CN102670551B - Felodipine osmotic pump type controlled release tablets - Google Patents
Felodipine osmotic pump type controlled release tablets Download PDFInfo
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- CN102670551B CN102670551B CN201110060846.0A CN201110060846A CN102670551B CN 102670551 B CN102670551 B CN 102670551B CN 201110060846 A CN201110060846 A CN 201110060846A CN 102670551 B CN102670551 B CN 102670551B
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Abstract
The invention provides a kind of novel felodipine osmotic pump type controlled release tablets, adopt ethyl cellulose and polyvidone as semipermeable membrane filmogen, preferably there is asymmetric flap-type, semipermeable membrane catabiosis can be overcome, reduce drug residue.Present invention also offers a kind of method improving felodipine osmotic pump type controlled release tablets ageing resistace, it is characterized in that adopting ethyl cellulose-polyvidone as semipermeable membrane material.In addition, present invention also offers ethyl cellulose-polyvidone compositions for the preparation of the purposes of felodipine osmotic pump type controlled release tablets with ageing resistace.
Description
Technical field
The present invention relates to a kind of felodipine osmotic pump type controlled release tablets, adopt ethyl cellulose-polyvidone as semipermeable membrane material, belong to field of pharmaceutical preparations.
Background technology
Felodipine is calcium ion antagonist, is mainly used in treating hypertension.
The sustained-release preparation of current listing has matrix sustained release tablet and elementary osmotic pump controlled release tablet.
Elementary osmotic pump controlled release tablet is suitable for the larger medicine of dissolubility, is unsuitable for the medicine that dissolubility is less.The dissolubility of felodipine is less, makes elementary osmotic pump controlled release tablet and there is residual large defect.
What osmotic pump type controlled release preparation was most widely used is two-chamber osmotic pump, has medicated layer and boosting layer, forms coyote hole and power house respectively.Medicated layer is made up of medicine and penetration enhancer and other adjuvants, and boosting layer is made up of the macromolecular material of one or more swellables and penetration enhancer.Take rear moisture and enter label by semipermeable membrane, medicated layer is absorbed water softening, and the macromolecular material imbibition of boosting layer, extruding is produced to coyote hole, medicine is discharged by small delivery aperture.Keep osmotic pressure constant, moisture can be kept to enter the constant airspeed of label, and then make the constant rate of macromolecular material imbibition, maintain osmotic pressure constant lastingly, reach rate of releasing drug constant.Owing to there being the motive force of boosting layer, be particularly suited for the medicine that dissolubility is less.
The characteristic of felodipine is suitable for developing two-chamber osmotic pump controlled-release tablet, its label is made up of medicine layer and boosting layer, due to the motive force having propellant, " the passive release " that become single chamber preparation is " Remote release ", drug residue is little, and rate of releasing drug is lastingly constant, and avoids the rate of releasing drug that the single chamber preparation release later stage causes because permeable pressure head declines and reduce, during whole release, rate of releasing drug is constant, is more conducive to the blood drug level of held stationary.
Semipermeable membrane is quite important to the control of drug release in Oros preparation.The semipermeable membrane of different materials composition, different to the permeability of water, namely relevant with the infiltration coefficient of film, the most generally use cellulose acetate, other also has document to mention as ethyl cellulose etc.Adopt semipermeable membrane material conventional at present, osmotic pump type controlled release tablets prepared by such as cellulose acetate+Polyethylene Glycol, ethyl cellulose+Polyethylene Glycol, within a period of time just prepared, its release performance is good, but after storing a period of time, its release performance starts to decline, storage time is longer, declines more obvious, often specifies the latter half of effect duration at medicine, release performance obviously declines, and popular saying is aging.
Summary of the invention:
In order to overcome the defect of prior art, the invention provides a kind of novel two-chamber type felodipine osmotic pump controlled release tablet that can not remain Stable Release performance by storage time restriction before the deadline.We are through carefully studying and selecting semipermeable membrane material, be surprised to find that, semipermeable membrane adopts ethyl cellulose and polyvidone combination as semipermeable membrane filmogen, catabiosis can be overcome, the two-chamber type felodipine osmotic pump type controlled release tablets using the semipermeable membrane of this kind of material to make, not only can make drug slow and constant release, extend the effective blood drug concentration time, and blood drug level can be made more steady, reduce untoward reaction, and release performance can be kept in its expiration date of drug to stablize, release remains little.
