CN1785167A - Method for preparing composite delayed-release prepn. of non-narcotic analgesic - Google Patents
Method for preparing composite delayed-release prepn. of non-narcotic analgesic Download PDFInfo
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- CN1785167A CN1785167A CN 200510060989 CN200510060989A CN1785167A CN 1785167 A CN1785167 A CN 1785167A CN 200510060989 CN200510060989 CN 200510060989 CN 200510060989 A CN200510060989 A CN 200510060989A CN 1785167 A CN1785167 A CN 1785167A
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Abstract
A composite slow-release non-stupefacient sedative contains fast-release component (25-75%), slow-release component (25-75%), colloidal polymer (6-50%) and enteric coating material (5-40%). Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of common anti-inflammatory analgesic that contains, such as, ibuprofen or acetaminophen and another kind of non-narcotic powerful pain-stopping medicine composition, preparation and directional control technology such as the compound slow release preparation of tranadol hydrochloride and derivant thereof, especially the detailed description of compound sustained-released prescription of acetaminophen and tranadol hydrochloride and derivant thereof and disintegrating method, by improving dosage and administration time, be that the patient has better compliance.
Background technology
Acetaminophen adds phosphoric acid codeine (paracetamol
Add codeine), add liquor epinephrinae bitartratis ophthalmicus oxycodone (Vicodin
), add hydroxyl dihydrocodeinone (Tylox
) be to use at present the Oxycet of comparatively popularizing, in order in alleviating, severe pain.In two kinds of prescriptions of Aminodyne Compound-codeine or Aminodyne Compound-hydrocodone, codeine and hydrocodone play main analgesic activity respectively, and acetaminophen then plays auxiliary analgesic activity.Opioid drug for many years is as the analgesic that alleviates severe pain always, but they can produce many adverse side effects simultaneously, therefore can not repeat or heavy dose of administration.In " therapeutic pharmacology's principle " (1975, the 5th edition, the 245th page, the 15th chapter, J.Jaffe and W.Martin book, L.Goodman and A.Gilman edit), elaborated the content of relevant these side effect.This literary composition is pointed out, morphine ex hoc genus anne medicine as codeine, heroin, hydroxyl dihydrocodeinone, all belongs to opioid analgesic agent, can produce respiratory failure, constipation, autosadism and maltreat side effect such as tendency.
Different with opioid drug, non-opium medicine such as acetaminophen (APAP) and aspirin also have analgesic activity, and APAP and aspirin can not produce side effect such as habit-forming, toxicity.But APAP and aspirin can only alleviate moderate pain, (see " therapeutic pharmacology's principle " for details 1975, the 5th edition and opiates can effectively alleviate severe pain, the 325th page, the 15th chapter, Woodbury, D. and Fingl, E. and states, and L.Goodman and A.Gilman edit).
In order to reduce side effect, can be with opium and the compound use of non-opium analgesic.So both can reduce the consumption of opium, and can reach the analgesic effect of former high dose opium again.Existing relevant paper has proved this viewpoint.For example, A.Takemori was " New York science association annual report " (1976, the 262nd phase, the 281st page) in compared the multiple different analgesic effect of the Oxycet of forming by opiates and other analgesic, show subadditive (inhibition), enhancing property or super enhancing property effect respectively.R.Taber et al. points out that also the compound medicine of morphine and methadone (another kind of opium analgesic) shows the analgesic effect of enhancing property in " J.Pharm.Expt.Thera. " (1969, the 29th phase, the 169th chapter, the 1st joint).United States Patent (USP) points out that paracodin (a kind of opium analgesic) and ibuprofen (a kind of non-opium analgesic) are united when taking by a certain percentage for No. 4571400, can produce the analgesic effect of super enhancing property.A.Pircio et al. in " Arch.Int.Pharmacodyn. " (1978, the 116th phase, the 235th page) in report, Bu Tuofeiluo (a kind of opium analgesic) and APAP can produce superpower analgesic effect with 1: 125 mixed the time; And during with 1: 10 mixed, then there is not tangible superpower analgesic effect.
United States Patent (USP) discloses non-narcotic analgesics tramadol and acetaminophen compound recipe quick-release tablet prescription and instructions of taking thereof for No. 5336691.This patent points out, adult's dosage is to take 1-2 sheet (Ultracet in every 4-6 hour
TM).This compound tablet has cough-relieving and analgesic activity.And it also can alleviate the side effect of opium, as maltreats tendency, constipation, respiratory failure etc.
