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CN107693485A - A kind of nasal drops for being used to anaesthetize and preparation method thereof

CN107693485A - A kind of nasal drops for being used to anaesthetize and preparation method thereof - Google PatentsA kind of nasal drops for being used to anaesthetize and preparation method thereof Download PDF Info
Publication number
CN107693485A
CN107693485A CN201710272858.7A CN201710272858A CN107693485A CN 107693485 A CN107693485 A CN 107693485A CN 201710272858 A CN201710272858 A CN 201710272858A CN 107693485 A CN107693485 A CN 107693485A
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add
solution
parts
sodium
stir
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2017-04-24
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徐颖
叶茂
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Childrens Hospital of Chongqing Medical University
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Childrens Hospital of Chongqing Medical University
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2017-04-24
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2018-02-16
2017-04-24 Application filed by Childrens Hospital of Chongqing Medical University filed Critical Childrens Hospital of Chongqing Medical University
2017-04-24 Priority to CN201710272858.7A priority Critical patent/CN107693485A/en
2018-02-16 Publication of CN107693485A publication Critical patent/CN107693485A/en
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A kind of nasal drops for being used to anaesthetize, it is characterized in that, it is using hydrochloric acid Dexmedetomidine and ketalar as raw material, adds a certain amount of osmotic pressure regulator, bacteriostatic agent, antioxidant, cosolvent, pH adjusting agent, by concentrated compounding, it is dilute match somebody with somebody, filling, sterilizing, outsourcing step is made.A kind of nasal drops for being used to anaesthetize of the present invention need not establish special administration channel, patient medication process no pain, compliance is good, and product storage process stability is good, will not crystallization go bad, pH value of solution is almost unchanged in the effect phase, and microbial limit is qualified, and keeping life is up to more than 24 months, preparation process impurity increment is smaller, whole preparation process impurity increment is only 0.01%, and preparation process is simple and easy, is worth marketing.

Description Translated from Chinese 一种用于麻醉的滴鼻液及其制备方法Nasal drops for anesthesia and preparation method thereof

技术领域technical field

本发明主要涉及制药技术领域，具体涉及一种用于麻醉的滴鼻液及其制备方法。The invention mainly relates to the technical field of pharmacy, in particular to a nasal drop for anesthesia and a preparation method thereof.

背景技术Background technique

检查前镇静、特别是儿童检查前镇静是临床急需解决的难题，使用安全有效的药物是保证患儿顺利完成各种检查的关键。Pre-examination sedation, especially for children, is a clinical problem that needs to be solved urgently. The use of safe and effective drugs is the key to ensure that children can successfully complete various examinations.

目前国内常用的检查前镇静药物为水合氯醛口服药或咪达唑仑口服药，鲁米钠肌肉注射剂。这些镇静药物的药效及使用存在以下问题：(1)水合氯醛口服剂：是目前门诊最常用的儿童检查前镇静药剂，由于其口感非常苦涩，很多孩子都拒绝服用或者服用后引起呕吐，导致误吸风险增加，甚至有生命危险。另外，水合氯醛代谢产物具有活性、也有时会引起苏醒延迟；同时，该药剂首过效应明显，镇静效果不确定，常常导致镇静失败，许多孩子常常需要反复多次用药。(2)咪达唑仑口服剂：镇静效果不好，成功率仅为60～75％。(3)鲁米钠肌肉注射剂：镇静成功率为80％左右，但伴有疼痛刺激，对患儿产生伤害。At present, the commonly used sedative drugs before examination in China are oral chloral hydrate or midazolam, and intramuscular injection of sodium lumina. The efficacy and use of these sedatives have the following problems: (1) chloral hydrate oral agent: it is the most commonly used sedative agent for children before examination in outpatient clinics. Because its mouthfeel is very bitter, many children refuse to take it or cause vomiting after taking it. Increased risk of aspiration, even life threatening. In addition, the metabolites of chloral hydrate are active and sometimes cause delayed awakening; at the same time, the drug has an obvious first-pass effect, and the sedative effect is uncertain, which often leads to sedation failure, and many children often need repeated medications. (2) Oral midazolam: the sedative effect is not good, and the success rate is only 60-75%. (3) Lumin sodium intramuscular injection: the success rate of sedation is about 80%, but it is accompanied by painful stimulation, which will cause harm to the children.

盐酸右美托咪啶为美托咪定的右旋异构体,属咪唑类的衍生物，是一种高选择性α2受体激动剂，化学名为：(+)-4-(S)-[1-(2,3-二甲基苯基)乙基]-1H-咪唑盐酸盐，作用于脑干蓝斑核内α2受体而产生良好的镇静作用，但单独使用2ug/kg右美托咪啶镇静后，容易被外界刺激惊醒，转醒率可达50％左右，导致镇静失败；较大剂量盐酸右美托咪啶(>2ug/kg)，可产生心动过缓现象。Dexmedetomidine hydrochloride is the dextro isomer of medetomidine, which is a derivative of imidazoles. It is a highly selective α2 receptor agonist, and its chemical name is: (+)-4-(S) -[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole hydrochloride, acting on α2 receptors in the nucleus of the locus coeruleus of the brainstem to produce a good sedative effect, but alone 2ug/kg After sedation with dexmedetomidine, it is easy to be awakened by external stimuli, and the awakening rate can reach about 50%, resulting in failure of sedation; large doses of dexmedetomidine hydrochloride (>2ug/kg) can cause bradycardia.

氯胺酮为NMDA受体拮抗剂，有镇痛镇静及交感兴奋作用，但一般其使用需要的剂量较大，容易引起血压升高和存在苏醒期躁动的情况。Ketamine is an NMDA receptor antagonist, which has analgesic, sedative and sympathetic stimulation effects, but generally its use requires a relatively large dose, which can easily cause blood pressure to increase and agitation during recovery.

