Summary of the invention
The object of the invention provides 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 is formed by arginine Ibuprofen and codeine phosphate.
Concrete scheme of the present invention is:
A kind of pharmaceutical composition is made up of arginine Ibuprofen, codeine phosphate and pharmaceutically acceptable carrier.
Wherein the weight ratio of arginine Ibuprofen and codeine phosphate preferred 14~45: 1.
More preferably 25~32: 1.
More preferred weight ratio is 28~29: 1.
Highly preferred weight ratio is 28.5: 1.
Pharmaceutically acceptable carrier is meant one or more inert, avirulent solid or liquid filler material, auxiliary agents etc., and their not reverse and reactive compounds or patient have an effect.
The dosage form of the present composition can be commonly used through the intestinal dosage form on the pharmaceuticss such as tablet, capsule, pill, dispersible tablet, granule, powder.
Tablet for oral use and capsule contain traditional excipient such as diluent, lubricant, dispersant and binding agent.
The dosage of above activating agent will be different because of prescription.Through the quantitative analysis and the prescription optimization of arginine Ibuprofen and codeine phosphate analgesic activity, when arginine Ibuprofen is 60~347mg/kg, codeine phosphate is 2.1~12mg/kg, and analgesic activity shows as obvious synergistic; When arginine Ibuprofen is 85~170mg/kg, synergism was particularly evident when codeine phosphate was 3~6mg/kg.Learn in the test, arginine Ibuprofen and codeine phosphate weight ratio preferable range are 13.6~44.6: 1, the theoretical optimization prescription is arginine Ibuprofen 170mg/kg+ codeine phosphate 6mg/kg, weight ratio is 28.33: 1, according to this pharmacological tests, in the preparation oral formulations, the weight that preferably contains arginine Ibuprofen and codeine phosphate in the per unit preparation is 370mg: 8-27mg; 370mg: 8-15mg more preferably; The optimum weight proportioning is 370mg: 13mg.Described " per unit preparation " is meant: if tablet just refers to a tablet, the rest may be inferred.
Pharmaceutical composition of the present invention can be used for analgesia clinically, mainly is to be used for pain relieving of moderate cancer pain and postoperative pain.
In to compound preparation pharmacology test of the present invention, be surprised to find, arginine Ibuprofen and codeine phosphate compound preparation drug effect have concertedness, toxic and side effects has antagonism, clinical application has more safety, compare with ibuprofen and codeine (ibuprofen+codeine phosphate), onset is rapid, and analgesic effect is stronger, has reached unexpected effect.
Be part pharmacology test of the present invention and data below:
One, arginine Ibuprofen, codeine phosphate associating analgesic activity quantitative analysis and prescription optimization
1 purpose
Inquire into different proportion arginine Ibuprofen and codeine phosphate coupling,, and determine its optimization composition of prescription the inhibitory action of mice radiant heat stimulation pain model.
2 methods
2.1 experiment grouping and dosage setting
Mice fasting 8h is the mice group of 10 ± 2 seconds (s) with the basic threshold of pain of screening, is divided into 7 groups at random, 10 every group, and male and female half and half.Wherein 6 groups is the medication group of different proportionings, and 1 group is 0.9% normal saline matched group in addition.Each is organized medication (single gastric infusion) capacity and is the 0.2ml/10g body weight.According to preliminary experiment and with reference to external similar clinical drug prescription dosage, determine capacity and weak effect amount, i.e. the prescription dosage range of each component: arginine Ibuprofen 13-170mg/kg and codeine phosphate are 1.4-6mg/kg.Two medicines with 0.6,0.75 ratio, are arranged serial dosage respectively, and the dosage range that makes each medicine is between capacity and weak effect amount.By the design of weight method of completing the square, each dosage is evenly distributed to 6 compatibility groups (table 1).
The recipe design of table 1 arginine Ibuprofen and codeine phosphate (mg/kg)
The compatibility group | Arginine Ibuprofen (D1) | Codeine phosphate (D2) |
1 | 13(1) | 2.5(3) |
2 | 22(2) | 6.0(6) |
3 | 37(3) | 1.9(2) |
4 | 61(4) | 4.5(5) |
5 | 102(5) | 1.4(1) |
6 | 170(6) | 3.8(4) |
x | 67.5 | 3.35 |
D
max | 170 | 6 |
D
min | 13 | 1.4 |
In () is the serial number of dosage level; D
MaxBe the high limit of prescription dosage range, D
MinBe lower bound.