Therefore, first object of the present invention there are provided a kind of two-chamber type felodipine osmotic pump type controlled release tablets that can not remain stable release performance by storage time restriction before the deadline.
In order to investigate film composition and film aging between relation, we devise film loss of weight test.The test of film loss of weight is the test investigating membrane permeability by measuring the semipermeable membrane degree that weight reduces after water soaking process.Specifically, general semipermeable membrane by film-forming high molecular material (as cellulose acetate and ethyl cellulose, do not dissolve in water) and plasticizer (as the Polyethylene Glycol that dissolves in water or diethyl phthalate insoluble in water) or porogen (such as Polyethylene Glycol, polyvidone, water-soluble) composition, when film in vivo or external chance water time, soluble constituents (plasticizer be not combined with film-forming high molecular material or porogen) in semipermeable membrane namely can dissolve, film is made to produce micropore, namely water enter label from these micropores (also having the micropore of film-forming high molecular material itself) and impel drug release.Its ratio of dissolving is directly relevant to the permeability of film, and dissolve more, permeability is better.If medicine is in put procedure, plasticizer or porogen and film-forming high molecular material constantly be combined with each other, decline causing the ratio of soluble constituents, the permeability of film declines, the speed that water enters label declines, the rate of release of medicine also decreases, and the result of now film loss of weight test is that loss of weight declines.Otherwise if in put procedure, the ratio of soluble constituents remains constant, and namely membrane permeability remains unchanged, and the speed that water enters label is constant, and the rate of release of medicine also remains unchanged, the result of now film loss of weight test is that loss of weight also remains unchanged.The test of film loss of weight can well reflect the degree that the permeability of film and plasticizer (or porogen) are combined with film-forming high molecular material, and that is, film loss of weight tests the degree of aging that directly can reflect film.
The test of film loss of weight shows, the semipermeable membrane of cellulose acetate+Polyethylene Glycol, ethyl cellulose+Polyethylene Glycol combination all exist in put procedure film-forming high molecular material and Polyethylene Glycol continue be combined with each other, film loss of weight is caused constantly to decline, membrane permeability constantly declines, and rate of release also constantly declines.Its reason is that Polyethylene Glycol and be combineding with each other of film-forming high molecular material are constantly strengthened in put procedure, and is constantly weakened by the pore effect that autolysis produces; The film combination of ethyl cellulose+polyvidone, do not exist both in put procedure and be combined with each other, film loss of weight result of the test shows in whole put procedure, and the ratio of film loss of weight remains constant, and membrane permeability also keeps constant, rate of release is also constant, its reason is that polyvidone only has pore effect in film, very little with the interaction of film-forming high molecular material, in put procedure, the soluble constituents ratio of stripping from film remains constant, thus makes the permeability of film keep constant.To sum up, whether continue to combine with film-forming high molecular material, be determined by the character of material, polyvidone if can effectively improve the aging of semipermeable membrane.
Contrast test shows, when same label, use common semipermeable membrane material coating and the felodipine osmotic pump controlled release tablet obtained, such as, adopt cellulose acetate+Polyethylene Glycol, ethyl cellulose+Polyethylene Glycol as semipermeable membrane material coating, there is catabiosis all to some extent; By comparison, employing ethyl cellulose of the present invention and polyvidone, as the felodipine osmotic pump controlled release tablet of semipermeable membrane filmogen, eliminate catabiosis, can provide stable release performance within the effect duration of pharmaceutical preparation.