滴鼻液系指专供滴入鼻腔内使用的液体制剂，以前研制的滴鼻液以局部作用为主，广泛用来治疗各种鼻腔和鼻窦疾病，也可作为辅助用药用于与鼻病有关的临近器官疾患。近年来随着这一给药途径的深入研究，发现人类鼻腔粘膜表面积约为150cm2,呼吸区粘膜表层上皮细胞均有许多绒毛，可增加药物吸收的有效面积，鼻粘膜上皮下层有丰富的毛细血管、静脉窦、动-静脉吻合支、以及淋巴毛细血管交织网，使吸收的药物可迅速进入血循环，以提高鼻腔用药的生物利用度。Nasal drops refer to liquid preparations specially designed for dripping into the nasal cavity. Previously developed nasal drops are mainly used for local effects and are widely used to treat various nasal cavity and sinus diseases. They can also be used as auxiliary drugs for nasal diseases. diseases of adjacent organs. In recent years, with the in-depth study of this route of administration, it has been found that the surface area of the human nasal mucosa is about 150 cm 2 , and the epithelial cells of the mucosal surface in the respiratory area have many villi, which can increase the effective area for drug absorption. The subepithelial layer of the nasal mucosa is rich in capillaries. Blood vessels, venous sinuses, arterial-venous anastomotic branches, and lymphatic capillary interweave network, so that the absorbed drugs can quickly enter the blood circulation, so as to improve the bioavailability of nasal drugs.

综上所述，现有技术对盐酸右美托咪啶与氯胺酮的研究尚不能满足临床使用的需求，急需开发一种用于临床使用方便、起效迅速、安全有效的复方麻醉滴鼻液；目前，滴鼻液仍然存在储存过程稳定性较差，易析晶，溶液pH变化较大，微生物限度不易控制，货架期短、制备过程杂质增加明显等技术问题亟需解决。In summary, the prior art research on dexmedetomidine hydrochloride and ketamine can not meet the needs of clinical use, and there is an urgent need to develop a compound anesthetic nasal drop that is convenient for clinical use, has a rapid onset of effect, is safe and effective; At present, nasal drops still have technical problems such as poor storage stability, easy crystallization, large changes in solution pH, difficult control of microbial limit, short shelf life, and obvious increase of impurities in the preparation process, which need to be solved urgently.

发明内容Contents of the invention

本发明的目的在于提供一种稳定性好、产品不会分层结晶用于麻醉的滴鼻液。The object of the present invention is to provide a kind of nasal drop that has good stability, and the product will not stratify and crystallize for anesthesia.

本发明的另一目的在于提供上述用于麻醉的滴鼻液的制备方法。Another object of the present invention is to provide the preparation method of the above nasal drops for anesthesia.

本发明的目的是通过如下技术措施实现的：The purpose of the present invention is achieved through the following technical measures:

一种用于麻醉的滴鼻液，其特征在于，它是以盐酸右美托咪啶和盐酸氯胺酮为原料，加入一定量的渗透压调节剂、抑菌剂、抗氧化剂、助溶剂、pH调节剂，经过浓配、稀配、灌装、灭菌、外包步骤制得。A nasal drop for anesthesia, which is characterized in that it uses dexmedetomidine hydrochloride and ketamine hydrochloride as raw materials, adding a certain amount of osmotic pressure regulator, bacteriostat, antioxidant, cosolvent, pH adjustment The agent is prepared through the steps of concentrated preparation, thin preparation, filling, sterilization and outsourcing.

进一步，一种用于麻醉的滴鼻液，其特征在于，所述渗透压调节剂为氯化钠、氯化钾、葡萄糖、甘露醇中的一种或多种；所述抑菌剂为羟苯甲酯、羟苯乙酯、羟苯丁酯、苯扎氯铵、苯扎溴铵、苯甲酸、苯甲酸钠中的一种或多种；所述抗氧剂为维生素C、L-甲硫氨酸、硫代硫酸钠、亚硫酸钠、焦亚硫酸钠、半胱氨酸中的一种或多种；所述助溶剂为甘油、丙二醇、乙醇、聚乙二醇200中的一种；所述pH调节剂为盐酸、硫酸、磷酸、碳酸氢钠、碳酸钠、氢氧化钠、氢氧化钾中的一种。Further, a nasal drop for anesthesia, characterized in that, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, glucose, mannitol; the bacteriostatic agent is hydroxy One or more of benzoyl ester, ethylparaben, butylparaben, benzalkonium chloride, benzalkonium bromide, benzoic acid, sodium benzoate; the antioxidant is vitamin C, L-methyl sulfide One or more in amino acid, sodium thiosulfate, sodium sulfite, sodium pyrosulfite, cysteine; The cosolvent is one of glycerol, propylene glycol, ethanol, polyethylene glycol 200; the pH adjustment The agent is one of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide.

一种用于麻醉的滴鼻液，其特征在于，它是包括下列重量配比的原辅料：盐酸右美托咪啶1份、盐酸氯胺酮500～1000份、葡萄糖1000～3000份、羟苯乙酯20～80份、硫代硫酸钠200～500份、甘油15～35份、聚乙二醇200 20～60份、碳酸氢钠1～80份、纯化水5000～15000份。A nasal drop for anesthesia, characterized in that it comprises the following raw and auxiliary materials in the weight ratio: 1 part of dexmedetomidine hydrochloride, 500-1000 parts of ketamine hydrochloride, 1000-3000 parts of glucose, 20-80 parts of ester, 200-500 parts of sodium thiosulfate, 15-35 parts of glycerin, 20-60 parts of polyethylene glycol 200, 1-80 parts of sodium bicarbonate, 5000-15000 parts of purified water.

