CN103479639A - Application of morphinan quaternary ammonium salt derivative to blocking exogenous opioids - Google Patents
Application of morphinan quaternary ammonium salt derivative to blocking exogenous opioids Download PDFInfo
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- CN103479639A CN103479639A CN201310409642.2A CN201310409642A CN103479639A CN 103479639 A CN103479639 A CN 103479639A CN 201310409642 A CN201310409642 A CN 201310409642A CN 103479639 A CN103479639 A CN 103479639A
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- furan
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Abstract
The invention discloses application of a morphinan quaternary ammonium salt derivative to blocking exogenous opioids, in particular new application for fully or partially reversing the pharmacological action produced by opioid medicaments with nalfurafine and a medicinal salt thereof as active ingredients. The derivative can be used as an auxiliary medicament for relapse prevention after detoxification of opioid dependent patients, and can also be used for relieving respiratory depression caused after operation of an opioid medicament composite anesthetic, wakening the patients and treating overdose of the opioid medicaments and acute alcohol poisoning and the like.
Description
Technical field
The present invention be the morphinan quaternary ammonium salt derivative for blocking the purposes of exogenous opioid, belong to medical technical field.
Background technology
Hydrochloric acid is received furan, and to draw coffee be the morphinan quaternary ammonium salt derivative, and its structure is as follows
Be a kind of new selectivity kappa receptor agonist, retained 4 of norbinaltorphimine, the 5-epoxymorphinan framing structure, and attached group is removed.This compound has high selectivity to kappa receptor, externally shows potent kappa receptor agonist activity.Zoopery shows that this compound has the antipruritic effect, also has analgesic effect simultaneously.Therefore this compound is developed as the analgesic drug product of the patient of uremia pruritus medicine and treatment moderate and severe pain simultaneously.The itch indication of disease of its treatment hemodialysis patients is ratified
At least there are 4 kinds of opiate receptor hypotype: μ, κ, δ, σ in the central nervous system.Morphinoid drug is to veriform opiate receptor, and affinity and intrinsic activity are all incomplete same.Opioid drug can make teleneuron discharge the neurotransmitteies minimizings such as acetylcholine, noradrenaline, dopamine and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, thereby can regulate pain, emotion and stress.
The furan of receiving draws coffee as a kind of new selectivity kappa receptor agonist, sees that theoretically it has certain opioid drug, the characteristic of morphine for example, and morphine is the agonist of μ, κ, tri-kinds of receptors of δ, and the action intensity of three receptor subtypes is weakened successively.The furan of receiving draw coffee to the agonism of opiate receptor under the smaller dose with the morphine par, be weaker than on the whole morphine to receptor acting, the effect produced after itself and receptors bind is less than the morphine ceiling effect.So relative morphine, the furan of receiving draws coffee to can be used as partial agonist, produces antagonistic effect.The partial agonist added replaces full agonist get off from receptor, and whole opium effect is weakened.So the furan of receiving draws coffee to can be used as the antagonist of the strong opioid drug such as morphine for solving clinical relevant issues.Based on above analysis hypothesis, the present invention is directed to and receive furan and draw the new role of coffee to give further checking.
Summary of the invention
The present invention be the morphinan quaternary ammonium salt derivative for blocking the purposes of exogenous opioid, be receive furan draw coffee and pharmaceutical salts thereof as active component the new purposes for the pharmacological action that reverses wholly or in part opioid drug and produce; Comprise the ancillary drug as prevention of relapse after the Opioid Addicts detoxification; For removing the respiration inhibition of opioid drug combined anesthesia medicine due to postoperative, and waken patient; Excessive for opioid drug; Be used for acute alcoholism etc.;
Described active component is received furan and is drawn coffee to give with oral or injection system; Activity is received furan, and to draw the single dosage of coffee be 0.1 μ g-100mg; By the oral furan of receiving, draw the single dosage of coffee to be preferably 0.5-5 μ g, its pharmaceutical dosage form presented can be soft capsule, oral cavity dispersion membrane, buccal tablet, tablet, slow releasing tablet, capsule, slow releasing capsule etc.; Receive furan by injection and draw the single dosage of coffee to be preferably 0.2-2.5 μ g, its pharmaceutical dosage form presented can be injection with small volume, high-capacity injection, Injectable sterile lyophilized powder etc.; The furan of receiving draws administration number of times every day, administration cycle of coffee to need determine according to concrete indication, conventional therapy every day 1-3 time.
