CN103735545A - Applications of levorotary oxiracetam and oxiracetam in preparing drugs for preventing or treating coma - Google Patents
Applications of levorotary oxiracetam and oxiracetam in preparing drugs for preventing or treating coma Download PDFInfo
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Abstract
The invention provides applications of levorotary oxiracetam and oxiracetam in preparing drugs for preventing or treating coma. Experimental results indicate that levorotary oxiracetam has obvious awaking effect on coma caused by alcoholism, but dextrorotary oxiracetam basically has no effect, and the awaking effect of levorotary oxiracetam is two times of that of dextrorotary/levorotary mixed oxiracetam; levorotary oxiracetam has remarkable awaking effect on comas caused by both trauma and anesthesia.
Description
The present patent application is application number 2011103766076, November 23 2011 applying date, the dividing an application of denomination of invention " application in preparation prevention or treatment stupor medicine of levo-oxiracetam, oxiracetam ".
Technical field
The present invention relates to the medical usage of levo-oxiracetam, oxiracetam, be specifically related to levo-oxiracetam, the application of oxiracetam in preparation prevention or treatment stupor medicine.
Background technology
Oxiracetam (oxiracetam), be by Italian SmithKline Bi Qiemu company in 1974 synthetic nootropics first, this medicine went on the market in Italy in 1987, the raceme that oxiracetam is comprised of two kinds of isomers (S)-oxiracetam ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam); Report about oxiracetam, it can promote ATP in brain, promote acetylcholine to synthesize and strengthen the conduction of neural excitation, to the antidromicity due to anoxia is forgetful, there is an improved action, can hypermnesis, improving learning capacity, is one of active drug of the diseases such as treatment dementia of the Alzheimer type (AD), vascular dementia (VD).
Levo-oxiracetam ((S)-Esomeprazole) is the levo form of oxiracetam (Oxiracetam CAS62613-82-5), for white micro-crystals sprills, 135～136 ℃ of fusing points, optical rotation is-36.0 ° (C=1.00in water), and the dissolubility of levo-oxiracetam is obviously better than DL body.Levo-oxiracetam there is no the independent report as medicinal application at present.
CN101367757A discloses a kind of preparation method of (S)-Esomeprazole.It adopts (S)-4-halogen-3-hydroxybutyrate ester is that raw material reacts and obtains levo-oxiracetam under polar solvent and alkali condition, under alkali condition wherein, reaction is to add alkali by gradation in described course of reaction, drip chloro thing and control the mode of reaction pH, crude product obtains the acidic aqueous solution of product after cation exchange resin, adopt again anion exchange resin neutralization, after neutralizer is concentrated, obtain thick product, thick product by ethyl alcohol recrystallization once, again with methanol/acetone mixed solvent crystallization once or isopropyl alcohol recrystallization method once prepare levo-oxiracetam.
Stupor is because the most serious disturbance of consciousness that highly inhibition causes occurs network structure under cerebral cortex and cortex, and consciousness continues interrupt or completely lose highest neururgic height inhibitory state, is that patient realizes a kind of serious situation completely losing.Alcoholism (alcoholism) be three serious diseases that occur of stupor because of one of, along with increasing the weight of of the quickening of Modern Live rhythm and people's stress, alcoholic is increasing, and the appearance of the poisoning stupor of drunk and Alcoholic (alcohol coma) phenomenon is more and more general; Three serious diseases that due to wound, stupor occurs for stupor because of one of, also comparatively general because going into a coma due to traffic accident, the wound such as fall now; Due to surgery anesthesia, stupor is current common malpractice, some patient after anesthesia long " deep sound sleep ", there is no consciousness, due to anesthesia stupor for go into a coma three serious diseases because of one of.Thereby the short cure rate of waking up that how further improves stupor reduces mortality rate and improves arousal level and cognitive function is the key subjects that face now, addresses this problem and will have important practical significance.
Summary of the invention
The object of the present invention is to provide oxiracetam, the levo-oxiracetam purposes in pharmaceutical field, be specifically to provide oxiracetam, the application of levo-oxiracetam in preparation prevention or treatment stupor medicine.