发明人在研究过程中发现，特定的原辅料种类及用量配比，配合制备过程中特定的pH，再配合特定的原辅料处理方法，可使得上述用于麻醉的滴鼻液在制备过程中总杂质增量较小，储存过程稳定性好不会析晶，上述用于麻醉的滴鼻液，其特征在于，它包括下列重量配比的原辅料：盐酸右美托咪啶1份、盐酸氯胺酮600～800份、葡萄糖1800～2300份、羟苯乙酯30～60份、硫代硫酸钠300～400份、甘油20～29份、聚乙二醇200 30～50份、碳酸氢钠22～51份、纯化水9000～12000份；向配料罐中加入1/5处方量的纯化水，加入处方量的盐酸右美托咪啶、盐酸氯胺酮、葡萄糖、羟苯乙酯、硫代硫酸钠，设置转速为60～80转/min，搅拌，使溶解得溶液1，备用；另取一个配料罐，像其中加入2/5处方量的纯化水，加入处方量的甘油、聚乙二醇200，设置转速为60～80转/min，温度为40～50℃，搅拌混匀得溶液2，备用；将制得的溶液1和溶液2混和、搅拌混匀得溶液3，备用；向溶液中加入处方量的碳酸氢钠，调节溶液pH为5.5～6.0，随后再加入质量分数为0.1％～0.3％的活性炭，吸附脱色，用0.45μm的滤膜滤过，收集滤液，加入处方量余下的纯净水，搅拌混匀，超声脱气后经中间品检验合格后上流水线进行灌装，灌装过程需充入纯度99.99％的氮气使得罐内溶液中的含氧量不超过0.01％，经充氮气后封口。In the course of the research, the inventor found that the specific types and dosage ratios of raw and auxiliary materials, combined with the specific pH in the preparation process, and the specific processing methods of raw and auxiliary materials, can make the above-mentioned nasal drops for anesthesia total in the preparation process. The impurity increase is small, the storage process is stable and will not crystallize. The above-mentioned nasal drop for anesthesia is characterized in that it includes the following raw and auxiliary materials in the following weight ratio: 1 part of dexmedetomidine hydrochloride, 600 parts of ketamine hydrochloride ～800 parts, glucose 1800～2300 parts, ethylparaben 30～60 parts, sodium thiosulfate 300～400 parts, glycerin 20～29 parts, polyethylene glycol 200 30～50 parts, sodium bicarbonate 22～51 parts 9000-12000 parts of purified water; add 1/5 of the prescription amount of purified water to the batching tank, add the prescription amount of dexmedetomidine hydrochloride, ketamine hydrochloride, glucose, ethylparaben, sodium thiosulfate, set The rotation speed is 60-80 rpm, stir to dissolve solution 1, and set aside; take another batching tank, add 2/5 of the prescription amount of purified water, add the prescription amount of glycerin, polyethylene glycol 200, set The rotation speed is 60-80 rpm, the temperature is 40-50°C, stir and mix to obtain solution 2, and set aside; mix the prepared solution 1 and solution 2, stir and mix to obtain solution 3, set aside; add the prescription to the solution Amount of sodium bicarbonate, adjust the pH of the solution to 5.5-6.0, then add activated carbon with a mass fraction of 0.1%-0.3%, absorb and decolorize, filter with a 0.45 μm filter membrane, collect the filtrate, and add the remaining pure water in the prescribed amount , stir and mix well, after ultrasonic degassing, pass the intermediate product inspection and then go to the assembly line for filling. The filling process needs to be filled with nitrogen with a purity of 99.99% so that the oxygen content in the solution in the tank does not exceed 0.01%. After filling with nitrogen seal.

一种用于麻醉的滴鼻液的制备方法，其特征在于，它是按如下步骤制得的：A preparation method for nasal drops for anesthesia is characterized in that it is prepared according to the following steps:

1.浓配：向配料罐中加入1/5处方量的纯化水，加入处方量的盐酸右美托咪啶、盐酸氯胺酮、葡萄糖、羟苯乙酯、硫代硫酸钠，设置转速为60～80转/min，搅拌，使溶解得溶液1，备用；另取一个配料罐，像其中加入2/5处方量的纯化水，加入处方量的甘油、聚乙二醇200，设置转速为60～80转/min，温度为40～50℃，搅拌混匀得溶液2，备用；1. Concentrated preparation: add 1/5 of the prescription amount of purified water to the batching tank, add the prescription amount of dexmedetomidine hydrochloride, ketamine hydrochloride, glucose, ethylparaben, sodium thiosulfate, set the speed at 60~ 80 rev/min, stir to dissolve solution 1, set aside; take another batching tank, add 2/5 of the prescription amount of purified water, add the prescription amount of glycerin, polyethylene glycol 200, set the speed at 60~ 80 revolutions/min, the temperature is 40-50°C, stir and mix to obtain solution 2, set aside;

2.稀配：将步骤1中制得的溶液1和溶液2混和、搅拌混匀得溶液3，备用；向溶液中加入处方量的碳酸氢钠，调节溶液pH为5.5～6.0，随后再加入质量分数为0.1％～0.3％的活性炭，吸附脱色，用0.45μm的滤膜滤过，收集滤液，加入处方量余下的纯净水，搅拌混匀，超声脱气后经中间品检验合格，即可；2. Dilute preparation: Mix solution 1 and solution 2 prepared in step 1, stir and mix to obtain solution 3, and set aside; add the prescribed amount of sodium bicarbonate to the solution, adjust the pH of the solution to 5.5-6.0, and then add Activated carbon with a mass fraction of 0.1% to 0.3%, absorb and decolorize, filter with a 0.45 μm filter membrane, collect the filtrate, add the remaining pure water in the prescribed amount, stir and mix, and pass the intermediate product inspection after ultrasonic degassing. ;

3.灌封：中间体检验合格后上流水线进行灌装，灌装过程需充入纯度99.99％的氮气使得罐内溶液中的含氧量不超过0.01％，经充氮气后封口；3. Filling and sealing: After passing the inspection of the intermediate, it is filled on the assembly line. During the filling process, nitrogen gas with a purity of 99.99% must be filled so that the oxygen content in the solution in the tank does not exceed 0.01%. After filling the tank with nitrogen, it is sealed;

4.灭菌：将灌装好的滴鼻液半成品送入蒸汽灭菌锅灭菌，115℃灭菌32min，灭菌完成，按规定条件检漏；4. Sterilization: Put the semi-finished nasal drops filled into a steam sterilizer for sterilization, sterilize at 115°C for 32 minutes, and after the sterilization is completed, check for leaks according to the specified conditions;

5.检验：将灭菌后样品检查可见异物，将检验合格的样品进行包装，全检，入库。5. Inspection: Check the sterilized samples for visible foreign matter, pack the samples that pass the inspection, conduct a full inspection, and put them into storage.

