CN103860551A - Pharmaceutical composition containing etodolac and tramadol hydrochloride and application thereof - Google Patents
Pharmaceutical composition containing etodolac and tramadol hydrochloride and application thereof Download PDFInfo
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- CN103860551A CN103860551A CN201210551554.1A CN201210551554A CN103860551A CN 103860551 A CN103860551 A CN 103860551A CN 201210551554 A CN201210551554 A CN 201210551554A CN 103860551 A CN103860551 A CN 103860551A
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- etodolac
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Abstract
The invention belongs to the field of medicine, and particularly relates to a pharmaceutical composition and an application thereof in preparation of analgesic drugs. The pharmaceutical composition takes etodolac and tramadol hydrochloride as active pharmaceutical ingredients, wherein the ratio of etodolac to tramadol hydrochloride is preferably 0.1-100:1, more preferably 4-8:1. The pharmaceutical composition can be made into an appropriate pharmaceutical preparation for drug administration, such as oral preparations. A large number of pharmacological experiments confirm that etodolac and tramadol hydrochloride have a significant synergistic effect in treatment of pains caused by various factors. The pharmaceutical composition is strong in analgesic effect, low in untoward effects, and suitable for long-term application for patients with pains.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of pharmaceutical composition and application thereof for the treatment of pain, the pharmaceutical composition that is specifically related to contain etodolac and tramadol hydrochloride and the purposes for pain therapy thereof.
Background technology
Pain is the body a kind of protective response producing after sexual stimulus that comes to harm, often with the emotional activity such as frightened, nervous.Pain, except the not Anwai of reaction in sensorial misery and emotion, also can cause the disorder of physiological function, causes insomnia, even can bring out shock and threat to life.So, be necessary in order to alleviate severe pain and to prevent shock suitably to use analgesic clinically, in treatment disease and trauma nursing, have very important significance.
Analgesic is divided into two large classes, act on central nervous system's narcosis analgesic and the non-steroidal anti-inflammatory analgesics (NSAID) that acts on peripheral-system, central analgesics has very strong analgesic activity, but because its side effect is large, especially easily addiction and limited its application.That non-steroidal anti-inflammatory analgesics 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.
Tramadol is the weak opioid drug of amine phenyl ring alcohols synthetic, it is opioid receptor agonist, for central nervous system's analgesic, there is double action mechanism, both can be combined with central nervous system's weak opiate receptor, can suppress again monoamine neurotransmitter (5-hydroxy tryptamine and epinephrine) reuptake effect between spinal cord synapse.These two kinds of mechanism of action are mutually collaborative in the time of performance analgesic effect, heighten the effect of a treatment.The analgesia intensity of tramadol, in the time of Isodose, is equivalent to 1/5 of morphine, but is obviously better than other nonsteroid anti-inflammatory drugses, in being applicable to, Severe Cancerous pain, is classified as the second ladder of cancer pain three step analgesias treatments recommend medicine by WHO.The affinity of this medicine and opiate receptor than morphine a little less than 6000 times, substantially there is not addiction, can life-time service, therefore, under therapeutic dose, do not produce respiration inhibition, do not affect cardiovascular function, do not produce the untoward reaction such as constipation, dysuria yet.Such medicine belongs to Class B medicine in medical insurance catalogue, in cancer pain clinical practice at present, mostly is slow releasing tablet.
Etodolac is COX-2 high selectivity NSAID of new generation, its analgesic activity rapidly, definite, be better than or equal conventional analgesics.Take the analgesic activity of rear 2h, etodolac 200mg is better than aspirin 650mg; The analgesic activity of 2～12h after taking, etodolac 400mg is obviously better than codeine 60mg and adds acetaminophen 600mg.Cancer pain the first ladder medication is mainly NSAID (non-steroidal anti-inflammatory drug) clinically at present, mainly contain indomethacin, but cancer patient long-term taking toxic and side effects is many, and etodolac is its analog, analgesia effect is better than indomethacin, the inhibitory action synthetic to gastric mucosal cell prostaglandin is lower, and therefore GI irritation is lighter.Etodolac to hepatic and renal function without Persistent Effect, to elderly population also safer and easy tolerance.
NSAID (non-steroidal anti-inflammatory drug) is combined with opiates in the study hotspot of analgesic at present, and representative is the compound preparation-paracetamol and tramadol hydrochloride tablet to acetyl-amino phenol and tramadol, and first this medicine was gone on the market in the U.S. by FDA approval in calendar year 2001.But acetaminophen acute or that the property accumulated is excessive can cause serious hepatic injury, and is likely further developed into liver failure.In the U.S. and Britain, acetaminophen is excessive is the modal reason of hepatic injury, and its untoward reaction and unreasonable application receive much concern.
