CN1104895C - Composition comprising tramadol material and acetaminophen and its use - Google Patents
Composition comprising tramadol material and acetaminophen and its use Download PDFInfo
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- CN1104895C CN1104895C CN98107417A CN98107417A CN1104895C CN 1104895 C CN1104895 C CN 1104895C CN 98107417 A CN98107417 A CN 98107417A CN 98107417 A CN98107417 A CN 98107417A CN 1104895 C CN1104895 C CN 1104895C
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Abstract
The present invention relates to composition comprising tramadol and acetamidobenzene and application thereof. The applied tramadol relates to various kinds of tramadol. The composition can be used for treating symptoms caused by pain and cough on pharmacology. The composition hardly has the side effect of similar opium, such as abuse performance, tolerance, constipation and respiratory depression. In addition, each component of the composition is in definite proportional range. The medicinal effect of the composition is additive (synergetic).
Description
United States Patent (USP) discloses the phenol ester that a class analgesic cyclic alkanol replaces for No. 3652589, has the basic amine group in naphthenic ring.(1RS 2RS)-[(dimethylamino) methyl]-1-(3-anisyl) ring alcohol, is commonly referred to as tramadol wherein specifically to have introduced chemical compound.About a series of papers of pharmacology, toxicity and the clinical research of tramadol referring to ArzneimForsch (Drug Res.), 28 (1), 114 (1978).Driessen etc. are at Arch.Pharmacol., and 341, disclose the mechanism that tramadol produces its analgesic activity among the R104 (1990) and both not exclusively resembled class Opium, do not resemble the non-opioid mechanism of action yet.Having introduced the tramadol hydrochlorate about the VI time world conference (-6 days April 1 of nineteen ninety) summary of pain is the class Opium analgesics of the pure excitement of a kind of Orally active.Yet, clinical practice shows that tramadol lacks the anti-depressant typical side effects of many class Opium, for example respiration inhibition [is seen W.Vogel et al., Arzneim.Forsch (Drug Res), 28 (1) .183 (1978)], constipation [is seen I.Arend et al.Arzneim.Forsch. (Drug Res.), 28 (1) .199 (1978)], toleration [is seen L.Flohe et al., Arzneim.Forsch. (Drug Res.), 28 (1), 213 (1978)] and abuse liability [see T.Yanagita, Arzneim.Forsch. (Drug Res), 28 (1), 158 (1978)].When quick intravenous injection dosage is the 50mg tramadol, can produce certain side effect, this has only that tramadol just has makes face flushing and perspiration.Although these side effect are arranged, have non-class Opium and the active tramadol of class Opium and be still an extremely unique medicine.GrumenthalGMBH extensively sells tramadol as analgesics.
Therefore for many years, class Opium is used for treating severe pain as analgesics always, and still, they produce undesirable side effect, can not be repeatedly or with the high dose administration.Described side-effect problem can be proved by many documents and materials.For example referring to " ThePharmacological Basis of Therapeutics " book the 15th chapter 245 pages of (editor L.Goodman and A.Gilman of J.Jaffe and W.Martin, the 5th edition, 1975), wherein, disclosed morphine ex hoc genus anne material, for example codeine, hydrogenation codeinone and Genocodeine ketone all are the excited analgesics of class Opium, have side effect, as respiration inhibition, constipation and abuse liability.
For example acetyl amino phenyl (APAP) and Aspirin all can be used as analgesics as using opioid sub, non-class Opium.APAP, as Aspirin, it can not cause toleration, addiction and the toxicity of class Opium analgesics.Yet APAP and Aspirin only are used to alleviate moderate pain, and class Opium analgesics is used to alleviate serious pain [referring to Woodbury, D.and Fingl, E., " The Pharmacological Basis of Therapeutics ", 5th Ed; Goodman, L.and Gilman, A., Chapter 15, Pages 325 (1975)].
