[Overview]
Clindamycin phosphate, trade name Cleocinphosphate, chemical name 6-(1-methyl-trans Rohm and Haas-1-propyl-L-2-pyrrolidinecarboxamide)- 1-Thio-7(S)-chloro-6,7,8-trideoxy-L-threo-α-D-galactopyranoside-2-dihydrogen phosphate, a derivative of clindamycin A semi-synthetic derivative, it rapidly hydrolyzes clindamycin in the body and displays pharmacological activity. Compared with clindamycin, it has the characteristics of high antibacterial activity, fast absorption, strong fat solubility and permeability, and few side effects. It is widely distributed in the body and has high tissue concentration, especially in bone tissue. It has strong antibacterial effect on various Gram-positive bacteria and has few side effects. It is a broad-spectrum antibiotic that has both anti-anaerobic and aerobic effects. It is effective against most anaerobic bacteria except Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans and most methicillin-resistant strains of Staphylococcus aureus. It is clinically used for abdominal and pelvic infections caused by anaerobic bacteria including Bacteroides fragilis, Clostridium perfringens, Actinomyces, etc. It is also used for respiratory tract, joints, soft tissues, and bone tissues caused by sensitive Gram-positive bacteria. , biliary tract and other infections, sepsis, endocarditis, etc.
[Physical and Chemical Properties]
Clindamycin phosphate is a white crystalline powder, odorless and bitter in taste. Easily soluble in water and dilute alkali, slightly soluble in methanol, almost insoluble in ethanol and ether.
[Pharmacology and Toxicology]
Clindamycin phosphate is a chemical semi-synthetic clindamycin derivative. It has no antibacterial activity in vitro. After entering the body, it is rapidly hydrolyzed to clindamycin and displays its pharmacological activity. Therefore, its antibacterial spectrum, antibacterial activity and therapeutic effect are the same as clindamycin, but its fat solubility and permeability are better than clindamycin, and it can be administered by intramuscular injection and intravenous drip. Compared with lincomycin, this product has 4-8 times stronger antibacterial effect, good absorption, high bone concentration, and good curative effect on anaerobic bacterial infections. This product mainly has strong antibacterial activity against Gram-positive cocci and anaerobic bacteria, including Gram-positive cocci: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus (except Streptococcus phosphate), Streptococcus pneumoniae, Micrococcus spp. etc.; Anaerobic bacteria: Clostridium, Bacteroides, Clostridium, Propionibacterium, Eubacterium, anaerobic cocci, etc.
[Pharmacokinetics]
Injection administration can immediately obtain high blood concentrations, and then be widely distributed into tissues and body fluids. High concentrations can be reached in the lungs, tonsils, liver and gallbladder, peritoneal fluid, appendix, prostate, uterine fallopian tube, etc., especially in bone and joint tissues. It is characterized by high medium concentration. However, its ability to penetrate the blood-cerebrospinal fluid barrier is poor, and its concentration in brain tissue is low. After this product enters the body, it is quickly hydrolyzed into clindamycin under the action of alkaline phosphatase in the blood. The pharmacokinetics of normal people show that after a single intravenous infusion of 0.6g of this product, clindamycin in the blood immediately reaches the peak value, with a concentration of 11.09±2.02mg/L, and an 8-hour plasma concentration of 1.69±0.35mg/L. . After a single intramuscular injection of 0.6g, clindamycin in the blood reaches its peak value in 1 to 2 hours, with a concentration of 5.92±1.45mg/L. The 8-hour plasma concentration is 2.51±0.91mg/L, and the effective blood concentration can be maintained for 8 hours. above. After administration, this product is mainly metabolized in the liver and excreted in bile and feces. The antibacterial activity in feces can last for 5 days after stopping the drug. Partially excreted in urine. After intravenous drip and intramuscular injection of 0.6g of this product, the 8-hour excretion rates were 11.72±1.33% and 10.51±2.68% respectively.
[Preparation method]
Using lincomycin hydrochloride as the raw material, selective chlorination is performed without separation of Vilsmeier reagent, and the clindamycin alcoholate is precipitated in a saturated hydrogen chloride solution of ethanol, and then the clindamycin alcoholate is precipitated with triethyl orthoformate. The ester is used as the hydroxyl protecting agent, and finally phosphorus oxychloride (POCl3) is used as the phosphorylation reagent. After hydrolysis reaction and recrystallization, the product clindamycin phosphate is obtained. The synthesis route is shown in Figure 1.
Figure 1 shows the synthetic route of clindamycin phosphate
The steps are as follows:
1. Synthesis of clindamycin 2. In a dry 250ml three-necked flask, pass N2 protection, add 20ml DMF and 100ml 1,2-dichloroethane, cool to 0℃, add 20ml POCl3 dropwise while stirring, after the dripping is completed After incubating in an ice bath for about 30 minutes, add 20g of lincomycin hydrochloride 1 in batches. After the addition is completed, control the temperature at about 10°C for 1 hour, then react at room temperature for 1 hour, and then increase the temperature by 5 to 6°C every hour in an oil bath until 65 to 65°C. 70℃, incubate for 10 hours, and detect no raw materials by thin layer chromatography (TLC). Cool to room temperature.
2. Synthesis of clindamycin alcoholate 3. Transfer the above reaction solution to a 500ml beaker, cool it in an ice bath, and dropwise add 18% NaOH solution with mass fraction to pH 10~11 while stirring. Transfer to liquid separation. In the funnel, separate the lower organic phase, extract the water phase with ethyl acetate (40ml , dissolve it, add 25 ml of ethanol solution saturated with hydrogen chloride dropwise under cooling, and precipitate a white solid. Filter with suction, wash twice with ethyl acetate, and dry at 70°C to obtain 321g of white clindamycin alcoholate, yield 92%, melting point (mp) 142～144℃.
