CN101095666B - Novel hydrochloric acid tramadol sustained-release tablet and preparation method - Google Patents
Novel hydrochloric acid tramadol sustained-release tablet and preparation method Download PDFInfo
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- CN101095666B CN101095666B CN2007101429870A CN200710142987A CN101095666B CN 101095666 B CN101095666 B CN 101095666B CN 2007101429870 A CN2007101429870 A CN 2007101429870A CN 200710142987 A CN200710142987 A CN 200710142987A CN 101095666 B CN101095666 B CN 101095666B
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- tramadol hydrochloride
- ethanol
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Abstract
The invention discloses a new type sustained release tablets of tramadol hydrochloride and the preparation method. The sustained release tablets comprise tablet core and membrane clothing sheet. The tablet core contains sustained release capsule of tramadol hydrochloride with its weight being 80-90% of total weight of tablet core, and the sustained release capsule is prepared with tramadol hydrochloride and sustained release material with ratio being 1: 1.2-1.5. The sustained release capsule also contains 10% monoglyceride. The sustained release tablet is characterized by stable effective blood concentration, increased biological utilization rate, reduced side effect, good taste and small intake amount of one time per day.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical preparation, particularly a kind of is the preparation method of the new sustained release tablet of active component with tramadol or its salt, belongs to medical technical field.
Background technology
Tramadol (tramadol) is a kind of central action analgesic, has dual analgesic mechanism, promptly bring into play analgesic activity, have characteristics such as analgesic activity is strong, drug dependence is low, abuse potential is little, no many opioid agonist typical side effects by the reuptake of exciting opiates μ receptor and inhibition maincenter monoamine energy material (5-hydroxytryptamine and norepinephrine).
The relative half-life of tramadol is short, so need multiple dosing, but in order to keep the blood drug level of effective dose, reach therapeutic effect, the initial excessive of administration initial stage may cause more side effect, and underdosage is helpless to alleviate the patient suffering, reaches therapeutic effect.Present commercially available tramadol hydrochloride slow release tablet is a kind of held stationary blood drug level that helps, the sustained-release oral dosage forms of the analgesic effect of remaining valid, can reduce the side effect in taking, reduce medicining times, improve patient's compliance, its preparation technology is: earlier adjuvant and principal agent are mixed, add adhesive, make soft material, granulate, drying, tabletting gets finished product.The shortcoming of this technology is a complex process, to the equipment requirements height, owing to there are processes such as pulverizing, granulation, drying, also can bring certain pollution.
Publication number be the patent application of CN1642532A to have put down in writing a kind of be the tramadol sustained-release tablet of controlled-release material with the xanthan gum, this application also be with adjuvants such as principal agent and xanthan gum through simply mixing, tabletting and getting.Publication number provides a kind of tramadol hydrochloride slow release dripping pill and preparation method thereof for the CN1820738A patent application, but owing to need 80 ℃～90 ℃ high temperature in the preparation process, destroys the activity of medicinal ingredient easily.Though the release of tramadol can be controlled, be postponed to above-mentioned tramadol sustained-release dosage form to a certain extent, but still can not reach the treatment demand from causing that owing to long period administration at interval tramadol stable state effective blood drug concentration produces the angle that rises and falls, therefore need a kind of longer time to discharge tramadol and can after longer administration blanking time, be close to indeclinable slow release formulation by tramadol stable state effective blood drug concentration.
Summary of the invention
The invention solves present problems of the prior art, a kind of long-time release tramadol hydrochloride is provided and can after longer administration blanking time, be close to indeclinable slow releasing tablet by tramadol stable state effective blood drug concentration.The present invention also provides the preparation method of above-mentioned tramadol hydrochloride slow release tablet agent.
Tramadol hydrochloride slow release tablet agent provided by the invention is made of tramadol hydrochloride slow release tablet core and film coating, contains the tramadol hydrochloride slow release microcapsule that accounts for label gross weight 80%～90% in the label.
