CN1483407A - Medicinal composition containing rotundine for anayesia and giving up drug-taking - Google Patents
Medicinal composition containing rotundine for anayesia and giving up drug-taking Download PDFInfo
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Abstract
The present invention discloses a medicine composition for stopping pain and/or stopping drugs, it contains opium receptor complete excitant or opium receptor complete excitant with analgetic effective dose and rotundine with analgetic effective dose. Said medicine composition has strong analgetic effect and its addiction side effect is less.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains rotundine of easing pain and quitting drug abuse of being used to.
Background technology
Rotundine (rotundine) is the levo form of the tetrahydropalmatine that extracts from stephania plant, claims that again (L-tetrahydropalmatine L-THP), is famous Chinese medicine analgesic for rotundine or left-handed tetrahydropalmatine.Its oral absorption is good, analgesic activity many a little less than than opioid drug, but strong than antipyretic analgesic.100～200mg is oral, onset in 10～30 minutes, and effective time 2～5 hours is used for chronic persistence dull pain more.Jin nation chapter professor after years of research and found that rotundine is a selective d A
2Receptor antagonist, it not only can level suppress pain sensation conduction on spinal cord and spinal cord, promote the maincenter endogenous opiatepeptide to discharge, and plays analgesic activity, can also effectively suppress requirement and the psychic dependence of addiction animal to opioid drug, reduces withdrawal symptom.
Oxycodone (Oxycodone) is the opiate receptor full agonist, be this century the '20s come out in Europe, use more than 70 year in states such as America and Europes so far.Oxycodone hydrochloride and preparation thereof are all recorded in American Pharmacopeia USP X X III.Oxycodone is to be the semisynthetic opiates alkaloid of raw material with the thebaine, often makes tablet with hydrochlorate or terephthalate.Oxycodone is mainly used in the control clinically to severe pain.Oral, intramuscular injection, subcutaneous injection, intravenous injection and rectally are all effective.Oxycodone is oral can to reach injecting pathway drug effect over half, and effect continues 4～6 hours.Oral 5mg can be alleviated moderate pain, and 10～30mg can control the severe pain that postoperative, wound and cancer cause.During intramuscular injection, oxycodone 15mg is equivalent to morphine 10mg.Effect in 0.5～1.0 hour peaks behind the rectally, keeps 8～12 hours; And got final product onset in intravenous injection 5-8 minute, act on sustainable about 4 hours.Serious postoperative or wound pain, oxycodone is iv, im, sc or intravenous drip repeatedly.Oxycodone can be as the succedaneum of morphine control cancerous pain.Oxycodone oral administration biaavailability height is particularly suited for oral administration in order to the control cancerous pain.The untoward reaction of oxycodone is identical with morphine, except that dizzy, dizzy, calm, nausea and vomiting etc., and also easily tolerance and addiction.
The U.S. etc. have successfully developed the compound preparation of nonsteroidal antipyretic analgesic such as oxycodone and acetaminophen, aspirin, ibuprofen, and wherein oxycodone records in American Pharmacopeia with acetaminophen, aspirin compound preparation respectively.But the compound recipe of not seeing oxycodone and Hyndarin is used to the report that eases pain and/or quit drug abuse.
Summary of the invention
For providing a kind of addiction and dependency little potent analgesia compound recipe, the present inventor is through concentrating on studies discovery, and the experiment proved that, analgesic such as the Hyndarin of medicine effective quantity and oxycodone are formed compound recipe by a certain percentage, synergism is arranged on analgesic activity, can reduce untoward reaction such as addiction simultaneously.For example, two medicines are all used the minimum effective dose compatibility, no matter are that analgesia effect or untoward reaction all are better than patent formulation, are particularly reducing aspect the addiction significantly better than patent formulation.
