CN104622791A - Dezocine oral preparation - Google Patents
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Abstract
The invention discloses a dezocine oral preparation. A unit preparation of the dezocine oral preparation comprises 5-150 mg of dezocine and optional pharmaceutically acceptable auxiliary materials of the oral preparation. In addition, the invention also discloses a preparation method and application of the dezocine oral preparation. Clinical trials show that in a dosage range, the plasma concentration of the dezocine oral preparation disclosed by the invention is similar to that of a commercially available dezocine injection, and the dezocine oral preparation has slight adverse reactions, and is more convenient in administration.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of dezocine oral formulations, and the preparation method of said preparation, and the purposes for the treatment of pain.
Background technology
Dezocine (Dezocine), its chemical name is: amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5, the 11-methylene benzo cyclodecene-3-alcohol of 13-.CAS:53648-55-8。
Structural formula is as follows:
Dezocine is a kind of potent opium kind analgesics, such medicine has the effect of agonist and antagonist concurrently, by different from other opioid drugs to receptor subtype affinity and show different features, its analgesic activity is better than pentazocine, additive less, be mainly used in clinically in treatment Post operation to severe pain and chronic pain, the pain of internal organs angor and patient with advanced cancer, its intensity of easing pain, onset time and acting duration and maximum analgesic effect suitable with morphine, stronger than dolantin 5-9 times, side effect is slight, better tolerance, only gone on the market dezocine injection type at present both at home and abroad.
Chinese patent CN104257615A describes a kind of dezocine freeze-drying medicinal composition and preparation method thereof, uses dezocine, cosolvent, excipient, stabilizing agent and acid-base modifier to be mixed with solution, after lyophilizing, and the freeze-dried composition obtained.
Chinese patent CN104224734A describes a kind of dezocine freeze-drying medicinal composition and preparation method thereof by dezocine, freeze-dried excipient, the compositions such as antioxidant, soda acid pH adjusting agent.
Above patent all describe only the preparation method of freeze-drying preparation for injection; Relative injection administration, oral be the most frequently used is also the most convenient most economical means, and convenient drug administration, does not have misery, and medicine stability is high, can calculate dose accurately.But the instability that oral formulations absorbs, dezocine drug administration by injection, mainly at liver generation glucuronidation, mainly drains with the conjugate form of glucuronic acid.First pass effect of hepar all produces larger impact to drug absorption and effect, on the other hand, also do not have the report of the oral untoward reaction of dezocine at present, the untoward reaction different from injection may be there is by oral dezocine, these untoward reaction need by suitable dose and prescription, to avoid the generation of untoward reaction.Therefore foundation prior art develops a kind of oral formulations of dezocine is very difficult.
Summary of the invention
The present inventor has found a kind of dezocine oral formulations through large quantifier elimination, achieves oral administration and reach therapeutic effect under doses.
The object of the present invention is to provide a kind of oral formulations of dezocine.
The second object of the present invention is to provide the preparation method of above-mentioned dezocine oral formulations.
3rd object of the present invention is to provide the purposes of above-mentioned dezocine oral formulations.
Specifically, the invention provides a kind of oral formulations of dezocine, the per unit preparation of described dezocine oral formulations comprises the dezocine of 5mg ~ 150mg and the adjuvant of optional pharmaceutically acceptable oral formulations.So-called unit formulation refers to the every sheet in tablet, often propping up of oral administration solution, every bag of granule, or every capsules of capsule.
In a kind of preferred embodiment of the present invention, dezocine oral formulations provided by the invention, its unit dosage forms is oral three times of every day, and described dezocine oral formulations comprises the adjuvant of 5 ~ 50mg dezocine and optional pharmaceutically acceptable oral formulations.
In a kind of preferred embodiment of the present invention, dezocine oral formulations provided by the invention, its unit dosage forms is that every day is once oral, and described dezocine oral formulations comprises the adjuvant of 10 ~ 100mg dezocine and optional pharmaceutically acceptable oral formulations.