2.2 experimental technique
Keep 20 ℃ of room temperatures, mice is packed in the stationary magazine creel, outside afterbody was exposed to, following 1/3 place of afterbody was as the photostimulation point.Begin incubation period (TFL) to whipping reaction as the threshold of pain from irradiation.Before administration, measure 3 times earlier, each 5min at interval, getting its average is the basic threshold of pain.The different periods after the administration (10,20,30,40,60 and 120min) are measured the threshold of pain respectively.If the threshold of pain be elevated to 2 times of the basic threshold of pains not whipping promptly interrupt irradiation, in order to avoid scalded skin, and with the 2 times of calculating in the basic threshold of pain.
2.3 definitiveness test
Based on above experimental result, try to achieve the theoretical optimization prescription according to the weight method of completing the square, comprise coupling dosage, coupling ratio, test is confirmed again.20 of mices are divided into 2 groups at random by body weight, sex, 10 every group.One group is the theoretical optimization prescription, and another group is for the prescription of ceiling effect occurring.Experimental technique and observation index are the same, to determine optimum prescription.
2.4 date processing
Threshold of pain raising rate=((TFL-basis TFL after the administration)/basic TFL) * 100%
Data mean ± standard deviation (x ± s) expression, drug interaction analysis is finished by DAS (ver1.0) software; The group difference significance analysis is checked with t.
3 results
3.1 the different compatibility groups of arginine Ibuprofen and codeine phosphate are to the influence of the mice 30min threshold of pain
Each observes 120min after organizing the mice medication continuously, and the threshold of pain raising rate of each group is all greater than normal saline group (P<0.01).Maximum threshold of pain raising rate all appears in each compatibility group when 30min, maximum actual measurement effect group (Gmax) is a compatibility group 6, sees Table 2.Each compatibility group markization compatibility dosage (d) and effect thereof see Table 3.
Raising rate in the 30min threshold of pain after table 2 medication
The compatibility group | The dosage (mg/kg) of each component in the compatibility group | Threshold of pain raising rate (%) (x ± s) |
Codeine phosphate | Arginine Ibuprofen | |
1 | 2.5 | 13 | 37.08±13.36 |
2 | 6 | 22 | 64.02±16.36 |
3 | 1.9 | 37 | 40.89±15.90 |
4 | 4.5 | 61 | 72.25±16.78 |
5 | 1.4 | 102 | 50.41±15.24 |
6 | 3.8 | 170 | 74.33±22.56 |
The mark dosage (di) of table 3 arginine Ibuprofen and codeine phosphate and mutual (didj) thereof
Relation with coupling drug effect (threshold of pain raising rate %)
Group | d1 | d2 | d1d2 | Threshold of pain raising rate (x ± s) |
1 | 0.746 | 0.193 | 0.144 | 37.08±13.36 |
2 | 1.791 | 0.326 | 0.584 | 64.02±16.36 |
3 | 0.567 | 0.548 | 0.311 | 40.89±15.9 |
4 | 1.343 | 0.904 | 1.214 | 72.25±16.78 |
5 | 0.418 | 1.511 | 0.632 | 50.41±15.24 |
6 | 1.134 | 2.519 | 2.857 | 74.33±22.56 |
D is the mean of each compatibility dosage divided by its column dosage
3.2 arginine Ibuprofen and codeine phosphate coupling are to the inhibiting quantitative analysis of mice radiant heat stimulation pain model
Maximum threshold of pain raising rate all appears in each compatibility group when 30min, thus with the threshold of pain raising rate of 30min after the medication as analysis indexes, with the input of the data in the table 2 DAS software, analyze result's following (seeing accompanying drawing 1) with the weight method of completing the square:
A. two medicines are in uniting analgesia, its significance level codeine phosphate>arginine Ibuprofen.
B. two medicines coupling in the dosage range that table 1 sets, arginine Ibuprofen has synergism (P<0.05) to codeine phosphate.
C. the theoretical optimization prescription is: codeine phosphate 6mg/kg+ arginine Ibuprofen 170mg/kg, the coupling ratio is 1: 28.33.
3.3 definitiveness test
Experimental result sees Table 4.Theoretical optimization prescription and the prescription (G that ceiling effect occurs
Max) the 30min threshold of pain raising rate and the no difference of science of statistics of (in the table 2 the 6th group), but 60, the threshold of pain raising rate of 120min theoretical optimization group is all greater than G
MaxGroup (P<0.05).
