CN104188947A - Compound pharmaceutical composition of tapentadol hydrochloride and dexketoprofen trometamol - Google Patents
Compound pharmaceutical composition of tapentadol hydrochloride and dexketoprofen trometamol Download PDFInfo
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- CN104188947A CN104188947A CN201410423396.0A CN201410423396A CN104188947A CN 104188947 A CN104188947 A CN 104188947A CN 201410423396 A CN201410423396 A CN 201410423396A CN 104188947 A CN104188947 A CN 104188947A
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- Prior art keywords
- tapentadol hydrochloride
- dexketoprofen
- pharmaceutical composition
- dexketoprofen trometamol
- pain
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- ZELFLGGRLLOERW-YECZQDJWSA-N 3-[(2r,3r)-1-(dimethylamino)-2-methylpentan-3-yl]phenol;hydrochloride Chemical group Cl.CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 ZELFLGGRLLOERW-YECZQDJWSA-N 0.000 title claims abstract description 65
- 229960004143 tapentadol hydrochloride Drugs 0.000 title claims abstract description 63
- QUZMDHVOUNDEKW-MERQFXBCSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;(2s)-2-(3-benzoylphenyl)propanoic acid Chemical compound OCC(N)(CO)CO.OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 QUZMDHVOUNDEKW-MERQFXBCSA-N 0.000 title claims abstract description 36
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- DKYWVDODHFEZIM-NSHDSACASA-N dexketoprofen Chemical compound OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-NSHDSACASA-N 0.000 claims description 9
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a compound pain-relieving pharmaceutical composition which comprise the active ingredients of tapentadol hydrochloride and dexketoprofen trometamol. The invention also relates to a preparation method and application of a compound preparation of the pharmaceutical composition, wherein a dosage form of the compound preparation is an oral solid preparation. Tapentadol hydrochloride and dexketoprofen trometamol have a synergistic effect on the curative effect and antagonism on the toxicity, so that the compound pain-relieving pharmaceutical composition refers to a quick-acting, powerful and low-addiction compound pain-relieving preparation.
Description
Technical field
The present invention is field of pharmaceutical preparations, is specifically related to a kind of analgesic pharmaceutical composition, compound preparation that comprises active ingredient hydrochloric acid tapentadol hydrochloride and dexketoprofen trometamol and uses thereof.
Background technology
Tapentadol hydrochloride is a kind of novel strong central analgesics that has the exciting and norepinephrine of opiate receptor concurrently and heavily absorb inhibition dual function mode.On January 23rd, 2008, FDA Food and Drug Administration (FDA) has accepted tapentadol hydrochloride releases the new drug application of sheet, for the treatment of severe acute pain.Result of study shows, tapentadol hydrochloride does not rely on metabolism activation, there is no active metabolite, acute, inflammatory and chronic neuropathic pain model model are had to good effect, its usefulness is between morphine and tramadol, intravenous injection or the oral equal blood drug level that can obtain satisfaction, and than morphine more difficult generation analgesia tolerance and drug dependence, and more can improve side effect (especially gastrointestinal side-effect) than the strong opiates medicine of equivalent analgesic dose, be expected acute and chronic in better to prospect in severe pain treatment.
This product chinesization formal name used at school: 3-((1R, 2R)-3-(dimethylamino)-1-Ethyl-2-Methyl propyl group) phenolate hydrochlorate, English chemical name: 3-((1R, 2R)-3-(Dimethylamino)-1-ethyl-2-methylpropyl) phenol Hydrochloride, structural formula is as follows:
Healthy male volunteers single dose is oral
3-14celite acid tapentadol hydrochloride 100 mg, are equivalent to tapentadol hydrochloride 85.86mg.Actually accept radioactive carbon 1.867 MBq, or tapentadol hydrochloride intrinsic specific activity 21.74 kBq/mg.Result shows that oral tapentadol hydrochloride absorbs rapidly, and 1～2 h reaches peak serum concentration.Mainly occur with the metabolite form of combination at blood plasma, in conjunction with unconjugated tapentadol hydrochloride ratio be 24:1.In conjunction with the tapentadol hydrochloride peak concentration time (Tmax) at 1.25～2.0 h, the unconjugated tapentadol hydrochloride concentration of all volunteer's blood plasma is all very low, Cmax is 0.07 ± 0.03 g-eq base/m1), under overall tapentadol hydrochloride plasma concentration time graph, area (AUC) O～120 (unconjugated+combination) are approximately 64 of total body radiation carbon AUC 0～120, %, whole blood radioactive carbon Tmax is at 1.25～1.5 h.Similar with morphine (20～30), after intravenous injection, the clearance rate of 1531 ml/min is equivalent to hepatic blood flow (1400 ml/min).Tapentadol hydrochloride 10～80 mg and 75～200mg be intravenous injection and oral rear show dose linearity respectively, after every day 4 oral administrations, about 25～30h reaches steady statue, average accumulated factor is 1.8, this is mainly determined by dosing interval and the apparent t1/2 of tapentadol hydrochloride, and during administration, has no pharmacokinetic parameters change.