Described tramadol hydrochloride slow release microcapsule is made up of tramadol hydrochloride and slow-release material, and the weight ratio of tramadol hydrochloride and slow-release material is preferably 1:1.2～1.5.
Described slow-release material is preferably a kind of or its mixture in chitosan, the xanthan gum.
Another preferred version provided by the invention is that described tramadol hydrochloride slow release microcapsule surface also is enclosed with single hard acid glyceride, be dropout value feature, the saving material of realizing tramadol hydrochloride slow release tablet agent of the present invention, its used weight is preferably and accounts for 10% of microcapsule gross weight.
Contain 10%～20% pharmaceutic adjuvant in the label of the present invention, this pharmaceutic adjuvant is 10%～20% diluent, adhesive, lubricant; The wherein preferred lactose of diluent, adhesive preferably polyethylene ketopyrrolidine, the preferred magnesium stearate of lubricant.Lactose, polyvinylpyrrolidone, magnesium stearate are scattered in the label, and three's weight ratio is followed successively by 10:3:1.
Tramadol hydrochloride slow release tablet agent of the present invention is a film coating tablet, and its film coating preferably is made up of hydroxypropyl emthylcellulose, Pulvis Talci, magnesium stearate, and the weight proportion between the preferred three is followed successively by 6:4:1.Coated tablet of the present invention has been covered the bitterness of tramadol, than easier the swallowing of label of coating not, and has improved stability of formulation.
Tramadol hydrochloride slow release tablet agent provided by the invention, take once and get final product every day.Preferably contain 90mg in the per unit dosage form to the 150mg tramadol hydrochloride.
The present invention provides the preparation method of novel tramadol hydrochloride slow releasing tablet simultaneously, may further comprise the steps:
A, the preparation of label: get the slow-release material of recipe quantity, add distilled water, put in the hot bath, stir, take out the dissolving back, with tramadol hydrochloride emulsifying, add single hard acid glyceride mix homogeneously, transfer pH value to 5.0～6.0, adding distil water continues to stir, cooling then adds formalin and stirs, and transfers pH value to 8.0～9.0, microcapsule is solidified, the supernatant that inclines, vacuum drying, microcapsule granule, with gained microcapsule granule and lactose mix homogeneously, add the polyvinylpyrrolidone alcoholic solution and make soft material, the granulation of sieving, drying, granulate, add magnesium stearate again, mixing, suppress label.
Preparation method preferred version provided by the invention may further comprise the steps:
A, the preparation of label: the slow-release material of getting recipe quantity, add distilled water, put in 70 ℃～80 ℃ hot baths and stir, take out the dissolving back, with the tramadol hydrochloride quick emulsification, under constantly stirring, add single hard acid glyceride mix homogeneously, transfer pH value to 5.0～6.0 with 10% hydrochloric acid solution, adding distil water continues to stir, and places psychrolusia to cool off then, add 36% formalin and stir 10min～15min, transfer pH value to 8.0～9.0 with 10% sodium hydroxide solution, microcapsule is solidified about 1h, supernatant inclines, in 30 ℃ of vacuum dryings, get microcapsule granule,, add the polyvinylpyrrolidone alcoholic solution and make soft material gained microcapsule granule and lactose mix homogeneously, the granulation of sieving of 20 orders, 60 ± 5 ℃ dry down, and granulate adds magnesium stearate again, mixing, suppress label;
B, film coating: take by weighing hydroxypropyl emthylcellulose, Pulvis Talci, magnesium stearate add ethanol, dissolution filter gets film coating liquid, and the tramadol sustained-release label is put in the coating pan, be preheated to 50 ℃, the tramadol film coating liquid of spraying continuously gets the tramadol sustained-release sheet.
