CN1631876A - Preparation of sodium probenecid and potassium probenecid, compound injection prepared by sodium probenecid, potassium probenecid and beta-lactam antibiotics, and use thereof - Google Patents
Preparation of sodium probenecid and potassium probenecid, compound injection prepared by sodium probenecid, potassium probenecid and beta-lactam antibiotics, and use thereof Download PDFInfo
- Publication number
- CN1631876A CN1631876A CN 200410011287 CN200410011287A CN1631876A CN 1631876 A CN1631876 A CN 1631876A CN 200410011287 CN200410011287 CN 200410011287 CN 200410011287 A CN200410011287 A CN 200410011287A CN 1631876 A CN1631876 A CN 1631876A
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- Prior art keywords
- probenecid
- sodium
- potassium
- injection
- antibiotics
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- Granted
Links
- 239000007924 injection Substances 0.000 title claims abstract description 60
- 238000002347 injection Methods 0.000 title claims abstract description 60
- 239000003782 beta lactam antibiotic agent Substances 0.000 title claims abstract description 34
- 239000002132 β-lactam antibiotic Substances 0.000 title claims abstract description 34
- 229940124586 β-lactam antibiotics Drugs 0.000 title claims abstract description 31
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- QCCCFHDTBTUDEA-UHFFFAOYSA-M sodium;4-(dipropylsulfamoyl)benzoate Chemical compound [Na+].CCCN(CCC)S(=O)(=O)C1=CC=C(C([O-])=O)C=C1 QCCCFHDTBTUDEA-UHFFFAOYSA-M 0.000 title claims description 100
- 229960003081 probenecid Drugs 0.000 title claims description 76
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 title claims description 74
- 229910052700 potassium Inorganic materials 0.000 title claims description 56
- 239000011591 potassium Substances 0.000 title claims description 56
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 title claims description 39
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 210000004369 blood Anatomy 0.000 claims abstract description 44
- 239000008280 blood Substances 0.000 claims abstract description 44
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- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 25
- 230000008030 elimination Effects 0.000 claims abstract description 13
- 238000003379 elimination reaction Methods 0.000 claims abstract description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
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- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 17
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 16
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- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 claims description 5
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- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 claims 1
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention relates to a preparation of and compound injection formed by Beta-lactam antibiotics and it and its application, which belongs to chemical chemical tragacanth . Make intosodium salt and kali salt, combined with Beta-lactam antibiotics thy are then changes into powder injection; which can intravenous injection or intravenous drip with Beta-lactam antibiotics at the sametime. It can remarktably increase the square below the curve, prolong half life of blood elimination (t1/2Beta) of antibiotics, and the period of medicine density of Beta-lactam antibiotics in blood surpassing that of the corresponding germ MIC; it can also reduce abuse of antibiotics, avoid generation and development of bacterial strain tolerant to medicine, has good safety and curative effect, stable quality and convenient use.
Description
The technical field is as follows:
the invention relates to preparation of probenecid sodium and probenecid potassium, compound injection consisting of the probenecid sodium and the probenecid potassium and β -lactam antibiotics and application of the compound injection, wherein the compound injection comprises powder injection and freeze-dried powder injection, and belongs to the field of chemical pharmacy.
Background art:
probenecid can competitively inhibit the secretion of various β -lactam antibiotics in renal tubules and prolong the blood elimination half-life (t)1/2β) At present, no compound injection prepared from probenecid and β -lactam antibiotics exists, but only one oral compound preparation consisting of probenecid and ampicillin is available, namely ampicillin-probenecid capsuleThe compound injection comprising the probenecid (potassium) and the β -lactam antibiotics can reduce the dosage of the β -lactam antibiotics in the compound, thereby effectively reducing the occurrence and the development of bacterial drug resistance caused by ultrahigh-dose antibiotics, saving the resources of the antibiotics and reducing the abuse of the antibiotics, and because the probenecid (potassium) in the compound can prolong the blood elimination half-life of the antibiotics in the compound, the administration interval can be prolonged, and the compound injection is convenient for patientsThe use of (1).
Chemical structural formula of Probenecid
The invention content is as follows:
the invention aims to provide probenecid sodium and probenecid potassium and a preparation method thereof.