The advantage of slow release formulation is generally approved.The remarkable advantages of slow release formulation is to reduce dosage and increases patient's compliance.It is reported, adopt bioavailability preferably the multiparticulates system make oral opium slow-released analgesic agent active drug content in blood and can keep at least 24 hours (seeing United States Patent (USP) for details No. 6294195).The slow releasing tablet of acetaminophen can prepare with the following method: coating and not the acetaminophen particles of coating be pressed into lamellar, make the compound dosage form (seeing United States Patent (USP) for details No. 6126969) of rapid release and slow release.The slow releasing tablet of acetaminophen is generally made by the method for system wet granular, concrete steps are as follows: polyvinylpyrrolidone (PVP) is made mixture with fixed attention in the water-soluble or alcohol-water solvent, and adding acetaminophen, hydroxyethyl-cellulose and excipient (as microcrystalline Cellulose) are mixed, make wet grain, be dried then, granulate, again with powdered lubricant (as pregelatinized Starch), excipient, lubricant (as magnesium stearate), fluidizer (as silicon dioxide) mixing granulation, last tabletting is made the slow releasing tablet (seeing United States Patent (USP) No. 4820522) of acetaminophen.
Adopt suitable matrix tablet can make the controlled release form of opium kind analgesicses such as morphine, hydromorphone.According to No. 4990341 open introduction of United States Patent (USP), adopt American Pharmacopeia dissolution method II, hydromorphone is at 37 ℃, and rotating speed is 100rpm, in the 900ml buffer (pH1.6-7.2), discharges the 12.5-42.5% of total amount after 1 hour; Discharge the 25-55% of total amount after 2 hours; Discharge the 45-75% of total amount after 4 hours; Discharge the 55-85% of total amount after 6 hours.
Now on the market, have only the analgesic of single medicine slow release formulation on sale, as oxycodone, acetaminophen etc.Still the compound slow release preparation that does not have similar products.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above shortcomings in the prior art, and a kind of preparation method of compound slow release preparation of non-narcotic analgesics is provided, contain compound slow release preparation and technical recipe that two kinds of pain relieving compositions of non-opium active ingredient acetaminophen or ibuprofen and non-narcotic opium tranadol hydrochloride and derivant thereof are prepared from.
The present invention solves the problems of the technologies described above the technical scheme that is adopted: contain 100-1000mg acetaminophen or ibuprofen and 15-150mg tramadol or its salt, the ratio of two kinds of active ingredients is at 1: 1 to 10: 1, comprising:
1) immediate release section contains coccoid, pearl, graininess or the microplate shape medicine of the 25-75% of two kinds of effective ingredient;
2) slow-released part comprises:
(1) contains coccoid, pearl, graininess or the microplate shape medicine of the 25-75% of two kinds of effective ingredient;
(2) account for the gelatin polymer of total amount 6-50%, described slow-released part can comprise or not comprise enteric coatings, and coating accounts for the 5-40% of total amount.
Capsule of the present invention adopts USP disintegrating method II, at rotating speed is under the condition of 50rpm, in the disintegrate medium of imitative gastric juice, can discharge the 25-60% of total amount in the 1st hour, can pro-in 4 hours, discharge that burst size can not surpass 80% in the 50-90% of total amount and the pro-12 hours.
Capsule of the present invention, at least contain a kind of gelatin polymer, as hydroxypropyl methylcellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose, biogum, alginate, polyoxyethylene, carbonyl polrvinyl or carbonyl methyl cellulose salt; Described gelatin polymer in 25 ℃, concentration are 2% aqueous solution, is measured with the BrookfieldLV viscosimeter, and range of viscosities should be between the 60-7000000 centipoise, and comparatively ideal scope is between the 100-100000 centipoise.
Bead of the present invention, beadlet, granule or microplate can comprise or not comprise enteric coating, and coating material can be used polyacrylic, acetyl cellulose, hydroxypropyl methyl ether cellulose esters, polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate or Lac etc.
Comprise in the slow releasing tablet of the 100-1000mg of containing acetaminophen of the present invention or ibuprofen and 30-150mg tranadol hydrochloride or its salt:
1) slow-released part comprises: the 25-75% of (1) effective ingredient; (2) account for the gelatin polymer of total amount 6-50%, described slow-released part can comprise or not comprise enteric coatings, and coating accounts for the 5-40% of total amount;
2) immediate release section comprises: the 25-75% and partially mixed press strip of slow release or the tabletting that contain the medicine effective ingredient.
Tablet of the present invention, adopt USP disintegrating method II, at rotating speed is under the condition of 50rpm, in the disintegrate medium of imitative gastric juice, can in the 1st hour, discharge the 25-60% of medicine total amount, can pro-in 4 hours, discharge the 50-90% of medicine total amount, and burst size can not surpass 80% in the pro-12 hours.