本发明具有如下的有益效果：The present invention has following beneficial effect:

本发明一种用于麻醉的滴鼻液无需建立特殊给药通道，患者用药过程无痛苦，顺应性好，产品储存过程稳定性好，不会析晶变质，效期内溶液pH几乎无变化，微生物限度合格，产品有效期长达24个月以上，制备过程杂质增量较小，整个制备过程杂质增量仅为0.01％，制备过程简单易行，值得市场推广。The nasal drop for anesthesia of the present invention does not need to establish a special administration channel, the patient has no pain in the medication process, the compliance is good, the product storage process has good stability, no crystallization and deterioration, and the pH of the solution hardly changes within the validity period. The microbial limit is qualified, the product is valid for more than 24 months, the impurity increase in the preparation process is small, and the impurity increase in the entire preparation process is only 0.01%, the preparation process is simple and easy, and it is worthy of market promotion.

具体实施方式detailed description

下面通过实施例对本发明进行具体的描述，有必要在此指出的是以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，在不背离本发明精神和实质的情况下，对本发明方法、步骤或条件所作的修改或替换，均属于本发明的范围。The present invention is specifically described below by the examples. It is necessary to point out that the following examples are only used to further illustrate the present invention, and cannot be interpreted as limiting the protection scope of the present invention. Without departing from the spirit and essence of the present invention All modifications or replacements made to the methods, steps or conditions of the present invention fall within the scope of the present invention.

实施例1Example 1

一种用于麻醉的滴鼻液，按以下步骤制得：A kind of nasal drop for anesthesia is prepared according to the following steps:

成分Element 用量(重量份)Dosage (parts by weight) 盐酸右美托咪啶Dexmedetomidine Hydrochloride 1份1 copy 盐酸氯胺酮Ketamine hydrochloride 720份720 copies 葡萄糖glucose 2100份2100 copies 羟苯乙酯Ethylparaben 50份50 copies 硫代硫酸钠Sodium thiosulfate 350份350 copies 甘油glycerin 25份25 copies 聚乙二醇200polyethylene glycol 200 40份40 copies 碳酸氢钠sodium bicarbonate 36份36 copies 纯化水purified water 11000份11000 copies

制剂工艺：Preparation process:

1.浓配：向配料罐中加入1/5处方量的纯化水，加入处方量的盐酸右美托咪啶、盐酸氯胺酮、葡萄糖、羟苯乙酯、硫代硫酸钠，设置转速为60～80转/min，搅拌，使溶解得溶液1，备用；另取一个配料罐，像其中加入2/5处方量的纯化水，加入处方量的甘油、聚乙二醇200，设置转速为60～80转/min，温度为40～50℃，搅拌混匀得溶液2，备用；1. Concentrated preparation: add 1/5 of the prescription amount of purified water to the batching tank, add the prescription amount of dexmedetomidine hydrochloride, ketamine hydrochloride, glucose, ethylparaben, sodium thiosulfate, set the speed at 60~ 80 rev/min, stir to dissolve solution 1, set aside; take another batching tank, add 2/5 of the prescription amount of purified water, add the prescription amount of glycerin, polyethylene glycol 200, set the speed at 60~ 80 revolutions/min, the temperature is 40-50°C, stir and mix to obtain solution 2, set aside;

2.稀配：将步骤1中制得的溶液1和溶液2混和、搅拌混匀得溶液3，备用；向溶液中加入处方量的碳酸氢钠，调节溶液pH为5.5～6.0，随后再加入质量分数为0.1％～0.3％的活性炭，吸附脱色，用0.45μm的滤膜滤过，收集滤液，加入处方量余下的纯净水，搅拌混匀，超声脱气后经中间品检验合格，即可；2. Dilute preparation: Mix solution 1 and solution 2 prepared in step 1, stir and mix to obtain solution 3, and set aside; add the prescribed amount of sodium bicarbonate to the solution, adjust the pH of the solution to 5.5-6.0, and then add Activated carbon with a mass fraction of 0.1% to 0.3%, absorb and decolorize, filter with a 0.45 μm filter membrane, collect the filtrate, add the remaining pure water in the prescribed amount, stir and mix, and pass the intermediate product inspection after ultrasonic degassing. ;

3.灌封：中间体检验合格后上流水线进行灌装，灌装过程需充入纯度99.99％的氮气使得罐内溶液中的含氧量不超过0.01％，经充氮气后封口；3. Filling and sealing: After passing the inspection of the intermediate, it is filled on the assembly line. During the filling process, nitrogen gas with a purity of 99.99% must be filled so that the oxygen content in the solution in the tank does not exceed 0.01%. After filling the tank with nitrogen, it is sealed;

4.灭菌：将灌装好的滴鼻液半成品送入蒸汽灭菌锅灭菌，115℃灭菌32min，灭菌完成，按规定条件检漏；4. Sterilization: Put the semi-finished nasal drops filled into a steam sterilizer for sterilization, sterilize at 115°C for 32 minutes, and after the sterilization is completed, check for leaks according to the specified conditions;

5.检验：将灭菌后样品检查可见异物，将检验合格的样品进行包装，全检，入库。5. Inspection: Check the sterilized samples for visible foreign matter, pack the samples that pass the inspection, conduct a full inspection, and put them into storage.

为了更好的理解本发明，以下通过本发明稳定性试验来进一步阐述发明药物的有益效果，而非对本发明的限制。In order to better understand the present invention, the stability test of the present invention is used to further illustrate the beneficial effects of the inventive drug, rather than limiting the present invention.

实验一：本发明一种用于麻醉的滴鼻液稳定性实验Experiment 1: A stability experiment of nasal drops for anesthesia of the present invention

实验材料：Experimental Materials:

一种用于麻醉的滴鼻液样品：为实施例1制得A kind of nasal drop sample that is used for anesthesia: for embodiment 1 makes

加速实验方法：将实施例1制得的滴鼻液按上市包装，置加速实验箱中，一定时间取样，对考察项目进行检验。Accelerated test method: the nasal drops prepared in Example 1 are packaged on the market, placed in an accelerated test box, and a certain period of time is sampled to check the investigation items.

