CN103271889B - Novel paliperidone progressively-increarelease release osmotic pump preparation and preparation method thereof - Google Patents
Novel paliperidone progressively-increarelease release osmotic pump preparation and preparation method thereof Download PDFInfo
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- CN103271889B CN103271889B CN201310194346.5A CN201310194346A CN103271889B CN 103271889 B CN103271889 B CN 103271889B CN 201310194346 A CN201310194346 A CN 201310194346A CN 103271889 B CN103271889 B CN 103271889B
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Abstract
The present invention belongs to technical field of medicine, discloses a kind of 9-hydroxy-risperidone bilayer and increases progressively osmotic pump controlled release tablet and preparation method thereof.This osmotic pump preparation is by medicated layer, boosting layer composition label and the semi-transparent coating membrane composition be wrapped in drug release hole outside label, intermediate molecular weight polyoxyethylene (mean molecule quantity 900 is employed in medicated layer, 000 ~ 1,000,000) and a certain proportion of osmo active substance, make medicine layer hydration rate moderate, utilize double-deck label single coats that the release of active medicine can be made substantially to present and increase progressively releasing trend, and can maintain and increase progressively release 14 ~ 24h.Said preparation significantly can reduce adverse effect, improves the compliance of patient, and said preparation preparation is simultaneously simple, significantly simplifies the preparation technology increasing progressively osmotic pump preparation, is more conducive to suitability for industrialized production.
Description
Technical field
The invention belongs to technical field of medicine, relate to Novel paliperidone progressively-increarelease release osmotic pump preparation of a kind of technique simplification and preparation method thereof.
Background technology
Controlled releasing penetrant pump is slow controlled release technology of preparing comparatively ripe at present, and has such as: 1) seldom by the impact of the factors such as media environment pH value, gastrointestinal peristalsis and food, individual variation is little, and In vitro-in vivo correlation is good; 2) blood medicine is steady, and untoward reaction is little; 3) medicining times is few, and the compliance of patient is high, etc. advantage.Be widely deployed and apply.
Central nervous system (CNS) clinical drug application Problems existing: 1 erious adverse reaction, initial stage untoward reaction of especially taking medicine is obvious, and patient tolerability is poor, and easily stop using in midway; The 2 ordinary preparation initial stages of taking needed dose titration (namely slowly increasing dosage) to reduce the generation of untoward reaction, but took inconvenience; Steadily increase progressively delivery system can well address this problem.It can control blood drug level in early stage, can reach effective blood drug concentration again simultaneously, and blood medicine is steady, without the need to initial dose adjustment, takes simple, good patient compliance.
9-hydroxy-risperidone (9-hydroxyrisperidone) is risperidone active metabolite, and belong to atypical antipsychotic class medicine, its definite mechanism of action it be unclear that.Think that it passes through to block dopamine (D), 5-hydroxytryptamine 2A (5HT2) and adrenoceptor and disturb the intracellular signaling of neurotransmitter in patient's brain at present.The oral administration biaavailability of 9-hydroxy-risperidone is 28%, and plasma protein binding rate is 74%, and the half-life that end eliminates phase is about 23h, and apparent volume of distribution is 487L.The oral rear main untoward reaction of 9-hydroxy-risperidone comprises anxiety, drowsiness, dizzy, constipation and extrapyramidal symptoms etc.The release osmotic pump preparation that increases progressively of this medicine existing goes on the market at present both at home and abroad.
Current commercialized product is the three layers of osmotic pump preparation produced by Janssen company, and US Patent No. 20040092534 discloses this preparation.Said preparation contains the boosting layer medicated layer different with two content of dispersion, the semi-transparent clothing film of outsourcing, and its complex process, especially beats chip technology for three layers, needs three layers of comparatively special tablet machine, realizes difficulty.
Chinese patent CN 200910199425 disclose a kind of early stage about 5h can increase progressively release 9-hydroxy-risperidone double-layer osmotic pumping system, its label is made up of boosting layer and medicated layer, outsourcing water solublity contagion gown and a semi-transparent clothing film, control contagion gown thickness to control the infiltration of moisture, thus reach and increase progressively the effect of release early stage, but increase progressively release and only can maintain 5h.