Tablet of the present invention, at least contain following a kind of gel polymers, as hydroxypropyl methylcellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose, biogum, alginate, polyoxyethylene, carbonyl polrvinyl or carbonyl methyl cellulose salt; Described gelatin polymer in 25 ℃, concentration are 2% aqueous solution, is measured with the BrookfieldLV viscosimeter, and range of viscosities should be between the 60-7000000 centipoise, and comparatively ideal scope is between the 100-100000 centipoise.
Slow-released part of the present invention, can comprise or not comprise enteric coating, coating material can be used polyacrylic, acetyl cellulose, hydroxypropyl methyl ether cellulose esters, polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate or Lac etc.
Slow-released part of the present invention comprises:
1) slow-released part comprises: coccoid, the pearl of the 25-75% of (1) effective ingredient, graininess or microplate shape medicine; (2) account for the gelatin polymer of total amount 6-50%, described slow-released part can comprise or not comprise enteric coatings, and coating accounts for the 5-40% of total amount;
2) immediate release section comprises: the 25-75% and partially mixed press strip of slow release or the tabletting that contain the medicine effective ingredient.
Slow-released part of the present invention, adopt USP disintegrating method II, at rotating speed is under the condition of 50rpm, in the disintegrate medium of imitative gastric juice, can in the 1st hour, discharge the 25-60% of total amount, can pro-in 4 hours, discharge the 50-90% of total amount, and burst size can not surpass 80% in the pro-12 hours.
Slow-released part of the present invention, at least contain following a kind of gel polymers, as hydroxypropyl methylcellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose, biogum, alginate, polyoxyethylene, carbonyl polrvinyl or carbonyl methyl cellulose salt; Described gelatin polymer in 25 ℃, concentration are 2% aqueous solution, is measured with the BrookfieldLV viscosimeter, and range of viscosities should be between the 60-7000000 centipoise, and comparatively ideal scope is between the 100-100000 centipoise.
The slow-released part of slow release prescription of the present invention, can comprise or not comprise enteric coating, coating material can be used polyacrylic, acetyl cellulose, hydroxypropyl methyl ether cellulose esters, polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate or Lac etc.
The compound slow-releasing medicine that the present invention makes with above-mentioned preparation process prescription, within an hour, tranadol hydrochloride and active metabolite human body blood drug level thereof promptly reach more than the 150ng/mL after the single oral dose administration; Ibuprofen or acetaminophen human body blood drug level promptly reach more than the 4ug/mL; Within 8 hours, the average blood drug level of tranadol hydrochloride and active metabolite thereof maintains between the 50-250ng/mL, and the average blood drug level of ibuprofen or acetaminophen maintains between the 0.5-5ug/m.
Novelty of the present invention has been to propose to contain compound slow release preparation and the technical recipe that non-opium active ingredient acetaminophen or ibuprofen and non-narcotic opium tranadol hydrochloride and two kinds of pain relieving compositions of derivant thereof are prepared from.
The present invention has better curative effect for dissimilar pain.
The present invention proposes contains the compound sustained-released prescription that acetaminophen or ibuprofen and tranadol hydrochloride active ingredient prepare by a certain percentage, can greatly improve the analgesic curative effect.
Prescription and dosage form that the present invention proposes can make analgesia time keep at least 8 hours, obviously improve the convenient and compliance of patient's medication.
The specific embodiment:
The present invention is intended to propose to contain the compound sustained-released prescription of acetaminophen or ibuprofen and tranadol hydrochloride.The present invention proposes to make compound slow release preparation as a kind of analgesia method with acetaminophen or ibuprofen and tranadol hydrochloride.Pain therapy had both required the symptom that eases the pain rapidly, required analgesic activity can continue the long time again.Adopt USP disintegrating method II can record analgesia duration of the present invention, described prescription is in the imitative gastric juice disintegrate medium of 50rpm at rotating speed, can discharge the 25-60% of total dose in the 1st hour.In the pro-4 hours, discharge the 50-90% of total dose, and burst size can not surpass 80% in the pro-12 hours.
The special proposition of the present invention contains the release storehouse of the controlled release preparation of acetaminophen or ibuprofen and tranadol hydrochloride.And it also is that effectively other compositions comprise compositions such as Yi Rong, slightly soluble and indissoluble that this prescription and other multiple medicine or active component mix.Therefore, the present invention's fixed component of being not limited only to discharge under certain condition and other active component.
