WO2016184381A1 - 右旋奥拉西坦在制药领域中的应用 - Google Patents

右旋奥拉西坦在制药领域中的应用 Download PDF

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WO2016184381A1
WO2016184381A1 PCT/CN2016/082396 CN2016082396W WO2016184381A1 WO 2016184381 A1 WO2016184381 A1 WO 2016184381A1 CN 2016082396 W CN2016082396 W CN 2016082396W WO 2016184381 A1 WO2016184381 A1 WO 2016184381A1
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oxiracetam
dextrorotatory
dextrorotatory oxiracetam
epilepsy
compound
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French (fr)
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叶雷
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Chongqing Runze Pharmaceutical Co Ltd
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Chongqing Runze Pharmaceutical Co Ltd
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Priority to EP16795868.5A priority Critical patent/EP3299016B1/en
Priority to KR1020177033298A priority patent/KR20170137910A/ko
Priority to JP2018512469A priority patent/JP6527290B2/ja
Priority to US15/574,846 priority patent/US20180147183A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to the medical use of dextrorotatory oxiracetam, in particular to the application of dextrorotatory oxiracetam in the preparation of antiepileptic drugs.
  • D-Oxaxitan ((R)-4-hydroxy-2-oxo-1-pyrrolidinoacetamide) is the right-handed body of oxiracetam (Oxiracetam CAS 62613-82-5), which is disclosed in CN102603607A Preparation.
  • oxiracetam (Oxiracetam CAS 62613-82-5)
  • both racemic oxiracetam and levorotaxantan can enhance memory, improve learning ability, and improve cognitive dysfunction in patients, while right-handed ola Seatan is not effective for cognitive dysfunction.
  • dextrorotatory oxiracetam alone as a pharmaceutical application.
  • epilepsy is a common chronic neurological disease characterized by repeated sudden onset of loss of consciousness with convulsions, usually caused by transient abnormal synchronization activities of neurons in the brain, but Its specific pathogenesis is still unclear.
  • epilepsy can occur at any time, and there is no warning before the general attack, it is extremely harmful; plus epilepsy patients are often accompanied by depression, anxiety, migraine, infertility, low libido, autism and other complications, so It is very difficult to treat epilepsy.
  • the main anti-epileptic drugs are phenytoin, sodium valproate, carbamazepine, phenobarbital, lamotrigine, levetiracetam, etc.
  • the clinical response shows that these drugs have many side effects, mainly It is characterized by the decline of cognitive function such as mental development, language expression, learning and memory, and fetal malformations such as craniofacial deformity, congenital heart defects, and toe dysplasia. It has been reported that oxiracetam is used as an adjuvant therapy for patients with epilepsy for the treatment of cognitive and behavioral disorders after epilepsy.
  • antiepileptic drugs have an inhibitory effect on the central nervous system, while mixed oxiracetam has enhanced The conduction of nerves excites, promotes nervous system activity, enhances memory, improves learning ability, and improves forgetfulness. Oxacetam does not have anti-epileptic effects. Therefore, it is necessary to develop new anti-epileptic drugs.
  • the present invention aims to provide the use of dextrorotacetam in the field of pharmacy, in particular to provide the use of dextrorotacetam in the preparation of a medicament for preventing or treating epilepsy.
  • the present invention specifically relates to the use of dextrorotatory oxiracetam as a medicament for the prevention or treatment of epilepsy, as an application for acute epileptic seizures.
  • the invention specifically relates to the use of dextrorotatory oxiracetam as a medicament for the preparation of a medicament for preventing or treating epilepsy, as a medicament for epileptic seizures; as a partial seizure drug for epilepsy; as an application of a drug for status epilepticus.
  • the above-mentioned application of the right-handed oxiracetam in the preparation of a medicament for preventing or treating epilepsy can be specifically prepared as a pharmaceutical composition having the active ingredient of dextro-oxiracetam, and the dosage form can be an oral preparation such as a tablet or a pill. , powder, granules, capsules, etc.; injections such as powder for injection, lyophilized powder for injection, etc., the above dosage forms can be prepared according to conventional methods.
  • the above dosage forms are preferably oral capsules, tablets and injections.
  • the dose of the above-mentioned dextrorotatory oxiracetam composition is 400 mg or more per day (including 400 mg), preferably 400 to 2000 mg/day, and more preferably 800 to 1600 mg/day.
  • a medicament for preventing or treating epilepsy using a dextrorotatory oxiracetam compound or a pharmaceutical composition containing a dextrorotatory oxiracetam compound relates to a medicament for preventing or treating epilepsy using a dextrorotatory oxiracetam compound or a pharmaceutical composition containing a dextrorotatory oxiracetam compound.
  • a pharmaceutical composition for preventing or treating epilepsy comprising a dextro-raceracetam compound, and a pharmaceutically acceptable adjuvant.
  • a method of preparing a pharmaceutical composition for preventing or treating epilepsy which comprises preparing a dextrorotatory oxiracetam compound together with a pharmaceutically acceptable adjuvant.
  • It relates to the preparation of a medicament for preventing or treating an acute epileptic seizure using a dextrorotatory oxiracetam compound or a pharmaceutical composition containing a dextrorotatory oxiracetam compound.
  • a pharmaceutical composition for preventing or treating an acute epileptic seizure comprising a dextro-raceracetam compound, and a pharmaceutically acceptable adjuvant.
  • a method of preparing a pharmaceutical composition for preventing or treating an acute epileptic seizure comprising preparing a dextrorotatory oxiracetam compound together with a pharmaceutically acceptable adjuvant.
  • It relates to a medicament for preventing or treating a systemic episode of epilepsy using a dextrorotatory oxiracetam compound or a pharmaceutical composition containing a dextrorotatory oxiracetam compound.
  • a pharmaceutical composition for preventing or treating a systemic episode of epilepsy comprising a dextro-raceracetam compound and a pharmaceutically acceptable adjuvant.
  • a method of preparing a pharmaceutical composition for preventing or treating a systemic episode of epilepsy comprising preparing a dextrorotatory oxiracetam compound together with a pharmaceutically acceptable adjuvant.
  • It relates to the preparation of a medicament for preventing or treating a partial seizure of epilepsy using a dextrorotatory oxiracetam compound or a pharmaceutical composition containing a dextrorotatory oxiracetam compound.
  • a pharmaceutical composition for preventing or treating a partial seizure of epilepsy comprising a dextrorotatory oxiracetam compound, and a pharmaceutically acceptable adjuvant.