14the tapentadol hydrochloride mass balance of C labelling studies have shown that, rapidly, after administration 4h, 50% above dosage is discharged from tapentadol hydrochloride excretion, in 24 h, drain the radioactivity response rate that exceedes 95%, 48 h urine and exceed 98%, apparent half-life (t) 3.93 h.Excretion is nearly all through kidney, 99% is discharged by urine, and wherein 69% radioactive marker is with the form (glucosiduronic acid and sulfate) of combination, about 27% with other metabolites and 3 with tapentadol hydrochloride original shape by urinating discharge, only l% discharges through feces, by expiration CO.Discharge and more can ignore, this proves the metabolic stability of labeled drug, the conjugate (96%) that almost all dosage metabolism is non-activity, and after 5 d, excretion reaches complete equipilibrium (average recovery rate 99.9%) greatly.
The idea of " balance analgesia " more and more comes into one's own in pain therapy field.In the U.S., prescription analgesic is the most frequently used prescription drug, by the analgesic of use in conjunction different mechanisms, can strengthen analgesic effect, simultaneously because the dosage of every kind of medicine is compared with the low adverse reaction reduction that makes.
Pain is numerous disease clinical symptoms, is come to harm a kind of protective response of sexual stimulus of body.Analgesic is divided into two large classes, acts on central nervous system's narcosis analgesic and acts on the non-steroid class anti-inflammatory analgesic of peripheral-system, and central analgesics has very strong analgesic activity, but because its side effect is large, especially easily addiction and limited its application.That non-steroid class anti-inflammatory analgesic is that a class has is antipyretic, the medicine of analgesia and antiinflammatory action, is the essential drugs for the treatment of pain, and analgesic activity is weaker than the former, but side effect is relatively little, is considered to a line choice drug in treatment in slight and moderate pain.
Dexketoprofen trometamol is used for an acute pain disease, the pain that be applicable to short-term elimination wound and postoperative pain, swell and ache, bitterly violent and a variety of causes causes.Tablet or injection can be used for alleviating moderate to violent postoperative pain, comprise abdominal part, chest, gynecological, oral cavity, orthopedic and prostatectomy.In addition, also can alleviate acute kidney glue pain, biliary colic, toothache, wound pain, trigeminal neuralgia, cancer Encelialgia, and various pains that just can come into force with morphine or Pethidine that are essential in the past.
Moderate pain is clinical common symptom, patient is large in number and widely distributed, as various postoperative pain, cancer pain etc., for this class case, it is inadequate using non-steroid class anti-inflammatory analgesic class medicine analgesic effect, conventionally need to use narcosis analgesic, but because often needing repeat administration easily to produce dependency.In clinical analgesia, often by two class analgesic administering drug combinations, to strengthen analgesic effect, reduce the dosage of narcosis analgesic, especially reduce the use amount of the strong dependency medicines such as morphine, at present this class compound preparation of listing has ammonia phenol oxycodone sheet and capsule, ibuprofen and codeine etc., but needs for treatment, and clinical needs have more that quick acting, analgesic effect are better, the less medicine of side effect.
The compound recipe of tapentadol hydrochloride and dexketoprofen trometamol composition, clinical do not have medicinal.The analgesic of two kinds of different mechanism of action is share, both can strengthen analgesic effect, extend action time, can reduce again dosage, reduce toxicity incidence rate.
