技术领域technical field
本发明涉及一种注射用过氧化碳酰胺冻干制剂、其制备方法及其用途。The invention relates to a freeze-dried preparation of carboamide peroxide for injection, its preparation method and its application.
背景技术Background technique
人体内氧储甚微，需要从外界不断供给。现已了解氧是在线粒体和微粒体内被利用的。因此，缺氧可被认为是氧供给不足，线粒体内氧分压降低，而引起的细胞代谢障碍。治疗缺氧的基本目的在于提高线粒体内的氧分压。气体是以弥散原理通过生物膜，这些膜包括细胞膜、核膜、内质网、高尔基复合体、线粒体膜以及溶酶体膜等，即膜两侧的气体分子总是在由分压高的一侧向分压低的一侧弥散，因此，气体分压是决定其通过生物膜的主要因素。缺氧时血氧分压降低，线粒体内的氧分压相应降低。从氧离曲线可知，严重缺氧时，氧分压与饱和度的关系处于氧离曲线的陡直部分，血氧分压稍有升高，血氧饱和度就有较多的增加，这种关系表明提高氧分压水平对治疗缺氧有重要意义。Oxygen storage in the human body is very small and needs to be continuously supplied from the outside world. Oxygen is now known to be utilized within mitochondria and microsomes. Therefore, hypoxia can be considered as a cellular metabolic disorder caused by insufficient oxygen supply and decreased partial pressure of oxygen in mitochondria. The basic purpose of treating hypoxia is to increase the partial pressure of oxygen in the mitochondria. Gas passes through biological membranes based on the principle of diffusion. These membranes include cell membranes, nuclear membranes, endoplasmic reticulum, Golgi complexes, mitochondrial membranes, and lysosome membranes. The side with the lower lateral partial pressure diffuses, therefore, the gas partial pressure is the main factor determining its passage through the biofilm. When hypoxia occurs, the partial pressure of oxygen in the blood decreases, and the partial pressure of oxygen in the mitochondria decreases accordingly. It can be seen from the oxygen dissociation curve that in severe hypoxia, the relationship between oxygen partial pressure and saturation is in the steep part of the oxygen dissociation curve, and the blood oxygen partial pressure increases slightly, and the blood oxygen saturation increases a lot. The relationship shows that increasing the oxygen partial pressure level is of great significance in the treatment of hypoxia.
对于各类低氧血症，常用的治疗方法为吸氧法，但疗效不理想，使用不方便，而注射用内给氧是一种复合物，注入体内后，逐渐分解出过氧化氢，再经过氧化氢酰催化作用，释放出氧，氧与血液中血红蛋白结合，提供给缺氧组织；有效地治疗和抢救低氧血症患者，改善心慌、气短、胸闷、紫绀等症状，同时，对临床休克、外科手术恢复治疗，效果显著，作用持久。对于缺氧引起的胎儿宫内窘迫、妊高症等临床常见综合症，用药后胎心恢复快、改善明显，提高NST(胎儿在母体的健康指数)评分：孕妇血氧分压升高显著，持续时间可达4小时以上，有助于降低剖腹产率，且为手术抢救胎儿争取时间。For all kinds of hypoxemia, the commonly used treatment method is oxygen inhalation method, but the curative effect is not ideal, and it is inconvenient to use. The internal oxygen supply for injection is a compound. After being injected into the body, hydrogen peroxide is gradually decomposed, and then Through the catalysis of hydrogen peroxide, oxygen is released, and the oxygen is combined with hemoglobin in the blood to provide to hypoxic tissues; effectively treat and rescue patients with hypoxemia, improve symptoms such as palpitation, shortness of breath, chest tightness, cyanosis, etc. Shock, surgical recovery treatment, the effect is remarkable and the effect is long-lasting. For common clinical syndromes such as fetal distress and pregnancy-induced hypertension caused by hypoxia, the fetal heart rate recovers quickly and improves significantly after medication, and improves the NST (fetal health index in the mother's body) score: the blood oxygen partial pressure of pregnant women increases significantly, The duration can reach more than 4 hours, which helps to reduce the rate of caesarean section and buys time for the operation to rescue the fetus.
注射用过氧化碳酰胺作为一种静脉给氧制剂，因其比直接吸入医用氧气作用迅速，已经被普遍接受和使用。注射用过氧化碳酰胺注入体内后能分解出过氧化氢，再经过氧化氢酶催化作用释放出氧，氧直接与血红蛋白结合，进入细胞膜(包括红细胞膜)和线粒体内，从而提高氧分压及血氧饱和度，缓解缺氧状态。碳酸酰胺通过肾以原形排出体外。Carbamide peroxide for injection has been widely accepted and used as an intravenous oxygen preparation because it acts faster than direct inhalation of medical oxygen. Carbamide peroxide for injection can decompose hydrogen peroxide after injection into the body, and then release oxygen through the catalysis of catalase. Oxygen saturation, relieve hypoxic state. Carbonic acid amide is excreted unchanged through the kidneys.
目前国内市场上仅有过氧化碳酰胺的无菌分装的粉末，在使用过程中因氧气在注射部位局部的快速释放而产生的疼痛，却无法克服，给其应用推广带来一定难度。At present, there is only aseptic subpackaged powder of carboxamide peroxide on the domestic market, but the pain caused by the local rapid release of oxygen at the injection site during use cannot be overcome, which brings certain difficulties to its application and promotion.
发明内容Contents of the invention
本发明的目的在于提供一种注射用过氧化碳酰胺冻干制剂，该制剂加入了赋形剂，避免了在制备中过氧化碳酰胺的分解，同时使组份中的过氧化碳酰胺分子充分进入赋形剂的构架中，在临床使用时减慢了释放速度，降低了注射过程中因过氧化碳酰胺的快速分解释放产生氧气、碳酸酰胺而造成的疼痛。The object of the present invention is to provide a kind of carbamide peroxide lyophilized preparation for injection, this preparation has added excipient, has avoided the decomposition of carbamide peroxide in preparation, makes the carbamide peroxide molecule in the component fully simultaneously Entering the framework of excipients slows down the release rate during clinical use and reduces the pain caused by the rapid decomposition and release of carboamide peroxide to produce oxygen and carbonic acid amide during injection.
