CN102670542A - Tramadol hydrochloride osmotic pump controlled release tablet - Google Patents
Tramadol hydrochloride osmotic pump controlled release tablet Download PDFInfo
- Publication number
- CN102670542A CN102670542A CN201110064634XA CN201110064634A CN102670542A CN 102670542 A CN102670542 A CN 102670542A CN 201110064634X A CN201110064634X A CN 201110064634XA CN 201110064634 A CN201110064634 A CN 201110064634A CN 102670542 A CN102670542 A CN 102670542A
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- CN
- China
- Prior art keywords
- ethyl cellulose
- semipermeable membrane
- polyvidone
- tramadol hydrochloride
- osmotic pump
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 title claims abstract description 45
- 229960003107 tramadol hydrochloride Drugs 0.000 title claims abstract description 45
- 230000003204 osmotic effect Effects 0.000 title claims abstract description 44
- 238000013270 controlled release Methods 0.000 title claims abstract description 35
- 239000012528 membrane Substances 0.000 claims abstract description 89
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 54
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 54
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 54
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 54
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 48
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 26
- 230000032683 aging Effects 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 239000011248 coating agent Substances 0.000 claims description 45
- 238000000576 coating method Methods 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 229920003081 Povidone K 30 Polymers 0.000 claims description 10
- 239000007888 film coating Substances 0.000 claims description 8
- 238000009501 film coating Methods 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 6
- 230000003679 aging effect Effects 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 210000002784 stomach Anatomy 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 35
- 239000003814 drug Substances 0.000 abstract description 29
- 239000000463 material Substances 0.000 abstract description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 4
- 230000003712 anti-aging effect Effects 0.000 abstract 2
- 208000020442 loss of weight Diseases 0.000 description 33
- 230000035699 permeability Effects 0.000 description 23
- 238000003556 assay Methods 0.000 description 18
- 238000005516 engineering process Methods 0.000 description 18
- 239000002202 Polyethylene glycol Substances 0.000 description 17
- 229920001223 polyethylene glycol Polymers 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 229920002301 cellulose acetate Polymers 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 230000007774 longterm Effects 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000004080 punching Methods 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 5
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 239000003361 porogen Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- 208000035404 Autolysis Diseases 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- -1 acetate-Polyethylene Chemical group 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002431 foraging effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028043 self proteolysis Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 229940078987 tramadol hydrochloride 50 mg Drugs 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a novel single-chamber tramadol hydrochloride osmotic pump controlled release tablet preparation. A semi-permeable membrane containing ethyl cellulose (EC) and polyvidone (PVP) is coated on the surface of a medicament table core, so that the phenomenon of ageing of the semi-permeable membrane can be avoided, and medicament residues are reduced. The invention further provides a method for improving the anti-ageing performance of a single-chamber tramadol hydrochloride 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 single-chamber tramadol hydrochloride osmotic pump controlled release tablet with anti-ageing performance.
Description
Technical field
The present invention relates to a kind of tramadol hydrochloride osmotic pump type controlled release tablet, belong to field of pharmaceutical preparations.
Background technology
Tramadol hydrochloride is the central analgesia medicine; Bring into play analgesic activity through exciting opiates μ receptor and the reuptake that suppresses maincenter monoamine ability material (5-hydroxy tryptamine and norepinephrine); Be used for treating due to the multiple reason, severe pain, comprise cancer pain, fracture or wound, various postoperative pain, toothache, neuralgia etc.Clinical basic demand to this type medicine is can long-acting controlling symptoms.
What tramadol hydrochloride went on the market the earliest is ordinary preparation, and need take 2-3 time every day, and blood concentration fluctuation is big, and peak concentration is too high, and untoward reaction is serious.The tramadol hydrochloride slow release preparation of listing has improved compliance later on, has reduced untoward reaction simultaneously to a certain extent.
Because the tramadol hydrochloride slow release 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's body, so its blood drug level still has bigger fluctuation, are difficult to control and expect to have certain uncertainty; Its useful effect persistent period and side effect size also vary with each individual, and individual variation is big, has uncontrollability.
The principle of osmotic pump preparation is to be used as release power with the permeability of medicine self and some short penetrating agent; After taking; Moisture gets in the sheet from clothing film (semipermeable membrane); Make to form very high osmotic pressure in the sheet, thereby the saturated aqueous solution of medicine in the sheet is disengaged by the surperficial drug release hole of sheet; The volume that penetrates into water in the semipermeable membrane in its volume and unit interval equates, thereby reaches the effect of constant speed release medicine.