Because there is obvious individual variation in this product, during application, should determine dosage and whether need multiple dosing by the doctor according to patient's concrete condition.
But this product venoclysis, injection or intramuscular injection administration.The intravenous injection onset is the fastest, while being adapted at emergency treatment, uses.
Because some opioid acting duration may surpass this product, so reply patient continuous care, in case of necessity, should repeat to give this product.
Venoclysis venoclysis this product can be diluted with normal saline or glucose solution.Appropriate this product is added in above any liquid of 500ml.Mixed liquor should be used in 24 hours, and surpassing 24 hours untapped residual mixed liquor must abandon.React the control drip velocity according to the patient.
The adult uses
But the excessive 0.2-2.5 of intravenous injection this product first of opioid drug μ g, if do not obtain desirable antagonism and the improvement effect of respiratory function, can be every duplicate injection administration in 2～3 minutes.If yet there are no reaction after giving 10 μ g, just should consider this diagnosis problem.If can not intravenously administrable, but intramuscular administration.
Postoperative opioid drug depression effect partly is corrected in the depression effect that opium after opioid drug is used in operation, and smaller dose this product effectively usually.This product dosage should react to determine according to the patient.While correcting respiration inhibition first, should be every 2～3 minutes, intravenous injection 0.2 μ g～0.5 μ g, until produce desirable effect, have unobstructed breathing and lucidity, without obvious pain and discomfort.Be greater than must dosage this product can obviously reverse analgesia and rising blood pressure.Equally, reversing the burden that can cause nausea too soon, vomits, perspires or circulate increases.The amount that needs to repeat to give this product in 1～2 hours interval depends on dosage, administration type (short effect type is long effect type still) and the interval time of the opioid drug of last use.
Severe ethanol intoxication 0.8～2 μ g, repeat administration 0.4～1 μ g after a hour.
Patient to opioid drug tolerance or generation drug dependence: this product can cause the acute withdrawal symptom to the patient of opioid drug tolerance or drug dependence.When first or SM, answer these patients of close observation withdrawal symptom whether to occur.At least should medication again after 2-5 minute, reach greatest treatment efficacy to increase dosage.Substitute the principle of successively decreasing first quick and back slow, tapered dosage dosage should be grasped by doctor's advice.
This product is oral can be used as the ancillary drug of prevention of relapse after the Opioid Addicts detoxification.1. stage of preparation: (1) starts to take medicine in first 7～10 days and did not abuse opioid drug.(2) detection of urine morphine should be negative.As positive, the furan of receiving draws the coffee treatment to delay, until carry out after urine morphine feminine gender again.2. induction period: the beginning care should be used to for the treatment of, slowly increase and receive furan and draw the dosage of coffee.General 3～5 days of induction period, this phase purpose is that the pill taker is progressively reached to be received furan and draws the suitable taking dose of coffee, and induction period carries out when being in hospital.3 maintenance phases: dosage: every day oral 0.5-5 μ g, a decoction being taken at a draught.In principle as long as there be possibility relapse, should take and receive furan and draw coffee to prevent.