Oxycodone and rotundine are united use, and the ratio of the two is an oxycodone: rotundine 1: 2 to 1: 100 (weight with parent compound oxycodone or rotundine represents that this method for expressing is suitable in full).But a little less than the too little analgesic activity of oxycodone dosage, the excessive sedation of Hyndarin dosage is strong, and it is strong to make compound recipe reach analgesic activity, and dependency and other side effect are little.In order to select the optimal dose compatibility, the present inventor is 1 with oxycodone dosage, with Hyndarin 3,5,10,15,20 multiple dose compatibilities, is determined at the amount effect curve on the mice hot plate method, comparison curves slope and ED
50Value.The result shows, the slope of curve basically identical of each ratio prescription, ED
50Value reduces with oxycodone dosage and increases.But two medicines are at the ED of 1: 5,1: 10,1: 15 and 1: 20 compatibility
50The content of oxycodone is all very approaching in the value, ED
90The dosage difference of oxycodone is bigger in the value, and the content of 1: 5 and 1: 10 group of oxycodone is all about 5mg/kg, and 1: 15 and 1: 20 group are close, all 2.8mg/kg (see Table 1 and table 2).For avoiding the excessive sedation that causes of Hyndarin dosage, oxycodone and Hyndarin serve as preferred with 1: 5～1: 10 ratio compatibility.
The ED of table 1. oxycodone and Hyndarin different proportion compatibility
50Value
Absolute content (mg/kg) oxycodone: Hyndarin ED
50(mg/kg)
The oxycodone Hyndarin
1∶3?????????10.3±3.8??????????2.47????????????8.13
1∶5?????????10.6±2.9??????????1.72????????????8.58
1∶10????????18.0±6.3??????????1.64????????????16.40
1∶15????????23.0±6.4??????????1.44????????????21.56
1∶20????????28.6±6.2??????????1.36????????????27.20
The mice hot plate method, 55 ℃
The maximum effective dose of table 2. oxycodone and Hyndarin different proportion compatibility relatively
Absolute content (mg/kg) oxycodone: Hyndarin ED
90(mg/kg)
The oxycodone Hyndarin
1∶3????????43.3±13.2????????10.8????????????32.5
1∶5????????30.0±14.9????????5.0?????????????25.0
1∶10???????52.8±16.3????????4.8?????????????48.0
1∶15???????44.5±15.7????????2.8?????????????41.7
1∶20???????58.0±16.6????????2.8?????????????55.2
The mice hot plate method, 55 ℃
Studies show that oxycodone hydrochloride 5mg reaches ideal analgesic effect with the dosage range of rotundine 50mg to 100mg is internal energy, untoward reaction is reduced to minimum level.
Two medicines are all with analgesia maximum effective dose (oxycodone 43mg/kg, Hyndarin 48mg/kg) oral back different time, on hot plate method, measure the threshold of pain, the result shows the peak time basically identical (0.5～1h) of two medicines, but the effective time of rotundine is slightly longer than oxycodone, may be excessive relevant with dosage.Preliminary conclusion, the pharmacodynamics process of two medicines meets the prescription requirement.
Analgesic oxycodone in the analgesia compound recipe of the present invention can be examined opiate receptor partial agonists such as opiate receptor full agonist such as ketone, morphine or dihydro Chinese mugwort holder coffee and buprenorphine with hydrogen and replace, and obtains essentially identical effect.
Pharmaceutical composition of the present invention can be made into peroral dosage forms such as tablet, Film coated tablets, capsule, granule, powder, pill, dry suspension, oral cavity disintegration tablet, dispersible tablet.
Pharmaceutical composition of the present invention also comprises one or more conventional formulation adjuvant such as microcrystalline Cellulose, lactose, starch, dextrin, PVPP, carboxymethyl starch sodium, PVP, HPMC, sucrose, hydroxypropyl cellulose, ethyl cellulose, stearic acid, magnesium stearate, Pulvis Talci, silicon dioxide etc. except that comprising two active component of oxycodone and rotundine.
Pharmaceutical composition of the present invention can prepare by the preparation process of routine, and for example the tablet among the present invention mixes each composition earlier, wet granulation, and drying, granulate carries out tabletting and/or coating again, or uses the direct powder compression tabletting; And for example, the granule among the present invention mixes each composition, wet granulation, drying, granulate, packing earlier.
Oral formulations of the present invention can be used for treating chronic cancer patient pain, acute postoperative pain, the pain of chronic rheumatic disease, sudden neuralgia, other chronic non-cancer patient pain.