In embodiments of the invention, dezocine oral formulations provided by the invention, being selected from tablet, capsule, granule or oral administration solution etc. can by the pharmaceutical dosage form of oral administration.Here, described tablet comprises the tablet that conventional tablet, slow releasing tablet, controlled release tablet or dispersible tablet etc. can be taken orally; Described capsule comprises common capsule and the various capsule such as slow release, controlled release; Described granule is sugary or not sugary granule.
In embodiments of the invention, dezocine oral formulations provided by the invention is preferably tablet, is more preferably slow releasing tablet.
In a preferred embodiment of the invention, dezocine oral formulations provided by the invention is dezocine tablet, and the adjuvant of wherein said pharmaceutically acceptable oral formulations comprises filler, disintegrating agent, binding agent and lubricant.
In a preferred embodiment of the invention, dezocine oral formulations provided by the invention is dezocine slow releasing tablet, and the adjuvant of wherein said pharmaceutically acceptable oral formulations comprises filler, slow-release material, binding agent and lubricant.
In embodiments of the invention, dezocine oral formulations provided by the invention, wherein, described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, pre-paying starch, mannitol, sorbitol, preferably microcrystalline cellulose.
In embodiments of the invention, dezocine oral formulations provided by the invention, wherein, described slow-release material is selected from one or more in hypromellose, hyprolose, methylcellulose, ethyl cellulose, preferred hypromellose.
In embodiments of the invention, dezocine oral formulations provided by the invention, wherein, described disintegrating agent is selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross linked polyvinyl pyrrolidone, cross-linked carboxymethyl cellulose are received, one or more in dried starch.
In embodiments of the invention, dezocine oral formulations provided by the invention, wherein, one or more in described binding agent hyprolose, methylcellulose, ethyl cellulose, polyvidone or polyvinylpolypyrrolidone.
In embodiments of the invention, dezocine oral formulations provided by the invention, wherein, described lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, fumaric acid sodium stearate.
Second aspect, the invention provides the preparation method of above-mentioned dezocine oral formulations, and the method comprises and being mixed by the adjuvant of the dezocine of 5mg ~ 150mg with optional pharmaceutically acceptable oral formulations, and is mixed with the dosage form of Orally-administrable.
The third aspect, the invention provides and applied to the medicine of severe pain and chronic pain patient in preparation treatment after surgery by above-mentioned dezocine oral formulations.
Dezocine oral formulations provided by the invention contains the dezocine of specified quantitative, effectively can to treat in Post operation to severe pain and chronic pain, not only achieve therapeutic effect, simultaneously avirulence ill effect by taking or once-a-day take for three times on the one.Be used for chronic pain compared to the dezocine injection of prior art, be administered once every 3 ~ 6 hours when needing; Oral dezocine oral formulations of the present invention is by the oral effect achieving drug administration by injection, and the slow release formulation of employing dezocine is taken once a day for chronic pain.
Accompanying drawing explanation
Fig. 1: the Drug-time curve (N=5) of healthy adult experimenter single oral different size dezocine slow releasing tablet.
Fig. 2: the Drug-time curve of the oral dezocine ordinary tablet of healthy adult experimenter or slow releasing tablet (10mg) compares (N=5).
Fig. 3: the Drug-time curve of the oral dezocine ordinary tablet of healthy adult experimenter or slow releasing tablet (15mg) compares (N=5).
Fig. 4: the Drug-time curve of the oral dezocine ordinary tablet of healthy adult experimenter or slow releasing tablet (20mg) compares (N=5).
Fig. 5: the Drug-time curve of the oral dezocine ordinary tablet of healthy adult experimenter or slow releasing tablet (25mg) compares (N=5).
Fig. 6: the Drug-time curve of the oral dezocine ordinary tablet of healthy adult experimenter or slow releasing tablet (30mg) compares (N=5).
Fig. 7: the mode Drug-time curve (N=15) of dezocine (15mg) different dosing in healthy adult experimenter.
Detailed description of the invention
By following specific embodiment, reader can be helped better to understand the present invention, but following example can not be interpreted as limiting the present invention.