Summary of the invention
The object of the present invention is to provide a kind of quick-acting, potent and low addiction compound pain preparation.This compound preparation is applicable to the pain relieving of moderate cancer pain and postoperative pain.
Compound pain preparation of the present invention is the compound preparation that active component forms by tapentadol hydrochloride and dexketoprofen trometamol.
Concrete scheme of the present invention is:
A kind of pharmaceutical composition, is made up of smart tapentadol hydrochloride and dexketoprofen trometamol and pharmaceutically acceptable carrier.
Wherein the weight ratio of tapentadol hydrochloride (in tapentadol hydrochloride) and dexketoprofen trometamol (taking dexketoprofen) is 1～8:1.
Further preferred weight ratio is 2～6:1.
More preferred weight ratio is 3～5:1.
Highly preferred weight ratio is 3:1.
Compound preparation of the present invention can be made into oral solid formulation, comprises granule, ordinary tablet, chewable tablet, dispersible tablet, oral cavity disintegration tablet, buccal tablet, capsule, slow releasing tablet, slow releasing capsule etc.
On its tablet Chinese materia medica, acceptable carrier comprises filler, binding agent, diluent, lubricant and coating material.Filler can be selected from pregelatinized Starch, lactose; Binding agent optional in polyvidone, hydroxypropyl methylcellulose, carmethose, ethyl cellulose, microcrystalline Cellulose one or more, preferably microcrystalline cellulose, hydroxypropyl methylcellulose.Lubricant is selected from magnesium stearate, Pulvis Talci.
The dosage of above activating agent will be different because of formula.Through quantitative analysis and the prescription optimization of tapentadol hydrochloride and dexketoprofen trometamol analgesic activity, wherein analgesic activities the best of hydrochloric tapentadol hydrochloride (in tapentadol hydrochloride) 75mg, dexketoprofen trometamol (in dexketoprofen) 25mg in the per unit preparation of hydrochloric tapentadol hydrochloride (in tapentadol hydrochloride) 37.5mg, dexketoprofen trometamol (in the dexketoprofen) 12.5mg of small dimension or large specification in per unit preparation.Described " per unit preparation " refers to: if tablet just refers to a tablet, the rest may be inferred.
Pharmaceutical composition of the present invention can be used for analgesia clinically, is mainly used for the pain relieving of moderate cancer pain and postoperative pain.
In to compound preparation pharmacology test of the present invention, be surprised to find, the fragrant trometamol compound preparation of tapentadol hydrochloride and dextrorotation ketone drug effect has concertedness, toxic and side effects has Antagonism, clinical application has more safety, with the comparison of folk prescription tapentadol hydrochloride sheet, onset is rapid, and analgesic effect is stronger, has reached unexpected effect.
Detailed description of the invention
The following examples can conduct further description the present invention, but these embodiment should not served as limitation of the scope of the invention.
embodiment 137.5mg/12.5mg tapentadol hydrochloride dexketoprofen trometamol sheet
1, prescription
Table 1 37.5mg/12.5mg tapentadol hydrochloride dexketoprofen trometamol tablet recipe composition (1000)
2, preparation technology
(1) tapentadol hydrochloride is crossed 80 mesh sieves, and a Lactose hydrate, microcrystalline Cellulose, hydroxypropyl methylcellulose are crossed 60 mesh sieves, puts mix homogeneously in V-Mixer into;
(2) above-mentioned mixed powder is put in wet mixing pelletizer, and purified water slowly adds, shear granulation;
(3) granulate 60 DEG C and be dried;
(4) dry grain 24 mesh sieve granulate obtain granule 1;
(5) dexketoprofen trometamol is crossed 80 mesh sieves and is put in V-Mixer and mix homogeneously with silicon dioxide;
(6) corn starch and sodium carboxymethyl cellulose are crossed mix homogeneously in the rearmounted V-Mixer of 60 mesh sieves;
(7) granule 1 is mixed homogeneously with above-mentioned (5) V-Mixer;
(8) mix homogeneously with (6) V-Mixer above-mentioned (7), adds magnesium stearate mix homogeneously;
(9) tabletting and get final product.