本发明的目的在于提供一种注射用过氧化碳酰胺冻干制剂的制备方法。The object of the present invention is to provide a kind of preparation method of carbamide peroxide freeze-dried preparation for injection.
本发明的目的在于提供一种注射用过氧化碳酰胺冻干制剂在制备治疗各种低氧血症以及急性缺氧引起的胎儿窘迫等疾病方面的用途。The object of the present invention is to provide the use of a lyophilized preparation of carboamide peroxide for injection in the preparation and treatment of various hypoxemia and fetal distress caused by acute hypoxia.
本发明所述的一种注射用过氧化碳酰胺冻干制剂，包括过氧化碳酰胺和右旋糖酐，质量比为0.001～2∶0.001～2。A carbamide peroxide freeze-dried preparation for injection according to the present invention comprises carbamide peroxide and dextran in a mass ratio of 0.001-2:0.001-2.
其中，优选的注射用过氧化碳酰胺冻干制剂包括过氧化碳酰胺和右旋糖酐，质量比为0.05～1.5∶0.05～1.5。Among them, the preferred freeze-dried preparation of carboxamide peroxide for injection includes carboxamide peroxide and dextran, and the mass ratio is 0.05-1.5:0.05-1.5.
本发明的研究人员经研究发现，采用过氧化碳酰胺进入大分子物质的构架中可减慢释放速度，而注射过氧化碳酰胺患者会感到强烈的疼痛感是因为氧气在注射部位局部的快速释放造成，所以减缓过氧化碳酰胺的释放速度，可降低注射时的疼痛感。在冻干产品赋形剂中属于大分子量物质的有：右旋糖酐或水解明胶等，但从临床上安全性考虑优选使用右旋糖酐，右旋糖酐本身也可制成静脉注射剂，而水解明胶不能大量应用于静脉注射，所以本发明研究人员对赋形剂进行筛选，选择采用右旋糖酐作为赋形剂。The researchers of the present invention have found that the use of carbamide peroxide to enter the framework of macromolecular substances can slow down the release rate, and patients who inject carbamide peroxide will feel a strong sense of pain because of the local rapid release of oxygen at the injection site Therefore, slowing down the release rate of carboamide peroxide can reduce the pain during injection. Among the excipients of freeze-dried products, substances with large molecular weight include: dextran or hydrolyzed gelatin, etc., but dextran is preferred for clinical safety, and dextran itself can also be made into intravenous injections, while hydrolyzed gelatin cannot be used in large quantities for intravenous injection , so the researchers of the present invention screened the excipients and chose to use dextran as the excipient.
本发明所述的右旋糖酐的分子量为10000～42000，优选为32000～42000。The molecular weight of the dextran in the present invention is 10000-42000, preferably 32000-42000.
目前，过氧化碳酰胺粉末制剂一般不添加赋形剂，因此在使用过程中因氧气在注射部位局部的快速释放而会使患者感到强烈的疼痛感，本发明所述的注射用过氧化碳酰胺冻干制剂中过氧化碳酰胺分子充分进入右旋糖酐分子构架中，在临床使用过程中减缓了过氧化碳酰胺分解释放气体的速度，大大减少了因快速释放氧气而产生的疼痛。At present, carbamide peroxide powder preparations generally do not add excipients, so the patient will feel strong pain due to the local rapid release of oxygen at the injection site during use. The carbamide peroxide for injection of the present invention The carbamide peroxide molecule in the freeze-dried preparation fully enters the dextran molecular framework, which slows down the release of gas from the decomposition of carbamide peroxide during clinical use, and greatly reduces the pain caused by the rapid release of oxygen.
本发明所述的一种注射用过氧化碳酰胺冻干制剂的制备方法，包括如下步骤：A kind of preparation method of carbamide peroxide freeze-dried preparation for injection of the present invention comprises the following steps:
按配比将右旋糖酐加入80℃～90℃的注射用水，注射用水量与右旋糖酐的量比为1∶0.01～0.15，煮沸20～30分钟，降温过滤后，按配比加入过氧化碳酰胺，搅拌均匀过滤，最后经冷冻干燥而成。Add dextran to water for injection at 80°C to 90°C according to the ratio, the ratio of water for injection to dextran is 1:0.01~0.15, boil for 20 to 30 minutes, cool down and filter, add carbonamide peroxide according to the ratio, stir and filter evenly , and finally freeze-dried.
其中，右旋糖酐加入水后，可加入0.1～1‰的吸附剂，以去除热原，比如活性炭。Among them, after adding dextran to water, 0.1-1‰ of adsorbent can be added to remove pyrogens, such as activated carbon.
降温可采用逐步降温法，先循环降温至50℃～70℃，然后再降温至20℃～30℃。Gradual cooling method can be used for cooling, first cycle cooling to 50°C-70°C, and then cooling to 20°C-30°C.
右旋糖酐水溶液过滤所使用的滤材孔径为0.45～0.3μm，冻干灌装前过滤所使用的滤材孔径为0.1～0.3μm。The filter material used for filtering the dextran aqueous solution has a pore size of 0.45-0.3 μm, and the filter material used for filtering before freeze-drying and filling has a pore size of 0.1-0.3 μm.
本发明所述的冷冻干燥在冷冻干燥机内进行，冷冻工艺为：将配成的过氧化碳酰胺溶液在-40℃～-35℃维持1～3小时，然后升温至-10℃～0℃，保持2～6小时，再次进行降温至-40℃～-35℃维持1～2小时，真空度维持在15Pa以下，在24～36小时内，温度升至15℃～35℃，并保持1～3小时。Freeze-drying according to the present invention is carried out in a freeze-drying machine, and the freezing process is as follows: maintaining the prepared carbonamide peroxide solution at -40°C to -35°C for 1 to 3 hours, and then raising the temperature to -10°C to 0°C , kept for 2 to 6 hours, and then cooled to -40°C to -35°C for 1 to 2 hours, and the vacuum degree was kept below 15Pa. Within 24 to 36 hours, the temperature was raised to 15°C to 35°C, and kept for 1 ~3 hours.