Embodiment 1: prepared by dezocine oral administration solution
Dezocine oral administration solution
Method for making: take pulverizing, sieve after dezocine raw material, add the purified water of above-mentioned recipe quantity, lactic acid, dissolve after adjust ph to 3.8, filtration sterilization.
Embodiment 2: prepared by dezocine sheet
Dezocine tablet recipe:
Method for making: take pulverizing, sieve after dezocine raw material, mix with the lactose of above-mentioned recipe quantity, microcrystalline Cellulose, carboxymethylstach sodium, add the appropriate mix homogeneously of 10% hypromellose cellulose solution, make suitable soft material, cross 16 mesh sieves, make granule, 60 DEG C of oven dry, dry granule crosses 20 order granulate, adds magnesium stearate mix homogeneously, tabletting.
Embodiment 3: prepared by dezocine slow releasing tablet
Dezocine sustained-release tablet recipe:
Method for making: take pulverizing, sieve after dezocine raw material, mix homogeneously with the microcrystalline Cellulose of above-mentioned recipe quantity, PVP K30, add the mixing of 5%PVP 80% alcoholic solution again, make suitable soft material, cross 16 mesh sieves, make granule, 60 DEG C of oven dry, dry granule crosses 18 order granulate, adds hypromellose (K4M), magnesium stearate mix homogeneously, tabletting, coating and get final product.
Embodiment 4: prepared by dezocine sheet
1, dezocine sheet
Prescription:
Method for making: take pulverizing, sieve after dezocine raw material, mix with the lactose of above-mentioned recipe quantity, microcrystalline Cellulose, carboxymethylstach sodium, add the appropriate mix homogeneously of 10% hypromellose cellulose solution, make suitable soft material, cross 16 mesh sieves, make granule, 60 DEG C of oven dry, dry granule crosses 20 order granulate, adds magnesium stearate mix homogeneously, tabletting.
Embodiment 5: prepared by dezocine slow releasing tablet
Dezocine slow releasing tablet
Prescription:
Method for making: take pulverizing, sieve after dezocine raw material, mix homogeneously with the microcrystalline Cellulose of above-mentioned recipe quantity, PVP K30, add the mixing of 5%PVP 80% alcoholic solution again, make suitable soft material, cross 16 mesh sieves, make granule, 60 DEG C of oven dry, dry granule crosses 18 order granulate, adds hypromellose (K4M), magnesium stearate mix homogeneously, tabletting, coating and get final product.
Effect example 1: pharmacodynamic study
Whether effectively what dezocine went on the market both at home and abroad only has injection, the report of relevant oral curative effect, affect as judging the oral foundation of dezocine after therefore the contrast of employing Mouse and rat uses dezocine and morphine on heat radiation and hot plate induced pain.
Test medicine: the dezocine oral administration solution as described in embodiment 1
Positive drug: morphine hydrochloride injection
Administering mode: adopt normal saline dilution dezocine oral administration solution and morphine hydrochloride injection respectively, gastric infusion.Administration volume: 10ml/kg.
Dezocine is on the impact of mice heat radiation induced pain
Method: Female ICR mice, gastric infusion dezocine 5,10,20,40mg/kg, morphine 40mg/kg, contrast gives same volume normal saline.Mice induced pain incubation period is measured with light thermic pain instrument after 20 minutes.
Table 1: on the preclinical impact of photo-thermal induced pain after mouse stomach dezocine
In table, data are meansigma methods ± SD, n=10.*P<0.05，**p<0.01，***p<0.001
Result: when mouse stomach gives dezocine 10,20 and 40mg/kg, obviously can extend the mouse tail pain incubation period that photo-thermal causes.ED50 is 5.9mg/kg, ED95 is 9.9mg/kg.Under this experiment condition, 40mg/kg morphine also has the effect well extending TFL.
Dezocine is on the impact of mouse hot-plate induced pain
Method: male ICR mouse, is put on 55 DEG C of hot plates, and meter licks metapedes time and the threshold of pain first.Select the threshold of pain to be the mice of 20-35 second, gastric infusion dezocine after 5 hours (10,40,100mg/kg), or morphine (100mg/kg), contrast gives same volume normal saline.Be put on 55 DEG C of hot plates after 20 minutes, the metapedes time licked first by meter.