Tramadol hydrochloride slow release tablet agent provided by the present invention, tramadol hydrochloride is wrapped in the microcapsule made from slow-release material-chitosan or xanthan gum, and this microcapsule surface is surrounded by single hard acid glyceride.Because microcapsule involved in the present invention is to be slow-released carrier with chitosan or xanthan element, with single hard acid glyceride is outside blocker, therefore, have retardance and slow release dual function, the release of permission strict control tramadol on time function, and discharge tramadol in the release mode without any peak or paddy, drug release time is long and fully, release has very high repeatability.Have found that, the consumption of slow-release material will influence release profiles, the amount that increases slow-release material will delay tramadol and discharge, the inventor finds, the amount ratio of tramadol hydrochloride and slow-release material is controlled at 1:1.2～1.5, and the release of tramadol hydrochloride will be finished after specified 26 hours in such cases.
Tramadol hydrochloride slow release tablet agent blood drug level of the present invention is measured assay method: chromatographic column LichrosorbC
18(150mm * 4.6mm, 5 μ m).Behind the mark phenacetin, once extract in the 1.0ml blood sample, adding, carry out chromatography with the 7.0ml ether.Mobile phase is that (50mmol/l, PH3.5): acetonitrile=75:25 (V/V), flow velocity 1.0ml/min detects wavelength 271nm to sodium-acetate buffer.The result: linear equation is Y=0.9215c-0.146 (r=0.9990, n=7), linear concentration is 0.2～0.3 μ g/ml, and minimal detectable concentration is 0.1 μ g/ml blood plasma (signal to noise ratio=2), the averaging method response rate is 1102.35%, and RSD is all＜5% in a few days, in the daytime.Recording tramadol hydrochloride stable state effective blood drug concentration scope is 0.305 μ g/ml～0.737 μ g/ml.And then the tramadol hydrochloride blood drug level of mensuration and record single administration and secondary administration different time sections, per 24 hours of result takes tramadol hydrochloride slow release tablet agent of the present invention to the patient, remain the blood drug level of tramadol therapeutic dose in patient's body, thereby single dose administration has but reached the effect of multiple dose administration every day of the present invention, kept tramadol stable state effective blood drug concentration, make drug effect obtain giving full play to, improved bioavailability.
Technical scheme of the present invention compared with prior art, have following beneficial effect: (1) has overcome in the prior art short because of the relative half-life of tramadol, need multiple dosing, for the blood drug level of keeping effective dose reaches therapeutic effect, administration initial stage initial excessive causes more side effect; And underdosage is helpless to alleviate the patient suffering, can't reach therapeutic effect problem; (2) better kept patient's homeostasis effective blood drug concentration; (3) drug effect has obtained performance more fully, has improved bioavailability; (4) every day, single dose administration but reached the effect of multiple dose administration, had reduced the side effect in taking; (5) reduce medicining times, improved patient's compliance; (6) mouthfeel is good, and the patient is easier to be swallowed; (7) improved stability of formulation.
Description of drawings
Fig. 1 is the tramadol hydrochloride blood drug level of single administration and secondary administration different time sections.
The specific embodiment
1000, specification is 90mg.
Prescription:
The label film coating
Tramadol hydrochloride 90g hydroxypropyl emthylcellulose 3g
Chitosan 135g Pulvis Talci 2g
Lactose 17.9g stearic acid 0.5g
Polyvinylpyrrolidone 5.36g ethanol 100ml
Magnesium stearate 1.78g
Single hard acid glyceride 22.5g
Ethanol is an amount of
Preparation method:
A, the preparation of label: the slow-release material of getting recipe quantity, add distilled water, put in 70 ℃～80 ℃ hot baths and stir, take out the dissolving back, with the tramadol hydrochloride quick emulsification, under constantly stirring, add single hard acid glyceride to mix homogeneously, transfer pH value to 5.0～6.0 with 10% hydrochloric acid solution, adding distil water continues to stir, and places psychrolusia to cool off then, add 36% formalin and stir 10min～15min, transfer pH value to 8.0～9.0 with 10% sodium hydroxide solution, microcapsule is solidified about 1h, supernatant inclines, in 30 ℃ of vacuum dryings, get microcapsule granule,, add the polyvinylpyrrolidone alcoholic solution and make soft material gained microcapsule granule and lactose mix homogeneously, 20 orders sieve and granulate 60 ± 5 ℃, drying, granulate adds magnesium stearate again, mixing, suppress label;
B, film coating: take by weighing hydroxypropyl emthylcellulose, Pulvis Talci, magnesium stearate add ethanol, dissolution filter gets film coating liquid, and the tramadol sustained-release label is put in the coating pan, be preheated to 50 ℃, the tramadol film coating liquid of spraying continuously gets the tramadol sustained-release sheet.
