in the Macrogol 4000 aqueous solution, adds the acetone of recipe quantity, is stirred to dissolving, promptly gets.
3, semipermeable membrane coating: label is put coating in the multi-functional coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.
The coating weightening finish is 14.0%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
Three, release degree and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release degree and assay result such as table 9:
Table 9 embodiment 5 release degree and assay result
The result shows that embodiment 5 adopts cellulose acetate+Polyethylene Glycol to do the paroxetine hydrochloride osmotic pump controlled release tablet of semipermeable membrane material, and the initial release performance is all good, and along with increase standing time, constantly aging, rate of release is slack-off, residual obvious increase.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the result sees the following form 10:
Film loss of weight result after the long-term placement of table 10 room temperature
The explanation of film loss of weight experimental result; Prolongation along with standing time; The combination rate of Polyethylene Glycol and cellulose acetate constantly increases in the semipermeable membrane, causes soluble polyalkylene glycol moiety to reduce gradually, and the permeability of film is descended gradually; Rate of release reduces gradually, discloses the aging semipermeable membrane that is accompanied by cellulose acetate-Polyethylene Glycol all the time of film.
Embodiment 6 ethyl celluloses+Polyethylene Glycol is done semipermeable membrane material (comparative example 2)
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane coating fluid prescription
Two, detailed preparation technology
1, paroxetine hydrochloride label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology:
The Macrogol 4000 that takes by weighing recipe quantity is soluble in water, and ethyl cellulose is disperseed in the Macrogol 4000 aqueous solution, adds the ethanol of recipe quantity, is stirred to dissolving, promptly gets.
3, semipermeable membrane coating: label is put coating in the multi-functional coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.
The coating weightening finish is 10.2%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
Three, release degree and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release degree and assay result such as table 11:
Table 11 embodiment 6 release degree and assay result
The result shows that embodiment 6 adopts ethyl cellulose+Polyethylene Glycol to do the paroxetine hydrochloride osmotic pump controlled release tablet of semipermeable membrane material, and the initial release performance is all good, and along with increase standing time, constantly aging, rate of release is slack-off, residual obvious increase.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the result sees the following form 12:
Film loss of weight result after the long-term placement of table 12 room temperature
The experiment of film loss of weight shows that along with the prolongation of standing time, the semipermeable membrane loss of weight that adopts ethyl cellulose+Polyethylene Glycol to process constantly descends, and explains that the permeability of film constantly descends.
Embodiment 7
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane coating fluid prescription: with embodiment 2
3, contagion gown coating fluid prescription
4, enteric coating coating fluid prescription
Two, detailed preparation technology
1, paroxetine label preparation technology:
With embodiment 1
2, semipermeable membrane coating solution preparation technology
Take by weighing the 30 POVIDONE K 30 BP/USP 30 and the ethyl cellulose (N-100) of recipe quantity, stirring and dissolving is complete in the adding ethanol, promptly gets.
3, coating (semipermeable membrane): label is put coating in the multi-functional coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.Coating weightening finish 10.5%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
6, contagion gown coating solution preparation technology: take by weighing recipe quantity stomach dissolution type coating powder and add in the water of recipe quantity, stir, promptly get.
7, bag contagion gown: the tablet of laser boring is placed the coating pan coating, and weightening finish is 2.5%～5.0%.
8, enteric coating coating solution preparation technology: the triethyl citrate, Pulvis Talci that take by weighing recipe quantity are sheared (10000rpm shears 3min) evenly with cutter in water, and the Youteqi L30D-55 of recipe quantity is added in the above-mentioned solution, and stirring promptly gets.
9, enteric coated: the tablet that will wrap contagion gown places the coating pan coating, and the coating weightening finish is 9.0%.
Three, release degree and Determination on content and result
Discharging these article of measuring in [drug release determination] acid, according to drug release determination method (two appendix XD second methods of Chinese Pharmacopoeia version in 2005), adopt dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) second subtraction unit, is release medium with 0.1mol/L hydrochloric acid solution 750ml; Rotating speed is that per minute 150 changes, and operation in accordance with the law in the time of 2 hours, is taken out these article; Cut in the rearmounted 100ml measuring bottle, after adding that small amount of methanol is ultrasonic and making dissolving, be diluted to scale with release medium; Shake up, filter, precision is measured subsequent filtrate 1ml; Put in the 10ml measuring bottle, be diluted to scale, as need testing solution with release medium.Precision is measured 20 μ l, according to chromatographic condition under the assay item, injects chromatograph of liquid, the record chromatogram; It is an amount of that in addition precision takes by weighing the paroxetine hydrochloride reference substance, adds the small amount of methanol hydrotropy, and with release medium quantitatively dilution process contain among every 1ml paroxetine 12.5 μ g (specification: 12.5mg) or 25 μ g (specification: solution 25mg), measure with method.With every content A of calculated by peak area, 1-A is the burst size in acid, should be not more than 10% of paroxetine labelled amount by external standard method.
