2 English reference ceftazidime
3 Pharmacopoeia Standard of Kaifuding 3. 1 Name 3. 1. 1 Chinese name Kaifuding
3. 1.2 Chinese Pinyin Headgear
3. 1.3 English name ceftazidime
3.2 structural formula 3.3 molecular formula and molecular weight c22h22n6o7s2 5h2o? 636.65
3.4 Source (name) and content (potency) This product is (6r, 7r) 7 [(2amino-4 oxazolyl) [( 1 carboxyl 1 methyl ethoxy) imino] acetyl] amino] 2carboxyl-8 oxo-5thio 1 azabicyclo [ In terms of dry products, the content of C22H22N6O7S2 shall not be less than 95.0%.
3.5 Properties This product is white or white-like crystalline powder; Tasteless or slightly tasteless.
This product is slightly soluble in phosphate buffer (pH 6.0), slightly soluble in water or methanol, and insoluble in acetone or chloroform.
3.5. 1 absorption coefficient Take this product, weigh it accurately, add phosphate buffer (pH 6.0) to dissolve it, dilute it quantitatively, and make a solution containing about 10μg per 1ml, and follow the ultraviolet-visible spectrophotometry (Appendix IV A of Pharmacopoeia Part II, 20 10).
3.6 Identification (1) In the chromatogram recorded under the content determination, the retention time of the main peak of the test solution should be the same as that of the reference solution.
(2) The infrared absorption spectrum of this product should be consistent with the reference spectrum (7 18 in the infrared spectrum collection of drugs).
3.7 Check the acidity of 3.7. 1 Take this product, add water to make a solution containing 5mg per 1ml, and measure it according to law (Appendix ⅵ H of Pharmacopoeia Part II, 20 10), and the pH value should be 3.0 ~ 4.0.
3.7.2 Take 5 copies of this product, each with 0.6g, and add 5ml of sodium carbonate solution (1→100) to dissolve it. The solution should be clear and colorless; If it is turbid, it should not be thicker than the turbidity standard solution. 1 (appendix ⅸ b of Pharmacopoeia II, 20 10); If the color is developed, it shall not be deeper than the No.6 yellow or yellow-green standard colorimetric solution (the first method in Appendix VII A of Pharmacopoeia II, 20 10 edition).
3.7.3 Take this product as the relevant substance, add mobile phase A and mobile phase B (7: 93) to dissolve and dilute it, and make a solution of 0/.2 mg of kafudine per kloc-0 as the test solution; Accurately measure 1ml, put it in a 100ml volumetric flask, dilute it to scale with mobile phase A and mobile phase B (7: 93), and shake it evenly as a control solution. According to high performance liquid chromatography (Pharmacopoeia 20 10, Appendix V D), octadecylsilane bonded silica gel was used as filler. Mobile phase A is acetonitrile, and mobile phase B is phosphate buffer (dissolve 22.6g of ammonium dihydrogen phosphate in water, dilute it to 1000ml, and adjust the pH value to 3.9 with 10% phosphoric acid solution), and perform linear gradient elution according to the following table. Column temperature 35℃; The detection wavelength is 255 nm. Take 60mg of carvedilol reference substance, put it in a 50ml volumetric flask, add 5 ml of 0.1mol/L hydrochloric acid solution to dissolve it, dilute it with water to scale, and shake it well. Put it in a boiling water bath for 20 minutes, take it out and let it cool, and use it as a system suitability test solution. Inject 20μl into the liquid chromatograph and record the chromatogram. The theoretical plate number is not less than 3000 calculated by Foucault Ding Feng, and the separation degree between Foucault and its adjacent impurity peaks should be not less than 1.5. Inject 20μl of control solution into the liquid chromatograph, and adjust the detection sensitivity to make the peak height of the chromatographic peak of the principal component about 25% of the full scale. Accurately measure 20μl of the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. If there are impurity peaks in the chromatogram of the test sample, the area of a single impurity peak shall not be greater than 0.5 times (0.5%) of the main peak area of the reference sample, and the sum of impurity peak areas shall not be greater than 2 times (2.0%) of the main peak area of the reference sample. Impurity peaks smaller than 0.05 times of the main peak area of the reference substance can be ignored in the chromatogram of the test substance.