No matter be to make tablet or capsule, controlled release formulation of the present invention all comprises as the lower part: (1) rapid release composition, and acetaminophen wherein or ibuprofen and tranadol hydrochloride or its esters account for the 25-70% of total amount; (2) slow release composition contains acetaminophen or ibuprofen and tramadol and its esters that (a) accounts for total dose 30-75%; (b) gelatin polymer of preparation controlled release form in 25 ℃, concentration are 2% aqueous solution, is measured with the BrookfieldLV viscosimeter, and range of viscosities should be between about 60-7000000 centipoise, and comparatively ideal scope is between the 100-100000 centipoise; (3) can select for use some enteric solubility materials as coating, as polymer, acetyl cellulose, hydroxypropyl methyl ether cellulose esters, polyvinyl acetate, hydroxypropyl methylcellulose acetic acid succinate, cellulose acetate trimellitate or the Lac of acrylic acid and methacrylic acid.
In the compound tablet, the content of acetaminophen or ibuprofen and tramadol or its esters active constituents of medicine is advisable between 40-85%; The 6-50% that gelatin polymer accounts for total amount is advisable, and enteric polymer accounts for 40% of total amount and is advisable.
Dosage form of the present invention comprises and wherein contains one or more tablet and capsule such as spheroid, granule, powder and the mini small pieces of 2-12.
As described below, routine 1-4 has exemplified the releasing effect of acetaminophen or ibuprofen and tranadol hydrochloride compound recipe different dosage form.
Table one (example one)
| Sequence number | Composition | Rapid release dosage | Sustained-release dosage |
| 1 | Acetaminophen or ibuprofen | 200.0mg | 300mg |
| 2 | Tranadol hydrochloride | 20.0mg | 30.0mg |
| 3 | Microcrystalline Cellulose | 50.4mg | 8.8mg |
| 4 | Polyvinylpyrrolidone K-90 | 19.2mg | 17.6mg |
| 5 | Starch | 19.2mg | ------ |
| 6 | Cross-linked carboxymethyl cellulose sodium salt | 4.8mg | ------ |
| 7 | Sodium alginate (Keltone LV) | ----- | 35.2mg |
| 8 | Hydroxypropyl methylcellulose (Methocel K4M) | ----- | 39.6mg |
| 9 | Silica colloidal | 3.2mg | 4.4mg |
| 10 | Magnesium stearate | 3.2mg | 4.4mg |
| Amount to | 320.0mg | 440.0mg |
The preparation of immediate release section: from the 1-6 item of last table, respectively get in right amount, in high speed shear formula mixer-granulator or planetary mixer-granulator, mix.Place water or other the mixture that coagulates to form granule in this mixture, in exsiccator, carry out drying then.Afterwards, this dry thing is ground, the 9th and 10 prong materials were mixed during adding was gone up and shown then.The reuse tablet machine is pressed into the microplate that substance is 160mg with it.Above-mentioned steps is the conventional steps of present tablet manufacturing.
The preparation of slow-released part: the 1-3 from last table, respectively get in 7,8 an amount of, mixing in efficient shearing mixer-granulator or planetary mixer-granulator.Place water or other the mixture that coagulates to form granule in this mixture, in exsiccator, carry out drying then.Afterwards, this dry thing is ground, the 9th and 10 prong materials were mixed during adding was gone up and shown then.The reuse tablet machine is pressed into the microplate of substance 220mg with it.Above-mentioned steps is the conventional steps of present tablet manufacturing.At last, 2 rapid releases and 3 slow release microplates are poured in 1 capsules.
Table two (example two)
| Sequence number | Composition | Rapid release dosage | Sustained-release dosage |
| 1 | Acetaminophen or ibuprofen | 250.0mg | 250.0mg |
| 2 | Tranadol hydrochloride | 25.0mg | 25.0mg |
| 3 | Microcrystalline Cellulose | 36.4mg | 37.8mg |
| 4 | Polyvinylpyrrolidone K-90 | 18.0mg | 13.8mg |
| 5 | Starch | 18.0mg | ------ |
| 6 | Cross-linked carboxymethyl cellulose sodium salt | 5.4mg | ------ |
| 7 | Sodium alginate (Keltone LV) | ------ | 36.8mg |
| 8 | Hydroxypropyl methylcellulose (Methocel K4M) | ------ | 41.4mg |
| 9 | Silica colloidal | 3.6mg | 4.6mg |
| 10 | Magnesium stearate | 3.6mg | 4.6mg |
| 11 | The copolymer of methacrylic acid (Eudragit L30D) | ------ | 30.0mg |
| 12 | Talcum | ------ | 11.4mg |
| 13 | Triethyl citrate | ------ | 4.6mg |
| 14 | Purified water | ------ | (80mg) |
| Amount to | 360.0mg | 460.0mg |
The preparation of rapid release composition: from the 1-6 item of table 2, respectively get in right amount, in High Speed Stirring Machine or plane agitator, mix.This mixture coagulates at water or other and forms granule in mixture, carries out drying then in exsiccator.Afterwards, this dry thing is ground, the 9th and 10 prong materials were mixed during adding was gone up and shown then.The reuse tablet machine is pressed into the microplate of substance 180mg with it.Above-mentioned steps is the conventional steps of present tablet manufacturing.
