Application of Bo Medical Kang Freeze Dryer: Study on Application of Ultrafiltration Technology to Chuanhuning Freeze-dried Powder Needle

【Key words】 Ultrafiltration technology
【Abstract】 Objective To improve the quality of Chuanhuning freeze-dried powder. Methods The patented ultrafiltration technology of "high-purity Chuanhuning production process" was used to produce Chuanhuning freeze-dried powder needle and compared with other manufacturers' similar products for animal acute toxicity test. Results The ultra-filtration technology produced by the injection of Chuanhuning ld 50 was significantly higher than the same specifications produced by other manufacturers. The ld 50 of single intravenous administration reached 910 mg/kg, while the ld 50 in the national standard specification was 675 mg/kg. The ld 50 of a single intravenous administration of Chuanhuning injection was reported to be 580-620 mg/kg. Conclusion Ultrafiltration technology can greatly reduce the toxicity of Chuanhuning products for injection and improve clinical safety.
Chuanhuning for injection is a dehydrated andrographolide succinic acid half ester monopotassium salt prepared by esterification, dehydration and salt formation of Andrographolide extract, and adding ph regulator, sodium bicarbonate, etc. A sterile lyophilized powder needle for intramuscular or intravenous drip prepared by lyophilization of the excipient. For viral pneumonia, viral upper respiratory tract infections, etc. Andrographis paniculata, bitter taste, can clear away heat and detoxification, anti-inflammatory and pain relief. Can be used for acute bacterial dysentery, acute gastroenteritis, tonsillitis, pharyngitis and so on. In the early 1970s, Chinese researchers conducted an in-depth study on the extract of Andrographis paniculata. The results showed that the active ingredient was its diterpene lactone compound. Because diterpenoid lactone compounds are hardly soluble in water, they cannot meet clinical needs. By introducing different hydrophilic groups into the lactone structure to increase the water solubility of lactones, a variety of andrographolide injections have been prepared. Chuanhuning is the strongest anti-inflammatory and antipyretic effect. It has been widely used in clinical practice. In 1992, it was approved by the State Administration of Traditional Chinese Medicine as one of the first batch of essential Chinese medicines in the emergency department (room) of the National Traditional Chinese Medicine Hospital.
Through the Beijing Library, we analyzed 86 papers on Chuanhuning published in medical journals in recent years. Among the 24 articles that reported adverse reactions, except for one article that only wrote “Use Chuanhuning”, all the other 23 articles were reported. Water injection. Experts believe that Chuanhuning water injection is unstable, and the effective period is 30.5 days at room temperature. Because Chuanhuning is a diterpenoid lactone compound and has a conjugated double bond in the molecule, it has high chemical activity and is prone to hydrolysis and oxidation. In the production, high temperature sterilization is also required, which promotes the decomposition reaction. The pure Chuanhuning aqueous solution is slightly greenish, but the color of the Chuaning water injection in the domestic market is deep, and some even become yellow or brownish yellow. The toxic side effects of Chuanhuning water injection are mainly diarrhea in infants and young children, the incidence rate is 22%; individual leukopenia, anaphylactic shock, drug eruption, convulsions, itching, high fever, chills, difficulty breathing, purpura and so on. In order to improve the quality of Chuanhuning freeze-dried powder injection, this experiment studied the patented ultrafiltration technology of “High Purity Chuanhuning Production Process”, which was applied to the acute toxicity test of animals produced by this product and similar products of other manufacturers.
1 Production process
1.1 Instrument type 88-2 tangential flow ultrafilter, cl-25 peristaltic pump (military medical academy); millipore ultrafiltration membrane stack (molecular weight cutoff: 5000); Pilot 2-4 type freeze dryer (Beijing Bo Yikang experimental instrument Co., Ltd.;; Xilin bottle washing, drying, irrigation linkage production line.
1.2 Drugs and reagents Chuanhuning (injection grade, Chengdu Tiantaishan Pharmaceutical Co., Ltd.); sodium bicarbonate (injection grade, Shanghai Hongguang Chemical Plant); dextran 40 (injection grade, Luohe Huaying Pharmaceutical Co., Ltd.); activated carbon (for needle) , Shanghai activated carbon plant); sterile water for injection (factory production); ethanol (medicinal, Nanyang Tianguan Group alcohol plant); hydrochloric acid, sodium hydroxide are analytical reagents.