The release degree is got these article in the buffer, according to drug release determination method (two appendix XD second methods of Chinese Pharmacopoeia version in 2005), adopts dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) second subtraction unit, is release medium with 0.1mol/L hydrochloric acid solution 750ml; Rotating speed is that per minute 150 changes, and operation in accordance with the law is after 2 hours; Discard hydrochloric acid solution, in process container, add TRIS buffer (pH 7.5) 1000ml of the 50mmol/L that is preheated to 37 ℃, rotating speed is constant; Continue operation, when 2 hours, 5 hours and 8 hours, get solution 10ml respectively; Filter, and instant release medium of in process container, replenishing uniform temp, equal volume, precision is measured subsequent filtrate 20 μ l; According to chromatographic condition under the assay item, inject chromatograph of liquid, the record chromatogram; It is an amount of that precision takes by weighing the paroxetine hydrochloride reference substance in addition; Add the small amount of methanol hydrotropy; And with release medium quantitatively dilution process contain among every 1ml paroxetine 12.5 μ g (specification: 12.5mg) or 25 μ g (specification: solution 25mg), as reference substance solution, measure with method.Respectively by the burst size of external standard method with every different time in buffer of calculated by peak area.Every of these article should should be below 30% of labelled amount respectively mutually 2 hours, 5 hours burst sizes during with 8 hours, more than 50～70% and 80%, all should be up to specification.
[assay] is with embodiment 1
Release degree and assay result such as table 13:
Table 13 embodiment 7 release degree and assay result
The result shows that enteric coating is to the not influence of release behavior of paroxetine hydrochloride osmotic pump controlled release tablet.The paroxetine hydrochloride osmotic pump type enteric controlled release tablets of embodiment 7 increased weight 9.0% o'clock at enteric coating, and the 2h drug release is less than 10% in the acid; The weight ratio of semipermeable membrane ethyl cellulose/polyvidone is under 30: 18 the ratio, and the increase weight release performance of 10.5% o'clock medicine of semipermeable membrane is good, and does not have catabiosis basically after long-term the placement.
Four, film loss of weight experiment:
Experimental technique: after removing outer enteric coating and contagion gown, semipermeable membrane is peeled off from label, removed residual label powder in the above, weigh; Put into the stripping rotor that contains the 500ml distilled water, 37 ℃, press two appendix X of Chinese Pharmacopoeia version in 2005 C dissolution determination, first method (changeing the basket method) operation; Rotating speed is that per minute 50 changes, respectively at 1h, and the 2h sampling; 50 ℃ of oven dry are put and are chilled to room temperature, weigh.Calculate the loss of weight ratio.
Computing formula: film loss of weight percentage ratio (%)=(1-W
T/ W
0) * 100%
W
T: the film weight after the different sampling time point oven dry; W
0: the initial weight of film, the result sees the following form 14:
Film loss of weight result after the long-term placement of table 14 room temperature
The experiment of film loss of weight shows that along with the prolongation of standing time, the semipermeable membrane loss of weight that adopts ethyl cellulose and polyvidone to process keeps constant basically, explains that the stability of film and permeability keep constant basically.
Embodiment 8
One, prescription
1, label prescription (in 1000, specification: 12.5mg (in paroxetine)):
Medicated layer:
The boosting layer:
2, semipermeable membrane coating fluid prescription: with embodiment 2
3, contagion gown coating fluid prescription: with embodiment 7
4, enteric coating coating fluid prescription: with embodiment 7
Two, detailed preparation technology
1, paroxetine label preparation technology:
With embodiment 1
2, semipermeable membrane coating solution preparation technology
Take by weighing the 30 POVIDONE K 30 BP/USP 30 and the ethyl cellulose (N-100) of recipe quantity, stirring and dissolving is complete in the adding ethanol, promptly gets.
3, coating (semipermeable membrane): label is put coating in the multi-functional coating machine, and the tablet that regularly takes a morsel is weighed, and calculates the coating weightening finish.Coating weightening finish 10.8%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
6, contagion gown coating solution preparation technology: with embodiment 7
7, bag contagion gown: with embodiment 7
8, enteric coating coating solution preparation technology: with embodiment 7
9, enteric coated: the tablet that will wrap contagion gown places the coating pan coating.The coating weightening finish is 9.5%.