embodiment 275mg/25mg tapentadol hydrochloride dexketoprofen trometamol sheet
1, prescription
Table 2 75mg/25mg tapentadol hydrochloride dexketoprofen trometamol tablet recipe composition (1000)
2, preparation technology
(1) tapentadol hydrochloride is crossed 80 mesh sieves, and a Lactose hydrate, microcrystalline Cellulose, hydroxypropyl methylcellulose are crossed 60 mesh sieves, puts mix homogeneously in V-Mixer into;
(2) above-mentioned mixed powder is put in wet mixing pelletizer, and purified water slowly adds, shear granulation;
(3) granulate 60 DEG C and be dried;
(4) dry grain 24 mesh sieve granulate obtain granule 1;
(5) dexketoprofen trometamol is crossed 80 mesh sieves and is put in V-Mixer and mix homogeneously with silicon dioxide;
(6) corn starch and sodium carboxymethyl cellulose are crossed mix homogeneously in the rearmounted V-Mixer of 60 mesh sieves;
(7) granule 1 is mixed homogeneously with above-mentioned (5) V-Mixer;
(8) mix homogeneously with (6) V-Mixer above-mentioned (7), adds magnesium stearate mix homogeneously;
(9) tabletting and get final product.
embodiment 337.5mg/12.5mg tapentadol hydrochloride dexketoprofen trometamol capsule
1, prescription
Table 3 37.5mg/12.5mg tapentadol hydrochloride dexketoprofen trometamol capsule prescription composition (1000)
2, preparation technology
(1) tapentadol hydrochloride is crossed 80 mesh sieves, and a Lactose hydrate, microcrystalline Cellulose, hydroxypropyl methylcellulose are crossed 60 mesh sieves, puts mix homogeneously in V-Mixer into;
(2) above-mentioned mixed powder is put in wet mixing pelletizer, and purified water slowly adds, shear granulation;
(3) granulate 60 DEG C and be dried;
(4) dry grain 24 mesh sieve granulate obtain granule 1;
(5) dexketoprofen trometamol is crossed 80 mesh sieves, crosses in the rearmounted V-Mixer of 60 mesh sieves and mixs homogeneously with corn starch and sodium carboxymethyl cellulose;
(6) above-mentioned mixed powder is put in wet mixing pelletizer, and purified water slowly adds, shear granulation;
(7) granulate 60 DEG C and be dried;
(8) dry grain 24 mesh sieve granulate obtain granule 1;
(9) increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate, add magnesium stearate, mix encapsulating capsule and get final product.
embodiment 475mg/25mg tapentadol hydrochloride dexketoprofen trometamol capsule
1, prescription
Table 4 75mg/25mg tapentadol hydrochloride dexketoprofen trometamol capsule prescription composition (1000)
2, preparation technology
(1) tapentadol hydrochloride is crossed 80 mesh sieves, and a Lactose hydrate, microcrystalline Cellulose, hydroxypropyl methylcellulose are crossed 60 mesh sieves, puts mix homogeneously in V-Mixer into;
(2) above-mentioned mixed powder is put in wet mixing pelletizer, and purified water slowly adds, shear granulation;
(3) granulate 60 DEG C and be dried;
(4) dry grain 24 mesh sieve granulate obtain granule 1;
(5) dexketoprofen trometamol is crossed 80 mesh sieves, crosses in the rearmounted V-Mixer of 60 mesh sieves and mixs homogeneously with corn starch and sodium carboxymethyl cellulose;
(6) above-mentioned mixed powder is put in wet mixing pelletizer, and purified water slowly adds, shear granulation;
(7) granulate 60 DEG C and be dried;
(8) dry grain 24 mesh sieve granulate obtain granule 1;
(9) increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate, add magnesium stearate, mix encapsulating capsule and get final product.
embodiment 5dissolution determination
Dissolution by the dosage form of the method mensuration embodiment 1 with reference to " Chinese Pharmacopoeia " version in 2010 and embodiment 3 gained in different medium.
Dissolution parameters is as follows:
| Project | Parameter |
| Medium | Be respectively water, pH1. 2 chlorination of hydrochloric acid sodium solutions, pH4. 5 acetate buffers and pH6. 8 phosphate buffers |
| Medium volume | 900ml |
| Rotating speed | 50rpm |
| Sample time | 5、10、15、30、45min |
The dissolution fluid taking out is with after 0.45um filtering with microporous membrane, adopts the wherein content of tapentadol hydrochloride and dexketoprofen trometamol of high effective liquid chromatography for measuring, and calculates the dissolution of each time point tapentadol hydrochloride and dexketoprofen trometamol.