Ethyl cellulose and polyvidone coupling, normally as the filmogen of slow-release micro-pill, do not see the report of the semipermeable membrane for osmotic pump type controlled release tablets so far.Trace it to its cause, be that the mechanism of two kinds of dosage forms is different, the technical problem that thus will solve is also different.The Mechanism of Drug Release of slow-release micro-pill is based on diffusion mechanism, because the particle diameter of slow-release micro-pill is very little, hundreds and thousands of micropills are often comprised in a preparation unit, thus surface area is very large, the object of film control is to provide suitable membrane diffusion coefficient, thus making sustained release, its release characteristics meets Higuchi equation.The wherein most important point, film is now not semipermeable membrane, and not only water can enter, and medicine also can discharge through film.And the said osmotic pump type controlled release tablets of the present invention, its mechanism is based on osmotic pressure principle, its technical problem solved how to adopt suitable semipermeable membrane to enter in film to control moisture, and medicine can not discharge from semipermeable membrane, must discharge from the drug release hole of accomplishing fluently in advance, its release behavior meets Zero order release.Because the two mechanism is different, release characteristics is different, the technical problem solved is different, add the characteristic that ethyl cellulose permeability is on the low side, those of ordinary skill in the art cannot be recognized: in osmotic pump type controlled release tablets, semipermeable membrane can adopt ethyl cellulose and polyvidone as semipermeable membrane filmogen, and can effectively overcome semipermeable membrane catabiosis.
Felodipine osmotic pump controlled release tablet of the present invention adopts ethyl cellulose and polyvidone as semipermeable membrane filmogen, and the ratio that polyvidone accounts in semipermeable membrane filmogen is larger, and membrane permeability is larger, discharges faster; Coating weight gain is larger, and membrane diffusion resistance is larger, discharges slower.Wherein, for the weight ratio of ethyl cellulose and polyvidone, ratio as polyvidone is excessive, then membrane permeability is excessively good causes release can be too fast, otherwise the ratio of polyvidone is too small, then the too little release of membrane permeability was understood slow, or the permeability of semipermeable membrane is too responsive with coating weight gain change, makes technique restive.The weight ratio of the two generally can be selected to be 30: 16 ~ 20, and preferably the weight ratio of the two is 30: 18.For the coating weight gain of semipermeable membrane, the too small lepthymenia coating that easily causes that increases weight is uneven, there is the danger of film rupture in dispose procedure simultaneously; The blocked up technique that causes of the excessive film that increases weight is tediously long, less economical.When the weight ratio of general ethyl cellulose/polyvidone is 30: 16 ~ 20, coating weight gain can be chosen as 9% ~ 16%, and when the weight ratio of the two is 30: 18, the coating weight gain of preferred semipermeable membrane is 11% ~ 13%.The weight ratio of ethyl cellulose/polyvidone and both coating weight gain of semipermeable membrane can consider, as fast in discharged, suitably can reduce the ratio of polyvidone or increase coating weight gain, otherwise, as release is partially slow, suitably can increase the ratio of polyvidone or reduce coating weight gain.
The label of felodipine osmotic pump controlled release tablet of the present invention is double-layer tablet, and one deck is medicated layer, and another layer is boosting layer, can adopt the adjuvant of two-chamber osmotic pump controlled-release tablet well known in the art to form.Wherein, 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, then in double-layer tablet outsourcing with semipermeable membrane, and make a call to an aperture in upper strata (medicated layer) with laser, carry out film coating alternatively.In above-mentioned adjuvant, short osmo active substance comprises lactose, glucose, potassium chloride, sodium chloride, sodium sulfate, potassium sulfate, mannitol etc.; The hypromellose (HPMC), carbomer (Carbomer), carmethose (CMC-Na) etc. that have high molecular weight peo (PEO), high viscosity rank that hydrophilic expanded polymer is conventional; Other adjuvants comprise filler, suspending agent, adhesive, lubricant, wetting agent etc.
The flap-type of felodipine osmotic pump controlled release tablet of the present invention, it can be conventional symmetric form, namely the two sides of tablet is symmetrical (see accompanying drawing 1), medicated layer is identical with the angle of the angle of tablet side with the outer surface of boosting layer and all less, scrobicula punching (the A type drift namely in People's Republic of China's pharmaceutical machine industry standard JB20022-2004) the compacting flap-type out that such as this area is the most frequently used, is generally less than 120 °.Or the asymmetrical type that medicated layer projection degree is larger than boosting layer (see accompanying drawing 2), preferred asymmetrical type, the outer surface of its medicated layer and the angle angle 130-150 ° of tablet side, dark recessed punching (the Type B drift namely in People's Republic of China's pharmaceutical machine industry standard JB20022-2004) the compacting flap-type out such as adopting this area the most frequently used, preferably 135 °.The outer surface of described medicated layer and boosting layer and the angle of tablet side, refer to specifically on tablet longitudinal profile, the outer surface of medicated layer or boosting layer and the tangent line of outer surface curve of intersection, tablet side and the angle of tablet sided linear (see accompanying drawing 3, are respectively θ
1, θ
2).We study discovery, asymmetrical type is relative to symmetric form, the residual quantity in drug release latter stage can be reduced further, and because both sides curvature differs greatly, medicated layer and boosting layer can be distinguished in shape, the convex medicated layer heaved and smooth boosting layer make tablet just can automatically make medicated layer upward in transmission vibrations process, without the need to image identification system, greatly reduce the process costs of laser boring.