  • a method of preparing a pharmaceutical composition for preventing or treating a partial seizure of epilepsy which comprises preparing a dextrorotatory oxiracetam compound together with a pharmaceutically acceptable adjuvant.
  • It relates to the preparation of a medicament for preventing or treating epilepticus by using a dextrorotatory oxiracetam compound or a pharmaceutical composition containing a dextrorotatory oxiracetam compound.
  • a method of preparing a pharmaceutical composition for preventing or treating a status epilepticus comprising preparing a dextrorotatory oxiracetam compound together with a pharmaceutically acceptable adjuvant.
  • a method of treating epilepsy comprising administering to a patient a right-handed oxiracetam; the mode of administration is preferably oral or injection.
  • the purity of the right-handed oxiracetam raw material used in the preparation of the dextrorotatory oxiracetam-containing medicine for preventing or treating epilepsy of the present invention is preferably 99.0% or more (optical purity) in terms of weight percent.
  • Grade I gaze, slight vibration on the head and face
  • Grade IV generalized tonic convulsions with hind limbs standing
  • Class V A full-body tonic-clonic seizure with standing and falling.
  • An I-III episode occurs, which is a partial seizure of epilepsy
  • Grade IV and V episodes appear as a systemic episode of epilepsy
  • Olaracetam and Right Olaracetam were provided by Chongqing Dongze Pharmaceutical Technology Development Co., Ltd., batch number: Olaracetam: 20080917; Right Olaracetam: 20100205.
  • Mass spectrometry ionization mode electrospray ionization (ESI); ion polarity Positive; scanning mode is multiple reaction monitoring (MRM); scanning time is 100 ms.
  • the ion reactions used for the quantitative analysis were m/z (Oxiracetam) m/z 159.0 ⁇ m/z 113.9 and m/z 143.1 ⁇ m/z 126.0 (Pierra, respectively). Seatan).
  • oxiracetam standard 100.01mg of oxiracetam standard was accurately weighed by weight loss method, dissolved in ultrapure water, and fixed to the mark in a 100.0mL volumetric flask to prepare 1.0001mg/mL stock solution. Dilute to the corresponding concentration with ultrapure water when it is used.
  • Preparation of the right-handed oxiracetam standard 100.02mg of the right oxiracetam standard was accurately weighed by weight loss method, dissolved in ultrapure water, and adjusted to the mark in a 100.0mL volumetric flask to make 1.0002mg/mL. The stock solution is diluted to the corresponding concentration with ultrapure water when it is used.
  • Tmax was (1.583 ⁇ 0.465), (1.667 ⁇ 0.408) h, respectively; Cmax was (202.383 ⁇ 79.525), (85.790 ⁇ , respectively). 19.953) mg/ml; T1/2 were (0.922 ⁇ 0.131), (2.039 ⁇ 0.929) h, respectively; AUC0- ⁇ were (445.340 ⁇ 86.609), (242.262 ⁇ 31.343) mg*h/ml, respectively.
  • Tmax was (1.583 ⁇ 0.465), (1.667 ⁇ 0.408) h, respectively
  • Cmax was (202.383 ⁇ 79.525), (85.790 ⁇ , respectively). 19.953) mg/ml
  • T1/2 were (0.922 ⁇ 0.131), (2.039 ⁇ 0.929) h, respectively
  • AUC0- ⁇ were (445.340 ⁇ 86.609), (242.262 ⁇ 31.343) mg*h/ml, respectively.
  • P>0.05 the relative bioavailability of right oxiracetam was (112.2 ⁇ 11.6)%. There was no significant difference between the nonparametric test results (P>0.05
  • the toxicity of dextrorotatory oxiracetam and oxiracetam was compared under GLP conditions.
  • the dose was 5 g/kg, 10 animals per group, weighing 18.3 ⁇ 1.5 g, male and female, 0.5% CMC. After the liquid is prepared, it is orally administered.
  • the results showed that the animals in the two groups had normal activities and no obvious toxicity. There was no significant difference in toxicity between the two groups after 14 days of continuous observation.
  • Oxiracetam is a commercially available drug, and its pharmacokinetics, toxicology, and the like are common knowledge.
  • a rat model of epilepsy was induced by lithium chloride-pilocarpine, and levetiracetam was used as a positive control.
  • the acute episode of the rat model of epilepsy of lithium chloride-pilocarpine was used as the observation time. The way.
  • Levetiracetam tablets are used for the treatment of partial seizures in adults and children with epilepsy over 4 years of age.
  • the traits are blue oval film coated tablets, the specification is 0.25g/tablet, the manufacturer UCB Pharma SA, the initial dose of adult is 500mg/time, twice daily, ie 1000mg/60kg, 16.7mg/kg, converted according to body surface area
  • the dose for the rat was 100 mg/kg.
  • Zuo'ao and Zuo'an were prepared from pure water before use.
  • the left ethacetam sheet was prepared with 0.5% CMC before use to obtain the desired concentration of suspension.
  • the solvent control product was 0.5% CMC, batch number 2014010801, Chengdu Kelon Chemical Reagent Factory.
  • the sex and quantity of animals purchased: 50, male and female;
  • Relative humidity 40 to 70%
  • Lighting time alternate lighting 12h/12h daily.
  • the padding is corn cob, provided by Suzhou Shuangshi Experimental Animal Feed Technology Co., Ltd., and used for animal use after high temperature and high pressure steam sterilization.
  • Cage update frequency 2-3 times a week.
  • the disinfectant is alternately selected with 84 disinfectant, lysul and neostigmine, and the type of disinfectant is exchanged once a week.
  • the quarantine period is set to 7 days. During the period, the appearance and general state of the animals are observed and recorded daily. If the animal has abnormalities, it may affect the test. It should be removed and should not be used during the test.
  • Rat full-price pellet feed produced by the Experimental Animal Research Institute of Sichuan Medical College, meets the standard of GB14924.3-2001, and is used after sterilization by Co60 irradiation.
  • Feeding method free intake.
  • Autoclaved tap water is freely ingested by animal drinking water bottles.
  • the quarantine period uses the tail marking method, that is, the animal number is indicated by a marker line at the end of the rat. Prior to administration, they were grouped by stratified randomization grouping method and labeled with picric acid staining.
  • Levetiracetam was selected as a positive control, and the clinical dose was 1.5 times, that is, 150 mg/kg.
  • the clinical dose of oxiracetam was 800 mg/time, twice a day, ie 1600 mg/60 kg, 26.7 mg/kg, and the body surface area was converted to a rat dose of 160 mg/kg.