Specifically, the present invention relates to levo-oxiracetam as the application of going into a coma in medicine due to preparation prevention or treatment alcoholism; As the application of going into a coma in medicine due to preparation prevention or treatment anesthesia; As the application of going into a coma in medicine due to preparation prevention or treatment wound.The present invention relates to oxiracetam as the application of going into a coma in medicine due to preparation prevention or treatment alcoholism; As the application of going into a coma in medicine due to preparation prevention or treatment anesthesia; As the application of going into a coma in medicine due to preparation prevention or treatment wound.
Oxiracetam, the application of levo-oxiracetam in preparation prevention or treatment stupor medicine, can be prepared into specifically the pharmaceutical composition that active component is oxiracetam or levo-oxiracetam, dosage form can be injection as injectable powder, the dosage forms such as injection; Oral formulations, as tablet, drop pill, powder, granule, capsule etc.; Above dosage form all can make according to conventional method.
Above-mentioned dosage form is preferably oral capsule, tablet or injection.
The dosage of above-mentioned levo-oxiracetam oral formulations is 5～30mg/kg/ days, 10～20mg/kg/ days more preferably, and the dosage of levo-oxiracetam injection is 50～90mg/kg/ time.The dosage of above-mentioned oxiracetam oral formulations is 10～60mg/kg/ days, is more preferably 20～40mg/kg/ days, and the dosage of oxiracetam injection is 100～180mg/kg/ time.
Most preferably, the application in preparation prevention or treatment stupor medicine of levo-oxiracetam or oxiracetam, preferably adopting purity is that the levo-oxiracetam of more than 99.3% (optical purity) is as active component, by weight percentage.
In order further to verify medicinal effects of the present invention, inventor has carried out following test.
(1) pharmacokinetics and absolute bioavailability research in levo-oxiracetam animal body
The research that the pharmacokinetics contrast of take with DL body oxiracetam is prerequisite, determines that the gavage of Beagle dog and Bolos intravenous administration dosage are 50mg/kg.
Get 6 of the Beagle dogs of growing up, male female half and half, body weight 10.0 ± 0.5kg.Be divided at random three groups, 2 every group, male and female half and half.Adopt Latin square three cross-over experiments (seeing the following form 1), to the gavage of Beagle dog and Bolos intravenous administration, dosage is 50mg/kg.The sample that adopts the purity of levo-oxiracetam to reach 99.3% (optical voidness) is studied, one week, every kind of route of administration interval.Gastric infusion, in animal fasting administration after 12 hours, continues fasting 3 hours after administration.Before administration, get blank blood, after gastric infusion 0.083,0.25,0.5,0.75,1.0,1.5,2.0,4.0,6.0,8.0,12.0,24.0 hour; After Bolos intravenous administration 0.083,0.25,0.5,0.75,1.0,1.5,2.0,4.0,6.0,8.0,12.0,24.0 hour from forelimb venous blood sampling 1mL in heparinization test tube, centrifuging and taking blood plasma, measures blood plasma Chinese medicine concentration by LC-MS-MS method.The results are shown in following table 2-7.
Three cycles three of the table 1 Latin square experimental design Beagle dog grouping situation of reporting to the leadship after accomplishing a task
Note: ORT is oxiracetam; S-ORT is levo-oxiracetam
After the quiet note of dog and gavage 50mg/kg oxiracetam, levo-oxiracetam, blood plasma Chinese medicine concentration is listed in respectively table 2-4.