As one of preferred embodiment of the present invention, the invention provides a kind of felodipine osmotic pump controlled release tablet with ageing resistace, there is following prescription:
1, Core formulation (in 1000):
Medicated layer:
Boosting layer:
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription
| Composition | Consumption |
| Stomach dissolution type coating powder | 10g |
| Water | 100ml |
In above-mentioned prescription, preferred felodipine is 5g, 10g.
The coating weight gain of preferred semipermeable membrane is 9% ~ 16%, and the coating weight gain of film-coat is 2.5%-5.0%.
Above-mentioned embodiment further preferably, felodipine osmotic pump controlled release tablet of the present invention has following semipermeable membrane coating fluid prescription:
The coating weight gain of preferred semipermeable membrane is 11% ~ 13%.
The preparation technology of felodipine osmotic pump controlled release tablet of the present invention, can carry out concrete operations according to the known technology of osmotic pump type controlled release tablets, such as, mix, granulate, tabletting, coating etc.
Preferred preparation technology is as follows:
1, label preparation technology:
Label is double-layer tablet, and one deck is medicated layer, and another layer is boosting layer.
Preparation technology is as follows:
Medicated layer:
(1) felodipine and other medicated layer adjuvants sieve;
(2) felodipine and other medicated layer adjuvant mix homogeneously (except lubricant) of recipe quantity are taken;
(3) adhesive/wetting agent soft material is added;
(4) sieve granulation, dry, sieve granulate;
(5) mix lubricant adding recipe quantity is even.
Obtain medicated layer granule.
Boosting layer:
(1) osmo active substance and other adjuvants of recipe quantity are taken, mix homogeneously (except lubricant);
(2) adhesive/wetting agent soft material is added;
(3) sieve granulation, dry, sieve granulate;
(4) mix lubricant adding recipe quantity is even.
Obtain boosting layer granule.
Two parts granule is pressed into double-layer tablet.
2, semipermeable membrane coating solution preparation technology
Take PVP K30 and the ethyl cellulose (N-100) of recipe quantity, add stirring and dissolving in solvent and completely, to obtain final product.
3, semipermeable membrane coating: label is put coating in seed-coating machine, regularly take a morsel weighing tablets, calculates coating weight gain.
4, heat treatment, the solvent in removing semipermeable membrane.
5, laser boring: use laser-beam drilling machine by tablet from medicated layer one side perforating, aperture 0.3 ~ 0.7mm.
6, film-coat coating solution preparation technology: take recipe quantity coating powder soluble in water, stirs and get final product.
7, film coating: the tablet of laser boring is placed in coating pan coating.
In above-mentioned steps, the coating weight gain of semipermeable membrane at 9%-16%, preferably 11% ~ 13%; The coating weight gain of film-coat can be 2.5%-5.0%.
In above-mentioned steps, during compacting double-layer tablet, upper low punch can all use the scrobicula of this area routine to rush, be pressed into the symmetric form label that two sides is conventional form, such as adopt this area conventional pressing tablet the most frequently used scrobicula punching, the A type drift namely in People's Republic of China's pharmaceutical machine industry standard JB20022-2004; Preferably dark recessed punching and scrobicula punching press is adopted to make asymmetrical type label respectively, now medicated layer drift is dark recessed punching, such as can adopt this area conventional pressing tablet the most frequently used dark recessed punching, the Type B drift namely in People's Republic of China's pharmaceutical machine industry standard JB20022-2004; Boosting layer drift is scrobicula punching, such as adopt this area conventional pressing tablet the most frequently used scrobicula punching, namely the A type drift in People's Republic of China's pharmaceutical machine industry standard JB20022-2004, the flap-type of extrusion is the larger asymmetrical type of label medicated layer protrusion angle.