For reducing opioid side-effect problem, class Opium and other have been comprised that the medicine of non-class Opium analgesics combines, can reduce producing the required Opium consumption of suitable analgesia degree.Wherein some composition product also has the advantage that produces the synergic antalgic effect, prescription protection.For example, A.Takemori, Annals New York Acad.Sci., 281,262 (1976) disclose class Opium analgesics and the bonded compositions of non-analgesics medicine presents multiple effect, and promptly parfacies adds (inhibition), addition or superfacies and adds analgesic activity.R.Taber et al., J.Pharm.Expt.Thera., 169 (1), 29 (1969) disclose morphine and methadone, and the combination of another class Opium analgesics present summation action.No. 4571400, United States Patent (USP) disclose components such as paracodin, class Opium analgesics, ibuprofen, non-class Opium analgesics by a certain percentage in conjunction with the time, can provide superfacies to add effect.A.Pircio et al., Arch.Int.Pharmacodyn., 235,116 (1978) report Bus, another class Opium analgesics and acetyl amino phenyl (APAP), non-class Opium analgesics demonstrate superfacies with 1: 125 mixture and add analgesic activity, can not show then that with 1: 10 mixture significant superfacies adds analgesic activity on any statistics.
Equally, prepared the compositions of some non-class Opium analgesics,, paid particular attention to these compositionss and only have every kind of less component of need and produce the advantage that superfacies adds effect to avoid the side effect of class Opium association.G.Stacher et.al., Int.J.Clin.Pharmacol.Biopharmacy, 17,250 (1979) combinations that to have reported non-class Opium analgesics be TOL and APAP can obviously reduce the amount that produces the required TOL of analgesic activity.In addition, United States Patent (USP) discloses for No. 4260629 to be given by the compositions of specified weight than the APAP of scope and zomepirac, a kind of non-class Opium analgesics mammal is oral, can produce superfacies and add effect and ease the pain.In addition, United States Patent (USP) discloses for No. 4132788 when 5-aroyl-1-(rudimentary) alkyl pyrroles-2-acetogenin, when non-class Opium analgesics combines with APAP or Aspirin, can present superfacies and add the arthritis activity.But warning every day can not be heavy dose of or takes non-class Opium analgesics mixture and single non-class Opium analgesics (referring to D.Woodbury and E.Fingl at page 349) over a long time.
Yet, prior art does not disclose tramadol, the class Opium analgesics of a kind of " atypia ", it can or can combine with another kind of analgesics, cause minimizing side effect separately, or producing the compositions that contains tramadol material and another kind of analgesics, said composition presents superfacies and adds analgesic activity.
Have found that tramadol, comprise the hereinafter various forms of tramadols of definition, can combine, produce analgesic activity with APAP.Described combination makes the consumption of tramadol and APAP all be less than their needed amounts of the use same analgesic effect of generation separately.Because these two kinds of drug doses are all less, the side effect of association also all reduces on quantity and degree separately.Unexpectedly find to present the analgesia potentiation in conjunction with the compositions that generates by a certain percentage by tramadol and APAP.Compositions of the present invention also can be used for treatment cough disease.
Accompanying drawing is impartial excited figure, the analgesic effect that the mice abdomen that its expression tramadol hydrochlorate and acetyl amino phenyl compositions are brought out acetylcholine shrinks.
The invention provides the compositions that contains tramadol material and acetyl amino phenyl.Described tramadol material be (1S, 2S or 1S, 2S)-(dimethylamino methyl)-1-(3-anisyl)-Hexalin (tramadol), its any or its mixture of N-oxide derivative (" tramadol-N-oxide ").But also comprise one stereoisomer, stereoisomer mixture (comprising racemate), pharmaceutically acceptable amine salt (for example hydrochlorate), solvate and the polymorph of tramadol material.Described tramadol can be available from Grunenthal company or the method preparation of introducing for No. 3652589 according to the United States Patent (USP) of incorporating this paper as a reference into.