1000, specification is 100mg.
Prescription:
The label film coating
Tramadol hydrochloride 100g hydroxypropyl emthylcellulose 4.5g
Xanthan gum 140g Pulvis Talci 3g
Lactose 30.25g stearic acid 0.75g
Polyvinylpyrrolidone 9.08g ethanol 150ml
Magnesium stearate 3.03g
Single hard acid glyceride 24g
Ethanol is an amount of
Preparation method is with embodiment 1.
Embodiment 3
1000, specification is 110mg.
Prescription:
The label film coating
Tramadol hydrochloride 110g hydroxypropyl emthylcellulose 6g
Chitosan 143g Pulvis Talci 4g
Lactose 45.2g stearic acid 1g
Polyvinylpyrrolidone 13.56g ethanol 200ml
Magnesium stearate 4.52g
Single hard acid glyceride 25.3g
Ethanol is an amount of
Preparation method is with embodiment 1.
1000, specification is 120mg.
Prescription:
The label film coating
Tramadol hydrochloride 120g hydroxypropyl emthylcellulose 7.5g
Xanthan gum 143g Pulvis Talci 5g
Lactose 20.9g stearic acid 1.25g
Polyvinylpyrrolidone 6.28g ethanol 250ml
Magnesium stearate 2.09g
Single hard acid glyceride 26.3g
Ethanol is an amount of
Preparation method is with embodiment 1.
Embodiment 5
1000, specification is 130mg.
Prescription:
The label film coating
Tramadol hydrochloride 130g hydroxypropyl emthylcellulose 9g
Chitosan 156g Pulvis Talci 6g
Lactose 51.2g stearic acid 1.5g
Polyvinylpyrrolidone 15.32g ethanol 300ml
Magnesium stearate 5.12g
Single hard acid glyceride 28.6g
Ethanol is an amount of
Preparation method is with embodiment 1.
1000 consumptions, specification are 140mg.
Prescription:
The label film coating
Tramadol hydrochloride 140g hydroxypropyl emthylcellulose 10.5g
Xanthan gum 182g Pulvis Talci 7g
Lactose 40.6g stearic acid 1.75g
Polyvinylpyrrolidone 12.18g ethanol 350ml
Magnesium stearate 4.06g
Single hard acid glyceride 32.2g
Ethanol is an amount of
Preparation method is with embodiment 1.
Embodiment 7
1000, specification is 150mg.
Prescription:
The label film coating
Tramadol hydrochloride 150g hydroxypropyl emthylcellulose 12g
Chitosan, xanthan gum
Arbitrary proportion mixture 180g Pulvis Talci 8g
Lactose 58.9g stearic acid 2g
Polyvinylpyrrolidone 17.6g ethanol 400ml
Magnesium stearate 5.89g
Single hard acid glyceride 32.2g
Ethanol is an amount of
Preparation method:
A, the preparation of label: the slow-release material of getting recipe quantity, add distilled water, put in 70 ℃～80 ℃ hot baths and stir, take out the dissolving back, with the tramadol hydrochloride quick emulsification, under constantly stirring, add single hard acid glyceride to mix homogeneously, transfer pH value to 5.0～6.0 with 10% hydrochloric acid solution, adding distil water continues to stir, and places psychrolusia to cool off then, add 36% formalin and stir 10min～15min, transfer pH value to 8.0～9.0 with 10% sodium hydroxide solution, microcapsule is solidified about 1h, supernatant inclines, in 30 ℃ of vacuum dryings, get microcapsule granule,, add the polyvinylpyrrolidone alcoholic solution and make soft material gained microcapsule granule and lactose mix homogeneously, 20 orders sieve and granulate 60 ± 5 ℃, drying, granulate adds magnesium stearate again, mixing, suppress label;
B, film coating: take by weighing hydroxypropyl emthylcellulose, Pulvis Talci, magnesium stearate add ethanol, dissolution filter gets film coating liquid, and the tramadol sustained-release label is put in the coating pan, be preheated to 50 ℃, the tramadol film coating liquid of spraying continuously gets the tramadol sustained-release sheet.