Table 4 definitiveness two kinds of unitized doses of test (mg/kg) are to mice radiant heat stimulation pain model inhibitory action
Group | n | Codeine phosphate | Ibuprofen arginine | Threshold of pain raising rate (%) |
30min | 60min | 120min |
G
max | 10 | 3.8 | 170 | 70.58±23.02 | 42.48±15.59 | 21.46±14.43 |
The theoretical optimization group | 10 | 6 | 170 | 75.66±19.26 | 59.90±18.28 | 33.92±10.75 |
4 conclusions
Arginine Ibuprofen and codeine phosphate use in conjunction are according to the analgesic activity that the mice radiant heat is stimulated, its significance level codeine phosphate>arginine Ibuprofen.Arginine Ibuprofen has synergism to codeine phosphate.Optimum prescription is: arginine Ibuprofen 170mg/kg+ codeine phosphate 6mg/kg, the coupling ratio is 28.33: 1.
Two, the analgesic activity of arginine Ibuprofen, codeine phosphate coupling and independent medication respectively and interaction dosage range is quantitative
Analyze
1 purpose
Relatively arginine Ibuprofen, codeine phosphate coupling and the inhibitory action of the independent medication of difference to mice radiant heat stimulation pain model.Carry out quantitative analysis with reflection method, determine effective therapeutic dose scope.
2 methods
2.1 experiment grouping and dosage setting
Mice fasting 8h is 10 ± 2 seconds a mice group with the basic threshold of pain of screening, is divided into 21 groups at random, and 10 every group, male and female half and half are arranged serial dosage with 0.7 ratio, and the dosage setting sees Table 5.
Table 5 arginine Ibuprofen, codeine phosphate coupling and singly use test dose setting (mg/kg) to the mice analgesic activity
Arginine Ibuprofen group mg/kg | Codeine phosphate group mg/kg | Arginine Ibuprofen+codeine phosphate (28.33: 1) group |
Arginine Ibuprofen (mg/kg) | Codeine phosphate (mg/kg) |
41 | 1.4 | 41 | 1.4 |
58 | 2.1 | 58 | 2.1 |
83 | 2.9 | 83 | 2.9 |
119 | 4.2 | 119 | 4.2 |
170 | 6.0 | 170 | 6.0 |
243 | 8.6 | 243 | 8.6 |
347 | 12.2 | 347 | 12.2 |
2.2 test method
Optimize item test method down with quantitative analysis and prescription.
2.3 date processing
Threshold of pain raising rate=((TFL-basis TFL after the administration)/basic TFL) * 100%
(x ± s) expression, drug interaction analysis carries out statistical disposition by DAS software by reflection method to data with mean ± standard deviation.
3 results
Each is organized and observes 120min after the mice medication continuously, and maximum threshold of pain raising rate all appears in each group when 30min, thus with the threshold of pain raising rate of 30min after the medication as analysis indexes.Each is organized dosage and effect thereof and sees Table 6, two drug interactions and carry out quantitative analysis by reflection method, the results are shown in Figure 2.
4 conclusions
Arginine Ibuprofen and codeine phosphate coupling show as concertedness to the analgesic activity of mice radiant heat stimulation pain model.At arginine Ibuprofen 85-170mg/kg and codeine phosphate 3-6mg/kg, synergism is (Q>2) particularly significantly.
Table 6 arginine Ibuprofen and codeine phosphate list with and coupling to the analgesic activity of mice (x, n=10)
The arginine Ibuprofen group | The codeine phosphate group | Arginine Ibuprofen+codeine phosphate group |
mg/kg | Threshold of pain raising rate (%) | mg/kg | Threshold of pain raising rate (%) | Arginine Ibuprofen mg/kg | Codeine phosphate mg/kg | Threshold of pain raising rate (%) |
43 | 17.02 | 1.5 | 0.03 | 43 | 1.5 | 18.9 |
60 | 20.64 | 2.1 | 3.52 | 60 | 2.1 | 28.24 |
85 | 30.35 | 3.0 | 1.31 | 85 | 3.0 | 35.84 |
120 | 36.41 | 4.2 | 0.26 | 120 | 4.2 | 49.6 |
170 | 53.17 | 6.0 | 1.34 | 170 | 6.0 | 74.73 |
243 | 48.21 | 8.6 | 2.55 | 243 | 8.6 | 71.92 |
347 | 43.4 | 12.0 | 14.32 | 347 | 12.0 | 56.21 |
Three, arginine Ibuprofen, codeine phosphate coupling are to the quantitative analysis of chmice acute toxic action
1 purpose
Observe arginine Ibuprofen, the codeine phosphate coupling changes (strengthen, weaken or do not become) to chmice acute toxicity, many acute toxicities angle is determined the reasonability of prescription.