  • Right Austria and Zuo'ao selected half of the dose, namely 80mg/kg, 1.5 times 120mg/kg.
  • the dosage is 1ml/100g,
  • the model was observed after 7 days of continuous gavage administration. Since the concentration of plasma was peaked after administration of levetiracetam for 1.3 h (80 min), we selected each group to start modeling 80 minutes after the last administration.
  • Modeling method After several pre-tests, the following methods were selected: animal ip. Lithium chloride 3mmol/kg (1.5ml/L) 127mg/kg (12.7mg/ml, 1ml/100g body weight), after 24h, 37.5 The mg/kg pilocarpine was injected in three ip. injections at 12.5 mg/kg (2.5 mg/ml, 0.5 ml/100 g body weight) at intervals of 10 minutes.
  • Seizures were recorded within 3 hours after model establishment, seizure level, latency of each level, duration of seizures, number of episodes, and mortality were compared with model controls.
  • the above test results showed that all groups of animals showed different degrees of alkali nerve stimulation and different levels of convulsions after modeling, and there was a certain mortality within 1-7 days after modeling.
  • the mortality of the model control group was 40%, that of the left group was 50%, that of the left group was 30%, and that of the right group was 10%.
  • the percentage of epilepticus in each group was 60%, 70%, 40%, and 20%, respectively.
  • the percentage of SE in the right-orange group was significantly lower than that in the control group. From the above experimental data, compared with the model control group, the mortality and SE incidence rate of the right-oed group animals were significantly reduced, indicating that right oxiracetam can reduce the percentage of epilepticus in rats with pilocarpine epilepsy. , to reduce mortality, has a protective effect on epileptic rats.
  • the duration of V-grade episodes in the right-orange group was significantly lower than that in the control group (P ⁇ 0.05).
  • Rat model of epilepsy was ignited with pentylenetetrazol (PTZ), and sodium valproate was used as a positive control to observe whether right oxiracetam had anti-epileptic effect.
  • PTZ pentylenetetrazol
  • Oral gastrointestinal absorption is rapid and complete, peak plasma concentration is about 1 to 4 hours, and bioavailability is nearly 100%.
  • the maximum daily dose of 30mg/kg is used for humans.
  • the body surface area is converted into a rat dose of 185mg/kg, which is about 3 times. 500 mg/kg was used as the administration dose.
  • Pentylenetetrazol (PTZ), Sigma, MKBT 2860V, white powder, used NS to prepare a concentration of 7mg / ml for use.
  • the sex and quantity of animals purchased: 40, male;
  • Relative humidity 40 to 70%
  • Lighting time alternate lighting 12h/12h daily.
  • the padding is corn cob, provided by Suzhou Shuangshi Experimental Animal Feed Technology Co., Ltd., and used for animal use after high temperature and high pressure steam sterilization.
  • Cage update frequency 2-3 times a week.
  • the disinfectant is alternately selected with 84 disinfectant, lysul and neostigmine, and is exchanged once a week.
  • the type of venom The type of venom.
  • the quarantine period is set to 7 days. During the period, the appearance and general state of the animals are observed and recorded daily. If the animal has abnormalities, it may affect the test. It should be removed and should not be used during the test.
  • Rat full-price pellet feed produced by the Experimental Animal Research Institute of Sichuan Medical College, meets the standard of GB14924.3-2001, and is used after sterilization by Co60 irradiation.
  • Feeding method free intake.
  • Autoclaved tap water is freely ingested by animal drinking water bottles.
  • the quarantine period uses the tail marking method, that is, the animal number is indicated by a marker line at the end of the rat. After grouping, they were labeled with picric acid staining.
  • Rats were intraperitoneally injected with PTZ at a dose of 35 mg/kg (7 mg/ml, 0.5 ml/100 g body weight) of subconvulsant 3 times a week. Weighed before each ip, observed behavioral changes within 1-2 h after animal ip. Behavioral scores were based on the revised Racine score. Three consecutive episodes of grade 4 and above showed successful ignition.
  • the animals that were successfully ignited were selected for grouping, and the animals were randomly divided into 4 groups according to body weight, 8-10/group.
  • Sodium valproate was selected as the positive control, and the clinical dose was selected about 3 times, that is, 500 mg/kg. According to the results of previous trials, 120 mg/kg was selected as the low dose of right oxiracetam, and 3 times 360 mg/kg was taken as the high dose.
  • the dose was 1 ml/100 g, and it was administered by continuous gavage for 10 days.
  • the specific dose settings are as follows:
  • Each group of animals was administered 1 hour after daily administration (according to the peak time of sodium valproate) ip. PTZ 35 mg/kg, and then the behavioral changes within 2 hours were observed, and the behavioral score was performed according to the revised Racine score. Drug for 10 days.
  • the grading standards are the same as above.
  • Seizures were recorded within 2 hours after ip. PTZ daily, and the seizure level, latency, and mortality were recorded and compared with the model control group.
  • the right and positive drugs According to the incidence of symptoms above grade 4 and the onset of episodes, the right and positive drugs have obvious protective effects on the epilepsy model, which shows that the incidence of symptoms above grade 4 is significantly reduced and the incubation period is prolonged. Among them, the effect of the right high dose is most obvious.
  • the inventors unexpectedly found that dextrorotacetam has anti-epileptic activity, which has obvious effects on acute epileptic seizures, especially acute epileptic seizures; right-handed oxiracetam on epileptic seizures, partial seizures Both seizures and status epilepticus have a good inhibitory effect, and D-Oxacetam has high bioavailability and low toxicity, and is suitable for further development into an anti-epileptic drug.
  • the invention uses the right-handed oxiracetam raw material with a purity greater than 99.0%, which effectively eliminates the interference of other components in the medicine, and the right-handed oxiracetam is a single active ingredient, so that the quality of the medicine is more easily controlled, and the curative effect is more effective. clear.
  • the patient with the right-handed oxiracetam composition provided by the invention has strong adaptability and simple preparation method, and is advantageous for industrialization.
  • Fig.5 is a graph showing the incidence of symptoms of grade 4 or higher in the rat model of epilepsy induced by pentylenetetrazol (PTZ) in the right-handed oxiracetam
  • the prescription consists of:
  • the specific preparation method is as follows: firstly, the original auxiliary material is passed through an 80 mesh sieve, and the prescribed amount of dextrorotatory oxiracetam, lactose and microcrystalline cellulose are uniformly mixed. Fill the capsule directly.