? Retention time (minutes)? Mobile phase A(%)? Mobile phase B(%)? 0 ? 7 ? 93 ? 14 ? 7 ? 93 ? 29 ? 14 ? 86 ? 40 ? 14 ? 86 ? 4 1 ? 7 ? 93 ? 52 ? 7 ? 3.7.4 Molecular exclusion chromatography (Pharmacopoeia 20 10, Part II, Appendix ⅴ h) was used to determine the polymer of Kaifuding.
3.7.4. 1 chromatographic conditions and system applicability test: dextran gel G 10 (40 ~ 120μ m) was used as filler, the inner diameter of glass column was 1.0 ~ 1.4cm, and the column length was 45cm 0. 1mol/L phosphate buffer with 3.5% ammonium sulfate at pH 7.0 [0. 1mol/L disodium hydrogen phosphate solution -0. 1 mol/L sodium dihydrogen phosphate solution (6 1: 39)] as mobile phase A, water. Measure 1.5mg/ml blue dextran 2000 solution 100 ~ 200μ l, inject it into a liquid chromatograph, determine it with mobile phases A and B respectively, and record the chromatogram. According to the blue dextran 2000 peak, the theoretical plate number is not less than 500 and the tailing factor is less than 2.0. The retention time ratio of blue dextran 2000 peak in two mobile phase systems should be 0.93 ~ 1.07, and the retention time ratio of main peak in control solution to polymer peak in test solution and blue dextran 2000 peak in corresponding chromatographic systems should be 0.93 ~ 1.07. Weigh about 0.2g of carvedilol and 20mg of sodium carbonate, put them in a 10ml volumetric flask, dissolve them with 1.5mg/ml blue dextran 2000 solution, dilute to scale and shake well. Inject 100 ~ 200μ l into the liquid chromatograph, determine with mobile phase A, and record the chromatogram. The ratio of the peak height of polymer to the valley height between monomer and polymer should be greater than 1.5. In addition, taking mobile phase B as the mobile phase, accurately measure the control solution 100 ~ 200μ L, and inject it continuously for 5 times. The relative standard deviation of peak area should not exceed 5.0%.
Preparation of 3.7.4.2 reference solution Take appropriate amount of Kaifuding reference substance, accurately weigh it, add water to dissolve it, and quantitatively make a solution containing about 0.65438±0mg of Kaifuding per 65438±0ml.
3.7.4.3 method accurately weighs about 0.2g of this product and 20mg of sodium carbonate, puts it in a 10ml volumetric flask, adds a proper amount of water to dissolve it, then dilutes it to scale with water and shakes it well. Immediately and accurately measure 100 ~ 200μ l and inject it into the liquid chromatograph. Take mobile phase A as the determination mobile phase, and record the chromatogram. In addition, accurately measure the control solution of 100 ~ 200μ l and inject it into the liquid chromatograph. Take mobile phase B as the determination mobile phase, and record the chromatogram. According to the external standard method, the polymer containing carvedilol should not exceed 0.3% in terms of peak area.
3.7.5 Pyridine is determined by high performance liquid chromatography (Appendix ⅴ D of Pharmacopoeia II, 20 10).
3.7.5. 1 chromatographic conditions and system applicability test uses octadecylsilane bonded silica gel as filler; Acetonitrile -0.25mol/L ammonium dihydrogen phosphate solution (57.5 15g ammonium dihydrogen phosphate, dissolved in water and diluted to 2000ml)- water (300:100; 600) adjusting the pH value to 7.0 with ammonia solution as the mobile phase; The flow rate is1.0 ml per minute; The detection wavelength is 254 nm. The number of theoretical plates should be not less than 3000. Inject 20μl of control solution into the liquid chromatograph, and calculate the results of several injections. The relative standard deviation is less than 3.0%.
Preparation of 3.7.5.2 reference solution Accurately weigh about 1g pyridine, put it in 100ml volumetric flask, add water to dissolve and dilute it to scale, shake well, accurately measure 10ml, put it in 100ml volumetric flask, add water to dilute it to scale, shake well, and put it in/kloc-0. Before use, accurately measure 2ml, put it in a 200ml volumetric flask, dilute it to scale with phosphate buffer solution with pH 7.0 (weigh 5.68g anhydrous disodium hydrogen phosphate and 3.63g potassium dihydrogen phosphate, dissolve them in water and dilute them to 1000ml), and shake well as a control solution.