2 experimental techniques
Mice fasting 8h gets 150, and male and female half and half are divided into 15 groups at random, 10 every group.According to the preliminary experiment result, press LD
50Assay method is provided with the serial dosage (seeing Table 7) of two prescriptions usefulness and coupling.The administration volume is the 0.2ml/10g body weight.Observe after the disposable mouse stomach administration each dosage treated animal death condition in 7 days.
The anxious malicious test dose setting of the mice of table 7 arginine Ibuprofen and codeine phosphate list usefulness and coupling
The dosage group | Arginine Ibuprofen group (mg/kg) | Codeine phosphate group (mg/kg) | Arginine Ibuprofen+codeine phosphate group |
Arginine Ibuprofen (mg/kg) | Codeine phosphate (mg/kg) |
1 | 2343 | 625 | 2667 | 94 |
2 | 1875 | 500 | 2000 | 71 |
3 | 1500 | 400 | 1500 | 53 |
4 | 1200 | 320 | 1125 | 40 |
5 | 960 | 256 | 844 | 30 |
2 date processing
Gained data input DAS software carries out statistical disposition by parametric method.
3 results
Arginine Ibuprofen and codeine phosphate two components are single with seeing Table 8~10 with coupling animal dead rate.The analysis showed that through parametric method: arginine Ibuprofen and codeine phosphate were in ratio coupling in 28.33: 1, in the dosage range of being analyzed, through the interaction dynamics analysis of two medicine coupling acute toxicities, Q-value is the 0.48--2.68 scope, (Q<-1 is an antagonism, and promptly toxicity reduces; Q>1 is a synergism, and promptly toxicity strengthens;-1≤Q≤1 is an additivity, and promptly toxicity does not increase), the acute toxicity of two medicine couplings is antagonism or additivity, i.e. acute toxicity effect descends or does not increase (seeing Table 11).
The table 8 codeine phosphate list animal dead rate of (ig)
Group | Codeine phosphate (mg/kg) | Log10 dose (lgd) | Mortality rate (p) | P
2 | Probit |
1 | 625 | 2.7959 | 1.0 | 1.00 | 6.96 |
2 | 500 | 2.6990 | 0.8 | 0.64 | 5.84 |
3 | 400 | 2.6021 | 0.5 | 0.25 | 5.00 |
4 | 320 | 2.5051 | 0.3 | 0.09 | 4.48 |
5 | 256 | 2.4082 | 0.0 | 0.00 | 3.04 |
The table 9 arginine Ibuprofen list animal dead rate of (ig)
Group | Arginine Ibuprofen (mg/kg) | Log10 dose (lgd) | Mortality rate (p) | P
2 | Probit |
1 | 2343 | 3.3698 | 1 | 1 | 6.96 |
2 | 1875 | 3.2730 | 0.8 | 0.64 | 5.84 |
3 | 1500 | 3.1761 | 0.3 | 0.09 | 4.48 |
4 | 1200 | 3.0792 | 0.2 | 0.04 | 4.16 |
5 | 960 | 2.9823 | 0 | 0 | 3.04 |
Table 10 arginine Ibuprofen and codeine phosphate coupling (28.33: 1, animal dead rate ig)
Group | Arginine Ibuprofen+codeine phosphate group | The logarithm value of two pharmaceutical quantities sums | Mortality rate (p) | P
2 | Probit |
Arginine Ibuprofen (mg/kg) | Codeine phosphate (mg/kg) |
1 | 2667 | 94 | 3.44 | 0.9 | 0.81 | 6.28 |
2 | 2000 | 71 | 3.32 | 0.5 | 0.25 | 5.00 |
3 | 1500 | 53 | 3.19 | 0.3 | 0.09 | 4.48 |
4 | 1125 | 40 | 3.07 | 0.2 | 0.04 | 4.16 |
5 | 844 | 30 | 2.94 | 0.1 | 0.01 | 3.72 |
Table 11 arginine Ibuprofen and codeine phosphate coupling (mg/kg, the quantitative analysis of anxious toxic action ig)
Arginine Ibuprofen | Codeine phosphate | The actual measurement mortality rate | Corrected mortality | The expectation mortality rate | Q-value | The coupling result |
844 | 30 | 0.100 | 0.055 | 0.006 | 0.48 | + |
1125 | 40 | 0.200 | 0.143 | 0.056 | 0.86 | + |
1500 | 53 | 0.300 | 0.325 | 0.367 | -0.43 | + |
2000 | 71 | 0.500 | 0.582 | 0.849 | -2.68 | - |
2667 | 94 | 0.900 | 0.801 | 0.982 | -1.82 | - |
-expression Q-value<-1 belongs to antagonism interaction (toxicity reduction), and+expression Q refers between 1 and-1, symbolic animal of the birth year additivity interaction (toxicity does not increase).