The invention also aims to provide a compound injection consisting of probenecid sodium, probenecid potassium and β -lactam antibiotics and application thereof, wherein the probenecid sodium (potassium) and β -lactam antibiotics comprise penicillin antibiotics and cephalosporin antibiotics to form powder injection and freeze-dried powder injection, and the powder injection and the β -lactam antibiotics are simultaneously injected or instilled intravenously so as to effectively prolong the half-life period (t-time period) of the β -lactam antibiotics1/2) The area under the curve (AUC) is increased, the hemolytic property of the probenecid sodium (potassium) can be eliminated, the safety of the probenecid sodium (potassium) in a human body is protected, and the probenecid sodium (potassium) can be safely and effectively used as a new compound preparation to pass through a veinThe compound injection composed of probenecid sodium (potassium) and β -lactam antibiotics can be absorbed completely by human body because of directly entering blood circulation, can reach peak value quickly, and has rapid action and more obvious curative effect.
The technical scheme of the invention is realized as follows:
1. (1) probenecid sodium: p- [ (dipropylamino) sulfonyl]sodium benzoate
The structural formula is as follows:
the molecular formula is: c13H18NO4The molecular weight of SNa is: 307.34
(2) Probenecid potassium: p- [ (dipropylamino) sulfonyl]potassium benzoate
The structural formula is as follows:
the molecular formula is: c13H18NO4The molecular weight of K is: 323.45
2. (1) the preparation process of sulpir-sodium comprises the following steps (by weight):
firstly, 0.9-102 sodium hydroxide is dissolved in 11.5-1308 purified water (or water for injection) and is completely dissolved, 6.5-663 probenecid is added, the temperature is heated to 60 +/-10 ℃, the PH value is adjusted to 7.5-10, and the mixture is continuously stirred until the PH value is basically constant; filtering with 0.45 μm filter membrane at 60 + -10 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or off-white crystalline powder of probenecid sodium meeting human injection standard; the probenecid content of the product is not lower than 88.50% calculated on a dry product.
The chemical reaction formula is as follows:
(2) the preparation process of the probenecid potassium comprises the following steps (by weight ratio): :
firstly, dissolving 0.17-173.44 potassium hydroxide in 11.5-1308 purified water (or water for injection) for complete dissolution, adding 0.88-885.75 probenecid, heating to 60 +/-10 ℃, adjusting the pH value to 7.5-10, and continuously stirring until the pH value is basically constant; filtering with 0.45 μm filter membrane at 60 + -10 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or off-white crystalline powder of probenecid sodium meeting human injection standard; the probenecid content of the product is not lower than 86.25 percent calculated on a dry product.
The chemical reaction formula is asfollows:
3. the compound preparation consists of probenecid sodium (potassium) and β -lactam antibiotics, wherein probenecid is prepared into sodium (calculated by probenecid dry matter) or probenecid potassium (calculated by probenecid dry matter) and β -lactam antibiotics (calculated by each antibiotic dry matter) according to the proportion of 1: 1-3, and the mixture is subpackaged into powder injection after being mixed by a conventional process, wherein the β -lactam antibiotics comprise penicillin antibiotics and cephalosporin antibiotics;
penicillin antibiotics include: penicillin G and ampicillin.
Cephalosporin antibiotics include: cefazolin, cefuroxime, cefotaxime and cefoxitin.
4. The combination of probenecid sodium (potassium) and β -lactam antibiotics including penicillin antibiotics and cephalosporin antibiotics can effectively prolong the half-life (t) of β -lactam antibiotics1/2) The area under the curve (AUC) is increased, and the hemolysis of probenecid sodium (potassium) can be eliminated.
In order to better understand the essence of the invention, the new application of probenecid sodium (potassium) and β -lactam antibiotics in compound injection is illustrated by the test results
Ampicillin sodium/probenecid sodium acute toxicity test
1. Abstract
The test adopts the single intravenous and intraperitoneal injection administration route of the mouse to observe the acute toxicity reaction of the ampicillin sodium/probenecid sodium to the mouse and measure the LD of the intravenous injection mouse50And 95% of the confidence limits are 2594mg/kg and (2380-2858) mg/kg respectively; measuring the LD of the mice injected in the abdominal cavity50And 95% of the confidence limits are 3113mg/kg and (2880-3383) mg/kg, respectively.
2. Purpose(s) to
After single intravenous and intraperitoneal injection of ampicillin sodium/probenecid sodium into mice, toxicity reaction is observed and LD is determined50And provides acute toxicity test data for clinical application.
3. Test materials
(1) Medicine preparation: ampicillin sodium/probenecid sodium (3: 1) was dissolved in normal saline before testing and used
(2) Animals: ICR cleaning grade white mouse, weight 18-20g, provided by the Experimental animals center of the basic medical college of Jilin university, certification number: SCXK (Ger) 2003-0001.