Tramadol-N-oxide can be by following method preparation, promptly at organic solvent for example in methanol or the isopropyl alcohol, the tramadol free alkali with oxidant for example hydrogen peroxide (30%) (preferably not heating) under heating handle (referring to " Reagents For OrganicSynthesis ", L, 471, Fieser ﹠amp; Fieser eds., Wiley N.Y., (1987), B.Kelentey etal Arzneim.forsch., 7594 (1957).Reacting by heating needs 1 hour approximately, and reacting by heating does not need about 3 days.After the oxidation, described mixture is with reagent (PtO for example
2Or preferred Pt/C) handled about 1 day, eliminate excessive hydrogen peroxide.This mixture filters, then filtrate evaporation, residue ORGANIC SOLVENT MIXTURES (for example dichloromethane/ethyl acetate) recrystallization.
The O-demethyltramadol can be by following method preparation, it is the tramadol free alkali, under O-demethylation reaction condition, for example it and highly basic (as NaOH or KH phenylmercaptan .) and diethylene glycol (DEG) reaction, reflux is [(referring to Wildeset al. simultaneously, J.Org.Chem., 36,721 (1971)].This reaction was carried out about 1 hour, and then cooling is then with this reactant mixture of water treatment, acidify, with organic solvent such as ether extraction, alkalization is with halogenated organic solvent such as dichloromethane extraction, the extract drying, solvent evaporation, O-demethyl product, then through short-path distillation and change into corresponding salt and (for example use souring soln, the HCl Ethanol Treatment), recrystallization in ORGANIC SOLVENT MIXTURES (for example ethanol/ether).
The materia medica of acetyl amino phenyl is commented referring to B.Ameer et al., Ann.Int.Med., 87,202 (1977); The preparation of acetyl amino phenyl is referring to No. 2998450, United States Patent (USP), and it incorporates this paper as a reference into.
APAP and tramadol material are about existence in 1: 1 to 1: 1600 with tramadol to the weight ratio of APAP usually, and some ratio causes compositions to present the analgesia potentiation.For example, contain the compositions of a kind of tramadol material and APAP, preferably about 1: 5 to 1: 1600 of the ratio of described tramadol material: APAP, more preferably from about 1: 19 to 1: 800.
Most preferred ratio is about 1: 19 to 1: 50.Tramadol material in these weight ratio scopes and the compositions of APAP have presented the analgesia potentiation.In addition, the ratio of each component is that about 1: 1 and about 1: 5 concrete compositions are included in the scope of the present invention.
Can prepare the Pharmaceutical composition that contains as the well-mixed tramadol material of active component and acetyl amino phenyl and pharmaceutical carrier according to the conventional medicine preparation technique.Described carrier of a great variety, this depends on the dosage form of administration requirement, for example intravenous injection, oral or parenterai administration.The also available spray pattern administration of described compositions.With regard to the preparation oral dosage form composition, can use any medicinal medium commonly used, for example, during preparation oral liquid (as suspension, elixir and solution), can make water, glycols, oils, alcohols, flavoring agent, antiseptic, coloring agent etc.During preparation oral solid formulation (for example powder, capsule and tablet), operable carrier such as starch, sugar, diluent, granulation agent, lubricant, binding agent, disintegrating agent etc.Because tablet and capsule are easy to administration, they are oral dosage unit dosage forms of tool advantage, in the case, obviously use the solid medicinal carrier.In case of necessity, tablet can coat sugar-coat or casing by standard technique.For parenterai administration, carrier generally includes sterilized water, although can comprise other composition, for example helps dissolving or antiseptical composition.Also injection suspension can be prepared, in the case, appropriate liquid carrier, suspensoid etc. can be used.Described Pharmaceutical composition generally is dosage unit form, for example tablet, capsule, powder, injection, electuary etc., and contained active component is 0.1 to about 800mg/Kg, preferred about 0.3 to 200mg/Kg.