  • the prescription consists of:
  • the specific preparation method is as follows: firstly, the original auxiliary material is passed through an 80 mesh sieve, and the prescribed amount of dextrorotatory oxiracetam, starch and microcrystalline cellulose are uniformly mixed. Add 2% HPMC aqueous solution to soft material, granulate, dry, and granulate. Add the prescribed amount of talc powder to the granules, mix well and compress.
  • the prescription consists of:
  • the specific preparation method is as follows: firstly, the original auxiliary material is passed through an 80 mesh sieve, and the prescribed amount of right oxiracetam, lactose, sodium carboxymethyl starch is uniformly mixed. Add 10% PVP ethanol solution to soft material, granulate, dry, and granulate. Add the prescribed amount of talc powder to the granules, mix well and fill the capsules.
  • the specific preparation method is: weighing 50 g of dextrorotatory oxiracetam (purity of 99.3%), 150 g of glucose, 500 ml of water for injection, dissolved in a rare tank, temperature control Stir at 50-60 ° C until completely dissolved, cool the solution to 25 ° C, add decolorization to the above prepared solution, then remove the activated carbon by filtration, add the phosphate buffer to the pH of the solution. The value was adjusted to 4.0, and water for injection was added to 5000 ml, potted, and sterilized at 105 ° C for 30 minutes to obtain a right-handed oxiracetam injection.

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Abstract

本发明提供右旋奥拉西坦在制备预防或治疗癫痫药物中的应用。实验结果表明右旋奥拉西坦作为治疗癫痫全身性发作、癫痫部分性发作和癫痫持续状态的作用明显。

Description

右旋奥拉西坦在制药领域中的应用 技术领域
本发明涉及右旋奥拉西坦的医药用途，具体涉及右旋奥拉西坦在制备抗癫痫药物中的应用。
背景技术
右旋奥拉西坦((R)-4-羟基-2-氧代-1-吡咯烷乙酰胺)是奥拉西坦(Oxiracetam CAS 62613-82-5)的右旋体，CN102603607A公开了其制备方法。与混旋奥拉西坦和左旋奥拉西坦相比，混旋奥拉西坦和左旋奥拉西坦均可以增强记忆，提高学习能力，改善患者的认知功能障碍，而右旋奥拉西坦对认知功能障碍无效。目前尚无右旋奥拉西坦单独作为药物应用的报道。
业内人士都清楚，癫痫是一种常见的以反复突然发作的意识丧失伴抽搐为主要症状的慢性神经系统疾病，其发作通常是直接由大脑内神经元短暂的异常同步化活动所造成的，但其具体的发病机制目前仍不清楚。作为一种常见病，据世界卫生组织统计，全世界约有五千万人患有癫痫。由于癫痫可以任何时间发作，且一般发作前没有任何预兆，因而危害极大；加上癫痫患者还常常伴有抑郁、焦虑症、偏头痛、不育、性欲低、自闭症等并发症，因而治疗癫痫十分困难。
目前，用于抗癫痫的药物主要有苯妥英钠、丙戊酸钠、卡马西平、苯巴比妥、拉莫三嗪、左乙拉西坦等，临床反应显示这些药物都存在很多副作用，主要表现为智力发育、语言表达、学习记忆等认知功能的减退和颅面部畸形、先天性心脏缺陷、趾端发育不全等胎儿畸形。有报道显示奥拉西坦用于癫痫患者的辅助治疗，用于癫痫后认知和行为障碍的治疗，实质上抗癫痫药物是对中枢神经系统起抑制作用，而混旋奥拉西坦具有增强神经兴奋的传导、促进神经系统活跃，增强记忆、提高学习能力、对健忘有改进作用，奥拉西坦并不具有抗癫痫的功效。因而开发新的抗癫痫药物十分必要。
发明内容
本发明目的在于提供右旋奥拉西坦在制药领域的用途，具体是提供右旋奥拉西坦在制备预防或治疗癫痫药物中的应用。
本发明具体涉及右旋奥拉西坦作为制备预防或治疗癫痫药物中的应用，作为癫痫急性发作药物中的应用。
本发明具体涉及右旋奥拉西坦作为制备预防或治疗癫痫药物中的应用，作为癫痫全身性发作药物中的应用；作为癫痫部分性发作药物中的应用；作为癫痫持续状态药物中的应用。
上述右旋奥拉西坦在制备预防或治疗癫痫药物中的应用，具体来说可以制备成活性成分为右旋奥拉西坦的药物组合物，剂型可以是口服制剂，如片剂，滴丸剂，粉剂，颗粒剂，胶囊剂等；注射剂如注射用粉剂，注射用冻干粉等剂型，以上剂型均可以按照常规方法制得。
上述剂型优选为口服胶囊剂、片剂和注射剂。