Another Chinese patent CN201110060811 discloses one can aging-resistant 9-hydroxy-risperidone osmotic pump preparation, this patent research cellulose acetate and Polyethylene Glycol are as problem of aging during filmogen, this patent research shows, it is tightr that cellulose acetate and Polyethylene Glycol can combine along with the prolongation of memory time, Polyethylene Glycol pore ability is caused to decline, membrane permeability reduces (this patent claims this phenomenon to be aging), and uses ethyl cellulose and polyvidone can weaken this phenomenon as filmogen.This patent mainly protects this art for coating and prescription, does not mention the problem increasing progressively release.
The most ripe with plug-type double layer osmotic pump in the osmotic pump preparation of current release insoluble drug, wherein the application of macromolecular material polyoxyethylene is the most extensive, usual employing low-molecular-weight polyoxyethylene is as medicine layer suspensoid, high molecular weight peo is as boosting layer intumescent material, boosting layer promotes medicine layer drug suspension and discharges from small delivery aperture, can realize good constant release behavior.
Summary of the invention
The present invention is surprised to find when medicated layer polyoxyethylene molecular weight brings up to intermediate molecular weight level (i.e. mean molecule quantity 900,000 ~ 1,000,000) time, discharge to present and significantly increase progressively releasing effect, in conjunction with the controlled release mechanism of push-pull osmotic pump, the invention provides prescription composition and preparation method that a kind of double layer osmotic pump increasing progressively release that can realize 9-hydroxy-risperidone increases progressively controlled release tablet.
The polyoxyethylene model that the present invention is used and mean molecule quantity synopsis as follows:
Table 1 polyoxyethylene model and mean molecule quantity synopsis
The 9-hydroxy-risperidone bilayer that the present invention mentions increases progressively osmotic pumps and increases progressively controlled release tablet, and it comprises label and semipermeable clothing film, and label is made up of medicated layer, boosting layer.
Medicated layer is positioned at clothing film, and it is equipped with drug release hole, and this medicated layer compositions comprises active constituents of medicine, intermediate molecular weight polyoxyethylene and osmo active substance, and nonessential lubricant.
Active constituents of medicine comprises 9-hydroxy-risperidone and pharmaceutically acceptable salt, ester, and its proportion in medicated layer compositions is 0.5 ~ 20%(w/w), preferably 1 ~ 15%(w/w), more preferably 2 ~ 10%(w/w).
The polyoxyethylated mean molecule quantity of intermediate molecular weight is 900,000 ~ 1,000,000, polyoxyethylene proportion in medicated layer compositions is 30 ~ 80%(w/w), preferably 50 ~ 70%(w/w).
Osmo active substance comprises sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, fructose or their mixture, and in medicated layer compositions, proportion is 20 ~ 60% (w/w), preferably 20 ~ 45%(w/w).Osmo active substance and the polyoxyethylated ratio of intermediate molecular weight are 1:4 ~ 2:1(w/w simultaneously).
9-hydroxy-risperidone double layer osmotic pump of the present invention increases progressively in controlled release tablet, active component dosage is little, polyoxyethylene has certain viscosity, lubricant add the mobility that can help improve this product medicated layer, boosting layer granule granule in high speed tableting processes, improve the operability of technique, avoid the generation of sticking, improve content and the uniformity of dosage units of final pharmaceutical preparation.Lubricant used should not interact with this product active pharmaceutical ingredient, and it comprises stearic acid, magnesium stearate, sodium stearyl fumarate, Pulvis Talci, paraffin, castor oil hydrogenated and their mixture.Based on the gross weight of medicated layer compositions, lubricant proportion in medicated layer compositions is 0 ~ 3%(w/w), be preferably 0.5 ~ 2%(w/w).