本发明所述的制备过程均在无菌状态下进行，可在充氮装置下进行。The preparation process of the present invention is all carried out under aseptic conditions, and can be carried out under a nitrogen filling device.
具体地说，本发明所述的一种注射用过氧化碳酰胺冻干制剂的制备方法，包括如下步骤：Specifically, a kind of preparation method of carbamide peroxide freeze-dried preparation for injection of the present invention comprises the following steps:
A)按配比将右旋糖酐加入80℃～90℃的注射用水，搅拌均匀，加入0.1～1‰的活性炭吸附剂搅拌煮沸20～30分钟，循环降温至50～70℃，脱炭过滤后降温至20℃～30℃，再按配比加入过氧化碳酰胺，将药液充分搅拌均匀；A) Add dextran into water for injection at 80°C-90°C according to the proportion, stir evenly, add 0.1-1‰ activated carbon adsorbent, stir and boil for 20-30 minutes, cool down to 50-70°C in circulation, and cool down to 20°C after decarbonization and filtration ℃～30℃, then add carboamide peroxide according to the ratio, and stir the liquid thoroughly;
B)将配成的过氧化碳酰胺溶液在-40℃～-35℃维持1～3小时，然后升温至-10℃～0℃，保持2～6小时，再次进行降温至-40℃～-35℃维持1～3小时，真空度维持在15Pa以下，在24～36小时内，温度升至15℃～35℃，并保持1～3小时。B) Maintain the prepared carbonamide peroxide solution at -40°C to -35°C for 1 to 3 hours, then raise the temperature to -10°C to 0°C, keep it for 2 to 6 hours, and then lower the temperature to -40°C to - Maintain 35°C for 1-3 hours, keep the vacuum below 15Pa, within 24-36 hours, raise the temperature to 15°C-35°C, and keep it for 1-3 hours.
其优选的制备过程为：Its preferred preparation process is:
A)按配比将右旋糖酐加入80℃～90℃的注射用水，注射用水量与右旋糖酐的量比为1∶0.01～0.15，搅拌均匀，加入0.5～1‰的活性炭吸附剂搅拌煮沸25～30分钟，循环降温至50～60℃，将药液脱炭过滤，通冷凝水使将药液降温至20～25℃，再按配比加入过氧化碳酰胺，将药液充分搅拌均匀；A) Add dextran to water for injection at 80°C to 90°C according to the proportion, the ratio of water for injection to dextran is 1:0.01 to 0.15, stir evenly, add 0.5 to 1‰ of activated carbon adsorbent, stir and boil for 25 to 30 minutes, Circulate to cool down to 50-60°C, decarbonize and filter the liquid medicine, pass condensed water to cool the liquid medicine to 20-25°C, then add carbonamide peroxide according to the proportion, and stir the liquid medicine fully evenly;
B)将药液在-40℃～-35℃维持1～2小时，进行升温，升温至-10℃～-5℃左右直至有白色结晶析出并保持温度使析出完全，保持3～6小时，再次进行降温至-40℃～-35℃维持1～2小时，开始缓慢升华，真空度维持在15Pa以下，在26～32小时内，制品温度达到20℃～30℃，保持2～3小时。B) Keep the medicinal solution at -40°C to -35°C for 1 to 2 hours, then raise the temperature to about -10°C to -5°C until white crystals precipitate and keep the temperature to complete the precipitation, keep for 3 to 6 hours, Cool down again to -40°C to -35°C for 1 to 2 hours, start sublimation slowly, keep the vacuum below 15Pa, within 26 to 32 hours, the product temperature reaches 20°C to 30°C, and keep it for 2 to 3 hours.
本发明所述的注射用过氧化碳酰胺冻干制剂的制备方法中右旋糖酐经过活性炭处理滤过，过氧化碳酰胺溶解于右旋糖酐溶液中，过滤、灌装，整个配制过程在无菌充氮的条件下进行，避免了组份中的过氧化碳酰胺的分解；灌装后进行冻干，冻干过程中采用重结晶的方式，使过氧化碳酰胺分子充分进入右旋糖酐分子构架中，从而在临床使用过程中减缓了过氧化碳酰胺分解释放气体的速度，减少了因快速释放氧气而产生的疼痛。In the preparation method of the carbamide peroxide freeze-dried preparation for injection of the present invention, the dextran is filtered through activated carbon treatment, the carbamide peroxide is dissolved in the dextran solution, filtered and filled, and the whole preparation process is carried out under the condition of aseptic nitrogen filling. To avoid the decomposition of carbonamide peroxide in the components; lyophilize after filling, and use recrystallization during the freeze-drying process to make the carbonamide peroxide molecules fully enter the dextran molecular framework, so that it can be used clinically The process slows down the rate at which carbamide peroxide decomposes to release gas, reducing the pain caused by the rapid release of oxygen.
本发明所述的注射用过氧化碳酰胺(冻干)临床应用时静脉滴注。本发明所述的一种注射用过氧化碳酰胺冻干制剂在制备治疗各种低氧血症以及急性缺氧引起的胎儿窘迫等疾病方面的用途。The carboxamide peroxide for injection (freeze-drying) of the present invention is intravenously infused during clinical application. The application of the freeze-dried preparation of carboamide peroxide for injection according to the present invention in the preparation and treatment of various hypoxemia and fetal distress caused by acute hypoxia.
由本发明所述的方法制成的注射用过氧化碳酰胺(冻干)，性状为白色块状物，规格可以为0.05g、0.1g、0.5g、1g，最优选的规格为0.1g、1g。The carbamide peroxide for injection (freeze-drying) made by the method of the present invention is a white lump, and the specification can be 0.05g, 0.1g, 0.5g, 1g, and the most preferred specification is 0.1g, 1g .