4 conclusions
The mice LD of arginine Ibuprofen list time spent
50Be 1560.5mg/kg (ig) the mice LD of codeine phosphate list time spent
50Be 391.1mg/kg (ig).Arginine Ibuprofen and codeine phosphate are in the mice LD of ratio coupling in 28.33: 1
50Be 1824.0mg/kg (ig).Analysis-by-synthesis is at LD
50On the point, two medicine couplings present antagonism.By Different L D
kContrast, press the Q-value method and calculate, in the scope (in 28.33: 1 ratios) of arginine Ibuprofen 844-2667mg/kg+ codeine phosphate 30-94mg/kg, antagonism and additivity appear in the acute toxicity of two medicine couplings, i.e. acute toxicity effect decline or do not increase.Four, the pharmacodynamics test of arginine Ibuprofen, codeine phosphate coupling analgesic activity
1 purpose
The arginine Ibuprofen, codeine phosphate of the various dose inhibitory action to mice radiant heat stimulation pain model is inquired in this test, and carry out drug effect with ibuprofen and codeine and tramadol hydrochloride and compare, ibuprofen and codeine is ibuprofen and codeine phosphate compound preparation, the domestic listing kind that different proportionings are arranged, get the ibuprofen and codeine of suitable dosage ratio, carry out drug effect relatively with this compound preparation.
2 methods
2.1 grouping and dosage setting
Mice fasting 8h is 10 ± 2 seconds animal grouping with the basic threshold of pain of screening, is divided into 7 groups at random, 10 every group, and male and female half and half.Result of the test according to above weight method of completing the square and reflection method, getting arginine Ibuprofen 240mg/kg+ codeine phosphate 8.5mg/kg is high dose, in, low dose group successively decreases in 0.5 ratio, as positive control, each is organized drug dose and is provided with as follows with ibuprofen and codeine and tramadol hydrochloride:
1 blank group: 25-37 ℃ normal saline
2 tramadol groups: tramadol hydrochloride, 15mg/kg (according to the conversion of human dosage) ig.
3 ibuprofen and codeine groups: ibuprofen and codeine 69.2mg/kg (ibuprofen 65mg/kg+ codeine phosphate 4.2mg/kg), ig.
4 low dose group: arginine Ibuprofen 60mg/kg+ codeine phosphate 2.1mg/kg, ig.
Dosage group in 5: arginine Ibuprofen 120mg/kg+ codeine phosphate 4.2mg/kg, ig.
6 high dose group: arginine Ibuprofen 240mg/kg+ codeine phosphate 8.5mg/kg, ig.
Each is organized medication (single gastric infusion) capacity and is the 0.2ml/10g body weight.
2.2 experimental technique
Optimize item test method down with quantitative analysis and prescription.After administration 10,20,30,60,120,180 and 240min measure the threshold of pain respectively.
3 date processing
Threshold of pain raising rate=((TFL-basis TFL after the administration)/basic TFL) * 100%
Area (AUC) calculates with trapezoidal method under threshold of pain raising rate-time graph.Data mean ± standard deviation (x ± s) expression, pharmacodynamic analysis is finished by DAS software; The group difference significance analysis is checked with t; ED
50Use the NDST computed in software.