Table 2: mouse stomach dezocine causes hot plate licks the preclinical impact of foot
In table, data are meansigma methods ± SD, * * * P<0.001
Result: when mouse stomach gives dezocine 10,40 and 100mg/kg, obviously can extend mice and lick sufficient incubation period.ED50 is 9.4mg/kg, ED95 is 23.0mg/kg.Under this experiment condition, 100mg/kg morphine also has the well preclinical effect of prolongation.
Dezocine is on the impact of rat heat radiation induced pain
Method: Male Wistar Rats, fasting 12 hours, gastric infusion dezocine (1.25,2.5,5.0,10.0,20.0,40.0mg/kg), or morphine (5.0,10.0mg/kg), contrast gives same volume normal saline.Rat induced pain incubation period is measured with light thermic pain instrument after 20 minutes.
Table 3: on the preclinical impact of photo-thermal induced pain after rat oral gavage dezocine
Table Middle latency data are meansigma methods ± SD, * * p<0.01, * * * p<0.001
Result: refer to table 3.Rat oral gavage gives dezocine when being greater than 2.5mg/kg dosage, obviously can extend the rat tail pain incubation period that photo-thermal causes.ED50 is 1.5mg/kg, ED95 is 1.9mg/kg.Rat gives 10mg/kg morphine and also has the well preclinical effect of prolongation.
Conclusion: experimental result shows, and in mice heat radiation induced pain, mouse hot-plate induced pain and rat heat radiation induced pain model, the ED50 value of oral dezocine is respectively 5.9,9.4 and 1.5mg/kg.Under Isodose, the paroxysmal pain effect of dezocine is stronger.
Effect example 2: health volunteer's single oral dezocine ordinary tablet tolerance studies
EXPERIMENTAL DESIGN:
30 healthy adult experimenters, are divided into 6 groups at random according to body weight, often organize 5 people, give the dezocine conventional tablet described in embodiment 2,4, dosage is respectively 5,10,15,20,25,30mg.Play warm water delivery service on an empty stomach morning, single administration.
Carry out according to dosage principle from low to high, for security consideration, carry out 1 group of research every day, after confirmation last group of drug administration safety, just can carry out next group research.If front dose group the serious adverse events of 1 example occurs or number of cases >=50% of moderate and above adverse events occurs, test termination, no longer carry out subsequent dose test.
Result:
The main pharmacokinetic parameter of healthy adult experimenter oral various dose dezocine ordinary tablet is in table 1.The oral 5-30mg dezocine of experimenter, dezocine absorbs very rapid, T
maxfor 1.0-1.2h, eliminate slower t in vivo
1/2for 3.7-4.1h.Along with the increase of dosage, C
maxlinearly increase, see Fig. 1.Within the scope of 5-30mg, experimenter all safety and can tolerate, the adverse events occurred in process of the test is light moderate.Adverse events increases along with dosage, and occurrence frequency and degree be corresponding increase also.Main adverse events is: Nausea and vomiting, dizziness, perspiration etc.
Table 4: the main pharmacokinetic parameter (N=5) of healthy adult experimenter oral various dose dezocine ordinary tablet
Effect example 3: health volunteer's single: oral dezocine slow releasing tablet tolerance studies
EXPERIMENTAL DESIGN:
25 healthy adult experimenters, are divided into 5 groups at random according to body weight, often organize 5 people, give the dezocine slow releasing tablet of the embodiment of the present application 3 and 5 respectively, dosage is respectively 10,15,20,25mg, 30mg, play warm water delivery service on an empty stomach morning, single administration.
Carry out according to dosage principle from low to high, for security consideration, carry out 1 group of research every day, after confirmation last group of drug administration safety, just can carry out next group research.If front dose group the serious adverse events of 1 example occurs or number of cases >=50% of moderate and above adverse events occurs, test termination, no longer carry out subsequent dose test.