成人：一次1g，一日1～2次。儿童：按每公斤体重18mg给药，一次剂量不超过1g或遵医嘱。取本品1g，用5％、10％葡萄糖注射液或0.9％氯化钠注射液稀释至1ml含2～10mg溶液；或用100～500ml的5％、10％葡萄糖注射液或0.9％氯化钠注射液溶解1g，缓慢滴注60分钟以上。或先用5％、10％葡萄糖注射液或0.9％氯化钠注射液调节好滴速，再加入本品稀释到1ml含2～10mg溶液，缓慢滴注60分钟以上。Adult: 1g each time, 1-2 times a day. Children: Administer 18mg per kilogram of body weight, with a dose not exceeding 1g or follow the doctor's advice. Take 1g of this product, dilute it with 5%, 10% glucose injection or 0.9% sodium chloride injection to 1ml containing 2-10mg solution; or use 100-500ml of 5%, 10% glucose injection or 0.9% chloride Dissolve 1g of sodium injection and infuse slowly over 60 minutes. Or use 5%, 10% glucose injection or 0.9% sodium chloride injection to adjust the drip rate first, then add this product to dilute to 1ml containing 2-10mg solution, and slowly drip for more than 60 minutes.
本发明注射用过氧化碳酰胺(冻干)为注射用内给氧剂。注入体内后能被分解出过氧化氢，再经过氧化氢酶催化作用而释放出氧。氧直接与血液中血红蛋白结合，供给缺氧组织。碳酸酰胺通过肾以原形排出体外。本品LD50大于324mg/kg。The carboxamide peroxide (lyophilized) for injection of the present invention is an internal oxygen feeder for injection. After injected into the body, hydrogen peroxide can be decomposed, and then oxygen can be released through the catalysis of catalase. Oxygen is directly combined with hemoglobin in the blood to supply hypoxic tissues. Carbonic acid amide is excreted unchanged through the kidneys. The LD50 of this product is greater than 324mg/kg.
经过工艺方面的研究及改进，本发明的研究人员在注射用过氧化碳酰胺冻干制剂中添加赋形剂，并采用冷冻干燥工艺，不仅避免了组份中的过氧化碳酰胺的分解，而且使过氧化碳酰胺分子充分进入右旋糖酐的构架中，在临床使用时减慢了释放速度，大大降低了注射过程中因注射部位氧气的快速产生、释放而使人体产生的疼痛，同时还不影响过氧化碳酰胺的临床疗效，更便于临床应用；可用于在制备治疗各种低氧血症以及急性缺氧引起的胎儿窘迫等药物。Through technical research and improvement, the researchers of the present invention add excipients in the carbamide peroxide freeze-dried preparation for injection, and adopt the freeze-drying process, which not only avoids the decomposition of the carbamide peroxide in the components, but also Make carboamide peroxide molecules fully enter the framework of dextran, slow down the release speed in clinical use, greatly reduce the pain caused by the rapid generation and release of oxygen at the injection site during the injection process, and at the same time, it does not affect the The clinical curative effect of oxycarbamide is more convenient for clinical application; it can be used in the preparation of medicines for treating various hypoxemias and fetal distress caused by acute hypoxia.
具体实施方式Detailed ways
下面实施例进一步描述本发明，但所述实施例仅用于说明本发明而不是限制本发明。The following examples further describe the present invention, but the examples are only for illustrating the present invention rather than limiting the present invention.
实施例1Example 1
A)取200克80℃的新鲜注射用水于浓配罐中，加入10克的右旋糖酐(分子量为20000)，充分搅拌均匀，加入0.1‰的活性炭搅拌煮沸20分钟，循环降温至50℃，将药液脱炭过滤至稀配罐中，通冷凝水使将药液降温至20℃，加入10克的过氧化碳酰胺，同时启动配制系统内的充氮装置，使整个配制过程在密闭条件下进行，将药液充分搅拌均匀，定容，中间产品检验，将药液经终端过滤系统过滤至贮罐中，待灌装。A) Take 200 grams of fresh water for injection at 80°C in a concentrated preparation tank, add 10 grams of dextran (molecular weight is 20,000), stir well, add 0.1‰ activated carbon, stir and boil for 20 minutes, cool down to 50°C in circulation, and dissolve the medicine Decarbonize the liquid and filter it into the dilute preparation tank, pass condensed water to cool the liquid to 20°C, add 10 grams of carbonamide peroxide, and start the nitrogen filling device in the preparation system at the same time, so that the entire preparation process can be carried out under airtight conditions , fully stir the liquid medicine, constant volume, intermediate product inspection, filter the liquid medicine through the terminal filter system into the storage tank, to be filled.
B)根据过氧化碳酰胺的含量定装量，将药液灌装于西林瓶中，送入冻干箱中。B) According to the content of carboxamide peroxide, the amount is fixed, and the medicinal solution is filled in a vial and sent into a freeze-drying box.
C)制品在-40℃维持1小时，进行升温，升温至-5℃左右直至有白色结晶析出并保持温度使析出完全，保持4小时，再次进行降温至-40℃维持1小时。开始缓慢升华，真空度维持在15Pa以下，在24小时内，制品温度达到25℃并保持2小时。到冻干终点后，在高真空下压塞，压塞后放无菌空气出箱压盖、目检、包装即得。C) The product is maintained at -40°C for 1 hour, then the temperature is raised to about -5°C until white crystals are precipitated, and the temperature is maintained to complete the precipitation, kept for 4 hours, and then cooled to -40°C for 1 hour. Slow sublimation begins, the vacuum degree is maintained below 15Pa, and within 24 hours, the temperature of the product reaches 25°C and is maintained for 2 hours. After reaching the end point of freeze-drying, press the stopper under high vacuum, put the sterile air out of the box and press the cover after the stopper, perform visual inspection, and pack.