Following embodiment more specifically sets forth the present invention, but and unrestricted the present invention.Embodiment 1: tramadol and APAP are in conjunction with the preparation of dosage
The bonded preparation of the tramadol/APAP of different proportion prepares by following method, the tramadol liquid storage (concentration is shown with the milligram numerical table that every 10ml distilled water contains medicine) that at first prepares a certain concentration, for example the 8mg tramadol is dissolved in the 10ml water as free alkali, obtain high dose tramadol liquid storage, then, described tramadol liquid storage is with enough distilled water dilutings, prepare every 10ml distilled water and contain solution than the low dosage tramadol, then every 10ml dilute solution is added among the APAP of suitable milligram number, make it to mix, to reach the require ratio of tramadol than APAP.With regard to 1: 50 example: 400mg APAP free alkali is suspended in 10ml and contains in the solution and 2 Tween 80s (by the medicinal dispersant of Fisher scientific company production) of 8mg tramadol, form 1: 50 ratio, combination (8mg: 400mg) in promptly every 10ml water.Prepare the medicament of each ratio respectively with similar approach, to of the amount injection of every mice with the 10ml/Kg body weight.Embodiment 2: tramadol-N-oxide and APAP are in conjunction with the preparation of dosage
At first prepare tramadol-N-oxide, as described below: as tramadol hydrochlorate (0.5 mole) to be changed into free alkali in alkalization water (PH＞9), extract with ether then.Evaporate ether, get the crystalloid hydrate of tramadol, this solid is used Steam Heating under condition of high vacuum degree, removes many moisture as far as possible, gets the 131.5g product, and this product is dissolved in the methanol (500ml), adds 65g 30%H
2O
2, stirred 3 hours, add 65g 30% H again
2O
2, this reactant liquor at room temperature stirred 2.5 days, added about 10mgPtO
2/ C catalyst bubbles very lenitively, and other adds 10mg PtO
2(Pt/C is used in suggestion, is easy to remove), reactant mixture stirs and spends the night, filter by filter aid then, vacuum concentrated filtrate,＜40 ℃ of temperature heating, residue is dissolved in dichloromethane, because dichloromethane solution contains some colloidal state platinum, so dilute this solution to 1L with ethyl acetate, filter by nylon leaching film (aperture is 0.45 μ), get achromaticity and clarification filtrate, this filtrate is concentrated into 600ml, add ethyl acetate then continuously, keep the 80ml volume, heat this solution simultaneously, reach 74 ℃ until vapor (steam) temperature, be cooled to room temperature then, solid collected by filtration is washed with ethyl acetate, vacuum drying gets 126.6g tramadol-N-oxide (mp.159.5-160 ℃).
C
16H
25NO
3
Theoretical value: C, 68.78; H, 9.27; N, 5.01
Measured value: C, 68.65; H, 9.22; N, 4.99
Tramadol-N-oxide/bonded preparation of APAP different proportion prepares by following method.First do not have preparation contains a certain concentration that the mg medicine represents with every 10ml distilled water tramadol-N-oxide liquid storage, for example 8mg tramadol-N-oxide free alkali is dissolved in the 10ml water, generate high dose tramadol liquid storage, then, described tramadol-N-oxide liquid storage is with enough distilled water dilutings, prepare tramadol-N-oxide solution that every 10ml distilled water contains low concentration, solution with every 10ml dilution is added among the suitable mgAPAP then, make it combination, to reach the require ratio of tramadol-N-oxide than APAP.With regard to 1: 50 example: the 400mgAPAP free alkali is suspended in 10ml and contains in the solution and 2 Tween 80s (by the medicinal dispersant of Fisher scientific company production) of 8mg tramadol-N-oxide, form 1: 50 ratio, combination (8mg: 400mg) in promptly every 10ml water.Prepare the medicament of each ratio respectively with similar approach, every mice is injected with 10ml/Kg body weight dosage.Embodiment 3:O-demethyltramadol (-) and (+) enantiomer: the anti-amido phenyl ring alcohol of their synthetic and O-demethyl combines preparation with APAP.