Blood plasma Chinese medicine concentration (μ g/mL) after the quiet note of table 2Beagle dog 50mg/kg oxiracetam
ND: lower than 0.5 μ g/mL
Blood plasma Chinese medicine concentration (μ g/mL) after table 3Beagle dog gavage 50mg/kg levo-oxiracetam
ND: lower than 0.5 μ g/mL
Blood plasma Chinese medicine concentration (μ g/mL) after the quiet note of table 4Beagle dog 50mg/kg levo-oxiracetam
ND: lower than 0.5 μ g/mL
Pharmacokinetic parameter after table 5Beagle dog perfusion 50mg/kg levo-oxiracetam
Pharmacokinetic parameter after table 6Beagle dog gavage 50mg/kg levo-oxiracetam
Pharmacokinetic parameter after the quiet note of table 7Beagle dog 50mg/kg levo-oxiracetam
As can be seen here: after Beagle dog gavage 50mg/kg oxiracetam, AUC
0-∞be 165.04 ± 24.02h, clearance rate is 0.31 ± 0.04L/h/kg, peak time and reach peak concentration and be respectively 1.25 ± 0.27h, 39.67 ± 7.55 μ g/mL; After gastric infusion 50mg/kg levo-oxiracetam, AUC
0-∞be 160.97 ± 27.86h, peak time and reach peak concentration and be respectively 1.21 ± 0.53h, 41.28 ± 11.29 μ g/mL; AUC after Bolos intravenous administration
0-∞the absolute bioavailability that is 242.72 ± 37.75h estimation is 65.76 ± 9.12%, specifically referring to accompanying drawing 1 and accompanying drawing 2.
Reach a conclusion: levo-oxiracetam retains the medicine of former oxiracetam for parameter attribute.
(2) toxicological test
Under GLP experiment condition, compare the ICR mouse toxicity of levo-oxiracetam and oxiracetam, setting dosage is 5g/kg, every group of 20 animals, and male and female half and half, with oral gavaging after the preparation of 0.5%CMC liquid.Result shows: two treated animals are movable normal, without overt toxicity, presents, and 14 days none animals occur between dead two groups without obvious Difference In Toxicity Continuous Observation.The not medicative increase of levo-oxiracetam is described and increases toxicity simultaneously.
Oxiracetam is marketed drugs, and its pharmacokinetics, toxicity etc. are common practise.
(3) oxiracetam, levo-oxiracetam and the dextrorotation oxiracetam experimentation on the impact of ethanol induced mice stupor
One, experiment material
1, medicine and reagent: left oxiracetam, right oxiracetam and DL oxiracetam; Naloxone, purchased from Chongqing Yao You pharmaceutical Co. Ltd; Dehydrated alcohol, purchased from Shanghai Qiang Shun chemical reagent company limited.Normal saline is commercially available, each medicinal liquid matching while using.
2, the preparation of alcoholic solution: get dehydrated alcohol, become 30% alcoholic solution with normal saline dilution, face the used time and now join.
3, laboratory animal: male mice in kunming, body weight 18-22 gram.Licence: SCXK (river) 2008-14 is provided by Sichuan Province plant of laboratory animal special commission.Animal facility continues to keep barrier environment standard.The span of control of main environment index: temperature is 20.0-25.0 ℃, relative humidity is 40-70%.Rate of ventilation is 10-20 time/hour, optical illumination: dark=14h: 10h.Animal feeding in base box, 5, every box.
Two, experimental technique
1, mice Alcoholic stupor model preparation method: reference literature [1] (M.EL Yacoubi, C.Ledent, M.parmentier, et al.Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade[J] .Neuropharmacology, 2003,45 (7): 977-985) set up model, method is 30% alcoholic solution lumbar injection (0.2ml/10g).
2, mice state of consciousness method of discrimination:
Reference literature [2] (Jeffrey R.Stephens, Rene H.Levy.Effects of valproate and citrulline on ammonium-Induc-ed encephalopathy[J] .Epilepsia, 1994,35 (1): 164-171) realize differentiation: 1 grade, movable minimizing in cage; 2 grades, the movable minimizing of extremity accompanies ataxia; 3 grades, when back is placed on the bottom of cage, can roll (righting reflex existence), but can not stand; 4 grades, position can not be corrected at the bottom of being placed in cage in back, but the reaction of noxious stimulus is shown as to limbs retraction; 5 grades, righting reflex loss (Loss of Righting Reflex, LORR) and the reaction of shortage to noxious stimulus.4,5 grades are considered as animal and lie in a comatose condition.