上述右旋奥拉西坦组合物的给药剂量(右旋奥拉西坦化合物的含量)每天400mg以上(包括400mg)，优选400～2000mg/天，更优先为800～1600mg/天。
具体地说涉及，使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫的药物。
一种用于预防或治疗癫痫的药物组合物，其中含有右旋奥拉西坦化合物，以及药学上可接受的辅料。
一种制备用于预防或治疗癫痫的药物组合物的方法，其中包括将右旋奥拉西坦化合物与药学上可接受的辅料一起制得。
涉及，使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫急性发作的药物。
一种用于预防或治疗癫痫急性发作的药物组合物，其中含有右旋奥拉西坦化合物，以及药学上可接受的辅料。
一种制备用于预防或治疗癫痫急性发作的药物组合物的方法，其中包括将右旋奥拉西坦化合物与药学上可接受的辅料一起制得。
涉及，使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫全身性发作的药物。
一种用于预防或治疗癫痫全身性发作的药物组合物，其中含有右旋奥拉西坦化合物，以及药学上可接受的辅料。
一种制备用于预防或治疗癫痫全身性发作的药物组合物的方法，其中包括将右旋奥拉西坦化合物与药学上可接受的辅料一起制得。
涉及，使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫部分性发作的药物。
一种用于预防或治疗癫痫部分性发作的药物组合物，其中含有右旋奥拉西坦化合物，以及药学上可接受的辅料。
一种制备用于预防或治疗癫痫部分性发作的药物组合物的方法，其中包括将右旋奥拉西坦化合物与药学上可接受的辅料一起制得。
涉及，使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫持续状态的药物。
一种用于预防或治疗癫痫持续状态的药物组合物，其中含有右旋奥拉西坦化合物，以及药学上可接受的辅料。
一种制备用于预防或治疗癫痫持续状态的药物组合物的方法，其中包括将右旋奥拉西坦化合物与药学上可接受的辅料一起制得。
治疗癫痫方法，其包括向患者给药右旋奥拉西坦；给药方式优选为口服或注射。
本发明制备预防或治疗癫痫的含右旋奥拉西坦药物中所使用的右旋奥拉西坦原料纯度最好是99.0％以上(光学纯度)，以重量百分数计。
分级标准：抽搐行为评价采用修订的Racine分级标准
0级：无任何发作迹象；
I级：凝视，头面部轻微颤动；
II级：点头或湿狗样抖动
III级：前肢局限性惊厥；
IV级：具有后肢站立的全身强直性惊厥；
V级：具有站立伴摔倒的全身强直阵挛性发作。
出现I-III级发作，为癫痫部分性发作；
出现IV级、V级发作，为癫痫全身性发作；
出现IV-V级发作，持续30min，为SE(癫痫持续状态)。
为了进一步验证本发明药用效果，发明人进行了以下试验。
(一)右旋奥拉西坦动物体内药代动力学试验及生物利用度研究
1.试验材料
1.1试验药品
1.1.1标准品：
奥拉西坦、右奥拉西坦由重庆东泽医药科技发展有限公司提供，批号为：奥拉西坦：20080917；右奥拉西坦：20100205。
1.1.2内标：
内标：吡拉西坦，批号100386-200702(含量100.0％)，购于中国药品生物制品检定所。
3.2试剂
甲醇(MERK，色谱纯)、水(MILLI Q)、乙腈(TEDIA，色谱纯)。
3.3仪器
SHIMADZU LC-MS单四级杆质谱仪、Eppendorf 5430台式高速离心机、XW-80A旋涡混合器、SE812型氮吹仪及SE812J数控恒温水浴(北京帅恩科技有限责任公司)。
4血浆中奥拉西坦、右奥拉西坦LC-MS测定方法
4.1色谱条件
流动相：甲醇∶水(5∶95)
色谱柱：ZORBAX SB-Aq(2.1×100mm 3.5μ)
流速：0.1mL/min；
柱温：30℃；
进样量：10μL
4.2质谱检测参数
质谱离子化方式：电喷雾离子化(ESI)；离子极性Positive；扫描方式为多重反应监测(MRM)；扫描时间为100ms。用于定量分析的离子反应分别为m/z(奥拉西坦)m/z159.0→m/z113.9和m/z143.1→m/z126.0(吡拉 西坦)。
4.3标准溶液的配制
奥拉西坦标准品的配制：减重法精密称取奥拉西坦标准品100.01mg，用超纯水溶解，在100.0mL容量瓶中定容至刻度，配制成1.0001mg/mL贮备液，临用时用超纯水稀释到相应的浓度。
右旋奥拉西坦标准品的配制：减重法精密称取右奥拉西坦标准品100.02mg，用超纯水溶解，在100.0mL容量瓶中定容至刻度，配制成1.0002mg/mL贮备液，临用时用超纯水稀释到相应的浓度。
内标液：减重法精密称取吡拉西坦20.02mg，用超纯水溶解后，在100.0mL容量瓶中定容至刻度，配制成200.2ug/mL贮备液，临用时用超纯水稀释至相应的浓度备用。
4.4血浆样品的提取
吸取20μL含药血浆样品于1.5mLEppendorf管中，加入20μL的吡拉西坦(20μg/mL)内标液，旋涡器混匀30s，再向其加入500μL的乙腈，旋涡振荡5min后，以16000rpm离心10min后，取上清液过1ml SPE C18E小柱，收集滤液置38℃恒温水浴箱中氮气吹干，300μL流动相复溶，进样量10μL。
5毒代样品的测定结果
5.1奥拉西坦
5.1.1标线的制备及结果
取空白犬血浆20μL，加入奥拉西坦标准品配制的工作液，使血浆中奥拉西坦的浓度分别为0.167、0.33、0.67、1.33、2.67、4.0、6.67、13.33、26.67μg/mL，按“血浆样品的提取”项下操作，每种浓度各做1份样品。计算奥拉西坦的峰面积(As)与内标吡拉西坦的峰面积(Ai)的比值(f＝As/Ai)，以浓度(C)对比值(f)作直线回归，权重参数1/x，奥拉西坦的回归方程：y＝5.2117X-0.76985(r＝0.9970，权重1/x)
表1奥拉西坦标线数据表
Figure PCTCN2016082396-appb-000001
Figure PCTCN2016082396-appb-000002
奥拉西坦标准曲线图见图1.