4 results
Arginine Ibuprofen and codeine phosphate coupling stimulate the time-histories variation of model analgesic activity to see Fig. 3,4 to the mice radiant heat.Result of the test shows: (1) arginine Ibuprofen+codeine phosphate gastric infusion, high, middle dosage group 10min after administration begins, threshold of pain raising rate obviously increases (P<0.05, P<0.01vs blank group), low dose group 30min after administration begins, and threshold of pain raising rate obviously increases (P<0.05vs blank group); Tramadol group and ibuprofen and codeine group respectively after administration 20min and 60min begin to occur tangible threshold of pain raising rate and increase (P<0.05, P<0.01vs blank group).(2) threshold of pain raising rate (%) of 30min arginine Ibuprofen+codeine phosphate group reaches maximum after the administration, and the increase degree is dose-dependence, wherein high dose group is 68.20 ± 17.51 (P<0.01vs blank group), tramadol group and ibuprofen and codeine group all threshold of pain raising rate maximum occurs at 60min, are respectively 38.12 ± 17.05 and 24.26 ± 15.42 (P<0.01vs blank group).(3) arginine Ibuprofen+codeine phosphate height, middle dosage group still can obviously improve threshold of pain raising rate (P<0.01, P<0.05vs blank group) at administration 180min; Tramadol group and ibuprofen and codeine group in 180min threshold of pain raising rate also apparently higher than blank group (P<0.05).
As seen from Table 12, area (AUC) is all significantly greater than blank group (P<0.01) under the threshold of pain raising rate-time graph of tramadol group, ibuprofen and codeine group and height, middle dosage arginine Ibuprofen+codeine phosphate group, high dose group is higher than tramadol hydrochloride group and ibuprofen and codeine group (difference P<0.05, P<0.01), middle dosage group and two positive control drug zero differences.Maximum threshold of pain raising rate (E
Max) relatively go up, high, middle dosage arginine Ibuprofen+codeine phosphate group and two positive control drugs all are significantly higher than blank group (P<0.01), the effect of high dose group is better than two positive control drug groups (P<0.01), and the effect of middle dosage group is better than ibuprofen and codeine group (P<0.05).
Fragrant arginine+the codeine phosphate in table 12 Lip river (ig) is to mice thermal radiation model threshold of pain raising rate-time graph
Following area (AUC) and maximum threshold of pain raising rate (E
Max) influence (n=10, x ± s)
Group | Dose(mg/kg) | AUC(%·min) | E
max(%)
|
①Normal | NS | 228.34±1130.64 | 18.03±10.15 |
②Tramadol | Tramadol 15 | 4365.56±1709.5
c | 42.45±16.57
c |
③Ibu+Cod | Ibu 65+Cod 4.3 | 3120.35±1866.39
c | 32.85±12.96
b |
④Is+Cod | Is 60+Cod 2.1 | 1265.35±1159.03
fk | 23.63±14.44
e |
⑤Is+Cod | Is 120+Cod 4.3 | 3736.18±1726.41
c | 49.06±15.35
ck |
(⑥)Is+Cod | Is 240+Cod 8.5 | 6805.36±2347.06
cel | 68.20±17.51
cfl |
Annotate:
bP<0.05,
cP<0.01vs Group 1.;
eP<0.05,
fP<0.01vs Group 2.;
kP<0.05;
lP<0.01vs Group is 3..
5 conclusions
Experimental result shows, arginine Ibuprofen+codeine phosphate group stimulates model to have significant analgesia role to the mice radiant heat, in 10~180min, obviously increase threshold of pain raising rate, area (AUC) under maximum threshold of pain raising rate and the threshold of pain raising rate-time graph, and analgesic activity is dose dependent.Arginine Ibuprofen+codeine phosphate group can produce significant analgesia role behind administration 10min, and about 30min, produce maximum analgesic activity, all (be respectively 20min early than the tramadol hydrochloride group, 60min) (be respectively 60min with the ibuprofen and codeine group, 60min), in arginine Ibuprofen+codeine phosphate the dosage group 20 and during 30min threshold of pain raising rate apparently higher than two positive control drugs (P<0.01).Test the onset time of the analgesic activity that shows arginine Ibuprofen+codeine phosphate and reach the peak all faster than two positive control drugs.Maximum threshold of pain raising rate (E
Max) relatively go up, middle dosage group is higher than the ibuprofen and codeine group, high dose group is higher than tramadol hydrochloride group and ibuprofen and codeine group.The AUC value compares, and high dose group is higher than tramadol hydrochloride group and ibuprofen and codeine group, middle dosage group and two positive control drug zero differences.Holding time of the analgesic activity of arginine Ibuprofen+codeine phosphate group is similar to two positive drug, is 180min.Test prompting compound preparation analgesic activity is better than ibuprofen and codeine.