加速实验温度：40±2℃Accelerated experiment temperature: 40±2℃

湿度：RH75％±5％Humidity: RH75%±5%

考察时间：0、1、2、3、6月Inspection time: 0, 1, 2, 3, 6 months

考察指标：性状、pH、含量、有关物质、澄清度、微生物限度Inspection indicators: traits, pH, content, related substances, clarity, microbial limit

加速试验稳定性记录：Accelerated test stability records:

加速实验结果表明：加速6月样品与0月样品各项检测指标质量相当，表明本品加速实验6月，质量保持稳定，本品稳定性较好。The results of the accelerated test show that the quality of the test indicators of the sample in June and the sample in 0 month is equivalent, indicating that the quality of this product remains stable after the accelerated test in June, and the stability of this product is good.

长期实验方法：将实施例1制得的用于麻醉的滴鼻液按上市包装，置长期留样箱中，一定时间取样,对考察项目进行检验。Long-term experimental method: the nasal drops used for anesthesia prepared in Example 1 are packaged according to the market, put in a long-term sample retention box, take samples for a certain period of time, and check the investigation items.

加速实验温度：25±2℃Accelerated experiment temperature: 25±2℃

湿度：RH60％±10％Humidity: RH60%±10%

考察时间：0、3、6、9、12、18、24月Inspection time: 0, 3, 6, 9, 12, 18, 24 months

考察指标：性状、pH、含量、有关物质、澄清度、微生物限度Inspection indicators: traits, pH, content, related substances, clarity, microbial limit

长期试验稳定性记录：Long-term test stability records:

长期试验表明：本品长期试验24个月性状、pH、含量、有关物质、澄清度、微生物限度检查各项指标均无显著变化，均符合生产用质量标准草案的各项相关规定。本品长期试验24个月质量稳定，故本品有效期最少24个月，长期试验仍在继续考察过程中。The long-term test shows that the properties, pH, content, related substances, clarity, and microbial limit inspection indicators of this product have no significant changes after 24 months of long-term test, and all meet the relevant provisions of the draft quality standard for production. The quality of this product is stable for 24 months in the long-term test, so the validity period of this product is at least 24 months, and the long-term test is still in the process of investigation.

实验二：本发明一种用于麻醉的滴鼻液辅料种类及制备过程对杂质增加的影响Experiment 2: The impact of the type and preparation process of a kind of nasal drop auxiliary material for anesthesia on the increase of impurities of the present invention

1.试验方法：1. Test method:

一种用于麻醉的滴鼻液样品：按实施例1制备。A nasal drop sample for anesthesia: prepared according to Example 1.

一种用于麻醉的滴鼻液对照样品1：为缺少硫代硫酸钠的处方制得的样品，其制备工艺同实施例1。A kind of nasal drop control sample 1 for anesthesia: a sample prepared for a prescription lacking sodium thiosulfate, and its preparation process is the same as in Example 1.

一种用于麻醉的滴鼻液对照样品2：为缺少甘油的处方制得的样品，其制备工艺同实施例1。A nasal drop control sample 2 for anesthesia: a sample prepared for a prescription lacking glycerin, and its preparation process is the same as in Example 1.

一种用于麻醉的滴鼻液对照样品3：为缺少聚乙二醇200的处方制得的样品，其制备工艺同实施例1。A nasal drop control sample 3 for anesthesia: a sample prepared for a prescription lacking polyethylene glycol 200, and its preparation process is the same as in Example 1.

一种用于麻醉的滴鼻液对照样品4：处方为实施例1的处方，按如下制备方法制得：1.浓配：向配料罐中加入3/5处方量的纯化水，加入处方量的盐酸右美托咪啶、盐酸氯胺酮、葡萄糖、羟苯乙酯、硫代硫酸钠、甘油、聚乙二醇200，设置转速为60～80转/min，搅拌，使溶解得溶液，备用；2.稀配：向步骤1中制得的溶液加入处方量的碳酸氢钠，调节溶液pH为5.5～6.0，随后再加入质量分数为0.1％～0.3％的活性炭，吸附脱色，用0.45μm的滤膜滤过，收集滤液，加入处方量余下的纯净水，搅拌混匀，超声脱气后经中间品检验合格，即可；3.灌封：中间体检验合格后上流水线进行灌装，灌装过程需充入纯度99.99％的氮气使得罐内溶液中的含氧量不超过0.01％，经充氮气后封口；4.灭菌：将灌装好的滴鼻液半成品送入蒸汽灭菌锅灭菌，115℃灭菌32min，灭菌完成，按规定条件检漏；5.检验：将灭菌后样品检查可见异物，将检验合格的样品进行包装，全检，入库。A kind of nasal drop control sample 4 that is used for anesthesia: the prescription is the prescription of embodiment 1, makes according to the following preparation method: 1. thick mix: add the purified water of 3/5 prescription quantity in batching tank, add prescription quantity Dexmedetomidine hydrochloride, ketamine hydrochloride, glucose, ethylparaben, sodium thiosulfate, glycerin, polyethylene glycol 200, set the rotation speed at 60-80 rpm, stir, dissolve to obtain a solution, and set aside; 2. Dilute preparation: Add the prescribed amount of sodium bicarbonate to the solution prepared in step 1, adjust the pH of the solution to 5.5-6.0, then add activated carbon with a mass fraction of 0.1%-0.3%, adsorb and decolorize, and use 0.45 μm Filtrate through the filter membrane, collect the filtrate, add the remaining pure water in the prescription, stir and mix well, and pass the intermediate product inspection after ultrasonic degassing; The filling process needs to be filled with nitrogen with a purity of 99.99% so that the oxygen content in the solution in the tank does not exceed 0.01%, and the seal is sealed after filling with nitrogen; 4. Sterilization: send the semi-finished nasal drops that have been filled into a steam sterilizer Sterilization, sterilize at 115°C for 32 minutes, after the sterilization is completed, check for leaks according to the specified conditions; 5. Inspection: check the sterilized samples for foreign matter, and pack the samples that pass the inspection, and put them into storage after full inspection.