Table 5 dissolution medium is the dissolution data of water
Table 6 dissolution medium is the dissolution data of pH1. 2 chlorination of hydrochloric acid sodium solutions
Table 7 dissolution medium is the dissolution data of pH4. 5 acetate buffers
Table 8 dissolution medium is the dissolution data of pH6. 8 phosphate buffers
zoopery
One, the impact on electricity irritation mice Mus tail induced pain
Select 200 of the qualified NIH mices of quarantine.After mice is fixing, wipe afterbody sebum with 75% ethanol, after ethanol volatilization, afterbody is coated with skim conducting resinl.15 v voltages for female mice, male mice 20V voltage, continuously A pulse, frequency 1 Hz, ripple is wide be that the square wave of 10ms stimulates mouse tail 5s, continued stimulus 2 times, the person that do not shout once of shouting for 1 time if having stimulates the 3rd time, and the person that all do not shout for 2 times is superseded.Every minor tick is at least 10 min, reacts the stimulation number of times of the sum/reaction of shouting as Basic Pain Threshold to shout.Select 40 of qualified female mices, be divided at random 6 groups by Basic Pain Threshold, 10 every group, select 48 of qualified male mices, be divided at random 6 groups by Basic Pain Threshold, 8 every group.Be respectively 2 groups of embodiment 1 embodiment, tapentadol hydrochloride matched group and solvent matched group.Each group is 10,30,60,90 and 120min electricity irritation mice Mus tail before administration, after administration respectively, records the stoichiometric number of shouting of each electricity irritation, and is calculated as follows the analgesia suppression ratio of not shouting and reacting.
The impact (n=8) of table 9 on the effect of male mice electricity irritation induced pain
Note: compared with solvent matched group, * p<0.05, * * p<0.01.
The impact (n=10) of table 10 on the effect of female mice electricity irritation induced pain
Note: compared with solvent matched group, * p<0.05, * * p<0.01.
The analgesia suppression ratio (n=8) of table 11 to male mice electricity irritation induced pain
Note: compared with solvent matched group, * p<0.05, * * p<0.01.
The analgesia suppression ratio (n=10) of table 12 to female mice electricity irritation induced pain
Note: compared with solvent matched group, * p<0.05, * * p<0.01.
Two, the impact on rat Monoarthritis pain
Choose the qualified female sd inbred rats of quarantine, all adopt left ankle joint intracavitary administration complete Freund's adjuvant.Animal is with the shallow fiber crops of 5 % chloral hydrate (300mg/kg) lumbar injection, left lateral position, left side external malleolus surrounding skin is sterilized with 75% ethanol, from external malleolus, outside recess thrusts syringe needle subcutaneous, then turn to acropodium portion, lunge the ankle joint chamber between tibiofibula and astragalus, from the about 5mm of skin depth of needle.Exert pressure, inject adjuvant 0.05ml.
Within first 6 days, start the Basic Pain Threshold of the left and right sides hind leg ankle joint of measuring rat in administration, every other day once, totally 3 times, bend simultaneously, stretch arthralgia test scores.When measurement, first animal is put in special plastics cage, two back legs and tail expose outside, and bend, stretch arthralgia test scores after stablizing 30min.Slowly a side ankle joint for flexing animal, carries out once totally 5 times every 5s.If bend when joint animal without shout or the reaction of very brief significantly contracting lower limb scoring be 0; If occur, a kind of reaction scoring is 1; Both all occur, scoring is 2.The scoring of each stimulation gained is 0～2, and the general comment of every side ankle joint is divided into 0～10.Stretch arthralgia test scores identical with bending joint score calculation method.After scoring, use YLS-3E type electronics tenderness instrument to apply from the side the pressure increasing progressively continuously to Mus ankle joint, in the time that pressure is increased to a certain numerical value, rat will produce the reaction of contracting lower limb, and this force value is exactly Determination of Pain Threshold value.Every the every rear flank of rat limb is measured 2 times, causes scorching limb and causes scorching limb and hocket with non-, between each survey bitterly, is spaced apart about 5min, gets the Basic Pain Threshold of its average as the each hind leg of each Mus.