实施例2Example 2
A)取1000克90℃的新鲜注射用水于浓配罐中，加入100克的右旋糖酐(分子量为10000)，充分搅拌均匀，加入0.5‰的活性炭搅拌煮沸30分钟，循环降温至60℃，将药液脱炭过滤至稀配罐中，通冷凝水使将药液降温至25℃，加入0.05克的过氧化碳酰胺，同时启动配制系统内的充氮装置，使整个配制过程在密闭条件下进行，将药液充分搅拌均匀，定容，中间产品检验，将药液经终端过滤系统过滤至贮罐中，待灌装。A) Take 1,000 grams of fresh water for injection at 90°C in a concentrated preparation tank, add 100 grams of dextran (molecular weight: 10,000), stir well, add 0.5‰ of activated carbon, stir and boil for 30 minutes, cool down to 60°C in circulation, and dissolve the medicine Decarbonize the liquid and filter it into the dilute preparation tank, pass condensed water to cool the liquid to 25°C, add 0.05 g of carbonamide peroxide, and start the nitrogen filling device in the preparation system at the same time, so that the entire preparation process can be carried out under airtight conditions , fully stir the liquid medicine, constant volume, intermediate product inspection, filter the liquid medicine through the terminal filter system into the storage tank, to be filled.
B)根据过氧化碳酰胺的含量定装量，将药液灌装于西林瓶中，送入冻干箱中。B) According to the content of carboxamide peroxide, the amount is fixed, and the medicinal solution is filled in a vial and sent into a freeze-drying box.
C)制品在-40℃维持2小时，进行升温，升温至-10℃左右直至有白色结晶析出并保持温度使析出完全，保持2小时，再次进行降温至-40℃维持2小时。开始缓慢升华，真空度维持在15Pa以下，在30小时内，制品温度达到20℃并保持3小时。到冻干终点后，在高真空下压塞，压塞后放无菌空气出箱压盖、目检、包装即得。C) The product is maintained at -40°C for 2 hours, then heated up to about -10°C until white crystals are precipitated and kept at the temperature to complete the precipitation, kept for 2 hours, then cooled to -40°C for 2 hours. Slow sublimation begins, the vacuum degree is maintained below 15Pa, and within 30 hours, the temperature of the product reaches 20°C and is maintained for 3 hours. After reaching the end point of freeze-drying, press the stopper under high vacuum, put the sterile air out of the box and press the cover after the stopper, perform visual inspection, and pack.
实施例3Example 3
A)取5000克85℃的新鲜注射用水于浓配罐中，加入50克的右旋糖酐(分子量为32000)，充分搅拌均匀，加入1‰的活性炭搅拌煮沸25分钟，循环降温至65℃，将药液脱炭过滤至稀配罐中，通冷凝水使将药液降温至25℃，加入1500克的过氧化碳酰胺，同时启动配制系统内的充氮装置，使整个配制过程在密闭条件下进行，将药液充分搅拌均匀，定容，中间产品检验，将药液经终端过滤系统过滤至贮罐中，待灌装。A) Take 5,000 grams of fresh water for injection at 85°C in a concentrated preparation tank, add 50 grams of dextran (molecular weight is 32,000), stir well, add 1‰ of activated carbon, stir and boil for 25 minutes, circulate the temperature to 65°C, and dissolve the medicine The liquid is decarbonized and filtered into the dilute preparation tank, and the liquid is cooled to 25°C by passing condensed water, and 1500 grams of carbonamide peroxide is added, and the nitrogen filling device in the preparation system is started at the same time, so that the entire preparation process is carried out under airtight conditions , fully stir the liquid medicine, constant volume, intermediate product inspection, filter the liquid medicine through the terminal filter system into the storage tank, to be filled.
B)根据过氧化碳酰胺的含量定装量，将药液灌装于西林瓶中，送入冻干箱中。B) According to the content of carboxamide peroxide, the amount is fixed, and the medicinal solution is filled in a vial and sent into a freeze-drying box.
C)制品在-35℃维持1.5小时，进行升温，升温至0℃左右直至有白色结晶析出并保持温度使析出完全，保持5小时，再次进行降温至-35℃维持1.5小时。开始缓慢升华，真空度维持在15Pa以下，在26小时内，制品温度达到30℃保持2.5小时。到冻干终点后，在高真空下压塞，压塞后放无菌空气出箱压盖、目检、包装即得。C) The product is maintained at -35°C for 1.5 hours, then heated up to about 0°C until white crystals are precipitated and kept at the temperature for 5 hours, then cooled to -35°C for 1.5 hours. Start sublimation slowly, keep the vacuum below 15Pa, and within 26 hours, the product temperature reaches 30°C and keeps for 2.5 hours. After reaching the end point of freeze-drying, press the stopper under high vacuum, put the sterile air out of the box and press the cover after the stopper, perform visual inspection, and pack.
实施例4Example 4
A)取6000克90℃的新鲜注射用水于浓配罐中，加入900克的右旋糖酐(分子量为42000)，充分搅拌均匀，加入0.1‰的活性炭搅拌煮沸25分钟，循环降温至70℃，将药液脱炭过滤至稀配罐中，通冷凝水使将药液降温至30℃，加入30克的过氧化碳酰胺，同时启动配制系统内的充氮装置，使整个配制过程在密闭条件下进行，将药液充分搅拌均匀，定容，中间产品检验，将药液经终端过滤系统过滤至贮罐中，待灌装。A) Take 6,000 grams of fresh water for injection at 90°C in a concentrated preparation tank, add 900 grams of dextran (molecular weight is 42,000), stir well, add 0.1‰ of activated carbon, stir and boil for 25 minutes, cool down to 70°C in circulation, and dissolve the medicine The liquid is decarbonized and filtered into the dilute preparation tank, and the liquid is cooled to 30°C by passing condensed water, and 30 grams of carbonamide peroxide is added, and the nitrogen filling device in the preparation system is started at the same time, so that the entire preparation process is carried out under airtight conditions , fully stir the liquid medicine, constant volume, intermediate product inspection, filter the liquid medicine through the terminal filter system into the storage tank, to be filled.
B)根据过氧化碳酰胺的含量定装量，将药液灌装于西林瓶中，送入冻干箱中。B) According to the content of carboxamide peroxide, the amount is fixed, and the medicinal solution is filled in a vial and sent into a freeze-drying box.