Accurately weigh about 0.66g of this product by 3.7.5.3 method, put it in a 100ml volumetric flask, add phosphate buffer with pH 7.0 to dissolve and dilute it to scale (store it below 15℃, and complete sampling within 1 hour), shake it evenly, accurately measure 20μl, inject it into a liquid chromatograph, and record the chromatogram; Take another reference solution and determine it in the same way. According to the external standard method, the content of pyridine in the sample was calculated by peak area. It shall not exceed 0. 12%.
3.7.6 loss on drying takes this product and dries it under reduced pressure at 60℃ to a constant weight (Appendix VIII L of Pharmacopoeia II, 20 10), and the weight loss should be 13.0% ~ 15.0%.
3.7.7 Take this product 1.0g as residue on ignition, and check it according to law (Appendix VIII N of Pharmacopoeia 20 10 Edition II), and the residue shall not exceed 0.2%.
3.7.8 Take the residue left under the heavy metal residue on ignition, and check it according to law (the second method in Appendix VIII H of Pharmacopoeia 20 10), and the content of heavy metals shall not exceed 20 parts per million.
3.7.9 Take 5 copies of this product, 3.0g each, add 1% sodium carbonate solution (filtered by 0.45μm filter membrane), and check it according to law (Appendix ⅸ h of Pharmacopoeia Part II, 20 10 edition), which should comply with the regulations.
3.7. 10 insoluble particles Take 3 parts of this product, add 1% sodium carbonate solution (filtered by 0.45μm filter membrane) and dissolve it to make a solution containing 30mg per 1ml, and check it according to law (Appendix ⅸ C of Pharmacopoeia Part II, 20 10 edition), each.
3.7. 1 1 bacterial endotoxin Take this product and check it according to law (Appendix E of Pharmacopoeia II, 20 10 edition). The endotoxin content in every 1mg of kafuddin should be less than 0. 10EU (with 1% sodium carbonate solution containing no endotoxin,
3.7. 12 Take this product aseptically, dissolve it with an appropriate amount of sterile sodium carbonate solution (1→ 100), transfer it to a 0.9% sterile sodium chloride solution of not less than 500 ml, filter it by membrane, and check it according to law (Appendix H, Pharmacopoeia II, version 20 10).
3.8 The content was determined by high performance liquid chromatography (Pharmacopoeia 20 10, Part II, Appendix ⅴ D).
3.8. 1 chromatographic conditions and system applicability test uses octadecylsilane bonded silica gel as filler; Acetonitrile-pH 7.0 phosphate buffer (weighing 42.59g anhydrous disodium hydrogen phosphate and 27.22g potassium dihydrogen phosphate, dissolving in water and diluting to 1000ml) and water (40: 200: 1760) as the mobile phase; The flow rate is1.5ml per minute; The detection wavelength is 254 nm. Inject 20μl of control solution into the liquid chromatograph and record the chromatogram. The resolution of Kevlar peak and adjacent impurity peak should meet the requirements.
3.8.2 Determination method Accurately weigh 0.25g of this product, put it in a 250ml volumetric flask, add water to dissolve and dilute it to scale, shake it evenly, accurately measure 15ml, put it in a 100ml volumetric flask, add water to dilute it to scale, shake it evenly, accurately measure 20μl, and inject it into a liquid chromatograph to record the chromatogram; In addition, the reference substance of Kaifuding was determined by the same method, and the peak area was calculated by external standard method.
3.9 β -lactam antibiotics and cephalosporins.
3. 10 storage is sealed and stored in a cool and dark place.
3. 1 1 carvedilol preparation for injection
3. 12 Edition People's Republic of China (PRC) Pharmacopoeia 20 10 Edition
4 Instructions for Kaifuding 4. 1 Drug Name Kaifuding
4.2 English name ceftazidime
4.3 The alias of Kaifu Acadia; Fu Daxin; Fidelity letter; Ceftazidime; Cephalosporin thiamethoxam; Cefoxitin; Cefotaxime; Cefotaxime pentahydrate; Cefocarboxyl methylthioxime; Cefotaxime; Kev butyl five hydrate; Ceftazidime; Fortam; Fortaz; Kefadim; Tazicef is very beautiful.