In addition, present invention also offers a kind of method improving felodipine osmotic pump type controlled release tablets 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, coating weight gain is 9% ~ 16%, preferably the weight ratio of the two is 30: 18, and the coating weight gain of semipermeable membrane is 11% ~ 13%.
In addition, present invention also offers ethyl cellulose-polyvidone compositions for the preparation of the purposes of felodipine osmotic pump type controlled release tablets with ageing resistace, it is characterized in that adopting ethyl cellulose-polyvidone compositions as semipermeable membrane material, in compositions, the weight ratio of ethyl cellulose/polyvidone is 30: 16 ~ 20, coating weight gain is 9% ~ 16%, preferably the weight ratio of the two is 30: 18, and the coating weight gain of semipermeable membrane is 11% ~ 13%.
Accompanying drawing explanation
Fig. 1 common symmetric type osmotic pump controlled release tablet
Fig. 2 asymmetrical type osmotic pump controlled release tablet
Fig. 3 two rooms asymmetrical type osmotic pump tablet longitudinal profile schematic diagram
Detailed description of the invention:
Embodiment 1
One, prescription
1, Core formulation (1000, specification: 5mg):
Medicated layer:
Boosting layer:
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription
| Composition | Consumption |
| Stomach dissolution type coating powder | 10g |
| Water | 100ml |
Two, detailed preparation technology
1, felodipine label preparation technology:
Label is double-layer tablet, and one deck is medicated layer, and another layer is boosting layer.
Preparation technology is as follows:
Medicated layer:
(1) felodipine crosses 100 mesh sieves, sodium lauryl sulphate pulverized 100 mesh sieves, and sucrose, sodium chloride pulverized 80 mesh sieves;
(2) take the felodipine of recipe quantity, sucrose, sodium chloride, sodium lauryl sulphate, sodium carboxymethyl cellulose, put mix homogeneously in wet granulator;
(3) with 0.2% n-Propyl gallate 10% PVP K30 alcoholic solution soft material;
(4) cross 24 mesh sieves to granulate, 40 DEG C of dryings, cross 24 mesh sieve granulate;
(5) PVP K30 of recipe quantity, magnesium stearate mix homogeneously is added.
Obtain medicated layer granule.
Boosting layer:
(1) sodium chloride pulverized 80 mesh sieves;
(2) take the HPMC K4M of recipe quantity, microcrystalline Cellulose, sodium chloride, iron oxide red, put mix homogeneously in wet granulator;
(3) 8% PVP K30 70% alcoholic solution soft materials;
(4) cross 24 mesh sieves to granulate, 40 DEG C of dryings, cross 24 mesh sieve granulate;
(5) PVP K30 of recipe quantity, magnesium stearate mix homogeneously is added.
Obtain boosting layer granule.
Two parts granule 8mm circle is struck out double-layer tablet; Medicated layer drift is dark recessed punching (the Type B drift namely in People's Republic of China's pharmaceutical machine industry standard JB20022-2004), boosting layer drift is scrobicula punching (the A type drift namely in People's Republic of China's pharmaceutical machine industry standard JB20022-2004), and the angle of the outer surface of the label medicated layer pressed and the angle of tablet side is 135 °.
2, semipermeable membrane coating solution preparation technology
Take PVP K30 and the ethyl cellulose (N-100) of recipe quantity, add stirring and dissolving in ethanol and completely, to obtain final product.
3, semipermeable membrane coating: label is put coating in Multifunctional coating machine, regularly take a morsel weighing tablets, calculates coating weight gain.
Coating is to weightening finish about 9.0% and 11.0%.
4, heat treatment: 40 DEG C of dryings 16 hours.
5, laser boring: use laser-beam drilling machine by tablet from medicated layer one side perforating, aperture 0.3 ~ 0.7mm.
6, film-coat coating solution preparation technology: the coating powder taking recipe quantity is soluble in water, stirs and get final product.
7, film coating: the tablet of laser boring is placed in coating pan coating.Coating weight gain 2.5 ~ 5.0%.