United States Patent (USP) 5,336,691 disclose a kind of compositions that contains tramadol hydrochloride and acetaminophen, and wherein the weight ratio of tramadol hydrochloride and acetaminophen is 1: 1～1600.United States Patent (USP) 20,080,050,427 disclose the compositions that contains tramadol and meloxicam, wherein tramadol content is 25～800mg, meloxicam content is 0.5～1500mg, but the best proportioning of unexposed tramadol and meloxicam, does not relate to best proportioning and the corresponding pharmacological experimental data of tramadol and etodolac compositions.
Summary of the invention
In order to reduce the misery of pain patients, the clinical application that increases pain patients is selected, the invention provides a kind of for analgesic composition, this analgesic composition is taking etodolac and tramadol hydrochloride as active constituents of medicine, and its analgesic effect is strong, poisonous side effect of medicine is little, be applicable to the prolonged application of pain patients.Analgesic composition of the present invention is particularly useful for the treatment of moderate to severe acute pain, comprises bone injury ache, arthritis pain, cancer pain and postoperative pain etc.
The inventor is surprised to find etodolac through a large amount of pharmacological experiments and tramadol hydrochloride use in conjunction has synergism significantly at ease pain, drug effect part embodiment 1 of the present invention shows that the pharmaceutical composition Dichlorodiphenyl Acetate induced mice writhing model that contains etodolac and tramadol hydrochloride has good therapeutical effect, analgesic effect when its medicine analgesic effect is not only significantly better than two kinds of medicines and uses separately, be more better than both analgesic effects add and.Two kinds of Drug combinations can obviously reduce each plant demand, reduce untoward reaction and occur.Drug effect part embodiment 2 of the present invention shows that the pharmaceutical composition that contains etodolac and tramadol hydrochloride has good therapeutical effect to hot plate induced pain mouse model, analgesic effect when its medicine analgesic effect is not only significantly better than two kinds of medicines and uses separately, be more better than both analgesic effects add and.And can obviously reduce each plant demand, reduce untoward reaction and occur.
One of the object of the invention is to provide a kind of for analgesic composition, and the active constituents of medicine of this pharmaceutical composition is made up of etodolac and tramadol hydrochloride.Inventor finds by a large amount of pharmacological evaluation, and in this pharmaceutical composition, etodolac and tramadol hydrochloride are all can playing the synergistic therapeutic effect to pain therapy in proportion widely.According to the pain therapy effect of pharmaceutical composition and synergistic power, the weight ratio of etodolac and tramadol hydrochloride preferably 0.1～100: 1 in pharmaceutical composition of the present invention, more preferably 4～8: 1.
The present invention also provides the pharmaceutical preparation that contains aforementioned pharmaceutical compositions, pharmaceutical composition of the present invention can be prepared into suitable pharmaceutical preparation as required for pain therapy, as oral formulations, ejection preparation etc., the present invention is preferably oral formulations, and described oral formulations comprises and is preferably tablet, capsule, slow releasing tablet, pill, granule, dispersible tablet, powder.The selected adjuvant of described oral formulations can be starch, pregelatinized Starch, starch slurry, beta-schardinger dextrin-, carbomer, microcrystalline Cellulose, vitamin E, hydroxypropyl emthylcellulose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, Polyethylene Glycol (PEG), sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, mannitol, sodium lauryl sulphate, cross-linking sodium carboxymethyl cellulose, lactose, polyvinylpyrrolidone (PVP), crospolyvinylpyrrolidone, magnesium stearate, Pulvis Talci, micropowder silica gel, aspartame, orange flavor, sodium bicarbonate, sodium carbonate, in enteric coating powder partly or entirely.
The adjuvant used of above-mentioned preparation and preparation method all can adopt its conventional adjuvant and preparation method to make.In said medicine preparation, the content that contains etodolac in each preparation unit is 20mg～1500mg, and the content of tramadol hydrochloride is 15mg～200mg.