Three, release degree and assay result
Method of testing: with embodiment 7, release degree and assay result such as table 15:
Table 15 embodiment 8 release degree and assay result
The result shows that enteric coating is to the not influence of release behavior of paroxetine hydrochloride osmotic pump controlled release tablet.The paroxetine hydrochloride osmotic pump type enteric controlled release tablets of embodiment 8 increased weight 9.5% o'clock at enteric coating, and the 2h drug release is less than 10% in the acid; The weight ratio of semipermeable membrane ethyl cellulose/polyvidone is under 30: 18 the ratio, and the semipermeable membrane 10.8% o'clock medicine-releasing performance that increases weight is good, and does not have catabiosis basically after long-term the placement.
Four, film loss of weight experiment:
Experimental technique: with embodiment 7, the result sees the following form 16:
Film loss of weight result after the long-term placement of table 16 room temperature
The experiment of film loss of weight shows that along with the prolongation of standing time, the semipermeable membrane loss of weight that adopts ethyl cellulose and polyvidone to process keeps constant basically, explains that the stability of film and permeability keep constant basically.
Claims (13)
1. a paroxetine hydrochloride osmotic pump type enteric controlled release tablets comprises paroxetine hydrochloride osmotic pump type controlled release tablet and outer field enteric coating, it is characterized in that the semipermeable membrane of osmotic pump type controlled release tablet adopts ethyl cellulose and polyvidone as the semipermeable membrane filmogen.
2. paroxetine hydrochloride osmotic pump type enteric controlled release tablets as claimed in claim 1 is characterized in that the weight ratio of ethyl cellulose and polyvidone is 30: 16～20 in the semipermeable membrane filmogen of osmotic pump type controlled release tablet.
3. paroxetine hydrochloride osmotic pump type enteric controlled release tablets as claimed in claim 1 is characterized in that the weight ratio of ethyl cellulose and polyvidone is 30: 18 in the semipermeable membrane filmogen of osmotic pump type controlled release tablet.
4. paroxetine hydrochloride osmotic pump type enteric controlled release tablets as claimed in claim 2 is characterized in that the semipermeable membrane coating weightening finish of osmotic pump type controlled release tablet is 8%～14%.
5. paroxetine hydrochloride osmotic pump type enteric controlled release tablets as claimed in claim 3 is characterized in that the coating weightening finish of the semipermeable membrane of osmotic pump type controlled release tablet is 10%～12%.
6. like the described paroxetine hydrochloride osmotic pump type of the arbitrary claim of claim 1～5 enteric controlled release tablets; It is characterized in that the sheet type is the bigger asymmetrical type of label medicated layer degree of convexity, the lateral angle angle of the outer surface of medicated layer and tablet is 130 °～150 °.
7. paroxetine hydrochloride osmotic pump type enteric controlled release tablets as claimed in claim 6 is characterized in that the outer surface of medicated layer and the lateral angle angle of tablet are 135 °.
8. method of improving paroxetine hydrochloride osmotic pump type enteric controlled release tablets ageing resistace; It is characterized in that adopting the semipermeable membrane material of ethyl cellulose-polyvidone compositions as the osmotic pump type controlled release tablet; Wherein the weight ratio of ethyl cellulose/polyvidone is 30: 16～20, and the coating weightening finish is 8%～14%.
9. method as claimed in claim 8 is characterized in that the weight ratio for ethyl cellulose/polyvidone is 30: 18, and the coating weightening finish of semipermeable membrane is 10%～12%.
10. ethyl cellulose-polyvidone compositions is used to prepare the purposes of the paroxetine hydrochloride osmotic pump type enteric controlled release tablets with ageing resistace; It is characterized in that adopting the semipermeable membrane material of ethyl cellulose-polyvidone compositions as the osmotic pump type controlled release tablet; The weight ratio of ethyl cellulose-polyvidone is 30: 16～20 in the compositions, and the coating weightening finish is 8%～14%.
11. like the said purposes of claim 10; It is characterized in that adopting the semipermeable membrane material of ethyl cellulose-polyvidone compositions as the osmotic pump type controlled release tablet; The weight ratio of ethyl cellulose-polyvidone is 30: 18 in the compositions, and the coating weightening finish of semipermeable membrane is 10%～12%.
12. the paroxetine hydrochloride osmotic pump type enteric controlled release tablets with ageing resistace is characterized in that having following prescription:
1), label prescription (in 1000):
Medicated layer:
The boosting layer:
2), semipermeable membrane coating fluid prescription
3), contagion gown coating fluid prescription
4), enteric coating coating fluid prescription
13. paroxetine hydrochloride osmotic pump type enteric controlled release tablets as claimed in claim 12 is characterized in that having following semipermeable membrane coating fluid prescription:
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