CN102670547A - Tolterodine tartrate osmotic pump controlled release tablet - Google Patents
Tolterodine tartrate osmotic pump controlled release tablet Download PDFInfo
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- CN102670547A CN102670547A CN2011100601866A CN201110060186A CN102670547A CN 102670547 A CN102670547 A CN 102670547A CN 2011100601866 A CN2011100601866 A CN 2011100601866A CN 201110060186 A CN201110060186 A CN 201110060186A CN 102670547 A CN102670547 A CN 102670547A
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Abstract
The invention provides a novel tolterodine tartrate osmotic pump controlled release tablet. Ethyl cellulose and polyvidone are taken as semi-permeable membrane forming materials, and asymmetrical tablets are provided preferably, so that the phenomenon of ageing of a semi-permeable membrane can be avoided, and medicament residues are reduced. The invention further provides a method for improving the anti-ageing performance of the tolterodine tartrate osmotic pump controlled release tablet. The method is characterized in that: ethyl cellulose-polyvidone is taken as a semi-permeable membrane material. Moreover, the invention further provides an application of an ethyl cellulose-polyvidone composition to preparation of a tolterodine tartrate osmotic pump controlled release tablet with anti-ageing performance.
Description
Technical field
The present invention relates to a kind of Tolterodine tartrate osmotic pump type controlled release tablet, adopt ethyl cellulose-polyvidone, belong to field of pharmaceutical preparations as semipermeable membrane material.
Background technology
Tolterodine tartrate is competitive muscarinic receptor antagonist, is used to alleviate frequent micturition, urgent micturition and the urinary incontinence that overactive bladder causes.
What these article went on the market the earliest is day to obey 2 times ordinary preparation, and untoward reaction such as xerostomia are serious, and patient's compliance is poor.In addition, long-acting alleviation frequent micturition, urgent micturition and urinary incontinence symptom are the basic demands that overactive bladder is alleviated in treatment.Therefore, the common slow releasing preparation that has abroad gone on the market again and obeyed 1 day.
Because tartaric acid toterodine slow released 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.
Tolterodine tartrate 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 two-chamber type Tolterodine tartrate osmotic pump controlled release tablet of stablizing release performance before the deadline.We are surprised to find that through to the scrutinizing and selecting of semipermeable membrane material semipermeable membrane adopts ethyl cellulose and polyvidone to make up as the semipermeable membrane filmogen; Can overcome catabiosis; The two-chamber type Tolterodine tartrate osmotic pump type controlled release tablet of using 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 two-chamber type Tolterodine tartrate osmotic pump type controlled release tablet 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 Tolterodine tartrate osmotic pump controlled release tablet 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 Tolterodine tartrate osmotic pump controlled release tablet 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.
Tolterodine tartrate osmotic pump controlled release tablet of the present invention adopts ethyl cellulose and polyvidone as the semipermeable membrane filmogen, and the ratio that polyvidone accounts in the semipermeable membrane filmogen is big more, and 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 Tolterodine tartrate osmotic pump controlled release tablet 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 lactose, 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.
The sheet type of Tolterodine tartrate osmotic pump controlled release tablet 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 Tolterodine tartrate osmotic pump controlled release tablet with ageing resistace, have following prescription:
1, label prescription (in 1000):
Medicated layer:
The boosting layer:
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription
| Form | Consumption |
| The stomach dissolution type coating powder | ?10g |
| Water | ?100ml |
In the above-mentioned prescription, preferred Tolterodine tartrate is 2g, 4g.
The coating weightening finish of preferred semipermeable membrane is 8%～14%, and the weightening finish of the coating of film-coat is 2.5%-5.0%.
Above-mentioned embodiment further preferred, Tolterodine tartrate osmotic pump controlled release tablet 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 Tolterodine tartrate osmotic pump controlled release tablet according to the invention can carry out concrete operations according to the known technology of osmotic pump type controlled release tablet, for example mixes, granulation, tabletting, coating etc.
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) Tolterodine tartrate sieves with other medicated layer adjuvants;
(2) Tolterodine tartrate 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, film-coat coating solution preparation technology: it is soluble in water to take by weighing the recipe quantity coating powder, and stirring promptly gets.
7, bag film-coat: the tablet of laser boring is placed the coating pan coating.
In the above-mentioned steps, the coating of semipermeable membrane increases weight 8%～14%, and preferred 10%～12%; The coating weightening finish of film-coat can be 2.5%-5.0%.