4.4 antibiotic classification >: cephalosporin >: the third generation
4.5 dosage form injection: 0.25g, 0.5g,1.0g.
4.6 The pharmacological action of Kaifuding is highly stable to the broad-spectrum β -lactamase produced by Gram-negative bacilli; Strong antibacterial effect on gram-negative bacilli, obviously exceeding the first and second generation cephalosporins; However, the antibacterial effect on gram-positive cocci is not as good as that of the first generation and some second generation cephalosporins. Kaifuding is a cephalosporin with high activity in clinical application at present. Its in vitro effect on Pseudomonas aeruginosa is slightly weaker than that of some fluoroquinolones, but it is far stronger than piperacillin, apaxilin, azlocillin and carbenicillin, and also better than gentamicin and amikacin, and similar to or slightly better than tobramycin. Kaifuding has high antibacterial activity against Pseudomonas such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella, Indole positive and negative Proteus, Prudence, Salmonella, Serratia and Shigella, and Gram-negative bacilli such as yersinia enterocolitica. Some citrobacter, influenzae, moraxella catarrhalis and rhinoceros, staphylococcus and streptococcus are also sensitive to kavudine. However, methicillin-resistant staphylococci, enterococci and Listeria monocytogenes, most bacteroides fragilis and Clostridium difficile are resistant to caffordine.
4.7 pharmacokinetics of ceftazidime ceftazidime is not absorbed orally, but can be quickly and widely distributed in viscera, skin, muscles, bones, joints, sputum, ascites, pleural effusion, amniotic fluid, umbilical cord blood, bile, uterine appendages and myocardium after intravenous or intramuscular injection; Kefudine can penetrate the placental barrier and can also be distributed in aqueous humor and milk. Carvedilol is difficult to pass through the normal blood-cerebrospinal fluid barrier, but it can enter the cerebrospinal fluid through the damaged meninges when the meninges are damaged or inflamed. After intramuscular injection of 0.5g or 1g carvedilol in healthy adults, the plasma concentration of 1 ~ 1.2h reached the peak, which were 22.6mg/L and 38.3mg/L respectively. The peak plasma concentrations of carvedilol after intravenous injection and intravenous drip of 1.0g were 120.5mg/L and 105.7mg/L, respectively. The plasma concentration of carvedilol is dose-dependent, and the binding rate of serum protein is 10% ~ 17%. The plasma half-life of intramuscular injection, intravenous injection and intravenous drip is 2 hours. Normal people have no accumulation effect after repeated administration, but the drug excretion time of patients with renal insufficiency, newborns and premature infants is prolonged, and the plasma half-life is 2 ~ 2.5 times longer than that of healthy adults, so drugs can accumulate in the body. Carvedilol has almost no metabolism in the body, and is mainly excreted in urine in the form of highly active prototype drugs. Nearly 80% ~ 90% of the dose is excreted in urine within 24 hours of administration, and less than 1% can be excreted in bile. Therefore, the drug concentration in urine is very high, and the drug concentration in intestine is very small.
4.8 Indications of Kaifuding 1. Respiratory tract infection, such as pneumonia, bronchitis, lung abscess, pulmonary cystic fibrosis, infectious bronchiectasis, etc. Caffeine can also be used to treat patients with cystic fibrosis complicated with Pseudomonas aeruginosa infection.
2. Intra-abdominal infections such as cholecystitis, cholangitis and peritonitis.
3. Urinary and reproductive system infections, such as acute or chronic pyelonephritis, urethritis, adnexitis and pelvic inflammatory disease.
4. Skin and skin soft tissue infections, such as cellulitis, severe burns or traumatic infections.
5. Serious ear, nose and throat infections, such as otitis media, malignant otitis externa and sinusitis.
6. Bone and joint infections, such as osteitis, osteomyelitis and septic arthritis.
7. Other serious infections, such as septicemia and acute purulent meningitis.
8. Prevent infection before operation.
9. Kaifuding can also be used alone or in combination with other antibiotics for empirical treatment of patients with neutropenia and fever.