As described below, at first prepare the O-demethyltramadol: cooling down, diethylene glycol (125ml) is added in the hydrofining (9.5g), temperature maintenance to diethylene glycol (25ml) solution of this solution adding phenylmercaptan. (10ml), adds diethylene glycol (50ml) solution of (-) tramadol free alkali (9.3g) at＜50 ℃ then, the slow reflux of final reactant mixture 45 minutes, cooling then, is poured in the water.PH value transfers to about 3, and this mixture ether extraction is transferred about PH to 8 again, the gained mixture uses dichloromethane extraction more than 5 times, the extracting solution drying, the evaporation dichloromethane gets 4.6g oily title compound, should distill (Kugeizohr) and be dissolved in oxolane by oil, with ethanol/HCl solution-treated, get 2.3g salt, this salt recrystallization in ethanol/diethyl ether solution, drying, the salt (mp.242-3 ℃) [α] of 1.8g O-demethyltramadol (-) enantiomer
D 25=-32.9 (c=1, EtOH).
C
15H
23NO
2.HCl
Theoretical value: C, 63.04:H, 8.46:N, 4.90
Measured value: C, 63.00; H, 8.51; N, 4.94
In order to prepare (+) enantiomer of title compound, described reaction is carried out under the same conditions, and different is to use (+) tramadol free alkali to replace (-)-tramadol, gets (+) enantiomer of 2.8g O-demethyltramadol.
C
15H
23NO
2.HCl
Theoretical value: C, 63.04:H, 8.46:N, 4.90
Measured value: C, 63.14; H, 8.49:N, 4.86
O-demethyltramadol/bonded preparation of APAP different proportion prepares by following method: at first prepare with every 10ml distilled water and contain the certain density O-demethyltramadol liquid storage that the mg medicine is represented, for example 8mg O-demethyltramadol free alkali is dissolved in the 10ml water, generate high dose O-demethyltramadol liquid storage, then, described O-demethyltramadol liquid storage with enough distilled water dilutings, is prepared every 10ml distilled water and contains solution than the nor-tramadol of low dosage O-.Every 10ml dilute solution is added among the APAP of suitable mg number, makes it combination, to reach the require ratio of tramadol than APAP.With regard to 1: 50 example: 400mg APAP free alkali is suspended in 10ml O-demethyltramadol (8mg) solution and 2 Tween 80s (by the medicinal dispersant of Fisher scientific company), form 1: 50 ratio, combination (8mg: 400mg) in promptly every 10ml water.Prepare the medicament of each ratio respectively with similar approach, to of the amount injection of every mice with the 10ml/Kg body weight.
Embodiment 4: analgesic activities
Utilize CD1 male mice (body weight 18-24g) to measure the analgesic activities of the relevant present composition.Mice is all oral to be dissolved in the tramadol hydrochlorate (by alkali) in the distilled water fully and to be dissolved in distilled water fully or to contain acetyl amino phenyl (by alkali) in 2% (volume) Tween 80 distilled water of (containing 100% poly-Sorbitol oleate 80).This dose volume is 10ml/Kg.
Measure and relatively the method for the analgesic activities of variety classes analgesic be to prevent that the mouse web portion that acetylcholine brings out from shrinking [H.Collier et al., Br.J.Pharmaco1., 32.295 (1968)], this method and human effectiveness height correlation.
The intubate of feeding mice be equipped with the single tramadol hydrochlorate of various dosage, single acetyl amino phenyl, tramadol hydrochlorate and acetamido benzene in conjunction with preparation, or carrier, distilled water or contain the distilled water of 2% (volume) Tween 80 for example is to the induce reaction acetylcholine bromide of dosage of injection in the mouse peritoneum.This acetylcholine is dissolved in the distilled water fully, and concentration is 5.5mg/Kg, injects with the 0.20ml/20g ratio.For ease of estimating, " abdominal part contraction " is defined as and is attended by the abdominal muscle contraction that arch upward in the back and extremity stretch.After mice is accepted acetylcholine dosage, upright and begin, observe mice and whether had the abdominal part contractile response in 10 minutes, this time just in time is that mice is accepted orally give tramadol hydrochlorate, acetyl amino phenyl, tramadol and acetamido benzene in conjunction with after preparation or the excipient 30 minutes.Every mice is only used once.