C)制品在-38℃维持1小时，进行升温，升温至-10～℃左右直至有白色结晶析出并保持温度使析出完全，保持6小时，再次进行降温至-38℃维持2.5小时。开始缓慢升华，真空度维持在15Pa以下，在32小时内，制品温度达到35℃并保持1.5小时。到冻干终点后，在高真空下压塞，压塞后放无菌空气出箱压盖、目检、包装即得。C) The product is maintained at -38°C for 1 hour, then heated up to about -10°C until white crystals are precipitated and maintained at the temperature for complete precipitation, maintained for 6 hours, then cooled to -38°C for 2.5 hours. Slow sublimation begins, the vacuum degree is maintained below 15Pa, within 32 hours, the temperature of the product reaches 35°C and is maintained for 1.5 hours. After reaching the end point of freeze-drying, press the stopper under high vacuum, put the sterile air out of the box and press the cover after the stopper, perform visual inspection, and pack.
实施例5Example 5
A)取1000克80℃的新鲜注射用水于浓配罐中，加入50克的右旋糖酐(分子量为25000)，充分搅拌均匀，搅拌煮沸20分钟，循环降温至70℃，将药液过滤至稀配罐中，通冷凝水使将药液降温至30℃，加入500克的过氧化碳酰胺，同时启动配制系统内的充氮装置，使整个配制过程在密闭条件下进行，将药液充分搅拌均匀，定容，中间产品检验，将药液经终端过滤系统过滤至贮罐中，待灌装。A) Take 1,000 grams of fresh water for injection at 80°C in a concentrated preparation tank, add 50 grams of dextran (molecular weight: 25,000), stir well, stir and boil for 20 minutes, cool down to 70°C in circulation, and filter the medicinal solution until diluted In the tank, pass condensed water to cool the liquid medicine to 30°C, add 500 grams of carbonamide peroxide, and start the nitrogen filling device in the preparation system at the same time, so that the entire preparation process is carried out under airtight conditions, and the liquid medicine is fully stirred evenly , Constant volume, intermediate product inspection, filter the liquid medicine through the terminal filtration system into the storage tank, and wait for filling.
B)根据过氧化碳酰胺的含量定装量，将药液灌装于西林瓶中，送入冻干箱中。B) According to the content of carboxamide peroxide, the amount is fixed, and the medicinal solution is filled in a vial and sent into a freeze-drying box.
C)制品在-35℃维持2.5小时。进行升温，升温至-5℃左右直至有白色结晶析出并保持温度使析出完全，保持3小时，再次进行降温至-35℃维持1小时。开始缓慢升华，真空度维持在15Pa以下，在36小时内，制品温度达到15℃并保持3小时。到冻干终点后，在高真空下压塞，压塞后放无菌空气出箱压盖、目检、包装即得。C) Preparations were maintained at -35°C for 2.5 hours. The temperature was raised to about -5°C until white crystals were precipitated, and the temperature was maintained to complete the precipitation for 3 hours, and then the temperature was lowered to -35°C for 1 hour. Slow sublimation begins, the vacuum degree is maintained below 15Pa, and within 36 hours, the temperature of the product reaches 15°C and is maintained for 3 hours. After reaching the end point of freeze-drying, press the stopper under high vacuum, put the sterile air out of the box and press the cover after the stopper, perform visual inspection, and pack.
实验例1Experimental Example 1
本实验例为本发明冻干制剂注射用过氧化碳酰胺(冻干)最优选规格0.1g、1g外观、酸度、注射剂项下有关的各项规定项目的检测。This experimental example is the detection of the most preferred specification 0.1g, 1g appearance, acidity, injection item of carboamide peroxide for injection (lyophilized) of the present invention, acidity, and injection.
性状：本发明冻干制剂为白色块状物，符合质量标准规定。Properties: The freeze-dried preparation of the present invention is a white block, which meets the quality standard.
酸度：取本品4g，加新沸过的冷水15ml使溶解，依照中国药典2000年版二部附录VI H测定，本发明药物组合物注射液pH值为2.0～6.0，符合质量标准。Acidity: get this product 4g, add freshly boiled cold water 15ml and make dissolving, measure according to two appendix VI H of Chinese Pharmacopoeia version in 2000, the pH value of pharmaceutical composition injection of the present invention is 2.0～6.0, meets quality standard.
热原：取本品，加灭菌注射用水制成每1ml中含7.5mg的溶液，依法检查(中国药典2000年版二部附录XI D测定)剂量按家兔体重每kg缓缓注射2ml，本品符合规定。Pyrogen: get this product, add sterilized water for injection to make a solution containing 7.5mg per 1ml, check according to the law (measured in Appendix XID of Part Two of the Chinese Pharmacopoeia version in 2000) and slowly inject 2ml per kg of rabbit body weight. The product complies with the regulations.
无菌：取本品加灭菌生理盐水制成相当于0.2％的过氧化氢溶液，吸取5ml，加1.5％亚硫酸钠灭菌溶液5ml，混匀，放置10分钟，依法检查(中国药典2000年版二部附录XI H测定)，本品符合规定。Sterility: Take this product and add sterilized saline to make a hydrogen peroxide solution equivalent to 0.2%, draw 5ml, add 5ml of 1.5% sodium sulfite sterilized solution, mix well, leave it for 10 minutes, and check according to the law (Chinese Pharmacopoeia 2000 Edition II Part Appendix XI H Determination), this product complies with the regulations.
澄明度：取本品，每瓶加注射用水4ml溶解后，依法检查(中国药典2000年版二部附录I B)，本品符合规定。Clarity: get this product, add water for injection 4ml to dissolve after every bottle, check according to law (Chinese Pharmacopoeia 2000 edition two appendix I B), this product complies with the regulations.
装量差异：依法检查(中国药典2000年版二部附录I B)，本品符合规定。Differences in loading: According to inspection (Appendix I B of Part Two of the Chinese Pharmacopoeia 2000 Edition), this product complies with the regulations.