The preparation of slow release composition: from the 1-4 of table 2, respectively get in 7,8 an amount of, mixing in efficient shearing mixer-granulator or planetary mixer-granulator.Place water or other to coagulate mixture in mixture and form granule, in addition dry in exsiccator then.Afterwards, this dry thing is ground, add then that the 9th and 10 prong materials are mixed in the table 2.The reuse tablet machine is pressed into the microplate of substance 207mg with it.At last, make the coating of heavily about 13mg with 11-14 prong material in the table 2.Above-mentioned steps is the conventional steps of present tablet manufacturing.At last, 2 rapid releases and 3 slow release microplates are poured in 1 capsules.
Table three (example three and example four)
| Sequence number | Composition | Example three | Example four |
| 1 | Acetaminophen (micropowder shape) | 325.0mg | 390.0mg |
| 2 | Tranadol hydrochloride | 37.5mg | 45.0mg |
| 3 | Microcrystalline Cellulose | 22.5mg | 44.0mg |
| 4 | Polyvinylpyrrolidone K-30 | 20.0mg | 24.0mg |
| 5 | Hydroxypropyl methylcellulose (Methocel K100LV) | 40.0mg | 40.0mg |
| 6 | Hydroxypropyl methylcellulose (Methocel K4M) | 45.0mg | 45.0mg |
| 7 | Silica colloidal | 5.0mg | 6.0mg |
| 8 | Magnesium stearate | 5.0mg | 6.0mg |
| 9 | The copolymer of methacrylic acid (Eudragit L30D) | 32.5mg | ------ |
| 10 | Talcum | 12.2mg | ------ |
| 11 | Triethyl citrate | 5.3mg | ------ |
| 12 | Purified water | (81mg) | |
| 13 | Acetaminophen (micropowder shape) | 325.0mg | 260mg |
| 14 | Tranadol hydrochloride | 37.5mg | 30.0mg |
| 15 | Hydroxypropyl methylcellulose (Methocel | 17.5mg | 10.0mg |
| E5) | |||
| Amount to | 930.0mg | 900.0mg |
Example three is respectively got in right amount mixing in efficient shearing mixer-granulator or planetary mixer-granulator from the 1-6 item of table 3.Place water or other to coagulate mixture in this mixture and form granule, in exsiccator, carry out drying then.Afterwards, this dry thing is ground, the 7th and 8 prong materials were mixed during adding was gone up and shown then.The reuse tablet machine is pressed into the microplate of substance 500mg with it.Make the coating of heavily about 50mg then with 9-12 prong material in the table 3.By behind 10% the above-mentioned coating, the suspension that the 13-15 item is made in the reuse table 3 carries out coating at bag.The packaging technique of last reuse routine is made finished product.
Example four is respectively got in right amount mixing in efficient shearing mixer-granulator or planetary mixer-granulator from the 1-6 item of table 3.Place water or other to coagulate mixture in this mixture and form granule, in addition dry and dry thing ground in exsiccator then, add in the table 3 the 7th and 8 then and mixed.The reuse tablet machine is pressed into the microplate of substance 600mg with it.The suspension made from 13-15 prong material in the table 3 wraps up microplate then, as immediate release section.At last, with conventional peplos its coating is finished.