Boosting layer is positioned at clothing film, away from drug release hole one end, is made up of boosting layer composition, and described boosting layer composition comprises expanding material and nonessential osmo active substance, coloring agent and lubricant.
Expanding material is high molecular weight peo (mean molecule quantity 4,000,000 ~ 7,000,000), and expanding material proportion in promoting layer compositions is 40 ~ 100%(w/w), be preferably 60 ~ 100%(w/w), be more preferably 70 ~ 100%(w/w).
It is 0 ~ 30%(w/w that osmo active substance comprises sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, fructose or their mixture proportion in promoting layer compositions), be preferably 5 ~ 20%(w/w).
Lubricant comprises stearic acid, magnesium stearate, sodium stearyl fumarate, Pulvis Talci, paraffin, castor oil hydrogenated and their mixture, and in promoting layer compositions, proportion is 0 ~ 3%(w/w), be preferably 0.1 ~ 1.5%(w/w).
Coloring agent can adopt in iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black one or more, and their mixture, in medicated layer compositions, proportion is 0 ~ 2%(w/w), be preferably 0.1 ~ 1%(w/w).
Semipermeable clothing film is equipped with one or more drug release hole at medicated layer end surface, is made up of controlled capability compositions, comprises semipermeable polymer cellulose acetate and nonessential porogen and plasticizer.
Semi permeability clothing film by controlled release layer composition dissolves is made controlled release layer coating solution in suitable solvent, then adopts high-efficiency coating pot controlled release layer coating solution to be sprayed to drying formation on label.
Suitable solvent for the preparation of controlled release layer coating solution of the present invention comprises acetone, water, ethanol, isopropyl alcohol, dichloromethane, methanol, ethyl acetate, or their mixture.
Based on the total amount of controlled release layer compositions, cellulose acetate content is generally 80 ~ 100%(w/w), preferably 90 ~ 100%(w/w).
For regulating the Water permeability of semi permeability clothing film, porogen can be added wherein.Porogen can increase the moisture permeability of putamina, and based on the total amount of controlled release layer compositions, the consumption of porogen is about 0 ~ 50%(w/w usually), be preferably 0 ~ 10%(w/w).Described porogen can comprise propylene glycol, glycerol, polyvidone, polyethylene glycols, and their mixture.
Plasticizer can make putamina have better pliability and extensibility, and based on the total amount of controlled release layer compositions, the consumption of plasticizer is about 0 ~ 20 %(w/w usually), be preferably 0 ~ 15%(w/w).Described plasticizer can comprise Methyl Benzene-o-dicarboxylate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, citroflex A-4, glycerol acetate, Oleum Ricini, and composition thereof.
9-hydroxy-risperidone double layer osmotic pump of the present invention increases progressively controlled release tablet can provide the time cycle 14 ~ 24h increasing progressively rate of releasing drug, is preferably 16 ~ 20h.
" rate of releasing drug increased progressively " described in the present invention refers to: adopt drug release determination method, within a period of time from described putamina the speed of release of active agent, increase along with the time increases drug release rate.
The 9-hydroxy-risperidone double layer osmotic pump that present invention also offers described in preparation increases progressively the method for controlled release tablet, and this preparation method comprises following step:
(1) 9-hydroxy-risperidone, intermediate molecular weight polyoxyethylene, osmo active substance and lubricant are sieved, take above material, mix homogeneously by recipe quantity, powder vertical compression prepares medicated layer;
(2) dilatancy macromolecular material, osmo active substance, lubricant and coloring agent are sieved, and mix, powder vertical compression prepares boosting layer;
(3) apply bi-layer tablet press and medicine layer and boosting are laminated into double-deck label;
(4) semipermeable polymer material and water soluble pore formers is taken by recipe quantity, and in the acetone being dissolved in recipe quantity respectively and distilled water, the two mix homogeneously forms coating solution, label is put in coating pan and is carried out spray coating to predetermined weightening finish by those skilled in the art's usual manner, dry to remove residual solvent afterwards;
(5) beat at the medicated layer side laser of coated tablet or power auger one or more holes that diameter is 0.6 ~ 2.0mm, obtain 9-hydroxy-risperidone osmotic pumps and increase progressively controlled release tablet.