Three, the mensuration of release and content and result
[assay] lucifuge operates; get this product 10; every sheet is following operation respectively: this product put in mortar; add the grinding of a small amount of ethanol; be transferred in 250ml (specification: 5mg) or 500ml (specification: 10mg) measuring bottle with ethanol gradation; the ultrasonic felodipine that makes is dissolved; add ethanol dilution to scale; shake up; filter, get subsequent filtrate as need testing solution, according to ultraviolet visible spectrophotometry (China's coastal port two annex IVA); measure trap at the wavelength place of 362nm and 450nm respectively, calculate with differential technique; It is appropriate that another precision takes felodipine reference substance, adds dissolve with ethanol and dilute the solution made about containing felodipine 20 μ g in every 1ml, being measured in the same method, calculating every sheet content, get the meansigma methods of 10, to obtain final product.
Release: this product is got in lucifuge operation, according to drug release determination method (China's coastal port two annex XD first methods), adopt dissolution method (China's coastal port two annex XC) the second subtraction unit, tablet is put in sedimentation basket, (1mol/L sodium dihydrogen phosphate 206ml is got with the phosphate buffer containing 1% sodium lauryl sulphate, the disodium phosphate soln 196ml of 0.5mol/L, sodium lauryl sulphate 50.0g, add water to 5000ml, if necessary, being 6.5 by the sodium hydroxide solution adjust ph of 1mol/L) 500ml is release medium, rotating speed is 75 turns per minute, operate in accordance with the law, respectively at 2, 6 and 10 is constantly little, get solution 10ml, filter, and immediately in process container, supplement identical temperature, the release medium of same volume, get subsequent filtrate, according to ultraviolet visible spectrophotometry (China's coastal port two annex IVA), use 2cm absorption cell, absorption value is measured respectively at the wavelength place of 362nm and 450nm, calculate with differential technique, it is appropriate that another precision takes felodipine reference substance, add appropriate amount of ethanol and make dissolving, the solution made about containing felodipine 10 μ g (specification: 5mg) or 20 μ g (specification: 10mg) in every 1ml is quantitatively diluted by release medium, be measured in the same method, calculate the burst size of every sheet at different time.The every sheet of this product 2 hours, 6 hours with 10 little burst sizes constantly should should be mutually respectively into labelled amount more than 10% ~ 30%, 42% ~ 68% and 80%, all should conform with the regulations.
Release and assay results are shown in Table 1:
Table 1 embodiment 1 release and assay result
Result shows, the felodipine osmotic pump controlled release tablet release performance of embodiment 1 is good, and long-term placement does not have catabiosis substantially.
Four, film loss of weight experiment:
Experimental technique: after removing outermost layer film-coat, semipermeable membrane is peeled off from label, the residual label powder in the above of removing, weigh, put into the stripping rotor containing 500ml distilled water, 37 DEG C, by China's coastal port two annex XC dissolution determination first method (Rotating shaker) operations, rotating speed is 50 turns per minute, respectively at 1h, 2h sampling, 50 DEG C of oven dry, let cool to room temperature, weigh.Calculate loss of weight ratio.
Computing formula: film loss of weight percentage ratio (%)=(1-W
t/ W
0) × 100%
W
t: the film weight after different sampling time point oven dry; W
0: the initial weight of film, the results are shown in following table 2:
Table 2 room temperature place for a long time after film loss of weight result
The experiment of film loss of weight shows, along with the prolongation of standing time, the semipermeable membrane loss of weight adopting ethyl cellulose and polyvidone to make keeps constant substantially, illustrates that the stability of film and permeability keep constant substantially.
Embodiment 2
One, prescription
1, Core formulation: with embodiment 1
2, semipermeable membrane coating fluid prescription:
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, felodipine label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology
Take PVP K30 and the ethyl cellulose (N-100) of recipe quantity, add stirring and dissolving in ethanol and completely, to obtain final product.
3, semipermeable membrane coating: label is put coating in Multifunctional coating machine, regularly take a morsel weighing tablets, calculates coating weight gain.
Coating weight gain is respectively 11.0%, 13.0%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
6, film-coat coating solution preparation technology and film coating: with embodiment 1.
Three, release and content measuring result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release and assay results are shown in Table 3:
Table 3 embodiment 2 release and assay result
Result shows, the felodipine osmotic pump controlled release tablet of embodiment 2, and under the ratio of 30: 18, from the coating weight gain of 11.0% ~ 13.0%, release performance is all good, and long-term placement does not have catabiosis substantially.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the results are shown in following table 4:
Table 4 room temperature place for a long time after film loss of weight result
The experiment of film loss of weight shows, along with the prolongation of standing time, the semipermeable membrane loss of weight adopting ethyl cellulose and polyvidone to make keeps constant substantially, illustrates that the stability of film and permeability keep constant substantially.