一种用于麻醉的滴鼻液原料对照样品：取处方量的盐酸右美托咪啶、盐酸氯胺酮加纯化水，直接进样，临用新配，作为杂质基础数据。A raw material control sample of nasal drops for anesthesia: Take the prescribed amount of dexmedetomidine hydrochloride and ketamine hydrochloride plus purified water, directly inject the sample, and use it as the basic data of impurities.

2.试验结果见下表：2. The test results are shown in the table below:

3.实验结果及结论：实施例1的处方，配合特定制备工艺，有关物质增加仅为0.01％，明显优于其它对照样品。3. Experimental results and conclusions: the prescription of Example 1, combined with a specific preparation process, increases the related substances by only 0.01%, which is obviously better than other control samples.

实施例2Example 2

一种用于麻醉的滴鼻液，按以下步骤制得：A kind of nasal drop for anesthesia is prepared according to the following steps:

成分Element 用量(重量份)Dosage (parts by weight) 盐酸右美托咪啶Dexmedetomidine Hydrochloride 1份1 copy 盐酸氯胺酮Ketamine hydrochloride 600份600 copies 葡萄糖glucose 1800份1800 copies 羟苯乙酯Ethylparaben 30份30 copies 硫代硫酸钠Sodium thiosulfate 300份300 copies 甘油glycerin 20份20 copies 聚乙二醇200polyethylene glycol 200 30份30 copies 碳酸氢钠sodium bicarbonate 22份22 copies 纯化水purified water 9000份9000 copies

制剂工艺：照实施例1的制备工艺制得。Preparation process: prepared according to the preparation process of Example 1.

按实施例1的试验方法，实施例2样品稳定性试验结果表明加速6月样品质量稳定，长期24个月质量稳定，故本品有效期最少24个月；辅料种类及制备过程对杂质增加的影响试验结果表明实施例2的处方，配合特定的制备工艺，有关物质增加明显优于其对照样品。According to the test method of Example 1, the sample stability test results of Example 2 show that the quality of the sample is stable in June, and the quality is stable in 24 months for a long time, so the validity period of this product is at least 24 months; the impact of the type of auxiliary material and the preparation process on the increase of impurities The test results show that the prescription of Example 2, combined with a specific preparation process, increases related substances significantly better than its control sample.

实施例3Example 3

一种用于麻醉的滴鼻液，按以下步骤制得：A kind of nasal drop for anesthesia is prepared according to the following steps:

成分Element 用量(重量份)Dosage (parts by weight) 盐酸右美托咪啶Dexmedetomidine Hydrochloride 1份1 copy 盐酸氯胺酮Ketamine hydrochloride 800份800 copies 葡萄糖glucose 2300份2300 copies 羟苯乙酯Ethylparaben 60份60 copies 硫代硫酸钠Sodium thiosulfate 400份400 copies 甘油glycerin 29份29 copies 聚乙二醇200polyethylene glycol 200 50份50 copies 碳酸氢钠sodium bicarbonate 51份51 copies 纯化水purified water 12000份12000 copies

制剂工艺：照实施例1的制备工艺制得。Preparation process: prepared according to the preparation process of Example 1.

按实施例1的试验方法，实施例3样品稳定性试验结果表明加速6月样品质量稳定，长期24个月质量稳定，故本品有效期最少24个月；辅料种类及制备过程对杂质增加的影响试验结果表明实施例3的处方，配合特定的制备工艺，有关物质增加明显优于其对照样品。According to the test method of Example 1, the sample stability test results of Example 3 show that the quality of the sample is stable in June, and the quality is stable in 24 months for a long time, so the validity period of this product is at least 24 months; the impact of the type of auxiliary material and the preparation process on the increase of impurities The test results show that the prescription of Example 3, in conjunction with a specific preparation process, increases related substances significantly better than its control sample.

实施例4-6：一种用于麻醉的滴鼻液，按以下重量的原辅料制备而得，制备方法同实施例1：Embodiment 4-6: a kind of nasal drop that is used for anesthesia, obtains by the raw material preparation of following weight, preparation method is the same as embodiment 1:

按实施例1的试验方法，实施例4、5、6样品稳定性试验结果表明加速6月样品质量稳定，长期24个月质量稳定，故本品有效期最少24个月；辅料种类及制备过程对杂质增加的影响试验结果表明实施例4、5、6的处方，配合特定的制备工艺，有关物质增加明显优于其对照样品。By the test method of embodiment 1, the sample stability test result of embodiment 4,5,6 shows that accelerated June sample quality is stable, and long-term 24 months quality is stable, so this product is valid for at least 24 months; The test results of the impact of the increase of impurities show that the prescriptions of Examples 4, 5, and 6, combined with a specific preparation process, increase the related substances significantly better than their control samples.