Two of the object of the invention is to provide the medical usage of aforementioned pharmaceutical compositions, and this pharmaceutical composition is for the preparation of the purposes in analgesic.Pharmaceutical composition of the present invention can be used for analgesia clinically, goes for the treatment of moderate to severe acute pain, comprises bone injury ache, arthritis pain, cancer pain and postoperative pain etc.In medical usage described above, etodolac tramadol pharmaceutical composition can be prepared into suitable pharmaceutical preparation to facilitate medication according to the animal state of an illness and agents area, administration time and administration number of times for analgesic of the present invention pharmaceutical composition need to be determined according to the concrete diagnostic result of the state of an illness, within this technical scope of grasping those skilled in the art.For example, will be applied to the person to mice analgesic therapeutic scheme upper, all medicines can convert to the effective dose of mice by this medicine to people's effective dose, and this is apparent for the person of ordinary skill of the art.
Compared with prior art, pharmaceutical composition of the present invention has following outstanding advantage aspect treatment pain:
(1) compared with individually dosed etodolac or tramadol hydrochloride, pharmaceutical composition Dichlorodiphenyl Acetate induced mice writhing model and hot plate induced pain mouse model that the present invention contains etodolac and tramadol hydrochloride have good therapeutical effect, and shown good synergism, analgesic effect is strong.
(2) pharmaceutical composition of the present invention contains tramadol hydrochloride and etodolac, and the two drug combination has the synergistic while, reduces the two consumption, thereby reduces toxic and side effects, reduces untoward reaction and occurs.
(3) pharmaceutical composition of the present invention, with the form of therapy pain of fixed combination, compared with taking single medicine, has improved patient's compliance and compliance simultaneously.
(4) pharmaceutical composition of the present invention contains etodolac and tramadol hydrochloride, the two analgesic effect is good, drug safety is high, drug combination also shows good drug safety, is applicable to prolonged application, points out this medicine to can be developed into the analgesic into supplying long-term taking.
Detailed description of the invention
Further describe the present invention by specific implementation method below, but range of application of the present invention is not limited only to the following example.In content of the present invention, spirit and/or scope, the replacement to the technology of the present invention feature and/or combination, will be readily apparent to persons skilled in the art, and be included among the present invention.
Part I drug combination preparation of the present invention and preparation method thereof
Embodiment 1 tablet
Prescription
Preparation technology:
Medicine and adjuvant are crossed respectively to 80 mesh sieves, etodolac is fully mixed with 34 grams of microcrystalline Cellulose, 30 grams of pregelatinized Starch and 13 grams of cross-linked carboxymethyl fiber sodium, 10% starch slurry soft material processed, 18 mesh sieves granulations, are dried at 60 DEG C, obtain granule 1.Tramadol hydrochloride is fully mixed with 18 grams of microcrystalline Cellulose, 12 grams of pregelatinized Starch and 2 grams of cross-linked carboxymethyl fiber sodium, 10% starch slurry soft material processed, 18 mesh sieves are granulated, dry at 60 DEG C, obtain granule 2.Increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate, add magnesium stearate, mix tabletting, the heavy 500mg of sheet.
Embodiment 2 tablets
Prescription
Preparation technology is with embodiment 1.
Embodiment 3 tablets
Prescription
Preparation technology is with embodiment 1.
Embodiment 4 tablets
Prescription
Preparation technology is with embodiment 1.
Embodiment 5 tablets
Prescription
Preparation technology is with embodiment 1.
Embodiment 6 capsules
Prescription
Preparation technology:
Medicine and adjuvant are crossed respectively to 80 mesh sieves, etodolac is fully mixed with 49 grams of starch and 13 grams of cross-linking sodium carboxymethyl celluloses, 7%PVP solution soft material processed, 18 mesh sieves granulations, are dried at 60 DEG C, obtain granule 1.Tramadol hydrochloride is fully mixed with 20 grams of lactose, 20 grams of starch and 2 grams of cross-linking sodium carboxymethyl celluloses, 7%PVP solution soft material processed, 18 mesh sieves are granulated, dry at 60 DEG C, obtain granule 2.Increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate, add magnesium stearate, mix encapsulating capsule, the heavy 500mg of capsule.
Embodiment 7 capsules
Prescription
Preparation technology is with embodiment 6.
Embodiment 8 capsules
Prescription
Preparation technology is with embodiment 6.
Embodiment 9 capsules
Prescription
Preparation technology is with embodiment 6.
Embodiment 10 granules
Prescription
Preparation technology: first etodolac, tramadol hydrochloride are mixed homogeneously with beta-schardinger dextrin-, then after adding microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, methylcellulose, sodium lauryl sulphate to cross 16 mesh sieves, mix, after mix homogeneously with orange flavor, aspartame again.Mixture is granulated with 5% polyvidone ethanol, dry, granulate, and subpackage, to obtain final product.