Tramadol hydrochloride is suitable for processing the osmotic pump controlled-releasing tablet preparation, and the effective blood drug concentration longer duration, blood concentration fluctuation is little, side effect is little, individual variation is little, patient's compliance 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 single chamber type tramadol hydrochloride 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 single chamber type tramadol hydrochloride 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 single chamber type tramadol hydrochloride 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 tramadol hydrochloride 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 tramadol hydrochloride 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.
Tramadol hydrochloride 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 membrane permeability is more little, 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.Generally can select 30: 18～22, preferably the weight ratio of the two is 30: 20, and this moment, the permeability of film was more moderate.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 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 weight ratio of general ethyl cellulose and polyvidone is 30: 18～22 o'clock, and the coating weightening finish is 6%～12%, and the weight ratio of preferred, ethyl and polyvidone is 30: 20 o'clock, and the coating weightening finish is 8%～10%.
Tramadol hydrochloride osmotic pump controlled-releasing tablet preparation label according to the invention can adopt the elementary osmotic pump sheet to use adjuvant always, comprises osmo active substance, binding agent, lubricant etc.
Tramadol hydrochloride osmotic pump controlled-releasing tablet preparation according to the invention, its preparation method can be operated in order to the generality of preparation osmotic pump controlled-releasing tablet preparation according to this area in the prior art and carry out.The coating weightening finish that contains the semipermeable membrane of ethyl cellulose (EC) and polyvidone (PVP) is 6%～12%, preferred 8%～10%.
As one of preferred implementation of the present invention, the invention provides a kind of single chamber type tramadol hydrochloride osmotic pump controlled release tablet with anti-semipermeable membrane ageing properties, have following prescription:
1), label prescription (in 1000)
| Form | Consumption |
| Tramadol hydrochloride | 100g |
| Sucrose | 180g |
| Microcrystalline Cellulose | 80g |
| 8% 30 POVIDONE K 30 BP/USP, 30 70% alcoholic solution | In right amount |
| Magnesium stearate | 8g |
2), semipermeable membrane prescription
| Form | Consumption |
| Ethyl cellulose N100 | 30g |
| 30 POVIDONE K 30 BP/USP 30 | 18g～22g |
| Ethanol | 1000ml |
3), film coating prescription
| Form | Consumption |
| The stomach dissolution type coating powder | ?10g |
| Water | ?100ml |
As preferably, the single chamber type tramadol hydrochloride osmotic pump controlled release tablet of above-mentioned anti-semipermeable membrane ageing properties has following clothing film prescription:
| Form | Consumption |
| Ethyl cellulose N100 | 30g |
| 30 POVIDONE K 30 BP/USP 30 | 20g |
| Ethanol | 1000ml |
In addition; The present invention also provides a kind of method of improving single chamber type tramadol hydrochloride osmotic pump controlled release tablet ageing resistace; The semipermeable membrane that use contains ethyl cellulose (EC) and polyvidone (PVP) is wrapped in medicine sheet wicking surface, wherein EC: PVP=30: 18～22, and the coating weightening finish is 6%～12%.The weight ratio of preferred, ethyl and polyvidone is 30: 20, and the coating weightening finish is 8%～10%.Label can adopt the elementary osmotic pump sheet to use adjuvant always, comprises osmo active substance, binding agent, lubricant etc.
In addition; The present invention also provides ethyl cellulose and polyvidone compositions to be used to improve the purposes of single chamber type tramadol hydrochloride osmotic pump controlled release tablet ageing resistace; Said compositions is used to prepare single chamber type tramadol hydrochloride osmotic pump controlled release tablet semipermeable membrane; The weight ratio that it is characterized in that containing in the compositions ethyl cellulose and polyvidone is 30: 18～22, and this moment, the coating weightening finish was 6%～12%; Preferred weight ratio is 30: 20, and this moment, the coating weightening finish was 8%～10%.
The specific embodiment:
Embodiment 1: adopt ethyl cellulose+Polyethylene Glycol to do the control Example of semipermeable membrane filmogen
One, prescription
1, label prescription (in 1000)
| Form | Consumption |
| Tramadol hydrochloride | 100g |
| Sucrose | 180g |
| Microcrystalline Cellulose | 80g |
| 8% 30 POVIDONE K 30 BP/USP, 30 70% alcoholic solution | In right amount |
| Magnesium stearate | 8g |
2, semipermeable membrane prescription
| Form | Consumption |
| Ethyl cellulose N100 | ?30g |
| Macrogol 4000 | ?21g |
| Water | ?100ml |
| Ethanol | ?900ml |
3, film coating prescription
| Form | Consumption |
| The stomach dissolution type coating powder | ?10g |
| Water | ?100ml |
Two, preparation technology
1, label preparation
Tramadol hydrochloride is crossed 60 mesh sieves, and it is subsequent use that sucrose was pulverized 80 mesh sieves, takes by weighing tramadol hydrochloride, sucrose, the microcrystalline Cellulose mix homogeneously of recipe quantity; Use 70% alcoholic solution system soft material of 8% 30 POVIDONE K 30 BP/USP 30, cross 24 mesh sieves and granulate 40 ℃ of oven dry; Cross 24 mesh sieve granulate; The magnesium stearate mixing that adds recipe quantity, tabletting, pressure is controlled at 50-70N.