4.9 Contraindications of Kaifuding 1. Those who are allergic to Kaifuding or other cephalosporins.
2. Newborns tend to have jaundice or severe jaundice.
4. 10 Precautions 1. Those who are allergic to one cephalosporin may also be allergic to other cephalosporins; People who are allergic to penicillin, penicillin derivatives or penicillamine may also be allergic to cephalosporins.
2. Caution: (1) People who are allergic to penicillin should use it with caution; (2) The drug safety of pregnant women, premature infants and newborns has not been determined, so use it with caution; (3) Use with caution in patients with severe liver and renal insufficiency; (4) Use it with caution for people with high allergic constitution and the elderly and infirm.
3. The influence of drugs on the test value or diagnosis: (1) The urine glucose test of alkaline copper tartrate may be false positive; (2) About 5% patients can be directly tested positive for anti-human globulin (Coombs); (3) The values of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase occasionally increased, neutrophils decreased and eosinophils increased in a few patients after taking the medicine.
4. Check or monitor before and after medication: (1) Liver function and hemogram should be routinely monitored during long-term medication; (2) Patients with liver and kidney dysfunction and/or biliary obstruction should be monitored for blood drug concentration when using Kaifu. Use with caution in patients with colitis.
4. Adverse reactions of carvedilol 1. Rash, urticaria, erythema, drug fever, bronchospasm, serum sickness and other allergic reactions are common, and anaphylactic shock is rare.
2. Gastrointestinal tract: A few patients have gastrointestinal symptoms such as nausea, vomiting, loss of appetite, abdominal pain, diarrhea, flatulence, taste disorder, and occasionally pseudomembranous enteritis.
3. Central nervous system: after taking the medicine, the symptoms of central nervous system reaction such as headache, dizziness and abnormal sensation are occasionally seen; Seizures are rare.
4. Double infection: Long-term medication by a few patients can lead to a large number of drug-resistant bacteria, resulting in flora imbalance and double infection. Occasionally candidiasis (including thrush, inflammation, etc. ) and so on.
5. Long-term medication of a few patients may lead to vitamin K and vitamin B deficiency.
6. When intramuscular injection, induration and pain may occur at the injection site; When administered intravenously, if the dosage is too large or too fast, it may cause burning sensation of blood vessels, and in severe cases, it may cause thrombophlebitis.
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4. Usage and dosage of 1 2 Kaifuding1 (1) intramuscular injection: 0.5 ~ 1g each time, every 12 hours 1 time. Patients with severe infection and immunodeficiency (including neutropenia) can increase the dose to 2g each time, every 8 ~ 12 hours 1 time. Simple urinary tract infection is 0.25~0.5g12h. Complex urinary tract infection is 0.5g every 8 ~ 12 hours. Bone and joint infection is 2g every 12 hours. Simple pneumonia and skin and soft tissue infection are 0.5 ~1g every 8 hours; (2) Intravenous administration: 0.5 ~ 1g each time, every 12 hours 1 time. Severe immunodeficiency infection (including neutropenia) is 2g each time, every 8 ~ 12 hours 1 time. Simple urinary tract infection is 0.25~0.5g12h. Complex urinary tract infection is 0.5g every 8 ~ 12 hours. Bone and joint infection is 2g every 12 hours. Simple pneumonia and skin and soft tissue infection are 0.5 ~ 1g every 8 hours. Prophylactic drugs were used before prostate surgery, 1g was given during anesthesia induction, and the second dose was given when the catheter was removed. Patients with cystic fibrosis complicated with Pseudomonas aeruginosa infection but normal renal function should be given high dose carvedilol, daily dose 100 ~ 150 mg/kg, divided into three times; (3) Dosage of renal insufficiency: The recommended maintenance dose of carvedilol in patients with renal insufficiency is: creatinine clearance rate 3 1 ~ 50m l/ min, each time 1g, every time 1 2h1time; The creatinine clearance rate is 16 ~ 30ml per minute, each time 1g, every 24 hours 1 time; The creatinine clearance rate was 6 ~ 15 ml per minute, 0.5g each time, every 24 hours 1 time; Creatinine clearance rate