Embodiment 11 slow releasing tablet
Prescription
Preparation technology: take etodolac and the tramadol hydrochloride of recipe quantity, carbomer, hydroxypropyl cellulose, beta-schardinger dextrin-mix homogeneously.The 8% starch slurry solution of separately getting Sq, adds in mixed-powder, and soft material processed after mix homogeneously is granulated by 16 mesh sieves, and 60 DEG C following dry.After completing after dry, use 18 mesh sieves carry out granulate, sift out the fine powder in dry granular, mix, and then be mixed evenly with dry granule with the magnesium stearate of sieving, and tabletting, to obtain final product.
Part II pharmacodynamics embodiment part
The impact of the mouse writhing number of times that embodiment 1 etodolac tramadol hydrochloride compositions Dichlorodiphenyl Acetate causes
1. animal grouping and administration
70 of male ICR mouses, (20 ± 2) g, is divided into 7 groups at random by body weight, and 10 every group, the situation of specifically dividing into groups is as follows:
Etodolac capsule, tramadol, paracetamol and tramadol hydrochloride tablet are mixed with to suspension with normal saline respectively, then according to dosage setting, each administration group gastric infusion; Model group gavage gives equal-volume normal saline.
2. experimental technique and date processing
Mouse peritoneal injection acetic acid, causes abdominal cavity large area and more lasting pain stimulation, causes mice to produce writhing response.After each dosage group administration 1h, lumbar injection 0.7% acetic acid normal saline solution 0.1ml/10g, record is every writhing response number of times that mice occurs in 20min after injection acetic acid induced pain, calculates the writhing suppression ratio of each administration group.
Writhing suppression ratio=[(matched group writhing number of times-medicine group writhing number of times)/matched group writhing number of times] × 100%
Experimental data with
represent, adopt SPSS15.0 software to carry out variance analysis.
3. experimental result
Experimental result is in table 1
The impact of the mouse writhing number of times that table 1 etodolac tramadol hydrochloride compositions Dichlorodiphenyl Acetate causes
With model group comparison,
*p < 0.01; With the comparison of etodolac group,
aMP.AMp.Amp &p < 0.01;
With the comparison of tramadol hydrochloride group,
$ $p < 0.01; With the comparison of tramado hydrochloride group,
##p < 0.01.
Experimental result is as shown in Table 1 known, aspect the mouse writhing number of times that in each compositions treatment group, etodolac and tramadol hydrochloride cause at inhibition acetic acid, there is obvious synergism, its suppression ratio is not only significantly better than individually dosed group of two kinds of medicines, more be better than two kinds of medicine suppression ratio add and, the analgesic effect of pharmaceutical composition of the present invention is also significantly better than existing analgesic tramado hydrochloride.Specific as follows:
(1), compared with model group, each treatment group all has remarkable inhibitory action to writhing mouse writhing number of times due to mice acetic acid.
(2) compared with etodolac, the independent medication of tramadol hydrochloride, etodolac tramadol hydrochloride compositions group has utmost point significant difference (P < 0.01) to writhing inhibitory action, show that two medicines share and have synergism, and two medicines share in reaching same texts, can significantly reduce each single pharmaceutical quantities, and then reduce the generation of untoward reaction.
(3) compared with tramado hydrochloride group, etodolac tramadol hydrochloride compositions group has utmost point significant difference (P < 0.01) to writhing inhibitory action, and this pharmaceutical composition analgesic effect is better.
The impact of embodiment 2 etodolac tramadol hydrochloride compositionss on the reaction of mice hot plate induced pain
1. animal grouping and administration
By female ICR mice (20 ± 2) g, put on the intelligent hot-plate instrument of 55 ± 0.5 DEG C, recording mice vola contact hot plate to the incubation period (s) that occurs licking metapedes reaction is threshold of pain index, rejects the mice of response latency < 5s or > 30s or jump.Choose the qualified mice of 70 response latencies in 10～30s, be divided at random 7 groups according to the front threshold of pain of medicine and body weight, by following administration:
2. experimental technique and date processing
Continuously gastric infusion 5 days is measured respectively the threshold of pain 1 time of each administration group mice after administration 30,60,90, when 120min, and pain threshold exceedes 60s person and calculates with 60s.
Data with
represent, adopt SPSS15.0 software to carry out variance analysis.
3. experimental result
Experimental result is in table 2
The impact of table 2 etodolac tramadol hydrochloride compositions on the reaction of mice hot plate induced pain
With model group comparison,
*p < 0.05,
*p < 0.01; With the comparison of etodolac group,
aMP.AMp.Amp &p < 0.01;
With the comparison of tramadol hydrochloride group,
$ $p < 0.01; With the comparison of tramado hydrochloride group,
##p < 0.01.