Adopting American Pharmacopeia dissolution method II, is under the 50rpm condition at rotating speed, in the 1st hour above-mentioned a few assembly sides is placed the disintegrate medium of imitative gastric juice, is placed on afterwards in the disintegrate medium of imitative intestinal juice.The drug release situation of above-mentioned prescription is as follows:
The percentage ratio of table four---drug release
| Time (hour) | Example one | Example two | ||
| Acetaminophen | Tramadol | Acetaminophen | Tramadol | |
| 0 | 0 | 0 | 0 | 0 |
| 1 | 52.8±3.9 | 55.0±4.8 | 49.8±5.6 | 50.8±5.2 |
| 2 | 64.2±4.8 | 67.1±4.3 | 56.7±6.0 | 61.9±4.8 |
| 4 | 85.1±4.0 | 88.4±3.7 | 82.9±4.8 | 83.6±4.3 |
| 6 | 98.0±3.1 | 97.9±2.9 | 96.7±3.9 | 96.2±3.4 |
| 8 | 100.6±2.2 | 100.0±2.4 | 102.4±2.5 | 99.8±2.8 |
The percentage ratio of table five---drug release
| Time (hour) | Example three | Example four | ||
| Acetaminophen | Tramadol | Acetaminophen | Tramadol | |
| 0 | 0 | 0 | 0 | 0 |
| 1 | 49.6±6.2 | 49.8±5.5 | 53.1±5.3 | 55.5±4.5 |
| 2 | 65.5±5.1 | 66.4±4.6 | 68.2±4.8 | 71.4±4.2 |
| 4 | 82.8±4.8 | 84.8±3.7 | 89.0±4.2 | 89.6±4.0 |
| 6 | 97.1±3.5 | 97.7±2.5 | 98.1±3.6 | 99.0±3.1 |
| 8 | 101.3±2.6 | 101.0±2.3 | 100.7±2.7 | 101.3±2.6 |
Example four: the present invention finds in experiment how ibuprofen and song unite use under proper proportion, can improve analgesic effect, reduce bent many consumption and toxic and side effects. with the similar prescription of above-mentioned formulation development, can prepare compound sustained-released analgesia new drug equally,
During separately with ibuprofen 100mg/kg and 50mg/kg, the analgesia effective percentage of acetic acid writhing response is respectively 40% and 30%.Separately with bent many 30,20 with during 10mg/kg, the analgesia effective percentage of writhing response is respectively 50%, 20% and 10%.But after using ibuprofen 100mg/kg and 50mg/kg respectively, give respectively and song many 30,20 and 10mg/kg, the writhing response suppression ratio of each treated animal all is higher than single medicine corresponding dosage again.The analgesic activity of two medicines presents obvious synergistic.This experiment finds that ibuprofen and song are many all analgesic activity, and the two analgesic effect of share is better than single medicine of corresponding dosage,
Many and the ibuprofen synergism of table six salt love song
A) separately with single many or ibuprofen analgesic activity (acetic acid writhing method) of song of using
| Dosage (mg/kg) | n | Turn round the body number of times | Significant figure | Effective percentage (%) | ED 50 (95％CL) |
| Bent many | |||||
| 60 | 10 | 0±0 | 10 | 100 | 24.19 (19.85~29.48) mg/kg |
| 36 | 10 | 2.30±5.74 | 8 | 80 | |
| 21.6 | 10 | 5.80±5.88** | 5 | 50 | |
| 13 | 10 | 21.50± 10.04*** | 0 | 0 | |
| 7.8 | 10 | 39.30± 11.43*** | 0 | 0 | |
| Ibuprofen | |||||
| 463 | 10 | 0±0*** | 10 | 100 | 91.04 (67.43~122.91) mg/kg |
| 277.8 | 10 | 0.30±0.95*** | 10 | 100 | |
| 166.7 | 10 | 1.20±1.87*** | 8 | 80 | |
| 100 | 10 | 9.60±10.89*** | 5 | 50 | |
| 60 | 10 | 6.20±4.71*** | 3 | 30 | |
| Negative control | |||||
| 0 | 10 | 37.10±8.95 | / | / | |
* P＜0.01, Mann-Whitney U test. is compared with negative control group in * * * P＜0.001
Annotate: turn round body number of times≤3 time in the 15min, as effectively.
B) share ibuprofen and bent many analgesic activities (acetic acid writhing method)
C)
| Ibuprofen mg/kg | Bent many mg/kg | n | Turn round the body number of times | Significant figure | Effective percentage (%) |
| 0 | 0 | 10 | 34.30±10.63 | 0 | 0 |
| 30 | 10 | 7.20±7.47*** | 5 | 50 | |
| 20 | 10 | 11.40±9.08** | 2 | 20 | |
| 10 | 10 | 17.40±11.06** | 1 | 10 | |
| 50 | 0 | 10 | 7.30±6.88*** | 3 | 30 |
| 30 | 10 | 0.00±0.00*** ## | 10 | 100 | |
| 20 | 10 | 1.00±2.16*** ## | 8 | 80 | |
| 10 | 10 | 5.70±5.12*** # | 4 | 40 | |
| 100 | 0 | 10 | 7.70±7.56*** | 4 | 40 |
| 30 | 10 | 0.00±0.00*** ## | 10 | 100 | |
| 20 | 10 | 1.50±2.95*** ## | 8 | 80 | |
| 10 | 10 | 5.80±7.15*** ## | 5 | 50 |
* P＜0.01, Mann-Whitney U test. is compared with negative control group in * * * P＜0.001
#P＜0.05,
##P＜0.01 is compared Mann-Whitney U test. with the matched doses list with bent more
P＜0.05,
P＜0.01,
Mann-Whitney U test. is compared with the matched doses list in P＜0.01 with ibuprofen
Annotate: turn round body number of times≤3 time in the 15min, as effectively.