3, experiment grouping and design
150 animals are divided into 10 groups at random: model control group (only giving normal saline); 60,180,360mg/kg group DL oxiracetam is set up three groups, is respectively:; Dextrorotation oxiracetam is set up two groups, is respectively: 90,180mg/kg group; Levo-oxiracetam is set up three groups, is respectively: 30mg/kg, 90mg/kg and 180mg/kg group; One group of naloxone, dosage is 1.5mg/kg.After every treated animal model is successfully prepared, by random table grouping, righting reflex loss is tail vein injection administration after one minute.Observe mice righting reflex loss persistent period, the i.e. length of one's sleep.Experimental result statistical procedures: experimental data represents with x ± sd, more all adopts one factor analysis of variance and q check, inspection level: α=0.05 between each group.
Three, experimental result
Each length of one's sleep of organizing mice after administration is in Table 8:
The impact on ethanol induced mice stupor of table 8 oxiracetam, levo-oxiracetam and dextrorotation oxiracetam
From above result, levo-oxiracetam is shortly waken up effect obviously to what go into a coma due to alcoholism, and dextrorotation oxiracetam not have to act on substantially; DL oxiracetam also has certain effect to short the waking up of going into a coma due to alcoholism, and the short effect of waking up of levo-oxiracetam is about 2 times of DL oxiracetam.
(4) oxiracetam, levo-oxiracetam and dextrorotation oxiracetam waken experimentation to ketamine induced mice stupor
Ketamine is owing to having calmness, forget, ease pain and anaesthetize characteristic, for typical anesthetis, be widely used clinically, but find that ketamine calmness is excessively dark, the persistent period is long, often causing revives postpones or does not revive always, thereby brings potential life danger.For reviving, postpone or do not revive, clinical conventional analeptic has naloxone at present, studies levo-oxiracetam etc. herein to caused the Awakening Effect of mice stupor by ketamine.
1, materials and methods
150 of 1.1 laboratory animals and grouping Kunming mouses, male, body weight (25.3 ± 1.9) g, is provided by Sichuan Province plant of laboratory animal special commission, licence: SCXK (river) 2008-14.Animal facility continues to keep barrier environment standard.The span of control of main environment index: temperature is 20.0-25.0 ℃, relative humidity is 40-70%.Rate of ventilation is 10-20 time/hour, optical illumination: dark=14h: 10h.Animal feeding in base box, 5, every box.
With ketamine 120mg/kg lumbar injection, cause after stupor, select 120 of the successful mices of modeling to be divided into 10 groups (n=12) by random stratified block design: tri-groups of levo-oxiracetam 30,75,180mg/kg; Bis-groups of dextrorotation oxiracetam 30,180mg/kg; Tri-groups of DL oxiracetam 60,150,360mg/kg; Mono-group of naloxone 1.5mg/kg; Normal saline group (NS group).
20100205) and DL oxiracetam (commercially available prod, lot number: 20100105) 1.2 experimental drugs: levo-oxiracetam (according to patent application CN101367757A preparation), dextrorotation oxiracetam (commercially available prod, lot number:; Naloxone hydrochloride injection 1ml: 0.4mg (Chongqing Yaoyou Pharmaceutical Co., Ltd. produces, lot number 1001020); Ketaject injection 2ml: 0.1g (Jiangsu Province Heng Rui limited company produces, lot number KH091201).
1.3 experimental techniques and observation index mouse peritoneal injection ketamine 120mg/kg, 1min after righting reflex loss, each group is intravenous injection levo-oxiracetam 30,75,180mg/kg respectively; Dextrorotation oxiracetam 30,180mg/kg; DL oxiracetam 60,150,360mg/kg and naloxone 1.5mg/kg and normal saline 10ml/kg, observe the mice righting reflex loss persistent period (recovery time).Mice is continuous lie on the back for 3 times after 5s can not recover to stand into righting reflex loss, after continuous lying on the back for 3 times, recover to stand and recover into righting reflex.
1.4 statistical procedures data represent with x ± sd, with statistic software SPSS 12.0, carry out data analysis, and each group relatively adopts one factor analysis of variance, inspection level: α=0.05.
2, result
Levo-oxiracetam, dextrorotation oxiracetam and DL oxiracetam on the impact of the mice stupor persistent period due to ketamine in Table 9.