2 semipermeable membrane coating solution preparation technologies
The Macrogol 4000 that takes by weighing recipe quantity is water-soluble, and ethyl cellulose joins in the aqueous solution of Macrogol 4000 and disperses, and the ethanol that adds recipe quantity is stirred to dissolving, promptly gets.
3, bag semipermeable membrane
The tablet that presses put wrap semipermeable membrane in the high-efficiency coating machine, weightening finish is 10.5%.
4, heat treatment
With 40 ℃ of heat treatment 12h of the tablet that wraps semipermeable membrane.
5, punching
The heat-treatment tablet is put laser-beam drilling machine punching, aperture 0.3-0.7mm.
6, film-coat coating solution preparation technology
The film coating powder that takes by weighing recipe quantity is added to the water, and stirs, and promptly gets.
7, bag film-coat
The tablet that will punch is put and is wrapped film-coat in the high-efficiency coating machine, weightening finish 3-4%.
Three, content and drug release determination
Assay is measured according to HPLC (two appendix V of Chinese Pharmacopoeia version in 2005 D).
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be filler; With acetic acid-sodium-acetate buffer (pH4.5)-methanol (65: 35) is mobile phase; The detection wavelength is 271nm.Number of theoretical plate calculates by the tramadol peak and is not less than 1500.
Algoscopy is got 20 of these article, carefully removes coating, and accurate the title decided porphyrize; Precision takes by weighing fine powder an amount of (being equivalent to tramadol hydrochloride 50mg approximately), puts in the 100ml measuring bottle, and it is an amount of to add mobile phase, and supersound process makes dissolving; And be diluted to scale with mobile phase, and shake up, filter; Precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the tramadol hydrochloride reference substance, and precision is claimed fixed, adds the also quantitative dilution of mobile phase dissolving and process the solution that contains 0.5mg among every 1ml approximately, measures with method., promptly get with calculated by peak area by external standard method.
The release degree is got these article, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), adopts dissolution method first subtraction unit; With water 900ml is release medium, and rotating speed is that per minute 100 changes, operation in accordance with the law; When 2 hours, 5 hours and 8 hours, get solution 10ml respectively, filter; And the instant water that in stripping rotor, replenishes equal volume, uniform temp; Get subsequent filtrate,, measure absorbance in the wavelength of 271nm according to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A); It is an amount of that other gets the tramadol hydrochloride reference substance, accurate claims surely, is dissolved in water and dilutes and process the solution that contains 80 μ g among every 1ml approximately, measures with method.Calculate every burst size respectively at different time.Every of these article should be respectively below 30% of labelled amount in the burst size of 2 hours, 5 hours and 8 hours, more than 45%～70% and 80%, all should be up to specification.Release degree and assay result see the following form 1
Table 1 embodiment 1 release degree and content detection result
The result shows that embodiment 1 adopts ethyl cellulose+Polyethylene Glycol to do the tramadol hydrochloride osmotic pump controlled release tablet of semipermeable membrane material, and the initial release performance is all good, and along with increase standing time, constantly aging, rate of release is slack-off, residual obvious increase.
Four, film loss of weight experiment:
Experimental technique: remove film-coat, semipermeable membrane is peeled off from label, remove residual label powder in the above, weigh; Put into the stripping rotor that contains the 500ml distilled water, 37 ℃, press two appendix X of Chinese Pharmacopoeia version in 2005 C dissolution determination, first method (changeing the basket method) operation; Rotating speed is that per minute 50 changes, respectively at 1h, and the 2h sampling; 50 ℃ of oven dry are put and are chilled to room temperature, weigh.Calculate the loss of weight ratio.