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 Tolterodine tartrate osmotic pump type controlled release tablet ageing resistace; It is characterized in that adopting ethyl cellulose-polyvidone compositions as semipermeable membrane material, 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 Tolterodine tartrate osmotic pump type controlled release tablet with ageing resistace; It is characterized in that adopting ethyl cellulose-polyvidone compositions as semipermeable membrane material, 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: 2mg):
Medicated layer:
The boosting layer:
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription
| Form | Consumption |
| The stomach dissolution type coating powder | ?10g |
| Water | ?100ml |
Two, detailed preparation technology
1, Tolterodine tartrate 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) Tolterodine tartrate is crossed 100 mesh sieves, sodium lauryl sulphate was pulverized 100 mesh sieves, and sodium chloride was pulverized 80 mesh sieves;
(2) Tolterodine tartrate, sodium chloride, sodium lauryl sulphate, sodium carboxymethyl cellulose, the microcrystalline Cellulose that take by weighing recipe quantity are put mix homogeneously in the wet granulator;
(3) with 8% 30 POVIDONE K 30 BP/USP, 3070% alcoholic solution system soft material;
(4) cross 24 mesh sieves and granulate, 40 ℃ of dryings are crossed 24 mesh sieve granulate;
(5) magnesium stearate, 30 POVIDONE K 30 BP/USP 30 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, 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) magnesium stearate, 30 POVIDONE K 30 BP/USP 30 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.
6, film-coat coating solution preparation technology: the coating powder that takes by weighing recipe quantity is soluble in water, and stirring promptly gets.
7, bag film-coat: the tablet of laser boring is placed the coating pan coating.Coating weightening finish 2.5～5.0%.
Three, release degree and Determination on content and result
Assay is measured according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability use octadecylsilane chemically bonded silica to be filler, before analytical column, add pre-column; With acetonitrile-water-perchloric acid (450: 550: 2) is mobile phase; The detection wavelength is 220nm; Number of theoretical plate calculates by the tolterodine peak should be not less than 1500.
Algoscopy is got 10 of these article, puts in the mortar fully and grinds, all be transferred to 200ml (specification: 2mg) or 250ml (specification: 4mg) in the measuring bottle, it is an amount of to add methanol; Ultrasonicly make Tolterodine tartrate dissolving, put coldly, add methanol and be diluted to scale, shake up; Leave standstill, precision is measured supernatant 3ml (specification: 2mg) or 2ml (specification: 4mg), put in the 10ml measuring bottle, be diluted to scale with water-methanol (6: 2); Shake up, centrifugal, get supernatant as need testing solution.Precision is measured 25 μ l, injects chromatograph of liquid, the record chromatogram.It is an amount of that precision takes by weighing the Tolterodine tartrate reference substance in addition, processes the solution that contains 30 μ g among every 1ml approximately with water-methanol (6: 2) dissolving and quantitative dilution, measures with method., promptly get with calculated by peak area by external standard method.
Drug release determination is got these article, according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2005), adopts dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) first subtraction unit; [get potassium dihydrogen phosphate 7.2g and dipotassium hydrogen phosphate 8.2g with phosphate buffer (pH6.8); Be dissolved in water and be diluted to 1000ml, pH value should be 6.8 ± 0.1] 900ml is solvent, rotating speed is that per minute 100 changes; Operation in accordance with the law; In the time of 2 hours, 5 hours, 8 hours, get solution 5ml respectively, filter, and the instant above-mentioned solvent that in process container, replenishes uniform temp, equal volume; Get subsequent filtrate as need testing solution, it is an amount of that other gets the Tolterodine tartrate reference substance, and accurate the title decides, and adds the also quantitative dilution of above-mentioned dissolution with solvents and process the solution that contains 2.2 μ g (specification 2mg) or 4.4 μ g (specification 4mg) among every 1ml, as reference substance solution.Measure according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2005), use octadecylsilane chemically bonded silica to be filler, acetonitrile-0.02mol/L phosphoric acid solution (45: 55) is a mobile phase, and the detection wavelength is 285nm.Precision is measured above-mentioned reference substance solution and each 100 μ l of need testing solution, injects chromatograph of liquid respectively, calculates every burst size at different time by external standard method respectively with 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.