奥拉西坦样品的测定结果
表2 1-2号犬血测定数据表
Figure PCTCN2016082396-appb-000003
表3 1-1号犬血测定数据表
Figure PCTCN2016082396-appb-000004
表4 2-6号犬血测定数据表
Figure PCTCN2016082396-appb-000005
表5 2-5号犬血测定数据表
Figure PCTCN2016082396-appb-000006
表6 3-3号犬血测定数据表
Figure PCTCN2016082396-appb-000007
Figure PCTCN2016082396-appb-000008
表7 3-4号犬血测定数据表
Figure PCTCN2016082396-appb-000009
5.2(R)-奥拉西坦
5.2.1标线的制备及结果
取空白犬血浆20μL，加入右奥拉西坦标准品配制的工作液，使血浆中右奥拉西坦的浓度分别为0.067、0.167、0.33、0.67、1.33、2.67、4.0、6.67、13.33μg/mL，按“血浆样品的提取”项下操作，每种浓度各做1份样品。计算右奥拉西坦的峰面积(As)与内标吡拉西坦的峰面积(Ai)的比值(f＝As/Ai)，以浓度(C)对比值(f)作直线回归，权重参数1/x，右奥拉西坦的回归方程：y＝1.6811X-0.031244(r＝0.9949，权重1/x)
表8右奥拉西坦标线数据表
Figure PCTCN2016082396-appb-000010
Figure PCTCN2016082396-appb-000011
右旋奥拉西坦标准曲线图见图2。
5.2.2右奥拉西坦样品的测定结果
表9 1-5号犬血测定数据表
Figure PCTCN2016082396-appb-000012
表10 1-6号犬血测定数据表
Figure PCTCN2016082396-appb-000013
表11 2-3号犬血测定数据表
Figure PCTCN2016082396-appb-000014
Figure PCTCN2016082396-appb-000015
表12 2-4号犬血测定数据表
Figure PCTCN2016082396-appb-000016
表13 3-1号犬血测定数据表
Figure PCTCN2016082396-appb-000017
表14 3-2号犬血测定数据表
Figure PCTCN2016082396-appb-000018
奥拉西坦与右奥拉西坦在犬体内的主要药代动力学参数如下：Tmax分别为(1.583±0.465)、(1.667±0.408)h；Cmax分别为(202.383±79.525)、(85.790±19.953)mg/ml；T1/2分别为(0.922±0.131)、(2.039±0.929)h；AUC0-∞分别为(445.340±86.609)、(242.262±31.343)mg*h/ml。以奥拉西坦为参比，右奥拉西坦相对生物利用度为(112.2±11.6)％。经非参数检验结果无显著性差异(P＞0.05)。
(二)毒理试验
在GLP实验条件下比较右旋奥拉西坦和奥拉西坦的小鼠毒性，设定剂量为5g/kg，每组10只动物，体重18.3±1.5克，雌雄各半，用0.5％CMC液制得后口服灌服。结果显示：两组动物活动正常，无明显毒性呈现，连续观察14天无一动物发生死亡两组间无明显的毒性差异。
奥拉西坦为市售药物，其药代动力学、毒理等均为公知常识。
(三)右旋奥拉西坦抗癫痫实验研究
采用氯化锂-匹罗卡品造大鼠癫痫模型，以左乙拉西坦为阳性对照，选用氯化锂-匹罗卡品大鼠癫痫模型的急性发作期作为观察时间，采用预防给药的方式。
1实验材料与系统
1.1实验材料
供试品：
右奥拉西坦，原料，乳白色粉末，批号20100205，溶于水。
左奥拉西坦，白色粉末，批号091202，溶于水。
以上均由重庆东泽医药科技发展有限公司提供。
阳性对照品：
左乙拉西坦片，用于成人及4岁以上儿童癫痫患者部分性发作的加用治疗。性状为蓝色椭圆形薄膜包衣片，规格0.25g/片，生产企业UCB Pharma S.A，成人初始剂量为500mg/次，每日两次，即1000mg/60kg，16.7mg/kg，按体表面积折算为大鼠剂量为100mg/kg。
左奥和右奥临用前用纯净水制得，左乙拉西坦片临用前用0.5％CMC制得成所需浓度悬液。溶媒对照品采用0.5％CMC，批号2014010801，成都市科龙化工试剂厂。
试剂：
硝酸毛果云香碱(匹罗卡品)滴眼液，规格5ml：25mg，批号：14101901，山东博士伦福瑞达制药有限公司。临用前用NS稀释为3mg/ml浓度。
无水氯化锂，白色颗粒，分子量42.39，成都科龙化工试剂厂。用NS配成12.7mg/ml备用。
1.2实验系统
实验动物
品种/品系：SD大鼠
等级：SPF级
供应单位：成都达硕生物科技有限公司
生产许可证号：SCXK(川)2008-24
购入动物性别及数量：50只，雌雄各半；
购入时体重范围：120～150g
动物的饲养管理
动物饲养管理的环境条件
饲养房间：屏障系统动物实验室
环境等级：屏障系统
温度：20～25℃
相对湿度：40～70％；
换气次数：10-15次/小时
照明时间：每日12h/12h交替照明。
动物笼具：PC聚碳酸酯鼠盒(L×W×H：460mm×315mm×210mm)，由苏州市苏杭动物设备厂生产。
垫料：垫料为玉米芯，由苏州双狮实验动物饲料科技有限公司提供，经高温高压蒸汽灭菌消毒后用于动物使用。
笼具更新频率：每周更换2-3次。
清扫与消毒：每日试验操作和饲喂工作结束后清扫，然后由动物管理室进行消毒。消毒液交替选用84消毒液、来苏尔和新洁尔灭，每周一次轮流交换消毒液的种类。
检疫
检疫期设为7天，期间每日对动物外观、一般状态进行观察记录，若动物出现异常，可能对试验有影响，则应剔除，在试验时不得使用。
饲料
鼠全价颗粒饲料，由四川省医科院实验动物研究所生产，符合GB14924.3-2001标准，经Co60照射灭菌后使用。
给料方法：自由摄取。
饮用水
高压蒸汽灭菌自来水，由动物饮水瓶自由摄取。
2试验方法
2.1动物识别和编号
检疫期采用尾部标记法，即在鼠尾用记号笔划线表示动物号。给药前按体重分层随机化分组法分组，用苦味酸染色法进行标记。
2.2剂量设置
动物随机分为4组，10只/组。选择左乙拉西坦作为阳性对照，选用临床剂量的1.5倍，即150mg/kg。奥拉西坦的临床剂量为800mg/次，一日两次，即1600mg/60kg，26.7mg/kg，按体表面积折算为大鼠剂量160mg/kg。右奥和左奥则分别选其一半剂量，即80mg/kg，1.5倍即120mg/kg。给药量为1ml/100g， 连续灌胃给药7天后造模观察。由于左乙拉西坦给药1.3h(80min)后，血药浓度达峰，故我们每组均选择末次给药后80分钟开始造模，
具体剂量设置如下：