Addiction is that the activity by the maincenter reward system produces, and central DA nervous system and endogenous opiate system are two important component parts in the award mechanism in the brain.All natural award sexual stimuluses all are the changes of function by the maincenter reward system, cause finally that volt diaphragm nuclear (NAc) district DA burst size increases and the effect that produces.Oxycodone can exciting opium mu-receptor, DA is discharged increase and produces drug dependence reactions such as sense of euphoria, drug-seeking behavior, drug craving.Hyndarin can discharge the drug dependence that resists due to the oxycodone by suppressing DA.In addition, Hyndarin and oxycodone 5 usefulness can reduce its consumption, thereby have also reduced drug dependence potential.So this compound recipe probably becomes the potent analgesia compound recipe of no addiction.
Clinical analgesia effect prediction
Oxycodone and Hyndarin are clinical application, for understand the oxycodone compound recipe clinically analgesia effect and with animal test results whether significant difference is arranged, carried out a small amount of clinical case checking.Case is selected having an intense pain in the operation 24 hours, the angor due to cancer pain and the calculus.The medication single oral.The results are shown in Table 3.The angor that the oxycodone compound recipe is outer to orthopaedics, breast, abdominal postoperative pain and bile duct and renal calculus cause has stronger analgesic effect, effective percentage 100%, and effective time 4～7 hours also has better curative effect to cancer pain.
Table 3, oxycodone compound recipe are to the analgesic activity of the different operation wounds classification case load pain score (analgesia time of X ± SD) of relatively performing the operation
After the preceding administration of administration (hour)
Fracture 10 6.7 ± 1.0 1.2 ± 1.1 4.5 ± 2.2
Breast outer 6 6.3 ± 1.2 0.3 ± 0.7 5.1 ± 3.4
Abdomen outer 3 6.7 ± 1.7 0.0 ± 0.0 7.3 ± 3.1
Gynecological 6 7.0 ± 1.7 0.6 ± 1.2 8.2 ± 3.6
Calculus 5 9.4 ± 0.5 0.8 ± 0.7 7.0 ± 2.1
Cancer 5 6.0 ± 1.1 1.2 ± 1.1 6.2 ± 2.6
The specific embodiment
Describe the present invention in detail with embodiment below.
Embodiment 1. oxycodones/Rotundine Tablets---wet granule compression tablet
Oxycodone hydrochloride 5.046g
Rotundine 50.136g
Lactose 50.140g
Carboxymethyl starch sodium 2.100g
10%PVP K
30Alcoholic solution is an amount of
Magnesium stearate 1.010g
Make 1000
Preparation technology: all components is crossed 80 mesh sieves, and recipe quantity oxycodone hydrochloride, rotundine, lactose with suitable method mixing, are added 10%PVP K
30Alcoholic solution is an amount of, the system soft material, granulate with 18 mesh sieves, drying is 30 minutes in 50 ℃ of drying baker, with 16 mesh sieve granulate, add the carboxymethyl starch sodium and the magnesium stearate of recipe quantity, with suitable method mixing, with tablet machine above mixture is pressed into the tablet of suitable weight, every index should meet the requirement of Chinese Pharmacopoeia about tablet.
Embodiment 2, oxycodone/Rotundine Tablets---wet granule compression tablet
Oxycodone hydrochloride 5.027g
Rotundine 30.254g
Microcrystalline Cellulose 100.180g
Pregelatinized Starch 70.100g
20%PVP K
30Aqueous solution is an amount of
Magnesium stearate 2.010g
Make 1000
Preparation technology: all components is crossed 80 mesh sieves, and recipe quantity oxycodone hydrochloride, rotundine, microcrystalline Cellulose, pregelatinized Starch with suitable method mixing, are added 20%PVP K
30Aqueous solution is an amount of, and the system soft material is granulated with 18 mesh sieves, drying is 50 minutes in 50 ℃ of drying baker, with 16 mesh sieve granulate, adds magnesium stearate, with suitable method mixing, with tablet machine above mixture is pressed into the tablet of suitable weight, every index should meet the requirement of Chinese Pharmacopoeia about tablet.
Embodiment 3, oxycodone/Rotundine Tablets---direct compression process tabletting
Oxycodone hydrochloride 5.101g
Rotundine 40.354g
Microcrystalline Cellulose 100.180g
Magnesium stearate 3.043g
Micropowder silica gel 1.025g
Make 1000
Preparation technology: with each component mix homogeneously of recipe quantity, with the punch die tabletting of φ 8mm.Every index should meet the requirement of Chinese Pharmacopoeia about tablet.