实验例2Experimental Example 2
本实验例为本发明冻干制剂注射用过氧化碳酰胺(冻干)最优选规格0.1g、1g成分的定性测定。This experimental example is the qualitative determination of the most preferred specifications of 0.1 g and 1 g of carboamide peroxide for injection (lyophilized) of the lyophilized preparation of the present invention.
(1)本品0.1g，加水1ml使溶解，加等量硝酸，发生白色结晶性沉淀。(1) 0.1g of this product, add 1ml of water to dissolve, add the same amount of nitric acid, a white crystalline precipitate occurs.
(2)取本品0.25g，加稀硫酸2滴与水10ml使溶解，分为两份，一份加重铬酸钾试液数滴，即显蓝色(并产生气泡)，放置则渐变为黄棕色，另一份加等容的乙醚(或乙酸乙酯)后，加重铬酸钾试液，摇匀，乙醚(或乙酸乙酯)层显蓝色，下层水溶液显淡黄色或几乎无色。(2) Take 0.25g of this product, add 2 drops of dilute sulfuric acid and 10ml of water to dissolve it, and divide it into two parts. One part adds a few drops of potassium chromate test solution, and it will appear blue (and generate bubbles), and it will gradually change to Yellowish brown, after adding equal volume of diethyl ether (or ethyl acetate) to the other part, add potassium chromate test solution, shake well, the diethyl ether (or ethyl acetate) layer is blue, and the lower aqueous solution is light yellow or almost colorless .
(3)取本品0.1g，加稀硫酸与水各1ml溶解后，加高锰酸钾试液数滴，摇匀，紫色即消失。(3) Take 0.1g of this product, add 1ml of dilute sulfuric acid and 1ml of water to dissolve, add a few drops of potassium permanganate test solution, shake well, and the purple color will disappear.
本发明冻干制剂以上项目的检查均符合规定。The inspections of the above items of the freeze-dried preparation of the present invention all meet the requirements.
实验例3Experimental Example 3
本实验例为本发明冻干制剂注射用过氧化碳酰胺(冻干)最优选规格0.1g、1g物理指标的测定。This experimental example is the determination of the most preferred specifications of 0.1 g and 1 g of physical indicators of carboamide peroxide for injection (lyophilized) of the freeze-dried preparation of the present invention.
(1)氯化物：取本品0.2g，依法检查(中国药典2000年版二部附录VIII A)，与标准氯化钠溶液1.0ml的对照液比较，不得更浓(0.005％)。(1) Chloride: take 0.2g of this product, check according to the law (Chinese Pharmacopoeia 2000 edition two appendix VIII A), compared with the control solution of standard sodium chloride solution 1.0ml, it should not be more concentrated (0.005%).
(2)硫酸盐：取本品2g，依法检查(中国药典2000年版二部附录VIII B)，与标准硫酸钾溶液2.0ml制成的对照液比较，不得更浓(0.01％)。(2) Sulphate: Take 2g of this product, check according to the law (Chinese Pharmacopoeia 2000 edition two appendix VIII B), compared with the control solution made of standard potassium sulfate solution 2.0ml, it should not be more concentrated (0.01%).
(3)盐：取本品2g，加水20ml溶解后，滤过，滤液分为二等份，一份中加稀硫酸2ml，另一份中加水2ml，静置2小时，两液应同样澄清。(3) Salt: Take 2g of this product, add 20ml of water to dissolve, filter, divide the filtrate into two equal parts, add 2ml of dilute sulfuric acid to one part, add 2ml of water to the other part, let stand for 2 hours, the two liquids should be clarified .
(4)干燥失重：取本品适量，以五氧化二磷为干燥剂，室温下干燥2小时，减失重量不得过3.0％。(4) Weight loss on drying: Take an appropriate amount of this product, use phosphorus pentoxide as a desiccant, dry at room temperature for 2 hours, and the weight loss should not exceed 3.0%.
(5)炽灼残渣：取本品2g，在60℃干燥2小时，依法检查(中国药典2000年版二部附录VIII N)，不得过0.1％。(5) Residue on ignition: Take 2g of this product, dry it at 60°C for 2 hours, check according to the law (Appendix VIII N of Part Two of the Chinese Pharmacopoeia, 2000 Edition), and it must not exceed 0.1%.
(6)重金属：取本品1g，置烧杯中，加浓氨溶液15ml使溶解后，于水浴上蒸干，再加浓氨溶液10ml溶解，继续在水浴上蒸干，再蒸1～2小时，然后加适量水溶解后，依法检查(中国药典2000年版二部附录VIII H)，含重金属不得过百万分之十。(6) Heavy metal: take 1g of this product, put it in a beaker, add 15ml of concentrated ammonia solution to dissolve it, evaporate to dryness on a water bath, add 10ml of concentrated ammonia solution to dissolve, continue to evaporate to dryness on a water bath, and then steam for 1 to 2 hours , and then add an appropriate amount of water to dissolve, and check according to the law (Appendix VIII H of Part Two of the Chinese Pharmacopoeia 2000 Edition), and the heavy metal content must not exceed 10 parts per million.
(7)砷盐：取本品1g，按重金属检查项下方法除净过时氧化氢，自“置烧杯中至再蒸发1～2小时”，加水23ml与盐酸5ml溶解后，依法检查(中国药典2000年版二部附录VIII J第一法)，含砷量不得过百万分之二。(7) Arsenic salt: take 1g of this product, remove obsolete hydrogen oxide according to the method under the inspection item of heavy metals, add 23ml of water and 5ml of hydrochloric acid to dissolve after "put in a beaker and evaporate for 1-2 hours", and then inspect according to the law (Chinese Pharmacopoeia 2000 edition of the second appendix VIII J first method), the arsenic content shall not exceed two parts per million.
本发明冻干制剂以上项目的检查均符合规定。The inspections of the above items of the freeze-dried preparation of the present invention all meet the requirements.
实验例4Experimental example 4
本实验例为本发明冻干制剂注射用过氧化碳酰胺(冻干)最优选规格0.1g、1g的定量测定。This experimental example is the quantitative determination of the most preferred specifications of 0.1 g and 1 g of carboamide peroxide (lyophilized) for injection of the lyophilized preparation of the present invention.