Beneficial effect of the present invention is embodied in:
1. have unique release behavior, medicine is all the time with the rate of releasing drug progressively increased progressively release active constituents of medicine, and overall blood drug level steadily rises.Untoward reaction can be reduced to greatest extent, the dose titration at the initial stage of taking medicine can be avoided again simultaneously, significantly improve the compliance of patient.
2. the impact by factors such as media environment pH value, gastrointestinal peristalsis and foods is little, has good In vitro-in vivo correlation;
3. the phenomenon that blood concentration fluctuation common oral preparation can being avoided to cause is larger;
4. reduce medicining times, greatly improve the safety of drug use, effectiveness and compliance.
5. the present invention adopts the osmosis pump control-release system of double-deck label bag one deck clothing film namely to achieve to increase progressively release, sheet equipment is beaten without the need to special three layers compared with increasing progressively controlled release tablet with commercially available bladder type three layers, increasing progressively disclosed early stage with Chinese patent CN 200910199425 to discharge compared with osmotic pump preparation without the need to bag contagion gown operation, significantly simplifies production technology.
Accompanying drawing explanation
Fig. 1 is the release profiles with lower molecular weight polyoxyethylated 9-hydroxy-risperidone double layer osmotic pump constant speed controlled release tablet prepared in accordance with the present invention in embodiment 1.From result, when polyoxyethylene molecular weight is lower, present Zero order release.
Fig. 2 produced according to the present inventionly in embodiment 2 has the release profiles that the polyoxyethylated 9-hydroxy-risperidone double layer osmotic pump of intermediate molecular weight increases progressively controlled release tablets.From result, when polyoxyethylene molecular weight is moderate, presents and increase progressively release.
Fig. 3 is the release profiles that medicine layer prepared in accordance with the present invention has a lower ratio osmotically active composition in embodiment 3 9-hydroxy-risperidone double layer osmotic pump increases progressively controlled release tablet.When medicine layer osmo active substance ratio is lower, clothing film is easily by spalling.
Fig. 4 is the release profiles that medicine layer prepared in accordance with the present invention has a higher proportion osmotically active composition in example 4 9-hydroxy-risperidone double layer osmotic pump increases progressively controlled release tablet.When medicine layer osmo active substance ratio is higher, increases progressively and discharge well and film spalling problem of having no clothes.
Fig. 5 is that the 9-hydroxy-risperidone double layer osmotic pump prepared according to embodiment 2 increases progressively the release profiles of controlled release tablet in different release medium, and result shows, and the release of said preparation is hardly by the impact of PH values.
Fig. 6 is that the 9-hydroxy-risperidone double layer osmotic pump prepared according to embodiment 2 increases progressively the average rate of release figure of controlled release tablet in pH6.8 release medium, and result shows, and its rate of release is rising gradually.
Fig. 7 is the release profiles that commercially available bladder type 9-hydroxy-risperidone osmotic pumps increases progressively controlled release tablet (trade name: Rui Da, 6mg specification), and result shows the release of the osmotic pumps of inventing in commercially available prod and this patent without significant difference.
Fig. 8 is the average rate of release figure that commercially available bladder type 9-hydroxy-risperidone osmotic pumps increases progressively controlled release tablet (trade name: Rui Da, 6mg specification).
Detailed description of the invention
The present invention is illustrated further below in conjunction with embodiment:
Embodiment 1
Preparation technology:
(1) medicine layer supplementary material is sieved, take above material by recipe quantity, mix homogeneously;
(2) boosting layer adjuvant is sieved, weigh and mix;
(3) apply bi-layer tablet press and medicine layer and boosting are laminated into double-deck label;
(4) take cellulose acetate and porogen by recipe quantity, and in the acetone being dissolved in recipe quantity respectively and distilled water, the two mix homogeneously forms coating solution, label puts coating pan internal spraying coating to weightening finish 11%, dry to remove residual solvent afterwards;
(5) beat at the medicated layer side laser of coated tablet or power auger two holes that diameter is 1.5mm, obtain 9-hydroxy-risperidone osmotic pumps and increase progressively controlled release tablet.