The specific embodiment
Embodiment 1
Prescription:
Arginine Ibuprofen 370 grams
Codeine phosphate 13 grams
Starch 69 grams
Lactose 20 grams
Cross-linking sodium carboxymethyl cellulose 15 grams
Magnesium stearate 2.5 grams
7%PVP solution 10.5 grams
1000 of fills
Preparation technology:
Medicine and adjuvant are crossed 80 mesh sieves respectively, arginine Ibuprofen is fully mixed with 49 gram starch and 13 gram cross-linking sodium carboxymethyl celluloses, 7%PVP solution system soft material, 18 mesh sieves are granulated, and 60 ℃ of dryings down get granule 1.Codeine phosphate and 20 gram lactose, 20 gram starch and 2 gram cross-linking sodium carboxymethyl celluloses are fully mixed, and 7%PVP solution system soft material, 18 mesh sieves are granulated, and 60 ℃ dry down, gets granule 2.Increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate add magnesium stearate, mixing, encapsulating capsule, the heavy 500mg of capsule.
Embodiment 2
Prescription:
Arginine Ibuprofen 370 grams
Codeine phosphate 13 grams
Microcrystalline Cellulose 52 grams
Pregelatinized Starch 42 grams
Cross-linking sodium carboxymethyl cellulose 15 grams
Magnesium stearate 2.5 grams
10% starch slurry, 5.5 grams
Suppress 1000
Preparation technology:
Medicine and adjuvant are crossed 80 mesh sieves respectively, arginine Ibuprofen is fully mixed with 34 gram microcrystalline Cellulose, 30 gram pregelatinized Starch and 13 gram cross-linking sodium carboxymethyl celluloses, 10% starch slurry system soft material, 18 mesh sieves are granulated, and 60 ℃ of dryings down get granule 1.Codeine phosphate and 18 gram microcrystalline Cellulose, 12 gram pregelatinized Starch and 2 gram cross-linking sodium carboxymethyl celluloses are fully mixed, and 10% starch slurry system soft material, 18 mesh sieves are granulated, and 60 ℃ dry down, gets granule 2.Increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate add magnesium stearate, mixing, tabletting, the heavy 500mg of sheet.
Embodiment 3
Prescription:
Arginine Ibuprofen 370 grams
Codeine phosphate 8 grams
Microcrystalline Cellulose 71 grams
Lactose 23 grams
Polyvinylpolypyrrolidone 15 grams
Magnesium stearate 2.5 grams
7%PVP solution 10.5 grams
1000 of fills
Preparation technology:
Medicine and adjuvant are crossed 80 mesh sieves respectively, arginine Ibuprofen is fully mixed with 56 gram microcrystalline Cellulose and 13 gram polyvinylpolypyrrolidone, 7%PVP solution system soft material, 18 mesh sieves are granulated, and 60 ℃ of dryings down get granule 1.Codeine phosphate and 23 gram lactose, 15 gram microcrystalline Cellulose and 2 gram polyvinylpolypyrrolidone are fully mixed, and 7%PVP solution system soft material, 18 mesh sieves are granulated, and 60 ℃ dry down, gets granule 2.Increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate add magnesium stearate, mixing, encapsulating capsule, the heavy 500mg of capsule.
Embodiment 4
Arginine Ibuprofen 370 grams
Codeine phosphate 15 grams
Microcrystalline Cellulose 72 grams
Starch 15 grams
Carboxymethyl starch sodium 20 grams
Magnesium stearate 2.5 grams
10% starch slurry, 5.5 grams
Suppress 1000
Preparation technology:
Medicine and adjuvant are crossed 80 mesh sieves respectively, arginine Ibuprofen is fully mixed with 60 gram microcrystalline Cellulose and 18 gram carboxymethyl starch sodium, 10% starch slurry system soft material, 18 mesh sieves are granulated, and 60 ℃ of dryings down get granule 1.Codeine phosphate and 12 gram microcrystalline Cellulose, 15 gram starch and 2 gram carboxymethyl starch sodium are fully mixed, and 10% starch slurry system soft material, 18 mesh sieves are granulated, and 60 ℃ dry down, gets granule 2.Increase progressively principle by equivalent, granule 1 and granule 2 are fully mixed, 16 mesh sieve granulate add magnesium stearate, mixing, tabletting, the heavy 500mg of sheet.