The specific embodiment
Embodiment mono-, hydrochloric acid are received furan and are drawn the effect of coffee to the mice Opiate withdrawal symptoms
Test method
1, morphine-dependent mice is urged and is given up the prophylactic treatment test: 40 of mices, and male and female half and half are divided into 4 groups at random: 1 group is the NS matched group, 2 groups is the morphine matched group, 3 groups is that hydrochloric acid is received furan and drawn coffee sheet (3 μ g/ sheet) group, and 4 groups is that hydrochloric acid is received furan and drawn coffee injection (1.5 μ g/ prop up) group.Except 1 group, all the other respectively organize the equal subcutaneous injection morphine of mice 30mg/kg, and 2 times/days (interval 6h) continuous 4 days, causes the physical dependence model of morphine in mice.3,4 groups when giving morphine at every turn, give hydrochloric acid and receive furan and draw coffee sheet or injection, last to morphine after 2-3h, each is organized the equal ig naloxone of mice 8mg/kg and carries out challenge test, weight loss situation after mouse jump number of times and 2h respectively organized in 10min in record after urging.
2, the heroin dependence mice is urged and gives up the prophylactic treatment test: 40 of mices, and male and female half and half are divided into 4 groups at random: 1 group is the NS matched group, 2 groups is the heroin matched group, 3 groups is that hydrochloric acid is received furan and drawn coffee sheet (3 μ g/ sheet) group, and 4 groups is that hydrochloric acid is received furan and drawn coffee injection (1.5 μ g/ prop up) group.Except 1 group, all the other respectively organize the equal subcutaneous injection heroin of mice 16mg/kg, 2 times/days, continuous 4 days, cause the physical dependence model of mice to heroin.3,4 groups when giving heroin at every turn, giving hydrochloric acid receives furan and draws coffee sheet or injection, last to heroin after 2-3h, each is organized the equal ig naloxone of mice 8mg/kg and carries out challenge test, weight loss situation after mouse jump number of times and 2h respectively organized in 10min in record after urging.。
Experimental result:
1, hydrochloric acid is received furan and drawn coffee Syndrome of Morphine Dependent mice to urge to give up the prophylactic treatment result: continuous 4 days, subcutaneous injection morphine 30mg/kg, every day 2 times, caused the physical dependence of morphine in mice, after urging with naloxone, can occur jumping and the withdrawal symptoms such as weight loss.Each receive furan to hydrochloric acid when giving morphine and draw coffee can obviously reduce number of skips and the body weight change of mice, in Table 1
Table 1 hydrochloric acid is received furan and is drawn the naloxone of coffee Morphine dependent Mice to urge experiment (± S, N=10)
| Group | Jump incidence rate % | Number of skips | Weight loss g |
| NS | 0 | 0 | 0.41±0.11 |
| Morphine | 90 | 12±7 | 0.92±0.23 |
| Hydrochloric acid is received furan and is drawn the coffee sheet | 60 | 5±2 | 0.50±0.31 |
| Hydrochloric acid is received furan and is drawn the coffee injection | 60 | 4±2 | 0.52±0.30 |
2, hydrochloric acid is received furan and is drawn coffee to urge and to give up the prophylactic treatment result the heroin dependence mice: continuous 4 days, subcutaneous injection heroin 16mg/kg, every day 2 times, can cause the physical dependence of mice to heroin, after urging with naloxone, the withdrawal symptoms such as jump and weight loss can appear.Each when giving heroin to hydrochloric acid receive furan draw coffee obviously to reduce to urge after mouse jump number of times and weight loss.In Table 2
Table 2 hydrochloric acid is received furan and is drawn coffee to urge experiment (± S, N=10) to the naloxone of Heroin-dependent mice
| Group | Jump incidence rate % | Number of skips | Weight loss g |
| NS | 0 | 0 | 0.35±0.16 |
| Heroin | 80 | 11±6 | 0.88±0.43 |
| Hydrochloric acid is received furan and is drawn the coffee sheet | 50 | 4±2 | 0.47±0.30 |
| Hydrochloric acid is received furan and is drawn the coffee injection | 50 | 4±1 | 0.50±0.25 |