Embodiment 2
Preparation technology: (with embodiment 1).
Embodiment 3
Preparation technology: (with embodiment 1) coating weight gain is 14%.
Embodiment 4
Preparation technology: (with embodiment 1) coating weight gain is 14%.
Embodiment 5
Core formulation:
Preparation technology: (with embodiment 1) coating weight gain is 14%.
According to " the People's Republic of China's pharmacopeia " version in 2010 two drug release determination method first methods, release medium is 1000mL 0.1mol/L HCl, pH6.8 PBS and pH7.4 PBS, the different impact on release of comparative medium pH value, rotating speed 50 rmin
-1, medium temperature (37 ± 0.5) DEG C.Sample 5mL respectively at 3,6,9,12,15,18,20,24h, supplement equal-volume equality of temperature release medium simultaneously.Cross Liquid Detection after 0.45 μm of microporous filter membrane.
Embodiment 6
According to the release result of embodiment 5, calculate the average rate of release of each time point, and map.
Embodiment 7
According to the drug release determination method in embodiment 5, release medium is the release profiles that 1000mL pH6.8 PBS detects commercially available 9-hydroxy-risperidone slow releasing tablet (Rui Da).
Embodiment 8
According to the release result of embodiment 7, calculate the average rate of release of commercially available each time point of 9-hydroxy-risperidone slow releasing tablet (Rui Da), and map.
Claims (8)
1. a 9-hydroxy-risperidone bilayer increases progressively osmotic pump controlled release tablet, it comprises label and semipermeable clothing film, it is characterized in that: label is made up of medicated layer, boosting layer, semipermeable clothing film is equipped with one or more drug release hole at medicated layer end surface, be made up of controlled capability compositions, be selected from semipermeable polymer cellulose acetate, described medicated layer, comprise active constituents of medicine, intermediate molecular weight polyoxyethylene and osmo active substance, boosting layer comprises expanding material; Described active constituents of medicine, be selected from 9-hydroxy-risperidone and pharmaceutically acceptable salt, ester, its proportion in medicated layer compositions is 0.5 ~ 20%, described intermediate molecular weight polyoxyethylene, its mean molecule quantity is 900,000 ~ 1,000,000, in medicated layer compositions, proportion is 30 ~ 80%; Described boosting layer, is positioned at clothing film, away from drug release hole one end, be made up of boosting layer composition, be selected from expanding material, osmo active substance, coloring agent and lubricant, expanding material is high molecular weight peo, mean molecule quantity 4,000,000 ~ 7,000,000, in boosting layer composition, proportion is 40 ~ 100%, and described osmo active substance proportion in boosting layer composition is 0 ~ 30%; Lubricant proportion in boosting layer composition is 0 ~ 3%; Coloring agent proportion in boosting layer composition is 0 ~ 2%.
2. a kind of 9-hydroxy-risperidone bilayer increases progressively osmotic pump controlled release tablet as claimed in claim 1, it is characterized in that: described osmo active substance, is selected from sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, fructose or their mixture.
3. a kind of 9-hydroxy-risperidone bilayer increases progressively osmotic pump controlled release tablet as claimed in claim 1, it is characterized in that: in described medicated layer, comprise lubricant, be selected from stearic acid, magnesium stearate, sodium stearyl fumarate, Pulvis Talci, paraffin, castor oil hydrogenated and their mixture, in medicated layer compositions, proportion is 0 ~ 3%.
4. a kind of 9-hydroxy-risperidone bilayer increases progressively osmotic pump controlled release tablet as claimed in claim 1, it is characterized in that: described osmo active substance is selected from sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, fructose or their mixture, lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate, Pulvis Talci, paraffin, castor oil hydrogenated and their mixture, coloring agent be selected from iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black one or more, and their mixture.