Embodiment 4, oxycodone/rotundine Film coated tablets
1. sheet core component oxycodone hydrochloride 5.096g
Rotundine 30.248g
Lactose 50.821g
Carboxymethyl starch sodium 2.108g
Starch slurry is an amount of
Magnesium stearate 1.105g
Make 1000
2. coating material hydroxypropyl emthylcellulose 50.011g
Oleum Ricini 5.012g
Tween 80 2.002g
Propylene glycol 10ml
Titanium dioxide 8.028g
95% ethanol 500ml
Water 100ml
Preparation technology: all components is crossed 80 mesh sieves, with recipe quantity oxycodone hydrochloride, rotundine, the suitable method mixing of lactose, it is an amount of to add starch slurry, and the system soft material is granulated with 18 mesh sieves, drying is 50 minutes in 50 ℃ of drying baker, with 16 mesh sieve granulate, add the carboxymethyl starch sodium and the magnesium stearate of recipe quantity, with suitable method mixing, with tablet machine above mixture is pressed into the tablet of suitable weight, every index should meet the requirement of Chinese Pharmacopoeia about tablet.
The preparation of coating solution: take by weighing recipe quantity HPMC, spend the night with 95% soak with ethanol.Add Tween 80, propylene glycol, Oleum Ricini mixing, add water and make the HPMC dissolving, measure 20% standby as polishing liquid.Be suspended in the surplus solution titanium dioxide standby.
Art for coating: label is placed coating pan, and rotating speed 16r/min sprays into coating solution, dries up, and hockets.Sprayed after drying and got final product, coating weightening finish 2～4%.Use an amount of polishing of polishing liquid at last.
Embodiment 5, oxycodone/rotundine Film coated tablets
1. sheet core component oxycodone hydrochloride 5.096g
Rotundine 25.248g
Lactose 50.821g
Carboxymethyl starch sodium 2.108g
Starch slurry is an amount of
Magnesium stearate 1.105g
Make 1000
2. coating material hydroxypropyl emthylcellulose 50.011g
Oleum Ricini 5.012g
Tween 80 2.002g
Propylene glycol 10ml
Titanium dioxide 8.028g
95% ethanol 500ml
Water 100ml preparation method is with embodiment 4.
Embodiment 6, oxycodone/rotundine capsule
Oxycodone hydrochloride 5.087g
Rotundine 75.211g
Starch 70.125g
10%PVP K
30Alcoholic solution is an amount of
Magnesium stearate 1.520g
Make 1000
Preparation technology: all components is crossed 80 mesh sieves, and recipe quantity oxycodone hydrochloride, rotundine, starch with suitable method mixing, are added 10%PVP K
30Alcoholic solution is an amount of, and the system soft material is granulated with 18 mesh sieves, drying is 30 minutes in 50 ℃ of drying baker, with 16 mesh sieve granulate, adds magnesium stearate, with suitable method mixing, above mixture is irritated into the capsule of suitable weight, every index should meet Chinese Pharmacopoeia about capsular requirement.
Embodiment 7, oxycodone/rotundine oral cavity disintegration tablet
Oxycodone hydrochloride 5.011g
Rotundine 15.307g
Mannitol 15.344g
Microcrystalline Cellulose 100.180g
Crosslinked polyvidone 80.106g
Aspartame 1.021g
Sodium bicarbonate 50.211g
Anhydrous citric acid 15.034g
Micropowder silica gel 1.544g
Magnesium stearate 3.043g
Flavoring orange essence 0.502g
Make 1000
Preparation technology: with each component mix homogeneously of recipe quantity, with the punch die tabletting of φ 9mm.Disintegrate rapidly, no grittiness, good mouthfeel in the oral cavity.Be 5～50 seconds disintegration, and other should meet general rule requirement under the Chinese Pharmacopoeia tablet item.
The analgesic activity of embodiment 8, oxycodone hydrochloride and different pharmaceutical compatibility
Materials and methods: female mice, to place (HUGO SACHS ELEKTRONIK, MODEL-DS37, German product) on 55 ℃ of hot plates, timing at once ends when foot occurs licking or stamp metapedes the first time, and the gained time is the basic threshold of pain before the administration.To after being subjected to reagent po 60min (matched group is a normal saline), animal is placed on the hot plate then, survey the threshold of pain again, 8 animals of every dosage group.Licking foot not occur in 60 seconds or to stamp metapedes is analgesia 100%.Self relatively to calculate analgesia percentage rate (computing formula is as follows) before and after the administration, with logit software ED
50Value.