Press R.J.Tallarida et al., Life Sci., the issuable superfacies additivity of compositions of 45,947 (1989) each fixed proportion of method determination and analysis of introducing.This method comprises measures the amount of the mixture that requires to produce given level effect [for example 50% (ED50mix)], is determined at desired corresponding amt under simple additivity (ED50 add) condition then.For a certain concrete fixed proportion, work as ED50
Mix＜ED50
AddThe time, then have the superfacies additivity.ED50
MixAnd ED50
AddAmount be stochastic variable; ED50
MixBe to calculate by given fixed proportion dose response curve; ED50
AddBe to get by the ED50 adduction of two kinds of medicines under the additivity condition, estimating.Then, pass through Student ' s t-check, with ED50
MixWith ED50
AddCompare.The ED50 value of independent tramadol hydrochlorate is 5.5 (4.8-6.4) mg/Kg, and the ED50 value of independent acetamido benzene is 164.3 (122.7-219.9) mg/Kg.
Under the exact dose ratio of tramadol hydrochlorate and acetyl amino phenyl, measure influencing each other between tramadol and the acetyl amino phenyl.With the experimental design of each discrete dosages form completely randomization that can make test, studied bonded multiple (general 4-6 kind) code dosage analgesic effect after 30 minutes of each selection.
What the mouse web portion that Table I data declaration tramadol hydrochlorate and acetyl amino phenyl bring out acetylcholine shrank influences each other, and be illustrated among Fig. 1 [referring to S.Loewe with the impartial excitement of Loewe, Pharm.Rev.9:237 (1957) is about making and the ultimate principle of impartial excited figure], as shown in Figure 1, the ED50 value oblique line that connects two kinds of given medicines is illustrated respectively in different component ratio following time, the simple addition of effect.Two dotted lines near this oblique line have been determined 95% confidence interval.Drop on the ED50 value representation superfacies additivity under the curve (between this ED50 line and initial point), in other words, represent beyond thought increase effect.The oblique dotted line that is stretched to each side by origin of coordinate represents that mice accepts medicine in conjunction with the used APAP of preparation and the dose ratio of tramadol.The line of ordering by each ED50 of tramadol and APAP compositions is represented 95% confidence interval of ED50 value.Test data as shown in Figure 1 shows that the ratio of tramadol and APAP is that the compositions of 1: 1 to 1: 1600 (by curve representation) provides beyond thought superfacies and adds effect, because ED50
MixLess than ED
Add
Table 1
Tramadol: APAPPharmaceutical composition dosage (mg/kg, p.o.) ((tramadol: APAP) tramadol of 95%CI ' s) of the ED50 during 30min
APAPThe analgesia tramadol
APAPList-tramadol 20 3/15
3 0 4/15
4 0 14/45
6 0 20/45 5.5
8 0 40/60 (4.8-6.4)
10 0 15/15
16 0 14/151000∶1 3.75 0.00375 1/13
7.5 0.0075 8/15 7.0 0.01