Claims (11)
1, a kind of preparation method of compound slow release preparation of non-narcotic analgesics is characterized in that: contain 100-1000mg acetaminophen or ibuprofen and 15-150mg tramadol or its salt, the ratio of two kinds of active ingredients is at 1: 1 to 10: 1, comprising:
1) immediate release section contains coccoid, pearl, graininess or the microplate shape medicine of the 25-75% of two kinds of effective ingredient;
2) slow-released part comprises:
(1) contains coccoid, pearl, graininess or the microplate shape medicine of the 25-75% of two kinds of effective ingredient;
(2) account for the gelatin polymer of total amount 6-50%, described slow-released part can comprise or not comprise enteric coatings, and coating accounts for the 5-40% of total amount.
2, capsule according to claim 1, adopt USP disintegrating method II, at rotating speed is under the condition of 50rpm, in the disintegrate medium of imitative gastric juice, can in the 1st hour, discharge the 25-60% of total amount, can pro-in 4 hours, discharge that burst size can not surpass 80% in the 50-90% of total amount and the pro-12 hours.
3, capsule according to claim 1, at least contain a kind of gelatin polymer, as hydroxypropyl methylcellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose, biogum, alginate, polyoxyethylene, carbonyl polrvinyl or carbonyl methyl cellulose salt; Described gelatin polymer in 25 ℃, concentration are 2% aqueous solution, is measured with the BrookfieldLV viscosimeter, and range of viscosities should be between the 60-7000000 centipoise, and comparatively ideal scope is between the 100-100000 centipoise.
4, bead according to claim 1, beadlet, granule or microplate can comprise or not comprise enteric coating, and coating material can be used polyacrylic, acetyl cellulose, hydroxypropyl methyl ether cellulose esters, polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate or Lac.
5, comprise in the slow releasing tablet of the 100-1000mg of containing acetaminophen according to claim 1 or ibuprofen and 30-150mg tranadol hydrochloride or its salt:
1) slow-released part comprises: the 25-75% of (1) effective ingredient; (2) account for the gelatin polymer of total amount 6-50%, described slow-released part can comprise or not comprise enteric coatings, and coating accounts for the 5-40% of total amount;
2) immediate release section comprises: the 25-75% and partially mixed press strip of slow release or the tabletting that contain the medicine effective ingredient.
6, according to the described tablet of claim 5, adopt USP disintegrating method II, at rotating speed is under the condition of 50rpm, in the disintegrate medium of imitative gastric juice, can in the 1st hour, discharge the 25-60% of medicine total amount, can pro-in 4 hours, discharge the 50-90% of medicine total amount, and burst size can not surpass 80% in the pro-12 hours.
7, according to the described tablet of claim 5, at least contain following a kind of gel polymers, as hydroxypropyl methylcellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose, biogum, alginate, polyoxyethylene, carbonyl polrvinyl or carbonyl methyl cellulose salt; Described gelatin polymer in 25 ℃, concentration are 2% aqueous solution, is measured with the BrookfieldLV viscosimeter, and range of viscosities should be between the 60-7000000 centipoise, and comparatively ideal scope is between the 100-100000 centipoise.
8, slow-released part according to claim 5, can comprise or not comprise enteric coating, coating material can be used polyacrylic, acetyl cellulose, hydroxypropyl methyl ether cellulose esters, polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate or Lac; 1) slow-released part comprises: coccoid, the pearl of the 25-75% of (1) effective ingredient, graininess or microplate shape medicine; (2) account for the gelatin polymer of total amount 6-50%, described slow-released part can comprise or not comprise enteric coatings, and coating accounts for the 5-40% of total amount; 2) immediate release section comprises: the 25-75% and partially mixed press strip of slow release or the tabletting that contain the medicine effective ingredient.
9, slow-released part according to claim 9, adopt USP disintegrating method II, at rotating speed is under the condition of 50rpm, in the disintegrate medium of imitative gastric juice, can in the 1st hour, discharge the 25-60% of total amount, can pro-in 4 hours, discharge the 50-90% of total amount, and burst size can not surpass 80% in the pro-12 hours.