Result:
Healthy adult experimenter oral various dose dezocine slow releasing tablet main pharmacokinetic parameter is in table 2.Experimenter's oral 10-30mg dezocine slow releasing tablet, absorption is obviously slowed down compared with ordinary tablet, T
maxfor 2.6-2.8h, eliminate in body and also significantly slow down, t
1/2for 5.7-5.9h.Along with the increase of dosage, C
maxlinearly increase.Within the scope of 10-30mg, experimenter all safety and can tolerate, the adverse events occurred in process of the test is light moderate.Adverse events increases along with dosage, and occurrence frequency and degree also increase.Main adverse events is: Nausea and vomiting, dizziness, perspiration etc.
Compared with the conventional tablet of same dosage, dezocine slow releasing tablet t
1/2and T
maxsignificant prolongation, C
maxthough reduce a little, but change is little, shows obvious slow release characteristic, sees Fig. 2 ~ 6.
Table 5: the main pharmacokinetic parameter (N=5) of healthy adult experimenter oral various dose dezocine slow releasing tablet
Effect example 4: in health volunteer, the pharmacokinetics of dezocine (15mg) different modes of administration compares
EXPERIMENTAL DESIGN:
15 adult healthy experimenters, are divided into 3 groups at random, adopt double 3 × 3 latin square experiment designs of 3 preparation 3 cycles.Take medicine by the order of injection dezocine 15mg, oral conventional tablet (15mg) and oral sustained release sheet (15mg) for one group; Take medicine by the order of oral sustained release sheet (15mg), injection dezocine 15mg and oral conventional tablet (15mg) for two groups; Take medicine by the order of oral conventional tablet (15mg), oral sustained release sheet (15mg) and injection dezocine 15mg for three groups; The cleaning phase is one week.
Result
In healthy adult experimenter, the main pharmacokinetic parameter of dezocine (15mg) different modes of administration is in table 3.The C of oral 15mg dezocine ordinary tablet and slow releasing tablet
maxbe respectively 15.8 ± 3.2 and 13.9 ± 2.9ng/ml; The T of oral 15mg dezocine ordinary tablet and slow releasing tablet
maxbe respectively 1.1 ± 0.3 and 2.7 ± 0.7h; The t of injection 15mg dezocine and oral 15mg dezocine ordinary tablet or slow releasing tablet
1/2be respectively 2.7 ± 0.8,3.8 ± 1.4 and 5.7 ± 2.1h; The AUC of injection 15mg dezocine and oral 15mg dezocine ordinary tablet or slow releasing tablet
0-16hbe respectively 85.6 ± 9.4,54.1 ± 6.1 and 54.1 ± 6.1ugh/L, the absolute bioavailability of dezocine ordinary tablet and slow releasing tablet is respectively 63.20% and 65.40%, sees Fig. 7.Adverse events: the adverse events that drug administration by injection occurs is for feeling sick (2/15), vomitting (1/15), dizzy (1/15); The adverse events that oral conventional tablet occurs is dizzy (1/15); Oral sustained release sheet occurs without adverse events.Compare drug administration by injection, oral dezocine does not produce gastrointestinal side effect, and other untoward reaction are also little than injection.
Table 6: the main pharmacokinetic parameter (N=15) of dezocine (15mg) different modes of administration in healthy adult experimenter
Claims (10)
1. a dezocine oral formulations, its unit formulation comprises the dezocine of 1mg ~ 150mg and the adjuvant of optional pharmaceutically acceptable oral formulations.
2. dezocine oral formulations as claimed in claim 1, the dosage form of described oral formulations is selected from tablet, capsule, granule or oral administration solution, preferred conventional tablet or slow releasing tablet.
3. dezocine oral formulations as claimed in claim 2, wherein, containing dezocine 5 ~ 100mg in the unit dosage forms of described dezocine oral formulations, preferably, containing dezocine 5 ~ 50mg in the unit dosage forms of described dezocine oral formulations.
4. dezocine oral formulations as claimed in claim 3, wherein, described dezocine oral formulations is dezocine tablet, oral three times of every day.