Embodiment 3
One, prescription
1, Core formulation: with embodiment 1
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, felodipine label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology
Take PVP K30 and the ethyl cellulose (N-100) of recipe quantity, add stirring and dissolving in ethanol and completely, to obtain final product.
3, semipermeable membrane coating: label is put coating in Multifunctional coating machine, regularly take a morsel weighing tablets, calculates coating weight gain.
Coating weight gain is respectively 13.0%, and 16.0%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
6, film-coat coating solution preparation technology and film coating: with embodiment 1.
Three, release and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release and assay results are shown in Table 5:
Table 5 embodiment 3 release and assay result
Result shows, the felodipine osmotic pump controlled release tablet of embodiment 3, and under the ratio of 30: 20, from the coating weight gain of 13.0% ~ 16.0%, release performance is all good, and long-term placement does not have catabiosis substantially.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the results are shown in following table 6:
Table 6 room temperature place for a long time after film loss of weight result
The experiment of film loss of weight shows, along with the prolongation of standing time, the semipermeable membrane loss of weight adopting ethyl cellulose and polyvidone to make keeps constant substantially, illustrates that the stability of film and permeability keep constant substantially.
Embodiment 4
One, prescription
1, Core formulation: 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, felodipine label preparation technology: with embodiment 2, when difference is only compacting double-layer tablet, drift is all scrobicula punching, is pressed into conventional symmetric form label.
2, semipermeable membrane coating solution preparation technology: with embodiment 2
3, semipermeable membrane coating: technique: with embodiment 2, coating weight gain is 11.5%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
6, film-coat coating solution preparation technology and film coating: with embodiment 1.
Three, release and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release and assay results are shown in Table 7
Table 7 embodiment 4 release and assay result
Result shows, label is the felodipine osmotic pump controlled release tablet of conventional symmetric type, compared with asymmetrical type in embodiment 2, there is aging-resistant advantage equally, be only that release is lower slightly, during the point 10h of release end, residual quantity is bigger, but cumulative release also remains on more than 90%.
Four, film loss of weight experiment:
Experimental technique, with embodiment 1, the results are shown in following table 8:
Table 8 room temperature place for a long time after film loss of weight result
The experiment of film loss of weight shows, along with the prolongation of standing time, the semipermeable membrane loss of weight adopting ethyl cellulose and polyvidone to make keeps constant substantially, illustrates that the stability of film and permeability keep constant substantially.
Embodiment 5 cellulose acetate+Polyethylene Glycol does semipermeable membrane material (comparative example 1)
One, prescription
1, Core formulation: with embodiment 1
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, felodipine label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology
The Macrogol 4000 taking recipe quantity is soluble in water, is disperseed by cellulose acetate in Macrogol 4000 aqueous solution, adds the acetone of recipe quantity, is stirred to dissolving, to obtain final product.
3, semipermeable membrane coating: label is put coating in Multifunctional coating machine, regularly take a morsel weighing tablets, calculates coating weight gain.Coating weight gain is 14.0%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
6, film-coat coating solution preparation technology and film coating: with embodiment 1.
Three, release and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release and assay results are shown in Table 9:
Table 9 embodiment 5 release and assay result
Result shows, embodiment 5 adopts cellulose acetate+Polyethylene Glycol to do the felodipine osmotic pump controlled release tablet of semipermeable membrane material, and initial release performance is all good, and along with standing time increases, constantly aging, rate of release is slack-off, residual obviously increase.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the results are shown in following table 10:
Table 10 room temperature place for a long time after film loss of weight result
The explanation of film loss of weight experimental result, along with the prolongation of standing time, in semipermeable membrane, the combination rate of Polyethylene Glycol and cellulose acetate constantly increases, soluble polyalkylene glycol moiety is caused to reduce gradually, the permeability of film is declined gradually, rate of release reduces gradually, discloses film aging all the time along with the semipermeable membrane of cellulose acetate-Polyethylene Glycol.