Computing formula: film loss of weight percentage ratio (%)=(1-W
T/ W
0) * 100%
W
T: the film weight after the different sampling time point oven dry; W
0: the initial weight of film, the result sees the following form 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 increase 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 2: adopt cellulose acetate+Polyethylene Glycol to do the control Example of semipermeable membrane filmogen
1, label prescription: with embodiment 1
2, semipermeable membrane prescription
3, film coating prescription: with embodiment 1
Two, preparation technology
1, label preparation: with embodiment 1
2, the preparation technology of semipermeable membrane coating solution
The Macrogol 4000 that takes by weighing recipe quantity is water-soluble, and cellulose acetate joins in the aqueous solution of Macrogol 4000 and disperses, and the acetone that adds recipe quantity is stirred to dissolving, promptly gets.
3, bag semipermeable membrane
The tablet that presses put wrap semipermeable membrane in the high-efficiency coating machine, weightening finish is to 9.0%.
4, heat treatment: with embodiment 1
5, punching: with embodiment 1
6, film-coat coating solution preparation technology: with embodiment 1
7, bag film-coat: with embodiment 1
Three, release degree, assay and result:
Assay 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 cellulose acetate+Polyethylene Glycol that adopts at embodiment 2 is done the tramadol hydrochloride osmotic pump controlled release tablet of semipermeable membrane material, and the initial release performance is all good, and along with increase standing time, constantly aging, rate of release is slack-off, residual obvious increase.
Four, film loss of weight experiment
Experimental technique is with embodiment 1, and the result sees the following form 4:
Film loss of weight result after the long-term placement of table 4 room temperature
The explanation of film loss of weight experimental result; Increase 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 3 the present invention adopt ethyl cellulose+polyvidone to be the embodiment of semipermeable membrane filmogen
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane prescription
| Prescription | Consumption |
| Ethyl cellulose N100 | 30g |
| 30 POVIDONE K 30 BP/USP 30 | 18g |
| Ethanol | 1000ml |
3, film coating prescription: with embodiment 1
Two, preparation technology
1, label preparation: with embodiment 1
2, semipermeable membrane coating solution preparation technology
The ethyl cellulose that takes by weighing recipe quantity joins in the ethanol, and the polyvidone that is stirred to dissolving back adding recipe quantity is stirred to dissolving fully, promptly gets.
3, bag semipermeable membrane
The tablet that presses put wrap semipermeable membrane in the high-efficiency coating machine, weightening finish is to 6.0%, 8.0%.
4, heat treatment: with embodiment 1
5, punching: with embodiment 1
6, film-coat coating solution preparation technology: with embodiment 1
7, bag film-coat: with embodiment 1
Three, release degree and assay and result:
Assay 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 tramadol hydrochloride osmotic pump controlled release tablet of embodiment 3, and under 30: 18 ratio, release performance is all good under 6.0%～8.0% coating weightening finish, and long-term placement does not have catabiosis basically.
Four, film loss of weight experiment
Experimental technique is with embodiment 1, and 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 the present invention adopt ethyl cellulose+polyvidone to be the embodiment of semipermeable membrane filmogen
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane prescription
| Prescription | Consumption |
| Ethyl cellulose N100 | 30g |
| 30 POVIDONE K 30 BP/USP 30 | 20g |
| Ethanol | 1000ml |
3, film coating prescription: with embodiment 1
Two, preparation technology
1, label preparation: with embodiment 1
2, semipermeable membrane coating solution preparation technology
The ethyl cellulose that takes by weighing recipe quantity joins in the ethanol, and the polyvidone that is stirred to dissolving back adding recipe quantity is stirred to dissolving fully, promptly gets.
3, bag semipermeable membrane
The tablet that presses put wrap semipermeable membrane in the high-efficiency coating machine, weightening finish is to being respectively 8.0%, 10.0%.
4, heat treatment: with embodiment 1
5, punching: with embodiment 1
6, film-coat coating solution preparation technology: with embodiment 1
7, bag film-coat: with embodiment 1
Three, release degree, assay and result:
Assay 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, the tramadol hydrochloride osmotic pump controlled release tablet of embodiment 4, and under 30: 20 ratio, release performance is all good down for the coating weightening finish from 8.0%～10.0%, and long-term placement does not have catabiosis basically.
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 the present invention adopt ethyl cellulose+polyvidone to be the embodiment of semipermeable membrane filmogen
One, prescription
1, label prescription: with embodiment 1
2, semipermeable membrane prescription
| Prescription | Consumption |
| Ethyl cellulose N100 | 30g |
| 30 POVIDONE K 30 BP/USP 30 | 22g |
| Ethanol | 1000ml |
3, film coating prescription: with embodiment 1
Two, preparation technology
1, label preparation: with embodiment 1
2, semipermeable membrane coating solution preparation technology
The ethyl cellulose that takes by weighing recipe quantity joins in the ethanol, and the polyvidone that is stirred to dissolving back adding recipe quantity is stirred to dissolving fully, promptly gets.