5. dezocine oral formulations as claimed in claim 3, wherein, described dezocine oral formulations is dezocine slow releasing tablet, and every day is once oral.
6. dezocine oral formulations as claimed in claim 2, wherein, described dezocine oral formulations is dezocine ordinary tablet, and the adjuvant of pharmaceutically acceptable oral formulations wherein comprises filler, disintegrating agent, binding agent and lubricant.
7. dezocine oral formulations as claimed in claim 2, wherein, described dezocine oral formulations is dezocine slow releasing tablet, and the adjuvant of pharmaceutically acceptable oral formulations wherein comprises filler, slow-release material, binding agent and lubricant.
8. dezocine oral formulations as claimed in claim 6, wherein, described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, pre-paying starch, mannitol, sorbitol, preferably microcrystalline cellulose;
Described disintegrating agent is selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross linked polyvinyl pyrrolidone, cross-linked carboxymethyl cellulose are received, one or more in dried starch;
One or more in described binding agent hyprolose, methylcellulose, ethyl cellulose, polyvidone or polyvinylpolypyrrolidone;
Described lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, fumaric acid sodium stearate.
9. dezocine oral formulations as claimed in claim 7, wherein, described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, pre-paying starch, mannitol, sorbitol, preferably microcrystalline cellulose;
One or more in described binding agent hyprolose, methylcellulose, ethyl cellulose, polyvidone or polyvinylpolypyrrolidone;
Described lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, fumaric acid sodium stearate;
Described slow-release material is selected from one or more in hypromellose, hyprolose, methylcellulose, ethyl cellulose, preferred hypromellose.
10. the purposes of dezocine oral formulations according to any one of claim 1-9 in the medicine for the preparation for the treatment of pain.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510080325.XA CN104622791A (en) | 2015-02-13 | 2015-02-13 | Dezocine oral preparation |
| CN201810420839.9A CN108403651A (en) | 2015-02-13 | 2015-02-13 | dezocine oral preparation |
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| CN201510080325.XA CN104622791A (en) | 2015-02-13 | 2015-02-13 | Dezocine oral preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653446A (en) * | 2018-07-26 | 2018-10-16 | 四川大学华西医院 | A kind of surface anesthesia pharmaceutical composition, micro emulsion and its preparation method and application |
| CN111606816A (en) * | 2017-05-22 | 2020-09-01 | 扬子江药业集团有限公司 | Dezocine crystal form and preparation method thereof |
| CN111939145A (en) * | 2020-07-23 | 2020-11-17 | 深圳大学 | Application of dezocine in preparation of nicotinamide phosphoribosyltransferase inhibitor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1741790A (en) * | 2003-01-23 | 2006-03-01 | 株式会社太平洋 | Sustained-release preparations and method for producing the same |
| CN101578094A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations of oxymorphone and methods of use thereof |
| CN101578096A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104257615B (en) * | 2014-09-15 | 2017-09-01 | 扬子江药业集团有限公司 | A kind of dezocine freeze-drying medicinal composition and preparation method thereof |
-
2015
- 2015-02-13 CN CN201510080325.XA patent/CN104622791A/en active Pending
- 2015-02-13 CN CN201810420839.9A patent/CN108403651A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1741790A (en) * | 2003-01-23 | 2006-03-01 | 株式会社太平洋 | Sustained-release preparations and method for producing the same |
| CN101578094A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations of oxymorphone and methods of use thereof |
| CN101578096A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111606816A (en) * | 2017-05-22 | 2020-09-01 | 扬子江药业集团有限公司 | Dezocine crystal form and preparation method thereof |
| CN108653446A (en) * | 2018-07-26 | 2018-10-16 | 四川大学华西医院 | A kind of surface anesthesia pharmaceutical composition, micro emulsion and its preparation method and application |
| CN111939145A (en) * | 2020-07-23 | 2020-11-17 | 深圳大学 | Application of dezocine in preparation of nicotinamide phosphoribosyltransferase inhibitor |
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| CN108403651A (en) | 2018-08-17 |
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