15 0.015 15/15 (5.7-8.4) (0.1-0.1)100∶1 1.875 0.01875 0/15
3.75 0.0375 4/15 6.9 0.1
7.5 0.075 5/15 (5.2-9.0) (0.1-0.1)
15 0.15 15/1520∶1 1.875 0.09375 0/15
3.75 0.1875 4/15 6.5 0.3
7.5 0.375 7/15 (5.1-8.3) (0.3-0.4)
15 0.75 15/153∶1 3.75 1.25 3/30
7.5 2.5 12/30 7.8 2.6
15 5 28/30 (6.6-9.1) (2.2-3.0)1∶1 0.94 0.94 3/15
1.875 1.875 8/30
3.75 3.75 14/30 3.8 3.8
5 5 12/28 (3.0-4.8) (3.0-4.8)
7.5 7.5 24/30
15 15 15/151∶3 3.75 11.25 7/30
5 15 7/15 4.7 14.2
7.5 22.5 29/30 (4.3-5.2) (12.8-15.7)1∶5 2.5 12.5 7/30
5 25 8/30 4.0 19.8
10 50 30/30 (3.3-4.7) are pharmaceutical composition dosage (mg/kg.p.o.) 30min (16.7-23.4), the time the ED50 ((tramadol: APAP) tramadol of 95%CI ' s)
APAPThe analgesia tramadol
APAP1: 5.7 0.47 2.66 0/15
0.94 5.313 4/15
1.88 10.625 1/15 4.1 23.3
3.75 21.25 5/15 (3.0-5.7) (16.8-32.3)
7.5 42.5 11/15
15 85 15/151∶19 0.94 17.813 4/30
1.88 36.625 10/28
3.75 71.25 21/30 2.5 47.3
5 95 22/30 (2.0-3.0) (38.9-57.5)
7.5 142.5 29/30
15 285 15/151∶50 0.25 12.5 3/30
0.5 25 7/30
1 50 9/30 1.2 61.4
2 100 19/30 (1.0-1.5) (49.0-77.1)
4 200 27/30
8 400 30/301∶100 0.25 25 3/60
0.5 50 12/60
1 100 19/60 1.1 111.3
2 200 51/60 (1.0-1.3) (96.4-128.6)
4 400 55/60
8 800 30/301∶200 0.125 25 1/60
0.25 50 9/60
0.5 100 27/60 0.6 129.7
1 200 44/60 (0.6-0.8) (110.4-152.4)
2 400 48/60
4 800 30/301∶400 0.0625 25 2/15
0.125 50 4/30
0.25 100 18/30 0.2 95.1
0.5 200 12/15 (0.2-0.3) (75.4-119.8)
1 400 28/30
2 800 15/15 pharmaceutical composition dosage (mg/kg, p.o.) ((tramadol: APAP) tramadol of 95%CI ' s) of the ED50 during 30min
APAPThe analgesia tramadol
APAP1: 800 0.03125 25 4/30
0.0625 50 9/30
0.125 100 15/30 0.1 77.4
0.25 200 27/30 (0.1-0.1) (62.9-95.2)
0.5 400 30/301∶1600 0.03125 50 2/30
0.0625 100 14/30
0.125 200 22/30 0.1 125.7
0.25 400 27/30 (0.1-0.1) (102.7-153.8)
0.5 800 30/30 list-APAP 0 30 2/15
0 40 12/43
0 50 1/15
0 60 8/30
0 80 23/60
0 100 13/30 --- 164.3
0 120 13/30 (122.7-219.9)
0 160 10/30
0 200 13/25
0 240 14/25
0 400 12/15
0 800 13/15
Claims (4)
1, a kind of pharmaceutical composition that comprises tramadol material and acetyl amino phenyl is used for the treatment of purposes in the medicine of mammal pain in production, and the weight ratio of wherein said tramadol material and acetyl amino phenyl is 1: 1 to 1: 1600.
2, according to the purposes of the pharmaceutical composition of claim 1, the conjugate of the proportioning of wherein said tramadol material and acetyl amino phenyl is synergic pharmaceutical composition.
3, according to the purposes of the pharmaceutical composition of claim 1, wherein said tramadol material is the tramadol hydrochlorate.
4, according to the purposes of the pharmaceutical composition of claim 3, wherein said tramadol hydrochlorate is racemic.
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Non-Patent Citations (3)
| Title |
|---|
| THE MERK INDEX,第9版 1976-01-01 Merck&Co.,Inc,Rahway,New Jersey * |
| THE MERK INDEX,第9版 1976-01-01 Merck&Co.,Inc,Rahway,New Jersey;医红导报，10(4) 1991-01-01 陈朝元 * |
| 医红导报，10(4) 1991-01-01 陈朝元 * |
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