Experimental result: rotundine and oxycodone compatibility analgesic activity are the strongest, and can make the analgesia ED of oxycodone
50Dosage reduces 1-4 doubly.A little less than the effect of agmatine synergic antalgic, but the tolerance and the dependence effect of antagonism oxycodone are the strongest.Anti-inflammatory analgesic (as: aspirin, acetaminophen, ibuprofen) can both strengthen the analgesic activity of oxycodone, but needs dosage big, and toxic and side effects is (table 4) obviously.
The analgesic activity of table 4, oxycodone hydrochloride and different pharmaceutical compatibility
| Medicine | Dosage (mg/kg) | Analgesia (%) |
| Oxycodone hydrochloride | 4 | ?30.0 |
| Oxycodone hydrochloride (4mg/kg)+aspirin | 300 | ?24.0 |
| Oxycodone hydrochloride (4mg/kg)+acetaminophen | 200 | ?49.5 |
| Oxycodone hydrochloride (4mg/kg)+ibuprofen | 100 400 | 33.0 92.0 (toxicity is big) |
| Oxycodone hydrochloride (4mg/kg)+indometacin | 100 | ?72.3 |
| Oxycodone hydrochloride (4mg/kg)+ketamine | 6.2-12.5 | ?50.0 |
| Oxycodone hydrochloride (4mg/kg)+chlorpromazine | 12.5 50 | 23.3 100 (side effect is big) |
| Oxycodone hydrochloride (4mg/kg)+lignocaine | 100 | ?93.3 |
| Oxycodone hydrochloride (4mg/kg)+stable | 20 | ?53.4 |
| Oxycodone hydrochloride (4mg/kg)+nimodipine | 20 | ?34.4 |
| Oxycodone hydrochloride (4mg/kg)+Nifedipine | 20 | ?46.8 |
| Oxycodone hydrochloride (4mg/kg)+propranolol | 50 | ?72.5 |
| Oxycodone hydrochloride (4mg/kg)+bisoprolol | 5 | ?54.7 |
| Oxycodone hydrochloride (4mg/kg)+tetrahydropalmatine | 50 | ?80-100 |
| Oxycodone hydrochloride (4mg/kg)+rotundine | 20 | ?89.0 |
The analgesic activity of embodiment 9. oxycodones and rotundine various dose compatibility
Materials and methods: female mice, 55 ℃ of hot plate methods.(method is the same).
Experimental result: under 55 ℃ of hot plate temperatures, fixedly during the dosage of oxycodone, analgesic effect increases along with the increase of rotundine compatibility dosage, and is the strongest with the analgesic activity of oxycodone 4mg/kg dosage and rotundine 25mg/kg dose compatibility, reaches analgesia 100%.When improving hot plate temperature to 60 ℃ and fixedly during the different compatibility dosage of rotundine, analgesic activity is along with the dosage increase of oxycodone and increase, rotundine dosage be 25mg/kg and oxycodone dosage when being 5mg/kg analgesic effect reach 100% (table 5) substantially.
The analgesic activity of table 5, oxycodone and rotundine various dose compatibility relatively
Oxycodone (mg/kg) rotundine (mg/kg) analgesia (%) hot plate temperature (℃)
5???????????????---?????????????46.1???????????55℃
---?????????????25??????????????48.2
4???????????????15??????????????84.7???????????55℃
4???????????????20??????????????93.1
4???????????????25??????????????100
4???????????????15??????????????24.6????????????60℃
4???????????????20??????????????65.0
4???????????????25??????????????71.7
5???????????????15??????????????52.8????????????60℃
5???????????????20??????????????87.1
5???????????????25??????????????97.0
6???????????????15??????????????95.7????????????60℃
6???????????????20??????????????98.6
6???????????????25??????????????100
The analgesic activity of embodiment 10, morphine and rotundine various dose compatibility
Materials and methods: female mice, 55 ℃ of hot plate methods.(method is the same).
Experimental result: on the mice hot plate method, morphine list medicine analgesic dose is bigger, and the dosage that reaches maximum analgesic activity as share with rotundine, can obviously improve the analgesia rate of morphine, ED generally at 20-24mg/kg sc
50And ED
99Dosage is along with rotundine dosage increases and descend at double (seeing Table 6).