Figure PCTCN2016082396-appb-000019
2.3试验方法
造模方法：经过多次预试，选择如下方法造模：动物ip.氯化锂3mmol/kg(1.5ml/L)127mg/kg(12.7mg/ml，1ml/100g体重)，24h后，37.5mg/kg匹罗卡品分三次ip.注射，每次12.5mg/kg(2.5mg/ml，0.5ml/100g体重)，间隔10分钟。
由于每次观察动物数量有限，试验分为四批进行。
2.4观察指标
记录造模后3h内癫痫发作情况，发作级别、各级别的潜伏期、发作持续时间、发作次数，死亡率，与模型对照组比较。
3试验结果
所有大鼠均于第一次注射匹鲁卡品后5～10min出现胆碱能周围神经刺激症状。即竖毛、流涎、血泪症，并出现不同程度的以下表现，包括：少动、盯视、嘴部自动症、点头、眨眼、湿狗样晃动。
3.1死亡率和出现SE的动物数
Figure PCTCN2016082396-appb-000020
右旋奥拉西坦对氯化锂-匹罗卡品造大鼠癫痫模型中死亡率和SE出现率的影响见图3。
以上试验结果显示，造模后各组动物均出现不同程度的碱能周围神经刺激症状和不同级别的抽搐状况，在造模后1-7天内有一定的死亡率。模型对照组的死亡率为40％，左乙组为50％，左奥组为30％，右奥组为10％。各组出现癫痫持续状态的百分率分别为60％、70％、40％、20％，右奥组动物出现SE的百分比较对照组明显下降。从以上实验数据看出，与模型对照组比较，右奥组动物的死亡率和SE出现率都明显降低，说明右奥拉西坦可以降低匹罗卡品癫痫模型大鼠出现癫痫持续状态的百分率，降低死亡率，对癫痫大鼠具有保护作用。
3.2不同级别的动物数
Figure PCTCN2016082396-appb-000021
注：*表示与模型对照组经X2检验，P＜0.05
右旋奥拉西坦对氯化锂-匹罗卡品造大鼠癫痫模型中不同癫痫级别症状出现率的影响见图4。
以上试验中，各组动物基本全部出现I级和II级症状，左奥和右奥组动物有一半未出现III级及以上症状，右奥组出现IV级的动物数为20％，较模型对照组有显著性差异(P＜0.05)。说明右奥拉西坦可以明显降低模型大鼠出现IV级症状的数量，抑制癫痫发作。
3.3不同级别的潜伏期
Figure PCTCN2016082396-appb-000022
Figure PCTCN2016082396-appb-000023
实验数据显示，右奥组动物出现I级、II级和III级症状的潜伏期较模型对照组是呈现延长的趋势。说明右奥拉西坦可以延长模型动物出现癫痫部分发作时的时间，对癫痫大鼠具有保护作用。
3.4不同级别的发作次数或持续时间
Figure PCTCN2016082396-appb-000024
注：*表示与模型对照组经方差分析，P＜0.05
右奥组动物出现V级发作的持续时间较对照组明显下降(P＜0.05)。
说明右奥拉西坦可以减少模型动物出现V级发作的时间，对癫痫大鼠具有保护作用。
采用戊四氮(PTZ)点燃大鼠癫痫模型，以丙戊酸钠为阳性对照，观察右奥拉西坦是否有抗癫痫的作用。
1.供试品、对照品和试剂
供试品：
右奥拉西坦，原料，白色粉末，批号20150603，含量：99.92％，溶于水。由成都百途医药科技有限公司提供。
阳性对照品：
丙戊酸钠，批号140440，规格0.5g/片，赛诺菲杭州制药有限公司。口服胃肠吸收迅速而完全，约1～4小时血药浓度达峰值，生物利用度近100％。人用每日最大剂量30mg/kg，按体表面积折算为大鼠剂量为185mg/kg，取其3倍约 500mg/kg作为给药剂量。
右奥临用前用纯净水配制，丙戊酸钠片临用前用0.5％CMC配制成所需浓度悬液。溶媒对照品采用0.5％CMC，批号2014010801，成都市科龙化工试剂厂。
试剂：
戊四氮(PTZ)，Sigma，MKBT2860V，白色粉末，临用时用NS配成7mg/ml浓度备用。
2.实验系统
2.1实验动物
品种/品系：SD大鼠
等级：SPF级
供应单位：成都达硕生物科技有限公司
生产许可证号：SCXK(川)2008-24
购入动物性别及数量：40只，雄性；
购入时体重范围：120～150g
2.2动物的饲养管理
2.2.1动物饲养管理的环境条件
饲养房间：屏障系统动物实验室
环境等级：屏障系统
温度：20～25℃
相对湿度：40～70％；
换气次数：10-15次/小时
照明时间：每日12h/12h交替照明。
动物笼具：PC聚碳酸酯鼠盒(L×W×H：460mm×315mm×210mm)，由苏州市苏杭动物设备厂生产。
垫料：垫料为玉米芯，由苏州双狮实验动物饲料科技有限公司提供，经高温高压蒸汽灭菌消毒后用于动物使用。
笼具更新频率：每周更换2-3次。
清扫与消毒：每日试验操作和饲喂工作结束后清扫，然后由动物管理室进行消毒。消毒液交替选用84消毒液、来苏尔和新洁尔灭，每周一次轮流交换消 毒液的种类。
2.2.2检疫
检疫期设为7天，期间每日对动物外观、一般状态进行观察记录，若动物出现异常，可能对试验有影响，则应剔除，在试验时不得使用。
2.2.3饲料
鼠全价颗粒饲料，由四川省医科院实验动物研究所生产，符合GB14924.3-2001标准，经Co60照射灭菌后使用。
给料方法：自由摄取。
2.2.4饮用水
高压蒸汽灭菌自来水，由动物饮水瓶自由摄取。
3试验方法
3.1动物识别和编号
检疫期采用尾部标记法，即在鼠尾用记号笔划线表示动物号。分组后用苦味酸染色法进行标记。
3.2造模方法
大鼠腹腔注射PTZ，剂量为亚惊厥剂量35mg/kg(7mg/ml，0.5ml/100g体重)，每周3次。每次ip前称重，观察动物ip.后1-2h内的行为学变化，根据修订的Racine评分进行行为学计分。连续出现3次4级及以上的癫痫发作表示点燃成功。
根据前期预试，一般在注射PTZ第10次开始连续出现3次4级症状，造模成功。
3.3剂量设置
选择点燃成功的动物进行分组，动物按体重随机分为4组，8-10只/组。选择丙戊酸钠作为阳性对照，选用临床剂量的约3倍，即500mg/kg。根据前期试验结果，选择120mg/kg为右奥拉西坦的低剂量，取其3倍360mg/kg作为高剂量。给药量为1ml/100g，连续灌胃给药10天。具体剂量设置如下：
表1剂量设置
Figure PCTCN2016082396-appb-000025
Figure PCTCN2016082396-appb-000026
3.4试验方法
每组动物每天给药后1小时(按丙戊酸钠的达峰时间计)ip.PTZ 35mg/kg，然后观察2h内的行为学变化，根据修订的Racine评分进行行为学计分，连续给药10天。分级标准同上。
3.5观察指标
记录每天ip.PTZ后2h内癫痫发作情况，记录发作级别、潜伏期、死亡率，与模型对照组比较。
4试验结果
4.1模型筛选
41只动物造模期间共有3只动物死亡，筛筛选出27只点燃成功的动物，按照癫痫发作级数分组，每组7只动物左右。
4.2死亡率