10, slow-released part according to claim 9, at least contain following a kind of gel polymers, as hydroxypropyl methylcellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose, biogum, alginate, polyoxyethylene, carbonyl polrvinyl or carbonyl methyl cellulose salt; Described gelatin polymer in 25 ℃, concentration are 2% aqueous solution, is measured with the BrookfieldLV viscosimeter, and range of viscosities should be between the 60-7000000 centipoise, and comparatively ideal scope is between the 100-100000 centipoise; And slow-released part can comprise or not comprise enteric coating, and coating material can be used polyacrylic, acetyl cellulose, hydroxypropyl methyl ether cellulose esters, polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate or Lac.
11, according to claim 1-9, with the compound slow-releasing medicine that above-mentioned preparation process prescription is made, within an hour, tranadol hydrochloride and active metabolite human body blood drug level thereof promptly reach more than the 150ng/mL after the single oral dose administration; Ibuprofen or acetaminophen human body blood drug level promptly reach more than the 4ug/mL; Within 8 hours, the average blood drug level of tranadol hydrochloride and active metabolite thereof maintains between the 50-250ng/mL, and the average blood drug level of ibuprofen or acetaminophen maintains 0.5-5ug/m.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510060989 CN1785167A (en) | 2005-10-08 | 2005-10-08 | Method for preparing composite delayed-release prepn. of non-narcotic analgesic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510060989 CN1785167A (en) | 2005-10-08 | 2005-10-08 | Method for preparing composite delayed-release prepn. of non-narcotic analgesic |
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| Publication Number | Publication Date |
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| CN1785167A true CN1785167A (en) | 2006-06-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510060989 Pending CN1785167A (en) | 2005-10-08 | 2005-10-08 | Method for preparing composite delayed-release prepn. of non-narcotic analgesic |
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| CN101987092A (en) * | 2010-09-27 | 2011-03-23 | 苏州世林医药技术发展有限公司 | Novel pharmaceutical composition containing analgesic |
| CN102210688A (en) * | 2011-05-24 | 2011-10-12 | 赛乐医药科技(上海)有限公司 | Compound methoxyphenamine quick-release and sustained-release preparation |
| CN102264355A (en) * | 2008-10-27 | 2011-11-30 | 阿尔扎公司 | Extended release oral acetaminophen/tramadol dosage form |
| CN101700245B (en) * | 2009-10-10 | 2012-03-21 | 天圣制药集团股份有限公司 | Compound drug for curing colds and preparation technology thereof |
| CN102548544A (en) * | 2009-10-09 | 2012-07-04 | 永进药品工业株式会社 | Pharmaceutical composition with both immediate and extended release characteristics |
| CN102349900B (en) * | 2009-10-10 | 2013-01-02 | 天圣制药集团股份有限公司 | Preparation method of compound capsule for treating cold |
| CN102105136B (en) * | 2008-03-11 | 2014-11-26 | 蒂宝制药公司 | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
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- 2005-10-08 CN CN 200510060989 patent/CN1785167A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102105136B (en) * | 2008-03-11 | 2014-11-26 | 蒂宝制药公司 | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
| CN102264355A (en) * | 2008-10-27 | 2011-11-30 | 阿尔扎公司 | Extended release oral acetaminophen/tramadol dosage form |
| CN107028908A (en) * | 2008-10-27 | 2017-08-11 | 阿尔扎公司 | Extended release oral acetaminophen/tramadol dosage form |
| CN102548544A (en) * | 2009-10-09 | 2012-07-04 | 永进药品工业株式会社 | Pharmaceutical composition with both immediate and extended release characteristics |
| CN102548544B (en) * | 2009-10-09 | 2015-01-21 | 永进药品工业株式会社 | Pharmaceutical composition with both immediate and extended release characteristics |
| US9180101B2 (en) | 2009-10-09 | 2015-11-10 | Yungjin Pharm Co., Ltd. | Pharmaceutical composition simultaneously having rapid-acting property and long-acting property |
| CN101700245B (en) * | 2009-10-10 | 2012-03-21 | 天圣制药集团股份有限公司 | Compound drug for curing colds and preparation technology thereof |
| CN102349900B (en) * | 2009-10-10 | 2013-01-02 | 天圣制药集团股份有限公司 | Preparation method of compound capsule for treating cold |
| CN101987092A (en) * | 2010-09-27 | 2011-03-23 | 苏州世林医药技术发展有限公司 | Novel pharmaceutical composition containing analgesic |
| CN102210688A (en) * | 2011-05-24 | 2011-10-12 | 赛乐医药科技(上海)有限公司 | Compound methoxyphenamine quick-release and sustained-release preparation |
| CN102210688B (en) * | 2011-05-24 | 2013-04-03 | 赛乐医药科技(上海)有限公司 | Compound methoxyphenamine quick-release and sustained-release preparation |
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