The dissolution in vitro of tramadol hydrochloride slow release tablet agent of the present invention is investigated:
Record according to " Chinese Pharmacopoeia 2005 editions " two appendix XC dissolution method second methods.Dissolution test is to carry out in the pH value of 900ml0.05M is 6.8 phosphate buffer with tablet under 37 ℃, and the high performance liquid chromatography that has refractive index detector that is used for the detection of active chemical compound detects.Use the optical fiber dissolution system, to the second dervative correction method of 289nm scope rate of release carried out in site measurement at 283nm with wave-length coverage, dissolution parameters following (percent of mentioning below is percentage by weight):
About 30% tramadol discharges after 1 hour,
About 40% tramadol discharges after 2 hours,
About 55% tramadol discharges after 4 hours,
About 68% tramadol discharges after 8 hours,
About 75% tramadol discharges after 12 hours,
About 87% tramadol discharges after 18 hours,
About 93% tramadol discharges after 24 hours,
About 100% tramadol discharges after 26 hours.
Claims (7)
1. tramadol hydrochloride slow release tablet agent is made of tramadol hydrochloride slow release tablet core and film coating, it is characterized in that:
The preparation specification is that the prescription of 1000 tablets of tablets of 90mg is:
The label film coating
Tramadol hydrochloride 90g hydroxypropyl emthylcellulose 3g
Chitosan 135g Pulvis Talci 2g
Lactose 17.9g stearic acid 0.5g
Polyvinylpyrrolidone 5.36g ethanol 100ml
Magnesium stearate 1.78g
Single hard acid glyceride 22.5g
Ethanol is an amount of.
2. tramadol hydrochloride slow release tablet agent is made of tramadol hydrochloride slow release tablet core and film coating, it is characterized in that:
The preparation specification is that the prescription of 1000 tablets of tablets of 100mg is:
The label film coating
Tramadol hydrochloride 100g hydroxypropyl emthylcellulose 4.5g
Xanthan gum 140g Pulvis Talci 3g
Lactose 30.25g stearic acid 0.75g
Polyvinylpyrrolidone 9.08g ethanol 150ml
Magnesium stearate 3.03g
Single hard acid glyceride 24g
Ethanol is an amount of.
3. tramadol hydrochloride slow release tablet agent is made of tramadol hydrochloride slow release tablet core and film coating, it is characterized in that:
The preparation specification is that the prescription of 1000 tablets of tablets of 110mg is:
The label film coating
Tramadol hydrochloride 110g hydroxypropyl emthylcellulose 6g
Chitosan 143g Pulvis Talci 4g
Lactose 45.2g stearic acid 1g
Polyvinylpyrrolidone 13.56g ethanol 200ml
Magnesium stearate 4.52g
Single hard acid glyceride 25.3g
Ethanol is an amount of.
4. tramadol hydrochloride slow release tablet agent is made of tramadol hydrochloride slow release tablet core and film coating, it is characterized in that:
The preparation specification is that the prescription of 1000 tablets of tablets of 120mg is:
The label film coating
Tramadol hydrochloride 120g hydroxypropyl emthylcellulose 7.5g
Xanthan gum 143g Pulvis Talci 5g
Lactose 20.9g stearic acid 1.25g
Polyvinylpyrrolidone 6.28g ethanol 250ml
Magnesium stearate 2.09g
Single hard acid glyceride 26.3g
Ethanol is an amount of.