5. a kind of 9-hydroxy-risperidone bilayer increases progressively osmotic pump controlled release tablet as claimed in claim 1, it is characterized in that: containing porogen, plasticizer or both mixing in described semipermeable clothing film.
6. a kind of 9-hydroxy-risperidone bilayer increases progressively osmotic pump controlled release tablet as claimed in claim 1, it is characterized in that: described semipermeable clothing film, be by controlled release layer composition dissolves is made controlled release layer coating solution in suitable solvent, then adopt high-efficiency coating pot controlled release layer coating solution to be sprayed to drying formation on label.
7. a kind of 9-hydroxy-risperidone bilayer increases progressively osmotic pump controlled release tablet as claimed in claim 6, it is characterized in that: the described solvent selected from acetone be suitable for, water, ethanol, isopropyl alcohol, dichloromethane, methanol, ethyl acetate, or their mixture.
8. a kind of 9-hydroxy-risperidone bilayer increases progressively the preparation method of osmotic pump controlled release tablet as claimed in claim 1, it is characterized in that:
Comprise the following steps:
(1) 9-hydroxy-risperidone, intermediate molecular weight polyoxyethylene, osmo active substance and lubricant are sieved, take above material, mix homogeneously by recipe quantity, powder vertical compression prepares medicine layer;
(2) high molecular weight peo, osmo active substance, lubricant and coloring agent are sieved, and mix, powder vertical compression prepares boosting layer;
(3) apply bi-layer tablet press and medicine layer and boosting are laminated into double-deck label;
(4) cellulose acetate and water soluble pore formers is taken by recipe quantity, and in the acetone being dissolved in recipe quantity respectively and distilled water, the two mix homogeneously forms coating solution, label is put in coating pan and is carried out spray coating to predetermined weightening finish by those skilled in the art's usual manner, dry to remove residual solvent afterwards;
(5) beat at the medicated layer side laser of coated tablet or power auger one or more holes that diameter is 0.6 ~ 2.0mm, obtain 9-hydroxy-risperidone osmotic pumps and increase progressively controlled release tablet.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104257622B (en) * | 2014-10-01 | 2020-02-07 | 浙江华海药业股份有限公司 | Paliperidone controlled-release tablet and preparation method thereof |
| CN106265583B (en) * | 2015-05-29 | 2019-01-18 | 浙江京新药业股份有限公司 | A kind of 9-hydroxy-risperidone rate of release escalating formulation and preparation method thereof |
| CN107693502A (en) * | 2016-08-08 | 2018-02-16 | 北京天衡药物研究院有限公司 | 9-hydroxy-risperidone increment type release osmotic pump tablet and preparation method thereof |
| CN115350160B (en) * | 2022-10-20 | 2023-01-10 | 华润双鹤利民药业（济南）有限公司 | Paliperidone sustained-release preparation and preparation method thereof |
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| CN1684670A (en) * | 2002-07-29 | 2005-10-19 | 阿尔扎公司 | Methods and dosage forms for controlled delivery of paliperidone |
| CN101035519A (en) * | 2004-08-04 | 2007-09-12 | 阿尔扎公司 | Sustained drug release composition demonstrating an ascending zero order release pattern, methods of manufacturing such a composition |
| CN101711752A (en) * | 2009-11-26 | 2010-05-26 | 中国科学院上海药物研究所 | Controlled release preparation of benzo-isoxazole derivant and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1684670A (en) * | 2002-07-29 | 2005-10-19 | 阿尔扎公司 | Methods and dosage forms for controlled delivery of paliperidone |
| CN101035519A (en) * | 2004-08-04 | 2007-09-12 | 阿尔扎公司 | Sustained drug release composition demonstrating an ascending zero order release pattern, methods of manufacturing such a composition |
| CN101711752A (en) * | 2009-11-26 | 2010-05-26 | 中国科学院上海药物研究所 | Controlled release preparation of benzo-isoxazole derivant and preparation method thereof |
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