From table 2 experimental result, the effect of the each administration group equal threshold of pain that can improve mice compared with model group, wherein etodolac and tramadol hydrochloride have significant synergism aspect the raising mice threshold of pain, what the threshold of pain of compositions A, B, C group improved that effect is better than that two kinds of medicines use separately adding and, it is close with tramado hydrochloride that effect is improved in the threshold of pain, and wherein compositions C group has significant difference compared with tramado hydrochloride group.Specific as follows:
(1), compared with model group, each treatment group all has remarkable inhibitory action to hot plate induced pain mice pain.
(2) compared with etodolac, the independent medication of tramadol hydrochloride, etodolac tramadol hydrochloride compositions group has utmost point significant difference (P < 0.01) to hot plate model inhibitory action, show that two medicines share and have synergism, and two medicines share and can significantly reduce each single pharmaceutical quantities, and then the generation of reduction untoward reaction.
(3) compared with tramado hydrochloride group, etodolac tramadol hydrochloride compositions group has utmost point significant difference (P < 0.01) to hot plate induced pain inhibitory action, and this pharmaceutical composition is better to the analgesic effect of hot plate induced pain.
Owing to having described the present invention by above embodiment, any to be equal to replacement be all apparent for the present invention and be included among the present invention.
Claims (10)
1. a pharmaceutical composition, is characterized in that its active constituents of medicine is made up of etodolac and tramadol hydrochloride.
2. pharmaceutical composition as claimed in claim 1, is characterized in that in described pharmaceutical composition, the weight ratio of etodolac and tramadol hydrochloride is 0.1～100: 1.
3. pharmaceutical composition as claimed in claim 2, is characterized in that in described pharmaceutical composition, the weight ratio of etodolac and tramadol hydrochloride is 4～8: 1.
4. as the pharmaceutical composition as described in arbitrary in claim 1-3, it is characterized in that described pharmaceutical composition is oral formulations.
5. pharmaceutical composition as claimed in claim 4, is characterized in that described oral formulations is tablet, capsule, granule.
6. pharmaceutical composition as claimed in claim 5, is characterized in that described oral formulations is slow releasing preparation.
7. pharmaceutical composition as claimed in claim 4, described in it is characterized in that, wherein the content of etodolac is 20～1500mg in per unit preparation, the content 15～200mg of tramadol hydrochloride.
As claimed in claim 1 pharmaceutical composition in the purposes of preparing in analgesic.
9. purposes as claimed in claim 8, is characterized in that described pain is that moderate is to severe acute pain.
10. purposes as claimed in claim 9, is characterized in that described pain is bone injury ache, arthritis pain, cancer pain and postoperative pain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201210551554.1A CN103860551A (en) | 2012-12-10 | 2012-12-10 | Pharmaceutical composition containing etodolac and tramadol hydrochloride and application thereof |
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| CN201210551554.1A CN103860551A (en) | 2012-12-10 | 2012-12-10 | Pharmaceutical composition containing etodolac and tramadol hydrochloride and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115300515A (en) * | 2022-08-11 | 2022-11-08 | 南京红地生物科技有限公司 | Long-acting injection containing meloxicam and tramadol hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003080183A1 (en) * | 2002-03-19 | 2003-10-02 | Euro-Celtique S.A. | Pharmaceutical combination of the cox-2 inhibitor etodolac and opioids |
| US20080026054A1 (en) * | 2007-04-27 | 2008-01-31 | Nectid Inc. | Novel anelgesic combination |
| CN101652128A (en) * | 2007-03-02 | 2010-02-17 | 法纳姆公司 | Sustained release compositions using wax-like materials |
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2012
- 2012-12-10 CN CN201210551554.1A patent/CN103860551A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003080183A1 (en) * | 2002-03-19 | 2003-10-02 | Euro-Celtique S.A. | Pharmaceutical combination of the cox-2 inhibitor etodolac and opioids |
| CN101652128A (en) * | 2007-03-02 | 2010-02-17 | 法纳姆公司 | Sustained release compositions using wax-like materials |
| US20080026054A1 (en) * | 2007-04-27 | 2008-01-31 | Nectid Inc. | Novel anelgesic combination |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115300515A (en) * | 2022-08-11 | 2022-11-08 | 南京红地生物科技有限公司 | Long-acting injection containing meloxicam and tramadol hydrochloride |
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