The analgesic activity of table 6, morphine and rotundine various dose compatibility relatively
Medicine morphine ED
50Dosage (mg/kg) morphine ED
99Dosage (mg/kg)
Morphine 6.06 ± 0.90 22.04 ± 2.17
Morphine+rotundine 30mg/kg 3.96 ± 0.34 12.28 ± 1.63
Morphine+rotundine 50mg/kg 1.65 ± 0.40 10.85 ± 1.40
The analgesic activity of embodiment 11, buprenorphine and rotundine various dose compatibility
Materials and methods: female mice, 55 ℃ of hot plate methods.(method is the same).
Experimental result: buprenorphine is the opiate receptor partial agonist, analgesic activity than morphine a little less than, on the mice hot plate method, maximum analgesia rate is about 40%.But can significantly improve its analgesia usefulness with the rotundine compatibility, maximum analgesia rate can reach 100%.For example: buprenorphine list medicine does not detect analgesia ED
50Value, and add rotundine 30mg/kg po, ED
50Value is about 0.58mg/kg sc, adds rotundine 50mg/kg po, ED
50Value is about 0.088mg/kg sc, along with rotundine dosage increase buprenorphine not only effective dose reduce, analgesia usefulness also obviously improves (seeing Table 7).
The analgesic activity of table 7, buprenorphine and rotundine various dose compatibility relatively
The analgesia rate (%) of buprenorphine and rotundine various dose compatibility
(mg/kg)?????????0????????????30mg/kg???????????50mg/g
0.0??????10.7±10.2??????10.9±10.4????????15.6±6.3
0.4??????27.8±14.7??????46.1±22.9????????86.1±26.9
0.6??????31.3±10.8??????48.6±26.0????????85.2±27.9
1.0??????27.6±5.6???????65.1±31.6????????91.2±16.5
1.7??????39.4±15.3??????76.12±5.8????????88.0±22.3
2.8??????27.6±13.6??????56.4±32.7????????92.2±22.0
The dependence test of embodiment 12, oxycodone and Hyndarin
Materials and methods: male mice, 10 every group.Oxycodone, rotundine list medicine and oxycodone and Hyndarin compound recipe (by 1: 5) with 30,80,80mg/kg dosage, 3 times/day, successive administration 5 days, matched group sc normal saline.4h after the last administration, naloxone 10mgKg
-1Ip urges.Write down interior number of skips of every animal 15min and the weight loss behind the 1h.
Experimental result: do not see tangible withdrawal symptom when oxycodone and Hyndarin compound recipe (by 1: 5) group and rotundine treated animal are urged with naloxone, relatively there is not marked difference with the saline control group, and the withdrawal symptom of oxycodone treated animal is very obvious, compares difference highly significant (seeing Table 8) with the saline control group.
Table 8, oxycodone compound recipe cause mice dependency potential and measure
Drug dose withdrawal symptom weight loss
(mg/kg) jump rate (%) number of skips (X ± SD gram)
Saline is right--and 10 1.2 ± 2.3 0.23 ± 0.16
Oxycodone 30 100 65.2 ± 62.8
* *0.59 ± 0.14
* *
Hyndarin 80 00 0.20 ± 0.07
Oxycodone+Hyndarin 80 20 1.3 ± 4.1 0.33 ± 0.28
Embodiment 13, oxycodone and the acute toxicity test of Hyndarin compound recipe
Materials and methods: mice male and female half and half, 10 every group.Oxycodone, rotundine list medicine and oxycodone and rotundine compound recipe (the dosage ratio is 1: 5) are mixed with variable concentrations with distilled water, measure LD through the po approach
50Value, the administration treated animal is fasting 12h before experiment, calculates LD with the death toll of animal in after the administration 7 days
50Value (Bliss method).
Experimental result: oxycodone and Hyndarin dosage are measured LD to the mice single-dose by 1: 5 prescription
50, and carry out parallel comparison with each single medicine, the results are shown in Table 9.With probability and assessment method Q
50＜0.55, the remarkable antagonism of compound recipe toxicity.