Select the qualified rat of screening, according to causing scorching acroesthesia threshold, animal is divided into model control group, blank group, embodiment 1,2 groups of embodiment, tapentadol hydrochloride group, 10 every group at random.Respectively organize respectively at the medicine or the normal saline that within the 4th week, award respective concentration that cause after inflammation, successive administration 5 days, within after 0.5h, 1h, 2h, 4h and drug withdrawal 1 day after the administration medicine of the 1st, 3,5 days, measure respectively two hind leg threshold of pains and bend, stretch arthralgia test scores, each time point is surveyed the threshold of pain 1 time.
The 1st day each group rats with bilateral hind leg pain threshold (-X ± S, n=10) of subordinate list 13 administrations
Note: compared with model control group, 1. p<0.05,2. p<0.01; Compared with pain threshold before administration, 3. p<0.05,4. p<0.01.
The 3rd day each group rats with bilateral hind leg pain threshold (-X ± S, n=10) of subordinate list 14 administrations
Note: compared with model control group, 1. p<0.05,2. p<0.01; Compared with pain threshold before administration, 3. p<0.05,4. p<0.01.
The 5th day each group rats with bilateral hind leg pain threshold (-X ± S, n=10) of subordinate list 15 administrations
Note: compared with model control group, 1. p<0.05,2. p<0.01; Compared with pain threshold before administration, 3. p<0.05,4. p<0.01.
More than test shows: tapentadol hydrochloride and dexketoprofen trometamol not only curative effect have synergism, and its toxicity has Antagonism, are quick-acting, potent compound pain preparation.
Claims (9)
1. taking tapentadol hydrochloride and dexketoprofen trometamol as a pharmaceutical composition for active component, it is characterized in that: taking tapentadol hydrochloride and dexketoprofen trometamol as effective active composition, form with pharmaceutically suitable auxiliary material combination.
2. the pharmaceutical composition of claim 1, is characterized in that the weight ratio of tapentadol hydrochloride (in tapentadol hydrochloride) and dexketoprofen trometamol (taking dexketoprofen) is 1～8:1.
3. the pharmaceutical composition of claim 2, is characterized in that the weight ratio of tapentadol hydrochloride (in tapentadol hydrochloride) and dexketoprofen trometamol (taking dexketoprofen) is 2～6:1.
4. the pharmaceutical composition of claim 3, is characterized in that the weight ratio of tapentadol hydrochloride (in tapentadol hydrochloride) and dexketoprofen trometamol (taking dexketoprofen) is 3～5:1.
5. the pharmaceutical composition of claim 4, is characterized in that the weight ratio of tapentadol hydrochloride (in tapentadol hydrochloride) and dexketoprofen trometamol (taking dexketoprofen) is 3:1.
6. the pharmaceutical composition of any one in claim 1 to 5, can be made into oral solid formulation, comprises granule, ordinary tablet, chewable tablet, dispersible tablet, oral cavity disintegration tablet, buccal tablet, capsule, slow releasing tablet, slow releasing capsule etc.
7. the pharmaceutical composition of claim 5, wherein hydrochloric tapentadol hydrochloride (in tapentadol hydrochloride) 37.5mg, dexketoprofen trometamol (in dexketoprofen) 12.5mg in per unit preparation.
8. the pharmaceutical composition of claim 5, wherein hydrochloric tapentadol hydrochloride (in tapentadol hydrochloride) 75mg, dexketoprofen trometamol (in dexketoprofen) 25mg in per unit preparation.
In claim 1 to 8 pharmaceutical composition of any one for the preparation of the purposes of analgesic.
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| CN102908339A (en) * | 2007-11-23 | 2013-02-06 | 格吕伦塔尔有限公司 | Tapentadol compositions |
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| CN102908339A (en) * | 2007-11-23 | 2013-02-06 | 格吕伦塔尔有限公司 | Tapentadol compositions |
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| CN112603902A (en) * | 2020-12-07 | 2021-04-06 | 北京亚东生物制药有限公司 | Dexketoprofen trometamol capsule and preparation process thereof |
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