The impact on the mice stupor persistent period due to ketamine of table 9 levo-oxiracetam, dextrorotation oxiracetam and DL oxiracetam
As seen from the above table: levo-oxiracetam has the significant short effect of waking up within the scope of dosage 30-180mg/kg, DL oxiracetam also has effect within the scope of dosage 150-360mg/kg, and with the dosage same dose such as levo-oxiracetam under dextrorotation oxiracetam without any effect, positively with reference to medicine naloxone, stupor mice is also demonstrated to positive effect.
(5) short the wake up experimentation of left oxiracetam to rat traumatic coma
1, experiment material:
1.1 reagent and medicine
Left oxiracetam (according to patent application CN101367757A preparation); Naloxone hydrochloride injection 1ml: 0.4mg (Chongqing Yaoyou Pharmaceutical Co., Ltd. produces, lot number 1001020).
2, experimental technique
2.1 animal models and grouping administration
Laboratory animal adopts 50 of SD rats, clean level, and male, during experiment, body weight is 350～400g, purchased from great Ping hospital of Third Military Medical University medical experiment animal center, production licence: SLXK (Chongqing) 2007-0005.Animal facility continues to keep barrier environment standard.The span of control of main environment index: temperature is 20.0-25.0 ℃, relative humidity is 40-70%.Rate of ventilation is 10-20 time/hour, optical illumination: dark=14h: 10h.Animal feeding in base box, 5, every box.
2.2 Animal Model
Rat traumatic coma model with reference to Feeney method, set up rat experiment severe traumatic head injury model.The experiment power adopting is that 6000g/cm[is weight (g) * this rammer drop (cm) of rammer].With chloral hydrate, carry out after shallow degree anesthesia the depilation of calvarium portion, sterilization; Rat is fixed on stereotactic apparatus, and median incision is opened cranium, with dental burr 3mm and the boring of 3mm confluce, sagittal suture right side after coronal suture, expands bone window to 6mm * 6mm (front to coronal suture, left boundary is the right other 2mm of sagittal suture), keeps dura mater complete; The cylindric strike bar of heavy 30g (hitting end diameter 4.5mm), along highly discharging from 20cm in the sleeve pipe being vertically fixed on stereotactic apparatus, is hit to position and is boring point; After strike, with gelfoam local hemostasis, extremely after after active hemorrhage, sew up scalp.After modeling, reject dark with the dead at once animal of stupor degree, the 10 minutes above animals that go into a coma are selected.
2.3 grouping administrations
There are 30 animals selected the animal of causing stupor after hitting, are divided at random three groups, 10 every group.One group as model control group, gives normal saline, 0.5ml/100g; Give left oxiracetam, 125mg/kg for second group; The 3rd group to naloxone hydrochloride injection, 1mg/kg.Each group is all in stupor administration after latter 10 minutes, in the rearmounted cage of administration peace and quiet lie on the back lie foster.Respectively at 1,2,4,8 hour observation animal comatose state after administration, press scoring classification and give a mark.
2.4 rat comatose state stage divisions
1 grade: movable as usual in cage
2 grades: movable minimizing in cage
3 grades: movable minimizing and movement disorder in cage
4 grades: when back is placed on the bottom of cage, can roll (righting reflex existence) but can not stand
5 grades: righting reflex quench but pain stimulation is had to limbs retraction reaction
6 grades: righting reflex loss. reactionless to pain stimulation, earflap reflection simultaneously, absent corneal reflex. afterbody squeezes and can not elicit escape reaction.
Wherein 5,6 grades are considered to comatose state.
3, experimental result
Left oxiracetam to the effect of rat traumatic coma in Table 10.
The left oxiracetam of table 10, naloxone hydrochloride are to the effect of rat traumatic coma
Note: * represents to represent to compare P < 0.01 with matched group with matched group comparison P < 0.05 * *
As seen from the above table: model group animal from brain injury to 8 hours score values maintain more than 4 minutes, and there have 20% animal to occur to be dead.To rat state after left oxiracetam 125mg/kg1 hour to start to be clearly better, scoring average 5.1, relatively there were significant differences (P < 0.05) with matched group, demonstrate ever since obvious consciousness and improve effect, this organizes none animal generation death whole experimental session, illustrates that left oxiracetam is conclusive to the effect of rat traumatic coma.Same positive drug naloxone hydrochloride also presents the good short effect of waking up, and satisfactory for result, this and clinical application effect match.