Claims (5) Translated from Chinese

1.一种用于麻醉的滴鼻液，其特征在于，它是以盐酸右美托咪啶和盐酸氯胺酮为原料，加入一定量的渗透压调节剂、抑菌剂、抗氧化剂、助溶剂、pH调节剂，经过浓配、稀配、灌装、灭菌、外包步骤制得。1. a nasal drop for anesthesia is characterized in that, it is to take dexmedetomidine hydrochloride and ketamine hydrochloride as raw material, add a certain amount of osmotic pressure regulator, antibacterial agent, antioxidant, cosolvent, The pH regulator is prepared through the steps of concentrated preparation, thin preparation, filling, sterilization and outsourcing. 2.如权利要求1所述的用于麻醉的滴鼻液，其特征在于，所述渗透压调节剂为氯化钠、氯化钾、葡萄糖、甘露醇中的一种或多种；所述抑菌剂为羟苯甲酯、羟苯乙酯、羟苯丁酯、苯扎氯铵、苯扎溴铵、苯甲酸、苯甲酸钠中的一种或多种；所述抗氧剂为维生素C、L-甲硫氨酸、硫代硫酸钠、亚硫酸钠、焦亚硫酸钠、半胱氨酸中的一种或多种；所述助溶剂为甘油、丙二醇、乙醇、聚乙二醇200中的一种；所述pH调节剂为盐酸、硫酸、磷酸、碳酸氢钠、碳酸钠、氢氧化钠、氢氧化钾中的一种。2. the nasal drop for anesthesia as claimed in claim 1, is characterized in that, described osmotic pressure regulator is one or more in sodium chloride, potassium chloride, glucose, mannitol; The antibacterial agent is one or more of methylparaben, ethylparaben, butylparaben, benzalkonium chloride, benzalkonium bromide, benzoic acid, sodium benzoate; the antioxidant is vitamin C , L-methionine, sodium thiosulfate, sodium sulfite, sodium metabisulfite, cysteine or one or more; the co-solvent is one of glycerin, propylene glycol, ethanol, polyethylene glycol 200 ; The pH regulator is one of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide. 3.如权利要求1或2所述的用于麻醉的滴鼻液，其特征在于，它是包括下列重量配比的原辅料：盐酸右美托咪啶1份、盐酸氯胺酮500～1000份、葡萄糖1000～3000份、羟苯乙酯20～80份、硫代硫酸钠200～500份、甘油15～35份、聚乙二醇200 20～60份、碳酸氢钠1～80份、纯化水5000～15000份。3. The nasal drop for anesthesia as claimed in claim 1 or 2, characterized in that it is the raw and auxiliary materials comprising the following weight ratio: 1 part of dexmedetomidine hydrochloride, 500-1000 parts of ketamine hydrochloride, 1000-3000 parts of glucose, 20-80 parts of ethylparaben, 200-500 parts of sodium thiosulfate, 15-35 parts of glycerin, 20-60 parts of polyethylene glycol 200, 1-80 parts of sodium bicarbonate, purified water 5000~15000 copies. 4.如权利要求1、2或3所述的用于麻醉的滴鼻液，其特征在于，它包括下列重量配比的原辅料：盐酸右美托咪啶1份、盐酸氯胺酮600～800份、葡萄糖1800～2300份、羟苯乙酯30～60份、硫代硫酸钠300～400份、甘油20～29份、聚乙二醇200 30～50份、碳酸氢钠22～51份、纯化水9000～12000份；向配料罐中加入1/5处方量的纯化水，加入处方量的盐酸右美托咪啶、盐酸氯胺酮、葡萄糖、羟苯乙酯、硫代硫酸钠，设置转速为60～80转/min，搅拌，使溶解得溶液1，备用；另取一个配料罐，像其中加入2/5处方量的纯化水，加入处方量的甘油、聚乙二醇200，设置转速为60～80转/min，温度为40～50℃，搅拌混匀得溶液2，备用；将制得的溶液1和溶液2混和、搅拌混匀得溶液3，备用；向溶液中加入处方量的碳酸氢钠，调节溶液pH为5.5～6.0，随后再加入质量分数为0.1％～0.3％的活性炭，吸附脱色，用0.45μm的滤膜滤过，收集滤液，加入处方量余下的纯净水，搅拌混匀，超声脱气后经中间品检验合格后上流水线进行灌装，灌装过程需充入纯度99.99％的氮气使得罐内溶液中的含氧量不超过0.01％，经充氮气后封口。4. The nasal drop for anesthesia as claimed in claim 1, 2 or 3, characterized in that it comprises the following raw and auxiliary materials in the weight ratio: 1 part of dexmedetomidine hydrochloride, 600-800 parts of ketamine hydrochloride , 1800-2300 parts of glucose, 30-60 parts of ethylparaben, 300-400 parts of sodium thiosulfate, 20-29 parts of glycerin, 30-50 parts of polyethylene glycol 200, 22-51 parts of sodium bicarbonate, purified 9,000 to 12,000 parts of water; add 1/5 of the prescription amount of purified water to the batching tank, add the prescription amount of dexmedetomidine hydrochloride, ketamine hydrochloride, glucose, ethylparaben, sodium thiosulfate, set the speed to 60 ~80 rev/min, stir to dissolve solution 1, set aside; take another batching tank, add 2/5 of the prescription amount of purified water, add the prescription amount of glycerin, polyethylene glycol 200, set the speed to 60 ～80 revs/min, the temperature is 40～50℃, stir and mix to obtain solution 2, and set aside; mix the prepared solution 1 and solution 2, stir and mix to obtain solution 3, set aside; add the prescribed amount of carbonic acid to the solution Sodium hydrogen, adjust the pH of the solution to be 5.5-6.0, then add activated carbon with a mass fraction of 0.1%-0.3%, absorb and decolorize, filter with a 0.45 μm filter membrane, collect the filtrate, add the remaining pure water in the prescribed amount, stir and mix Evenly, after ultrasonic degassing and passing the intermediate product inspection, it will be filled on the assembly line. During the filling process, nitrogen with a purity of 99.99% should be filled so that the oxygen content in the solution in the tank does not exceed 0.01%. After filling with nitrogen, it will be sealed. 5.一种用于麻醉的滴鼻液的制备方法，其特征在于，它是按如下步骤制得的：5. A preparation method for nasal drops for anesthesia, characterized in that it is prepared as follows: A.浓配：向配料罐中加入1/5处方量的纯化水，加入处方量的盐酸右美托咪啶、盐酸氯胺酮、葡萄糖、羟苯乙酯、硫代硫酸钠，设置转速为60～80转/min，搅拌，使溶解得溶液1，备用；另取一个配料罐，像其中加入2/5处方量的纯化水，加入处方量的甘油、聚乙二醇200，设置转速为60～80转/min，温度为40～50℃，搅拌混匀得溶液2，备用；A. Concentrated preparation: Add 1/5 of the prescription amount of purified water to the batching tank, add the prescription amount of dexmedetomidine hydrochloride, ketamine hydrochloride, glucose, ethylparaben, sodium thiosulfate, set the speed at 60~ 80 rev/min, stir to dissolve solution 1, set aside; take another batching tank, add 2/5 of the prescription amount of purified water, add the prescription amount of glycerin, polyethylene glycol 200, set the speed at 60~ 80 revolutions/min, the temperature is 40-50°C, stir and mix to obtain solution 2, set aside; B.稀配：将步骤1中制得的溶液1和溶液2混和、搅拌混匀得溶液3，备用；向溶液中加入处方量的碳酸氢钠，调节溶液pH为5.5～6.0，随后再加入质量分数为0.1％～0.3％的活性炭，吸附脱色，用0.45μm的滤膜滤过，收集滤液，加入处方量余下的纯净水，搅拌混匀，超声脱气后经中间品检验合格，即可；B. Dilute preparation: Mix solution 1 and solution 2 prepared in step 1, stir and mix to obtain solution 3, and set aside; add the prescribed amount of sodium bicarbonate to the solution, adjust the pH of the solution to 5.5-6.0, and then add Activated carbon with a mass fraction of 0.1% to 0.3%, absorb and decolorize, filter with a 0.45 μm filter membrane, collect the filtrate, add the remaining pure water in the prescribed amount, stir and mix, and pass the intermediate product inspection after ultrasonic degassing. ; C.灌封：中间体检验合格后上流水线进行灌装，灌装过程需充入纯度99.99％的氮气使得罐内溶液中的含氧量不超过0.01％，经充氮气后封口；C. Filling: After passing the intermediate inspection, it will be filled on the assembly line. During the filling process, nitrogen gas with a purity of 99.99% must be filled so that the oxygen content in the solution in the tank does not exceed 0.01%, and it will be sealed after filling with nitrogen; D.灭菌：将灌装好的滴鼻液半成品送入蒸汽灭菌锅灭菌，115℃灭菌32min，灭菌完成，按规定条件检漏；D. Sterilization: Put the semi-finished nasal drops filled into a steam sterilizer for sterilization, sterilize at 115°C for 32 minutes, after the sterilization is completed, check for leaks according to the specified conditions; E.检验：将灭菌后样品检查可见异物，将检验合格的样品进行包装，全检，入库。E. Inspection: Check the sterilized samples for visible foreign matter, pack the samples that pass the inspection, conduct a full inspection, and put them into storage.