Embodiment bis-, hydrochloric acid are received furan and are drawn the treatment of coffee to the mice ethylism
40 mices, being divided at random matched group, Naloxone injection (2mg/ props up) group, Nalmefene injection (0.1mg/ props up) group, hydrochloric acid receives furan and draws coffee injection (1.5 μ g/ prop up) group, every group 10, lumbar injection 60% ethanol, 2min after the ethylism righting reflex loss, give the corresponding treatment medicine by subcutaneous injection, observe animal righting reflex recovery time, after giving ethanol, Mus is faced upward and puts desktop, in room temperature (20 ± 2 ℃), under quiet condition, it is righting reflex loss (LOR) that 60s voluntarily rights the person
Experimental result: in Table 3
Mice is after lumbar injection 60% ethanol 5.0g/kg, restlessness appears very soon, and then quiet unable, walk about and wave, be drunk shape, occur LOR after 2min, about 40min of persistent period, at naloxone, nalmefene, the hydrochloric acid of subcutaneous injection doses, receive after furan draws coffee, the mice righting reflex is obviously shortened recovery time, three groups of action effect there was no significant differences
The treatment (± S, N=10) of each group of table 3 to the mice ethylism
| Group | The LOR persistent period (min) |
| Matched group | 40.2±26.7 |
| The nalmefene injection | 16.9±11.3 |
| The naloxone injection | 18.4±6.6 |
| Hydrochloric acid is received furan and is drawn coffee injection | 20.5±8.1 |
Embodiment tri-, hydrochloric acid are received furan and are drawn the Awakening Effect of coffee to the ketamine combined anesthesia mice
Experimental technique
Model preparation and grouping: by randomized block design, mice is divided into to 3 groups, normal saline group, naloxone group, hydrochloric acid are received furan and are drawn the coffee group, 10 every group.Each is organized the equal intraperitoneal injection of ketamine of mice (120mg/kg) and makes the anesthesia model.Medication: the ketamine of intraperitoneal injection of anesthesia dosage (120mg/kg), 1min after righting reflex loss.Normal saline group mouse peritoneal injecting normal saline (10ml/kg), naloxone group lumbar injection naloxone (2mg/kg), hydrochloric acid is received furan and is drawn coffee group lumbar injection hydrochloric acid to receive furan to draw coffee (1.5 μ g/kg), and the administration volume is 0.1mL.
Evaluation criteria: the continuous rear 5s that lies on the back for 3 times of mice can not recover to stand into righting reflex loss, and the continuous rear recovery of lying on the back for 3 times is stood as the righting reflex recovery
Experimental result:
With the normal saline group, compare, naloxone group and hydrochloric acid are received and are all significantly shortened the length of one's sleep that furan draws coffee group mice, illustrate that above-mentioned different pharmaceutical all can antagonism ketamine syngignoscism; Hydrochloric acid is received furan and is drawn coffee group and naloxone group difference not significantly (P > 0.05), illustrate hydrochloric acid receive furan draw coffee and naloxone antagonism Patients Under Ketamine Anesthesia mice effect all ought, the results are shown in Table 4
The Awakening Effect (± S, N=10) of table 4 pair ketamine combined anesthesia mice
| Group | The length of one's sleep (min) |
| Matched group | 30.2±3.2 |
| The naloxone injection | 21.4±2.6 |
| Hydrochloric acid is received furan and is drawn coffee injection | 20.6±3.1 |
Embodiment tetra-, hydrochloric acid are received furan and are drawn coffee pelliculae pro cavo oris preparation
Making 1000 hydrochloric acid with the raw material of following weight proportion receives furan and draws coffee oral cavity diaphragm.
Preparation technology:
1. the furan of hydrochloric acid being received draws coffee, cetomacrogol 1000, polyvinyl alcohol, glycerol, sucralose and essence to be dissolved in suitable water, makes to dissolve, standby.
2. coating, and get final product.
Embodiment five, hydrochloric acid are received furan and are drawn coffee buccal tablets preparation
Making 1000 hydrochloric acid with the raw material of following weight proportion receives furan and draws the coffee buccal tablets.