5. tramadol hydrochloride slow release tablet agent is made of tramadol hydrochloride slow release tablet core and film coating, it is characterized in that:
The preparation specification is that the prescription of 1000 tablets of tablets of 130mg is:
The label film coating
Tramadol hydrochloride 130g hydroxypropyl emthylcellulose 9g
Chitosan 156g Pulvis Talci 6g
Lactose 51.2g stearic acid 1.5g
Polyvinylpyrrolidone 15.32g ethanol 300ml
Magnesium stearate 5.12g
Single hard acid glyceride 28.6g
Ethanol is an amount of.
6. tramadol hydrochloride slow release tablet agent is made of tramadol hydrochloride slow release tablet core and film coating, it is characterized in that:
The preparation specification is that the prescription of 1000 tablets of tablets of 140mg is:
The label film coating
Tramadol hydrochloride 140g hydroxypropyl emthylcellulose 10.5g
Xanthan gum 182g Pulvis Talci 7g
Lactose 40.6g stearic acid 1.75g
Polyvinylpyrrolidone 12.18g ethanol 350ml
Magnesium stearate 4.06g
Single hard acid glyceride 32.2g
Ethanol is an amount of.
7. tramadol hydrochloride slow release tablet agent is made of tramadol hydrochloride slow release tablet core and film coating, it is characterized in that:
The preparation specification is that the prescription of 1000 tablets of tablets of 150mg is:
The label film coating
Tramadol hydrochloride 150g hydroxypropyl emthylcellulose 12g
Chitosan, xanthan gum
Arbitrary proportion mixture 180g Pulvis Talci 8g
Lactose 58.9g stearic acid 2g
Polyvinylpyrrolidone 17.6g ethanol 400ml
Magnesium stearate 5.89g
Single hard acid glyceride 32.2g
Ethanol is an amount of.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101429870A CN101095666B (en) | 2007-08-14 | 2007-08-14 | Novel hydrochloric acid tramadol sustained-release tablet and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101429870A CN101095666B (en) | 2007-08-14 | 2007-08-14 | Novel hydrochloric acid tramadol sustained-release tablet and preparation method |
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| Publication Number | Publication Date |
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| CN101095666A CN101095666A (en) | 2008-01-02 |
| CN101095666B true CN101095666B (en) | 2010-10-06 |
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| CN110279760A (en) * | 2019-05-08 | 2019-09-27 | 丽水市中心医院 | A kind of preparation method of coptis chinensis total alkaloid intragastric floating sustained-release tablet |
| CN111751470B (en) * | 2020-07-07 | 2023-05-05 | 多多药业有限公司 | Detection control method for new impurities in tramadol hydrochloride preparation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1226824A (en) * | 1996-07-25 | 1999-08-25 | Asta药物股份公司 | Tramadol multiple unit formulations |
| CN1270026A (en) * | 1999-01-18 | 2000-10-18 | 格吕伦塔尔有限公司 | Controlled releasing Qumaduo preparation having stably releasing mode and preparing method thereof |
| CN1642532A (en) * | 2002-03-22 | 2005-07-20 | 西拉格股份公司 | Sustained release formulation of tramadol |
-
2007
- 2007-08-14 CN CN2007101429870A patent/CN101095666B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1226824A (en) * | 1996-07-25 | 1999-08-25 | Asta药物股份公司 | Tramadol multiple unit formulations |
| CN1270026A (en) * | 1999-01-18 | 2000-10-18 | 格吕伦塔尔有限公司 | Controlled releasing Qumaduo preparation having stably releasing mode and preparing method thereof |
| CN1642532A (en) * | 2002-03-22 | 2005-07-20 | 西拉格股份公司 | Sustained release formulation of tramadol |
Non-Patent Citations (2)
| Title |
|---|
| 李东等.***马多缓释片的工艺研究及质量控制.中国药业10 8.2001,10(8),20-21. |
| 李东等.***马多缓释片的工艺研究及质量控制.中国药业10 8.2001,10(8),20-21. * |
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