CN201710272858.7A 2017-04-24 2017-04-24 A kind of nasal drops for being used to anaesthetize and preparation method thereof Pending CN107693485A (en) Priority Applications (1) Application Number Priority Date Filing Date Title CN201710272858.7A CN107693485A (en) 2017-04-24 2017-04-24 A kind of nasal drops for being used to anaesthetize and preparation method thereof Applications Claiming Priority (1) Application Number Priority Date Filing Date Title CN201710272858.7A CN107693485A (en) 2017-04-24 2017-04-24 A kind of nasal drops for being used to anaesthetize and preparation method thereof Publications (1) Family ID=61169469 Family Applications (1) Application Number Title Priority Date Filing Date CN201710272858.7A Pending CN107693485A (en) 2017-04-24 2017-04-24 A kind of nasal drops for being used to anaesthetize and preparation method thereof Country Status (1) Cited By (8) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US20190262314A1 (en) * 2018-02-26 2019-08-29 Slayback Pharma Llc Ready-to-use dexmedetomidine compositions WO2021014108A1 (en) * 2019-07-25 2021-01-28 Laboratoires Grimberg Nasal or oral spray composition containing sulfur CN114306219A (en) * 2020-09-30 2022-04-12 四川普锐特药业有限公司 Stable R-ketamine pharmaceutical composition CN114306218A (en) * 2020-09-30 2022-04-12 四川普锐特药业有限公司 R-ketamine pharmaceutical composition for transmucosal administration meeting pharmaceutical antibacterial requirements US11478422B2 (en) 2018-06-27 2022-10-25 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them US11786508B2 (en) 2016-12-31 2023-10-17 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation US11806334B1 (en) 2023-01-12 2023-11-07 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens US11890272B2 (en) 2019-07-19 2024-02-06 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens Non-Patent Citations (2) Cited By (22) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US11931340B2 (en) 2016-12-31 2024-03-19 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation US11839604B2 (en) 2016-12-31 2023-12-12 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation US11786508B2 (en) 2016-12-31 2023-10-17 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation US20190262314A1 (en) * 2018-02-26 2019-08-29 Slayback Pharma Llc Ready-to-use dexmedetomidine compositions US11478422B2 (en) 2018-06-27 2022-10-25 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them US11497711B2 (en) 2018-06-27 2022-11-15 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them US11517524B2 (en) 2018-06-27 2022-12-06 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them US11559484B2 (en) 2018-06-27 2023-01-24 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them US11806429B2 (en) 2018-06-27 2023-11-07 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them US12109196B2 (en) 2019-07-19 2024-10-08 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens US11998529B2 (en) 2019-07-19 2024-06-04 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens US11890272B2 (en) 2019-07-19 2024-02-06 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens FR3099051A1 (en) * 2019-07-25 2021-01-29 Laboratoires Grimberg Nasal or oral spray composition containing sulfur WO2021014108A1 (en) * 2019-07-25 2021-01-28 Laboratoires Grimberg Nasal or oral spray composition containing sulfur CN114306219B (en) * 2020-09-30 2023-09-26 四川普锐特药业有限公司 Stable R-ketamine pharmaceutical composition CN114306218B (en) * 2020-09-30 2023-11-10 四川普锐特药业有限公司 Transmucosal administration R-ketamine pharmaceutical composition meeting pharmaceutical bacteriostasis requirements CN114306219A (en) * 2020-09-30 2022-04-12 四川普锐特药业有限公司 Stable R-ketamine pharmaceutical composition CN114306218A (en) * 2020-09-30 2022-04-12 四川普锐特药业有限公司 R-ketamine pharmaceutical composition for transmucosal administration meeting pharmaceutical antibacterial requirements US11806334B1 (en) 2023-01-12 2023-11-07 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens US11998528B1 (en) 2023-01-12 2024-06-04 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens US12090140B2 (en) 2023-01-12 2024-09-17 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens US12138247B2 (en) 2023-01-12 2024-11-12 Bioxcel Therapeutics, Inc. 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CN114159387B (en) 2022-08-19 Dextromethorphan hydrobromide oral solution Legal Events Date Code Title Description 2018-02-16 PB01 Publication 2018-02-16 PB01 Publication 2018-03-16 SE01 Entry into force of request for substantive examination 2018-03-16 SE01 Entry into force of request for substantive examination 2018-05-04 TA01 Transfer of patent application right 2018-05-04 TA01 Transfer of patent application right

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