Preparation technology:
1. the furan of hydrochloric acid being received draws coffee, and polyvidone is dissolved in suitable quantity of water and makes binding agent, standby;
2. by lactose and aforementioned adhesion agent soft material processed, 24 mesh sieves are granulated, 40 ℃ of dryings, 28 mesh sieve granulate;
3. aforementioned particles is fully mixed homogeneously with magnesium stearate, the stamping of 7mm scrobicula, obtain.
Embodiment six, hydrochloric acid are received furan and are drawn coffee tablet preparation
Making 1000 hydrochloric acid with the raw material of following weight ratio receives furan and draws the coffee sheet.
Preparation method:
1. the furan of hydrochloric acid being received draws coffee to be dissolved in suitable quantity of water and makes binding agent, standby.
2. by lactose, microcrystalline Cellulose, the abundant mix homogeneously of cross-linking sodium carboxymethyl cellulose, standby.
3. with the binding agent of step 1 preparation and the mixed powder soft material processed of step 2,20 orders are granulated, 40 ℃ of oven dry, 24 order granulate.
4. add the abundant mix homogeneously of magnesium stearate, the stamping of 7mm scrobicula, obtain.
Embodiment seven, hydrochloric acid are received furan and are drawn coffee slow releasing tablet preparation
Making 1000 hydrochloric acid with the raw material of following weight ratio receives furan and draws the coffee slow releasing tablet.
Preparation method:
1. the furan of hydrochloric acid being received draws coffee to be dissolved in suitable quantity of water and makes wetting agent, standby.
2. by lactose, the abundant mix homogeneously of hydroxypropyl cellulose, standby.
3. with the wetting agent of step 1 preparation and the mixed powder soft material processed in step 2,24 orders are granulated, 40 ℃ of oven dry, 40 order granulate.
4. add the abundant mix homogeneously of magnesium stearate, the stamping of 7mm scrobicula, obtain.
Embodiment eight, hydrochloric acid are received furan and are drawn coffee capsule preparation
Making 1000 hydrochloric acid with the raw material of following weight proportion receives furan and draws the coffee capsule.
Preparation technology:
1. the furan of hydrochloric acid being received draws coffee to be dissolved in suitable quantity of water, standby.
2. the furan of the hydrochloric acid in step 1 being received draws coffee solution fully to mix homogeneously with 5% starch slurry, standby.
3. by lactose, the abundant mix homogeneously of carboxymethyl starch sodium, standby.
4. by mixed powder soft material processed in binding agent and step 3 in step 2,24 orders are granulated, dry rear granulate.
5. add the abundant mix homogeneously of magnesium stearate, be packed in capsulae vacuus and get final product.
Embodiment nine, hydrochloric acid are received furan and are drawn coffee slow releasing capsule preparation
Making 1000 hydrochloric acid with the raw material of following weight proportion receives furan and draws the coffee capsule.
Preparation technology:
1. hydrochloric acid is received furan and is drawn the coffee crude drug to be dissolved in suitable quantity of water to make wetting agent, standby.
2. lactose is fully mixed homogeneously with hyprolose, standby.
3. by the mixed powder soft material processed of the wetting agent of step 1 and step 2,20 mesh sieves are granulated, 60 ℃ of dryings, 24 mesh sieve granulate.
4. add the abundant mix homogeneously of magnesium stearate, be packed in capsulae vacuus and get final product.
Embodiment ten, hydrochloric acid are received furan and are drawn coffee injection preparation
Making 1000 hydrochloric acid with the raw material of following weight proportion receives furan and draws coffee injection (specification 5ml:1.0ug)
Preparation technology:
1. detect the water for injection dissolved oxygen, guarantee that dissolved oxygen is less than 2.0ppm.
2. get water for injection 3200ml, dissolve the 310.8g arginine.After arginine all dissolves, add recipe quantity hydrochloric acid to receive furan and draw coffee, make abundant dissolving.
3. get water for injection 800ml, dissolve the 27.0g arginine.After arginine all dissolves, with the 1M hydrochloric acid solution, regulate pH value to 5.6-6.5.This solution is joined in above-mentioned solution (2) to mix homogeneously.