Release degree and assay result such as table 1:
Table 1 embodiment 1 release degree and assay result
The result shows that the Tolterodine tartrate osmotic pump 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: after removing the outermost layer film-coat, 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:
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, Tolterodine tartrate 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
6, film-coat coating solution preparation technology and bag film-coat: with embodiment 1.
Three, release degree and content measuring 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 Tolterodine tartrate 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
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, Tolterodine tartrate 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.
6, film-coat coating solution preparation technology and bag film-coat: 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 Tolterodine tartrate 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
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, Tolterodine tartrate 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 11.3%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
6, film-coat coating solution preparation technology and bag film-coat: 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 Tolterodine tartrate 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
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, Tolterodine tartrate 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 10.5%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
6, film-coat coating solution preparation technology and bag film-coat: 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 Tolterodine tartrate 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
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, Tolterodine tartrate 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, and the ethanol of adding side's amount 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 9.2%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
6, film-coat coating solution preparation technology and bag film-coat: 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 Tolterodine tartrate 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 film loss of weight of the semipermeable membrane that employing ethyl cellulose+Polyethylene Glycol is processed constantly descends, and explains that the permeability of film constantly descends.
Embodiment 7
One, prescription
1, label prescription (in 1000, specification: 4mg):
Medicated layer:
The boosting layer:
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription
| Form | Consumption |
| The stomach dissolution type coating powder | ?10g |
| Water | ?100ml |
Two, detailed preparation technology
1, Tolterodine tartrate 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 11.3%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
6, film-coat coating solution preparation technology and bag film-coat: 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 13 embodiment 7 release degree and assay result
The result shows that the Tolterodine tartrate osmotic pump controlled release tablet release performance of embodiment 7 is good, 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 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.
Claims (13)
1. a Tolterodine tartrate osmotic pump type controlled release tablet is characterized in that semipermeable membrane adopts ethyl cellulose and polyvidone as the semipermeable membrane filmogen.
2. Tolterodine tartrate osmotic pump type controlled release tablet as claimed in claim 1, the weight ratio that it is characterized in that ethyl cellulose and polyvidone is 30: 16～20.
3. Tolterodine tartrate osmotic pump type controlled release tablet as claimed in claim 1, the weight ratio that it is characterized in that ethyl cellulose and polyvidone is 30: 18.
4. Tolterodine tartrate osmotic pump type controlled release tablet as claimed in claim 2 is characterized in that the weightening finish of semipermeable membrane coating is 8%～14%.
5. Tolterodine tartrate osmotic pump type controlled release tablet as claimed in claim 3 is characterized in that the coating weightening finish of semipermeable membrane is 10%～12%.
6. like the described Tolterodine tartrate osmotic pump type of the arbitrary claim of claim 1～5 controlled release tablet; 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. Tolterodine tartrate osmotic pump type controlled release tablet 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 Tolterodine tartrate osmotic pump type controlled release tablet ageing resistace; It is characterized in that adopting ethyl cellulose-polyvidone compositions as semipermeable membrane material; 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 Tolterodine tartrate osmotic pump type controlled release tablet with ageing resistace; It is characterized in that adopting ethyl cellulose-polyvidone compositions as semipermeable membrane material; 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 ethyl cellulose-polyvidone compositions as semipermeable membrane material, the weight ratio of ethyl cellulose-polyvidone is 30: 18 in the compositions, the coating weightening finish of semipermeable membrane is 10%～12%.
12. the Tolterodine tartrate osmotic pump type controlled release tablet 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, film-coat coating fluid prescription
13. Tolterodine tartrate osmotic pump type controlled release tablet as claimed in claim 12 is characterized in that having following semipermeable membrane coating fluid prescription:
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| CN2011100601866A CN102670547A (en) | 2011-03-14 | 2011-03-14 | Tolterodine tartrate osmotic pump controlled release tablet |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011100601866A CN102670547A (en) | 2011-03-14 | 2011-03-14 | Tolterodine tartrate osmotic pump controlled release tablet |
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| CN1827092A (en) * | 2006-04-14 | 2006-09-06 | 浙江大学 | Osmotic pump type controlled release preparation of tolterodine |
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| CN1827092A (en) * | 2006-04-14 | 2006-09-06 | 浙江大学 | Osmotic pump type controlled release preparation of tolterodine |
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| CN101658508A (en) * | 2008-08-25 | 2010-03-03 | 天津中医药大学 | Novel enteric controlled-release tablet preparation and preparation method thereof |
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Application publication date: 20120919 |