Accompanying drawing explanation
Fig. 1: curve during for medicine after the oral levo-oxiracetam of each dog, oxiracetam and the left oxiracetam of quiet note, it is the test of the interior pharmacokinetics of levo-oxiracetam animal body and absolute bioavailability research, for every dog gavage 50mg/kg oxiracetam, and Plasma-time data figure of each dog after quiet note and gavage 50mg/kg levo-oxiracetam, wherein CK-sox is that levo-oxiracetam, CK-hox are DL oxiracetam.
Fig. 2: curve during for average medicine after the oral left oxiracetam of dog, oxiracetam and quiet note levo-oxiracetam, in the test of the interior pharmacokinetics of levo-oxiracetam animal body and absolute bioavailability research, for Begale dog gavage 50mg/kg oxiracetam, and average blood drug level-time data figure in blood plasma after quiet note and gavage 50mg/kg levo-oxiracetam, wherein CK-sox is that levo-oxiracetam, CK-hox are DL oxiracetam.
The specific embodiment
To describe several embodiments of the present invention below, but content of the present invention is not limited to this.
Embodiment 1:
Raw material forms:
(a) levo-oxiracetam (purity is 99.5%) 200mg/ grain
(b) lactose 80mg/ grain
(c) microcrystalline Cellulose 70mg/ grain
Take that to make 1000 levo-oxiracetam capsules be example, concrete preparation method is: first supplementary material is crossed to 80 mesh sieves, taken levo-oxiracetam, lactose, the microcrystalline Cellulose mix homogeneously of recipe quantity, directly capsule charge.
Embodiment 2:
Raw material forms:
Take that to make 1000 tablets of levo-oxiracetam tablets be example, concrete preparation method is: first supplementary material is crossed to 80 mesh sieves, take levo-oxiracetam, starch, the microcrystalline Cellulose mix homogeneously of recipe quantity, add 2%HPMC aqueous solution soft material processed, granulate, dry, granulate, to the Pulvis Talci that adds recipe quantity in granule, mix homogeneously, tabletting.
Embodiment 3:
Raw material forms:
Take that to make 1000 levo-oxiracetam capsules be example, concrete preparation method is: first supplementary material is crossed to 80 mesh sieves, take left oxiracetam, lactose, the carboxymethyl starch sodium mix homogeneously of recipe quantity, add 10%PVP alcoholic solution soft material processed, granulate, dry, granulate, to the Pulvis Talci that adds recipe quantity in granule, mix homogeneously, capsule charge.
Claims (5)
1. the application that levo-oxiracetam is gone into a coma in medicine due to preparation prevention or treatment wound.
2. application as claimed in claim 1, is characterized in that: the described medicine containing levo-oxiracetam is injection or oral formulations.
3. purposes as claimed in claim 1 or 2, is characterized in that: the levo-oxiracetam crude drug purity of described use is more than 99.3%, by weight percentage.
4. the application that oxiracetam is gone into a coma in medicine due to preparation prevention or treatment wound.
5. application as claimed in claim 4, is characterized in that: the described medicine containing oxiracetam is oral formulations or injection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106619523A (en) * | 2015-10-27 | 2017-05-10 | 重庆润泽医药有限公司 | (S)-4-hydroxy-dioxo-1-pyrrolidine acetamide particles and preparation method thereof |
| CN107510682A (en) * | 2016-06-15 | 2017-12-26 | 重庆润泽医药有限公司 | It is a kind of（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof |
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2011
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| 金磊: "《奥拉西坦的临床前药理学研究》", 《中国临床药理学与治疗学》 * |
| 陈玉林: "《吡拉西坦口服液》", 《中国新药杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106619523A (en) * | 2015-10-27 | 2017-05-10 | 重庆润泽医药有限公司 | (S)-4-hydroxy-dioxo-1-pyrrolidine acetamide particles and preparation method thereof |
| CN106619523B (en) * | 2015-10-27 | 2020-08-28 | 重庆润泽医药有限公司 | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof |
| CN107510682A (en) * | 2016-06-15 | 2017-12-26 | 重庆润泽医药有限公司 | It is a kind of（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof |
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