取本品0.1g，精密称定，置碘瓶中，加水25ml与冰醋酸5ml溶解后，加碘化钾2g，钼酸铵试液1滴，遮光放置10分钟，用硫代硫酸钠滴定液(0.1mol/L)滴定，至近终点时加淀粉指示液3ml，继续滴至蓝色消失，并将滴定的结果用空白实验校正，即得。每1ml的硫代硫酸钠滴定液(0.1mol/L)相当1.701mg的H2O2，本品按干燥品计算，含过氧化氢(H2O2)应为25.0～35.0％。Take 0.1g of this product, weigh it accurately, put it in an iodine bottle, add 25ml of water and 5ml of glacial acetic acid to dissolve, add 2g of potassium iodide, 1 drop of ammonium molybdate test solution, place it in the shade for 10 minutes, and use sodium thiosulfate titration solution (0.1 mol/L) titration, add 3ml of starch indicator solution near the end point, continue to drop until the blue color disappears, and correct the titration result with a blank experiment to obtain. Every 1ml of sodium thiosulfate titration solution (0.1mol/L) is equivalent to 1.701mg of H2 O2 , the product is calculated as a dry product, and the hydrogen peroxide (H2 O2 ) should be 25.0~35.0%.
本发明注射液经过三批的含量测定，结果如下(见表1)：Injection of the present invention is through three batches of assays, and the results are as follows (see Table 1):
□ 表1：过氧化氢含量测定结果(0.1g)
□ 表2：过氧化氢含量测定结果(1g)
以上实验例说明，用本发明工艺生产的注射用过氧化碳酰胺(冻干)质量稳定，各项指标均符合法定标准内容。The above experimental examples illustrate that the quality of the carbamide peroxide for injection (lyophilized) produced by the process of the present invention is stable, and each index meets the legal standard content.
比较例1Comparative Example 1
本比较例说明本发明冻干制剂与注射用过氧化碳酰胺无菌粉末具有相同的临床疗效。This comparative example illustrates that the freeze-dried preparation of the present invention has the same clinical curative effect as the sterile powder of carboamide peroxide for injection.
表3 2组治疗结果比较例(％) Table 3 2 groups of comparative examples of treatment results (%)
组别 例数 有效 无效Group Number of Cases Effective Invalid
本发明制剂组 103 103(100) 0(0)Preparation group of the present invention 103 103(100) 0(0)
无菌粉末组 96 96(100) 0(0)Sterile powder group 96 96(100) 0(0)
该比较例说明，本发明冻干制剂与无菌粉末具有相同的临床疗效。This comparative example shows that the freeze-dried preparation of the present invention has the same clinical curative effect as the aseptic powder.
比较例2Comparative Example 2
本比较例说明本发明冻干制剂与常规冻干制剂、注射用过氧化碳酰胺无菌粉末在临床应用上不良反应比较。This comparative example illustrates that the lyophilized preparation of the present invention is compared with conventional lyophilized preparations and carboamide peroxide sterile powder for clinical application in terms of adverse reactions.
表4 2组治疗结果比较例(％) Table 4 Comparison of treatment results in the 2 groups (%)
组别 例数 产生疼痛 轻微疼痛 无疼痛Groups Number of Cases Pain Slight Pain No Pain
常规冻干制剂组 92 82(89) 7(8) 3(3)Conventional freeze-dried preparation group 92 82(89) 7(8) 3(3)
本工艺制剂组 103 32(31) 40(39) 31(30)Preparation group of this process 103 32(31) 40(39) 31(30)
无菌粉末组 96 86(90) 6(6) 4(4)Sterile powder group 96 86(90) 6(6) 4(4)
本比较例说明，本发明冻干制剂比常规冻干制剂、无菌粉末制剂在临床应用时不良反应少。This comparative example shows that the freeze-dried preparation of the present invention has fewer adverse reactions than conventional freeze-dried preparations and sterile powder preparations in clinical application.
比较例3Comparative Example 3
本比较例说明本发明冻干制剂与注射用过氧化碳酰胺无菌粉末在工艺方面对产品的影响。This comparative example illustrates the influence of the lyophilized preparation of the present invention and the sterile powder of carboamide peroxide for injection on the product in terms of technology.
表5 两种制剂不同生产方式比较
比较例4Comparative Example 4
本比较例说明本发明冻干制剂与一般冻干制剂在工艺方面的不同。This comparative example illustrates the difference in process between the freeze-dried preparation of the present invention and the general freeze-dried preparation.
表6 与常规冻干方式比较
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100960553ACN100404027C (en) | 2004-11-26 | 2004-11-26 | A kind of lyophilized preparation of carboamide peroxide for injection, its preparation method and its application |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100960553ACN100404027C (en) | 2004-11-26 | 2004-11-26 | A kind of lyophilized preparation of carboamide peroxide for injection, its preparation method and its application |
| Publication Number | Publication Date |
|---|---|
| CN1634019Atrue CN1634019A (en) | 2005-07-06 |
| CN100404027C CN100404027C (en) | 2008-07-23 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100960553AExpired - Fee RelatedCN100404027C (en) | 2004-11-26 | 2004-11-26 | A kind of lyophilized preparation of carboamide peroxide for injection, its preparation method and its application |
| Country | Link |
|---|---|
| CN (1) | CN100404027C (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850067B (en)* | 2005-09-08 | 2011-03-16 | 周华英 | In vivo oxygen-supply solution for injection, and its preparing method and use |
| CN103432581A (en)* | 2013-03-22 | 2013-12-11 | 北京海思威科技有限公司 | Application of carbamide peroxide injection in inactivation of viruses for treating diseases |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850067B (en)* | 2005-09-08 | 2011-03-16 | 周华英 | In vivo oxygen-supply solution for injection, and its preparing method and use |
| CN103432581A (en)* | 2013-03-22 | 2013-12-11 | 北京海思威科技有限公司 | Application of carbamide peroxide injection in inactivation of viruses for treating diseases |
| Publication number | Publication date |
|---|---|
| CN100404027C (en) | 2008-07-23 |
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