Embodiment 6 ethyl celluloses+Polyethylene Glycol does semipermeable membrane material (comparative example 2)
One, prescription
1, Core formulation: with embodiment 1
2, semipermeable membrane coating fluid prescription
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, felodipine label preparation technology: with embodiment 1
2, semipermeable membrane coating solution preparation technology:
The Macrogol 4000 taking recipe quantity is soluble in water, is disperseed by ethyl cellulose in Macrogol 4000 aqueous solution, adds the ethanol of recipe quantity, is stirred to dissolving, to obtain final product.
3, semipermeable membrane coating: label is put coating in Multifunctional coating machine, regularly take a morsel weighing tablets, calculates coating weight gain.
Coating weight gain is 10.0%.
4, heat treatment: with embodiment 1.
5, laser boring: with embodiment 1.
6, film-coat coating solution preparation technology and film coating: with embodiment 1.
Three, release and content measuring and result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release and assay results are shown in Table 11:
Table 11 embodiment 6 release and assay result
Result shows, embodiment 6 adopts ethyl cellulose+Polyethylene Glycol to do the felodipine osmotic pump controlled release tablet of semipermeable membrane material, and initial release performance is all good, and along with standing time increases, constantly aging, rate of release is slack-off, residual obviously increase.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the results are shown in following table 12:
Table 12 room temperature place for a long time after film loss of weight result
The experiment of film loss of weight shows, along with the prolongation of standing time, the film loss of weight of the semipermeable membrane adopting ethyl cellulose+Polyethylene Glycol to make constantly declines, and illustrates that the permeability of film constantly declines.
Embodiment 7
One, prescription
1, Core formulation (1000, specification: 10mg)
Medicated layer:
Boosting layer:
2, semipermeable membrane coating fluid prescription: with embodiment 2
3, film-coat coating fluid prescription: with embodiment 1
Two, detailed preparation technology
1, felodipine label preparation technology: with embodiment 1.
2, semipermeable membrane coating solution preparation technology: with embodiment 1
3, semipermeable membrane coating: label is put coating in Multifunctional coating machine, regularly take a morsel weighing tablets, calculates coating weight gain.Coating weight gain is 11.7%.
4, heat treatment: with embodiment 1
5, laser boring: with embodiment 1
6, film-coat coating solution preparation technology and film coating: with embodiment 1.
Three, release and content measuring result
Drug release determination method: with embodiment 1
Content assaying method: with embodiment 1
Release and assay results are shown in Table 13:
Table 13 embodiment 7 release and assay result
Result shows, the felodipine osmotic pump controlled release tablet of embodiment 7, and under the ratio of 30: 18, under the coating weight gain of 11.7%, release performance is good, and long-term placement does not have catabiosis substantially.
Four, film loss of weight experiment:
Experimental technique: with embodiment 1, the results are shown in following table 14:
Table 14 room temperature place for a long time after film loss of weight result
The experiment of film loss of weight shows, along with the prolongation of standing time, the semipermeable membrane loss of weight adopting ethyl cellulose and polyvidone to make keeps constant substantially, illustrates that the stability of film and permeability keep constant substantially.
Claims (2)
1. there is a felodipine osmotic pump type controlled release tablets for ageing resistace, it is characterized in that there is following prescription:
1), Core formulation, in 1000:
Medicated layer:
Boosting layer:
2), semipermeable membrane coating fluid prescription
3), film-coat coating fluid prescription
。
2. felodipine osmotic pump type controlled release tablets as claimed in claim 1, is characterized in that having following semipermeable membrane coating fluid prescription:
。
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| CN201110060846.0A CN102670551B (en) | 2011-03-14 | 2011-03-14 | Felodipine osmotic pump type controlled release tablets |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931167A (en) * | 2006-06-28 | 2007-03-21 | 广州贝氏药业有限公司 | Double layer osmotic pump controlled release felodipine medicine composition |
| CN101879146A (en) * | 2009-05-08 | 2010-11-10 | 广州柏赛罗药业有限公司 | Controlled release preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931167A (en) * | 2006-06-28 | 2007-03-21 | 广州贝氏药业有限公司 | Double layer osmotic pump controlled release felodipine medicine composition |
| CN101879146A (en) * | 2009-05-08 | 2010-11-10 | 广州柏赛罗药业有限公司 | Controlled release preparation and preparation method thereof |
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