The acute toxicity comparative drug grouping number of animals LD of table 9, oxycodone compound recipe and each single medicine
50Be worth 95% fiducial limit
(only) (mg/kg po) (mg/kg po)
Oxycodone 10 524.2 431.8-609.4
Hyndarin 10 754.2 618.3-905.1
Hydroxyl+sieve 10 952.9 751.1-1143.0
Annotate: the mice fasting is gastric infusion after 12 hours
Claims (9)
1. one kind is used to the pharmaceutical composition that eases pain and/or quit drug abuse, it is characterized in that comprising the ease pain rotundine and the pharmaceutic adjuvant of the opiate receptor full agonist of effective dose or opiate receptor partial agonist, analgesia effective dose.
2. according to the pharmaceutical composition of claim 1, the proportion compatibility that it is characterized in that said opiate receptor full agonist or opiate receptor partial agonist and rotundine is 1: 3 to 1: 20 (weight ratio of parent compound).
3. according to the pharmaceutical composition of claim 2, it is characterized in that said opiate receptor full agonist is that oxycodone, hydrogen are examined ketone, morphine or dihydro Chinese mugwort holder coffee.
4. according to the pharmaceutical composition of claim 2, it is characterized in that said opiate receptor partial agonist is a buprenorphine.
5. according to the pharmaceutical composition of claim 3, it is characterized in that said opiate receptor full agonist is an oxycodone.
6. according to the pharmaceutical composition of claim 5, the proportion compatibility that it is characterized in that oxycodone and rotundine is 1: 3 to 1: 15 (weight ratio of parent compound).
7. according to the pharmaceutical composition of claim 5, the proportion compatibility that it is characterized in that oxycodone and rotundine is 1: 5 to 1: 10 (weight ratio of parent compound).
8. according to claim 5,6 or 7 pharmaceutical composition, the content that it is characterized in that the oxycodone parent compound is 5 milligrams.
9. any one pharmaceutical composition in the claim 1 to 8 is characterized in that it is a peroral dosage form.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1778300B (en) * | 2004-11-18 | 2010-09-08 | 山东绿叶天然药物研究开发有限公司 | Luotongding oral cavity disintegration tablet and preparation thereof |
| CN103637998A (en) * | 2013-12-09 | 2014-03-19 | 韩彬 | Sustained-release tablet containing oxycodone and rotundine |
| CN103877084A (en) * | 2014-04-14 | 2014-06-25 | 崔新明 | Externally used medicine for treating crissum anabrosis |
| CN106237333A (en) * | 2016-07-08 | 2016-12-21 | 杨征 | The medical usage of corydalmine |
| CN107936008A (en) * | 2016-10-13 | 2018-04-20 | 泰州华元医药科技有限公司 | Deuterated compound and its medical usage |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1243704A (en) * | 1998-07-31 | 2000-02-09 | 孙吉祖 | Quickly-acting analgesic |
| US6177567B1 (en) * | 1999-10-15 | 2001-01-23 | Boehringer Ingelheim Chemicals, Inc. | Method for preparing oxycodone |
-
2002
- 2002-09-18 CN CNB021306729A patent/CN1310646C/en not_active Expired - Lifetime
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1778300B (en) * | 2004-11-18 | 2010-09-08 | 山东绿叶天然药物研究开发有限公司 | Luotongding oral cavity disintegration tablet and preparation thereof |
| CN103637998A (en) * | 2013-12-09 | 2014-03-19 | 韩彬 | Sustained-release tablet containing oxycodone and rotundine |
| CN103637998B (en) * | 2013-12-09 | 2016-04-06 | 韩彬 | Comprise the slow releasing tablet of oxycodone and rotundine |
| CN103877084A (en) * | 2014-04-14 | 2014-06-25 | 崔新明 | Externally used medicine for treating crissum anabrosis |
| CN106237333A (en) * | 2016-07-08 | 2016-12-21 | 杨征 | The medical usage of corydalmine |
| CN107936008A (en) * | 2016-10-13 | 2018-04-20 | 泰州华元医药科技有限公司 | Deuterated compound and its medical usage |
| EP3517537A4 (en) * | 2016-10-13 | 2020-05-27 | Jingluweidai Information Consulting Service (Beijing) Co Ltd | Deuterated derivative of l-tetrahydropalmatine and medical use thereof |
| CN107936008B (en) * | 2016-10-13 | 2022-06-14 | 泰州华元医药科技有限公司 | Deuterated compound and medical application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1310646C (en) | 2007-04-18 |
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