3. Synthesis of cyclic orthoester 4. In a 500ml three-necked flask, add 200ml acetone and 20g clindamycin alcoholate 3 respectively. After stirring for 30 minutes, slowly add 40ml triethyl orthoformate into the system. Ester, stir and react at room temperature for 18 to 24 hours, TLC detects that there is no raw material. Filter, use 10ml dichloromethane, 150ml for the filter cakeDissolve in water, let stand for layering, separate the organic phase, and extract the aqueous phase with dichloromethane (30ml×3). Combine the organic phases, dry over anhydrous Na2SO4, and concentrate to dryness under reduced pressure.
Reactive diluent
4. Synthesis of phosphorylate 5. In a dry 500ml three-necked flask, pass N2 protection, add 350ml methylene chloride and 40ml triethylamine respectively, stir at room temperature for 30min, then cool to 10 with ice water Below ℃, slowly add 8.5ml of phosphorus oxychloride (POCl3) dropwise. After the dripping is completed, keep it at room temperature for 1 hour. Then dropwise add the above-mentioned cyclic orthoester 4 dissolved in dichloromethane and react at room temperature for 4 hours. TLC detects that there is no raw material. Ice Slowly add the reaction solution dropwise to a 10% mass fraction Na2CO3 solution under the bath for neutralization, separate the organic phase, extract the aqueous phase with dichloromethane (100ml×3), combine the organic phases, dry with Na2SO4, and subtract the organic phase Press and concentrate until thick.
5. Synthesis of Clindamycin Phosphate 6 Dissolve the above viscous substance with methylene chloride, drop it into cold water at 10°C, adjust the pH to 2~3 with dilute hydrochloric acid, and then raise the temperature to 25~30 Insulate and hydrolyze at ℃ for 4 hours, and follow the reaction with TLC. After the hydrolysis is completed, concentrate the reaction solution under reduced pressure, then add 50 ml of absolute ethanol to azeotrope. Add 100 ml of absolute ethanol, stir, let it stand for cooling and crystallization, filter, and wash with a small amount of ethanol. After drying at 70°C, a white solid 6 was obtained.
[Application]
Clindamycin Phosphate Injection is a colorless or slightly yellow clear liquid. Mainly used for the following various infectious diseases caused by Gram-positive bacteria:
1) Tonsillitis, suppurative otitis media, sinusitis, etc.
2) Acute bronchitis, acute exacerbation of chronic bronchitis, pneumonia, lung abscess and bronchiectasis combined with infection, etc.
3) Skin and soft tissue infections: boils, carbuncles, abscesses, cellulitis, trauma, burns and post-operative infections, etc.
4) Urinary system infection: acute urethritis, acute pyelonephritis, prostatitis, etc.
5) Others: osteomyelitis, sepsis, peritonitis and oral infection, etc. Used for various infectious diseases caused by anaerobic bacteria: 1) empyema, lung abscess, anaerobic pneumonia. 2) Skin and soft tissue infections and sepsis. 3) Intra-abdominal infection: peritonitis, intra-abdominal abscess. 4) Female pelvic and genital infections: endometritis, non-gonococcal fallopian tube and ovarian abscess, pelvic cellulitis and post-gynecological surgery infection, etc.
【Usage and Dosage】
It can be administered via deep intramuscular injection or intravenous drip. During intravenous infusion, every 0.3g needs to be diluted with 50-100ml of normal saline or 5% glucose solution to a concentration of less than 6mg/ml, and infused slowly, usually no more than 20mg per minute. 1. Mild to moderate infection: Adults take 0.6-1.2g a day, divided into 2-4 times (ql2h-q6h); children take 15-25mg/kg of body weight a day, divided into 2-4 times (ql2h-q6h) ). 2. Severe infection: Adults take 1.2-2.7g a day, divided into 2-4 times (ql2h-q6h); children take 25-40mg/kg of body weight a day, divided into 2-4 times (q12h-q6h).
【Adverse reactions】
1) After intramuscular injection, slight pain may occasionally occur at the injection site. Phlebitis may occur with long-term intravenous infusion. 2) Gastrointestinal reactions: nausea, vomiting, abdominal pain and diarrhea are occasionally seen. 3) Allergic reaction: A few patients may develop drug-induced rash. 4) Occasionally, it may cause neutropenia or eosinophilia. 5) A small number of patients may develop transient alkaline phosphatase, mild elevation of serum aminotransferase and jaundice. 6) A very small number of patients may develop pseudomembranous colitis.
【Contraindications】
Clindamycin phosphate is cross-resistant to lincomycin and clindamycin, and is contraindicated in those with a history of allergy to clindamycin or lincomycin.
[Notes]
1) Clindamycin phosphate has no cross-allergic reaction with penicillin and cephalosporin antibiotics and can be used for those allergic to penicillin.
2) Clindamycin phosphate is incompatible with ampicillin, phenytoin, barbiturates, aminophylline, calcium gluconate and magnesium sulfate.
3) Use with caution in patients with impaired liver and kidney function.
4) If pseudomembranous colitis occurs, vancomycin 0.125-0.5g can be taken orally, 4 times a day for treatment.
[Main reference materials]
[1]Sun Xiaohu. Optimization of the synthesis process of clindamycin phosphate[D]. Hefei University of Technology, 2009.
[2]He Huijuan. Development of clindamycin phosphate orally disintegrating tablets[D]. Zhengzhou University, 2010.
[3] Jiang Zhongliang, Xu Lingyue, Ma Dongxu, Guo Yiping. Research on the synthesis of clindamycin phosphate [J]. Journal of Tongji University (Natural Science Edition), 2004(12):1693-1695.