3, bag semipermeable membrane
The tablet that presses put wrap semipermeable membrane in the high-efficiency coating machine, weightening finish is to being respectively 10.0%, 12.0%.
4, heat treatment: with embodiment 1
5, punching: with embodiment 1
6, film-coat coating solution preparation technology: with embodiment 1
7, bag film-coat: with embodiment 1
Three, release degree, assay and result:
Assay 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, the tramadol hydrochloride osmotic pump controlled release tablet of embodiment 5, and under 30: 22 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 is 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 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 (11)
1. a single chamber type tramadol hydrochloride osmotic pump controlled release tablet is characterized in that semipermeable membrane adopts ethyl cellulose and polyvidone as filmogen.
2. tramadol hydrochloride osmotic pump controlled release tablet as claimed in claim 1, the weight ratio that it is characterized in that ethyl cellulose and polyvidone is 30: 18～22.
3. tramadol hydrochloride osmotic pump controlled release tablet as claimed in claim 1, the weight ratio that it is characterized in that ethyl cellulose and polyvidone is 30: 20.
4. tramadol hydrochloride as claimed in claim 2 passes through pump controlled-releasing tablet, it is characterized in that the weightening finish of semipermeable membrane coating is 6%～12%.
5. tramadol hydrochloride osmotic pump controlled release tablet as claimed in claim 3 is characterized in that the coating weightening finish of semipermeable membrane is 8%～10%.
6. method of improving single chamber type tramadol hydrochloride osmotic pump controlled release tablet ageing resistace; It is characterized in that semipermeable membrane adopts ethyl cellulose and polyvidone as filmogen; The weight ratio of ethyl cellulose and polyvidone is 30: 18～22, and the coating weightening finish is 6%～12%.
7. like the said method of improving single chamber type tramadol hydrochloride osmotic pump controlled release tablet ageing resistace of claim 6, the weight ratio that it is characterized in that ethyl cellulose and polyvidone is 30: 20, and the coating weightening finish is 8%～10%.
8. ethyl cellulose and polyvidone compositions are used to improve the purposes of single chamber type tramadol hydrochloride osmotic pump controlled release tablet ageing resistace, it is characterized in that the weight ratio of ethyl cellulose and polyvidone is 30: 18～22 in the said compositions, and the coating weightening finish is 6%～12%.
9. like the said purposes of claim 8, it is characterized in that the weight ratio of ethyl cellulose and polyvidone is 30: 20 in the said compositions, the coating weightening finish is 8%～10%.
10. single chamber type tramadol hydrochloride osmotic pump controlled release tablet with anti-semipermeable membrane ageing properties is characterized in that having following prescription:
1), label prescription (in 1000)
2), semipermeable membrane prescription
Form consumption
Ethyl cellulose N100 30g
30 POVIDONE K 30 BP/USP 30 18g～22g
Ethanol 1000ml
3), film coating prescription
Form consumption
Stomach dissolution type coating powder 10g
Water 100ml.
11., it is characterized in that having following semipermeable membrane prescription like the said single chamber type tramadol hydrochloride osmotic pump controlled release tablet of claim 10 with anti-semipermeable membrane ageing properties:
Form consumption
Ethyl cellulose N100 30g
30 POVIDONE K 30 BP/USP 30 20g
Ethanol 1000ml.
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| CN201110064634XA CN102670542A (en) | 2011-03-17 | 2011-03-17 | Tramadol hydrochloride osmotic pump controlled release tablet |
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| CN201110064634XA CN102670542A (en) | 2011-03-17 | 2011-03-17 | Tramadol hydrochloride osmotic pump controlled release tablet |
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Citations (5)
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| CN101732276A (en) * | 2009-12-26 | 2010-06-16 | 鲁南制药集团股份有限公司 | Tablet of isosorbide mononitrate |
| CN101827590A (en) * | 2007-10-16 | 2010-09-08 | 莱博法姆公司 | Bilayer composition for sustained release of acetaminophen and tramadol |
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2011
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| CN1625390A (en) * | 2002-02-01 | 2005-06-08 | 株式会社太平洋 | Multi-stage oral drug controlled-release system |
| CN101352426A (en) * | 2007-07-27 | 2009-01-28 | 鲁南制药集团股份有限公司 | Osmotic pump controlled release preparation composition and preparation thereof |
| CN101827590A (en) * | 2007-10-16 | 2010-09-08 | 莱博法姆公司 | Bilayer composition for sustained release of acetaminophen and tramadol |
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Application publication date: 20120919 |