给药期间，模型组有2只动物死亡，死亡率为25％，右奥低剂量组死亡一只动物，高剂量组和阳性对照组没有动物死亡。经卡方检验，未见统计学差异。
表2对死亡率的影响
Figure PCTCN2016082396-appb-000027
4.3 4级以上症状的发生率
表3-1 4级以上症状动物的发生率(％)
Figure PCTCN2016082396-appb-000028
表3-2 4级以上症状动物的发生率(％)
Figure PCTCN2016082396-appb-000029
注：与模型对照组比较，经卡方检验，*表示P＜0.05；**表示P＜0.01。
结果见表3-1、3-2和图5。结果显示，给药期间模型组动物四级以上症状出现的频率一直维持在较高水平(80％)，与模型组比较，三个给药组在给药初期未见明显差异，从D7(D指的是天数，D7为第七天)起，发生率明显降低，一直持续至给药末，具有统计学差异。右奥高剂量组动物从D7开始仅出现2-3级发作，未见4、5级症状发生。从发生率的曲线图也可看出，三个给药组的4、5级症状发生率明显低于模型对照组，以右奥高剂量组的效果最佳。
4.4潜伏期
结果见表4-1、4-2，在给药初期，各给药组与模型组比较，其发作潜伏期没有明显差异。从D4开始，阳性组动物和右奥高剂量组动物的发作潜伏期明显延长(P＜0.05、P＜0.01)，一直持续至给药末期。右奥低剂量组从D6开始，发作潜伏期较模型对照组明显延长(P＜0.05、P＜0.01)，一直持续至给药末期。
表4-1发作潜伏期数据(m，X±SD)
Figure PCTCN2016082396-appb-000030
表4-2发作潜伏期数据(m，X±SD)
Figure PCTCN2016082396-appb-000031
注：与模型对照组比较，单因素方差分析，*表示P＜0.05；**表示P＜0.01。
试验结果显示，造模后各组动物均出现不同程度的碱能周围神经刺激症状和不同级别的发作状况，造模期间有一定的死亡率(3/41)。给药期间也有动物死亡，其中模型对照组的死亡率为25％，阳性对照组为0，右奥低剂量组为14.3％，右奥高剂量组为0，右奥高剂量和阳性对照丙戊酸钠组的死亡率为0，就绝对值来看，对癫痫发作动物具有保护作用。
就4级以上症状的发生率和发作潜伏期的结果来看，右奥和阳性药对本癫痫模型均有明显的保护作用，表现在给药中后期4级以上症状发生率明显降低、发作潜伏期明显延长，其中以右奥高剂量的作用最为明显。
从本试验结果显示，右奥对该癫痫模型具有疗效，表现在死亡率、4级以上症状出现率都较模型对照组低，且发作潜伏期较模型对照也明显延长。
本发明有益效果是：
发明人意外发现右旋奥拉西坦具有抗癫痫活性，其对癫痫急性发作作用明显，尤其是癫痫急性大发作有明显的抑制作用；右旋奥拉西坦对癫痫全身性发作、癫痫部分性发作以及癫痫持续状态均有较好的抑制作用，而且右旋奥拉西坦生物利用度高，毒性低，适合进一步开发成为抗癫痫药物。本发明使用了纯度大于99.0％的右旋奥拉西坦原料，有效排除了药物中其他成分的干扰，而右旋奥拉西坦为单一活性成分，使得药品的质量更加容易控制，同时疗效更加明确。本发明提供的右旋奥拉西坦组合物患者适应性强，而且制备方法简单，利于工业化。
附图说明
图1奥拉西坦标准曲线图
图2右奥拉西坦标准曲线图
图3右旋奥拉西坦对氯化锂-匹罗卡品造大鼠癫痫模型中死亡率和SE出现率的影响
图4右旋奥拉西坦对氯化锂-匹罗卡品造大鼠癫痫模型中不同癫痫级别症状出现率的影响
图5右旋奥拉西坦对戊四氮(PTZ)点燃大鼠癫痫模型4级以上症状发生率曲线图
具体实施方式
下面将描述本发明的几个实施例，但本发明的内容并不局限于此。
实施例1
处方组成为：
(a)右旋奥拉西坦(纯度为99.5％)         200mg/粒
(b)乳糖                               80mg/粒
(c)微晶纤维素                         70mg/粒
以制成1000粒右旋奥拉西坦胶囊剂为例，具体制备方法是：先将原辅料过80目筛，称取处方量的右旋奥拉西坦、乳糖、微晶纤维素混合均匀，直接充填胶囊。
实施例2
处方组成为：
Figure PCTCN2016082396-appb-000032
以制成1000片右旋奥拉西坦片剂为例，具体制备方法是：先将原辅料过80目筛，称取处方量的右旋奥拉西坦、淀粉、微晶纤维素混合均匀，加2％HPMC水溶液制软材，制粒，烘干，整粒，向颗粒中加入处方量的滑石粉，混合均匀，压片。
实施例3
处方组成为：
Figure PCTCN2016082396-appb-000033
以制成1000粒右旋奥拉西坦胶囊剂为例，具体制备方法是：先将原辅料过80目筛，称取处方量的右奥拉西坦、乳糖、羧甲基淀粉钠混合均匀，加10％PVP乙醇溶液制软材，制粒，烘干，整粒，向颗粒中加入处方量的滑石粉，混合均匀，充填胶囊。
实施例4
以制成右旋奥拉西坦注射液为例，具体制备方法是：称量右旋奥拉西坦(纯度为99.3％)50g，葡萄糖150g，500ml注射用水溶解于稀配罐中，温度控制在50～60℃，搅拌直至完全溶解，将溶解液冷却到25℃，向上述配好的溶解液中加入活性炭脱色，再将其中的活性炭过滤除去，加入磷酸盐缓冲液将该溶解液的pH值调节为4.0，再加入注射用水至5000ml，灌封，在105℃灭菌30分钟，得到右旋奥拉西坦注射液。

Claims (8)

  1. 使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫的药物。
  2. 使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫急性发作的药物。
  3. 使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫全身性发作的药物。
  4. 使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫部分性发作的药物。
  5. 使用右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物制备用于预防或治疗癫痫持续状态的药物。
  6. 如权利要求1-5任一项所述的药物，其特征在于：所述右旋奥拉西坦化合物或含右旋奥拉西坦化合物的药物组合物，其给药剂量为不小于400mg/天。
  7. 如权利要求1-5任一项所述药物，其特征在于：所述右旋奥拉西坦化合物原料的光学纯度在99.0％以上，以重量百分数计。
  8. 如权利要求1-5任一项所述的药物组合物，其特征在于：其中含有右旋奥拉西坦化合物，以及药学上可接受的辅料；所述含有右旋奥拉西坦化合物原料的光学纯度在99.0％以上，以重量百分数计。
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