1.3 Production Process (Using Ultrafiltration Technology) (1) Dissolve Chuanhuning (API) in 50% ethanol and add 0.5% to 1% activated carbon (injection grade) in a sterile room (100 grade). At a temperature of ～30°C, the pH is adjusted to 6.5-6.7 with hydrochloric acid, and stirred for 30 minutes. The heat source material brought into the raw material during the production process is fully refluxed, so that the color is reduced by two color levels; the molecular retention is 5000. The ultrafiltration membrane is subjected to ultrafiltration to intercept the macromolecular plant protein of more than 5000 molecular weight; the ultrafiltrate is recrystallized, rinsed with non-pyrogen injection water, filtered, and then subjected to a compounding process. (2) Calculate the calculated amount of Chuanhuning essence in the sterile room (100 grades) in the batch room, and add 1.5ml of 1.5% sodium bicarbonate (injection grade) solution to the solution to dissolve and clarify; Add 10 ml of 10% dextran 40 (injection grade) solution, add pyrogen-free sterile water for injection to 3000 ml, mix well, adjust ph to 7.7 ± 0.2. Take the semi-finished product inspection, set the amount, sterilize and filter, freeze-dry and seal.
2 Acute toxicity test
According to the guidelines of the National Institute of Drug Administration "Guidelines for the Study of Biological Products in Chemicals and Therapeutics for Biological Products", the toxicity test for single dose of chemical drugs (ie acute toxicity test) was carried out. The acute toxicity test was conducted on Chuanhuning for injection. The acute toxicity and death caused by the drug once administered to the animal.
2.1 Test sample
2.1.1 Injection Chuanhuning Our company applied the ultrafiltration technology to produce 20020322, the specification is 0.2g, and the yellowish freeze-dried cake. Dilute to the desired concentration with sodium chloride injection immediately before use.
2.1.2 Chuanhuning for Injection Our company was commissioned by a pharmaceutical company in Heilongjiang to produce 200101163 batches with a specification of 0.2g and a yellowish freeze-dried cake. Dilute to the desired concentration with sodium chloride injection immediately before use.
2.1.3 Injection of Chuanhuning Our company purchased the 020503-1 batch of a pharmaceutical company in the market, the specification is 0.2g, and the yellowish freeze-dried cake. Dilute to the desired concentration with sodium chloride injection immediately before use.
2.2 Test animals Kunming mice were purchased from the Experimental Animal Center of Henan Province, and the certificate number: No. 99012. Animal feed was purchased from the Experimental Animal Center of Henan Province and was a standard pellet feed.
2.3 Test methods and results (1) Laboratory temperature: (20 ± 1) °C. (2) 180 healthy mice were taken on the basis of the pretest, and the body weight was (19.0±2.0) g. Male and female, each batch of drugs was randomly divided into 6 groups, 10 in each group. The ratio of high to low dose is set to 1:0.9. According to the results of the preliminary test, the test drugs were formulated into different concentrations, 20020322 batch numbers were 45.00, 40.50, 36.50, 32.80, 29.50, 26.60 mg/ml; 200101163 batch numbers were 45.00, 40.50, 36.45, 32.81, 29.52, 26.57, 23.91 mg /ml; 020503-1 Batch number is 44.55, 40.10, 36.09, 32.48, 29.23, 26.31g/ml, intravenous administration, volume 0.25ml/10g body weight, administration rate is 5s, immediately after administration, record animal Reaction and death. After the administration, starting from the high-dose group, some animals showed symptoms such as hypoactivity, convulsions, and soft limbs, and died in a state of inhibition. Animals may have different degrees of reaction and death time depending on the concentration of the test drug. Most of the death occurred within 30 minutes to 48 hours after the administration. The dead rats were immediately autopsied, and the major organs were observed with the naked eye. No obvious abnormalities were observed. The rats in each group were observed for 1 week, and the appearance behavior, appetite and feces of the animals were not significantly abnormal. At the end of the experiment, the weight of the surviving animals increased to (25.3±2.7), (26.1±3.4), (27.2±3.8). g. Experimental results The ld 50 value and the confidence limit were calculated using the bliss probability unit. The results are shown in Tables 1, 2 and 3. The ld 50 values ​​of the mice administered with Chuanhuning injection were: 910.16 mg/kg for batch number 20010322, 834.84～992.27 mg/kg for 95%, and 804.10 mg/kg for batch number 20010163, 95% of which was 95%. The limit of credit is 748.51~863.82mg/kg; the batch number 020503-1 is 820.70mg/kg, and its 95% confidence limit is 758.94~887.49mg/kg.
3 Discussion
The injection-using Chuanhuning ld 50 produced by ultrafiltration technology is significantly higher than the same specification products produced by other manufacturers. The ld 50 of single intravenous administration reaches 910 mg/kg, while the ld 50 in the national standard specification is 675 mg/kg [8]. The literature reports that the single intravenous administration of Chuanhuning injection has an ld 50 of 580-620 mg/kg [2]. Therefore, the toxicity of the Chuanhuning product for injection is greatly reduced, and the safety of the product in clinical use is improved.
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