4. add 0.2% active carbon in solution, 60 ℃ of insulations 20min, decarburizations while hot.
5. after solution is cooling, intermediate detects, standardize solution.
6. fine straining, fill, inflated with nitrogen, sealing by fusing.
7. sterilizing (121 ℃, 12min).
8. leak detection, lamp inspection.
9. packing, put in storage.
Embodiment 11, hydrochloric acid are received furan and are drawn coffee lyophilized formulations preparation
Making 1000 hydrochloric acid with the raw material of following weight proportion receives furan and draws coffee freeze-dried instant sheet
Preparation technology:
Get the 500ml purified water, add recipe quantity hydrochloric acid to receive furan and draw coffee, add mannitol, essence, trichlorine sugarcane to be stirred to dissolve, with sodium citrate solution, adjust pH value to 5.0-7.5, quantitative separating, in mould, is put lyophilizing in freezer dryer, obtains the freeze-dried instant sheet.
The lyophilization condition is :-40 ℃ of pre-freezes 4 hours, and the first stage is warming up to-10 ℃, time 2 h, vacuum drying 12 hours, second stage heats up in 1 hour from-10 ℃～30 ℃, and is incubated 4 hours.
Claims (10)
1. the morphinan quaternary ammonium salt derivative, for blocking the purposes of exogenous opioid, is characterized in that, using receive furan draw coffee and pharmaceutical salts thereof as active component the new purposes for the pharmacological action that reverses opioid drug wholly or in part and produced.
2. purposes claimed in claim 1, is characterized in that, as the ancillary drug of prevention of relapse after the Opioid Addicts detoxification.
3. purposes claimed in claim 1, is characterized in that, for removing the respiration inhibition of opioid drug combined anesthesia medicine due to postoperative, and wakens patient.
4. purposes claimed in claim 1, is characterized in that, excessive for opioid drug.
5. purposes claimed in claim 1, is characterized in that, for acute alcoholism.
6. purposes claimed in claim 1, is characterized in that, described active component is received furan and drawn coffee to give with oral or injection system.
7. purposes claimed in claim 6, is characterized in that, activity is received furan, and to draw the single dosage of coffee be 0.1 μ g-100mg.
8. purposes claimed in claim 7, is characterized in that, by the oral furan of receiving, draws the single dosage of coffee to be preferably 0.5-5 μ g, and its pharmaceutical dosage form presented can be capsule, oral cavity dispersion membrane, tablet etc.
9. purposes claimed in claim 7, is characterized in that, receives furan by injection and draw the single dosage of coffee to be preferably 0.2-2.5 μ g, and its pharmaceutical dosage form presented can be injection with small volume, high-capacity injection, Injectable sterile lyophilized powder etc.
10. purposes claimed in claim 7, is characterized in that, the furan of receiving draws administration number of times every day, administration cycle of coffee to need determine according to concrete indication, conventional therapy every day 1-3 time.
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| CN201310409642.2A CN103479639A (en) | 2013-09-10 | 2013-09-10 | Application of morphinan quaternary ammonium salt derivative to blocking exogenous opioids |
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| CN201310409642.2A CN103479639A (en) | 2013-09-10 | 2013-09-10 | Application of morphinan quaternary ammonium salt derivative to blocking exogenous opioids |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016163403A1 (en) * | 2015-04-07 | 2016-10-13 | ニプロ株式会社 | Oral film preparation |
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2013
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016163403A1 (en) * | 2015-04-07 | 2016-10-13 | ニプロ株式会社 | Oral film preparation |
| JPWO2016163403A1 (en) * | 2015-04-07 | 2018-02-01 | ニプロ株式会社 | Oral film formulation |
| JP2021138762A (en) * | 2015-04-07 | 2021-09-16 | ニプロ株式会社 | Oral film preparation |
| JP7347474B2 (en) | 2015-04-07 | 2023-09-20 | ニプロ株式会社 | Oral film formulation |
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