4. Method and results
(1) Ampicillin sodium/probenecid sodium mouse intravenous injection LD50Measurement of (2)
The group spacing was calculated to be 1: 0.85 based on the pre-test results and divided into 5 dose groups. Taking 50 mice, randomly dividing into 5 groups, each group comprises 10 mice, each half of male and female, injecting intravenously with 0.15ml/10g body weight, immediately observing and recording animal reaction symptom and death time after administration, continuously observing for 14 days, and calculating LD by SPSS processing software according to death rate of each dose group, wherein the results show that after administration of high dose group, mice have convulsion and death, after administration of other dose groups, activity is reduced, dead mice are immediately dissected, no abnormal change of organs is seen with naked eyes, and death number of mice is reduced along with reduction of drug dose50And 95% confidence limits, see table 1.
TABLE 1 ampicillin sodium/probenecid sodium intravenous injection mouse acute toxicity test results
Dose log dose animal number of death mortality LD50 and 95% confidence limits
mg/kg (X) (only) (%)
3375 3.53 10 10 100.00 2594mg/kg、
2868 3.46 10 6 60.00 (2380～
2438 3.39 10 3 30.00 2858)mg/kg
2072 3.32 10 2 20.00
1761 3.25 10 0 00.00
(2) Ampicillin sodium/probenecid sodium mouse intraperitoneal injection LD50Measurement of (2)
The group spacing was calculated to be 1: 0.85 based on the pre-test results and divided into 5 dose groups. Taking 50 mice, randomly dividing into 5 groups, each group comprises 10 mice, each half of male and female, performing intraperitoneal injection with 0.18ml/10g body weight, immediately observing and recording animal reaction symptoms and death time after administration, continuously observing for 14 days, and showing that after administration of high dose group, mice have convulsion and death, activity of other dose groups is reduced, dead mice are immediately subjected to autopsy, no abnormal change of organs is seen, and the death number of mice is reduced along with reduction of drug dose, and according to the death rate of each dose group, SPSS is usedProcessing software calculates its LD50And 95% confidence limits, see table 2.
TABLE 2 ampicillin sodium/probenecid sodium intraperitoneal injection mouse acute toxicity test results
Dose log dose number mortality LD50And 95% confidence limit
mg/kg (X) (only) (%)
4050 3.61 10 10 100.00 3113mg/kg、
3442 3.54 10 7 70.00 (2880～
2926 3.47 10 3 30.00 3383)mg/kg
2487 3.40 10 1 10.00
2114 3.33 10 0 00.00
5. Conclusion
Adopting single intravenous and intraperitoneal injection of ampicillin sodium/probenecid sodium in mice to measure LD of mice injected intravenously50And 95% of the confidence limits are 2594mg/kg and (2380-2858) mg/kg respectively; measuring the LD of the mice injected in the abdominal cavity50And 95% of the confidence limits are 3113mg/kg and (2880-3383) mg/kg, respectively.
Second, ampicillin sodium/probenecid sodium rat subacute toxicity test
1. In the test, ampicillin sodium/probenecid sodium is injected into the abdominal cavity of a rat in two doses, wherein the ampicillin sodium/probenecid sodium doses are respectively as follows: high dose 0.9 g/kg; low dose 0.4 g/kg; (corresponding to rat LD)501/2.5, 1/5.5). The volume of the intraperitoneal injection is 0.5ml/100g of body weight, and the subacute toxicity test result is continuous for three weeks, so that the ampicillin sodium/probenecid sodium has no obvious influence on the food intake, the appearance behavior, the body weight, the hair growth, the excrement excretion and the like of animals; the organ coefficient has no obvious difference compared with the control group; the blood routine has no obvious difference compared with the control group; the UREA nitrogen (UREA) in the blood biochemical index is slightly increased in the high dose group, and is different from the control group (P is less than 0.05, and other indexes are not higher than the control groupThe difference is obvious, and the morphological change of each organ in the pathological histological examination has no obvious difference from that of a control group. And (4) prompting: prolonged administration may cause an increase in transient urea nitrogen.
2. The test aims to observe and determine whether a toxic reaction is generated due to drug accumulation after the rats are subjected to long-term intraperitoneal injection of ampicillin sodium/probenecid sodium, and provide target organs of the toxic reaction and the reversible degree of damage of the target organs, thereby providing test basis for the safety of clinical medication.
3. Test materials
(1) Medicine preparation: ampicillin sodium/probenecid sodium (3: 1) was dissolved in normal saline before testing and used
(2) Animals: wistar rats, weighing 80-100g, male and female halves, were provided by the animal center of the basic medical college of Jilin university. Quality certification number: SCXK (Ger) 2003-0001.
4. Test method
Wistar rats with the age of 6-8 weeks (the weight is 80-100 g) are adopted in the test, after the animals are normally bred and adapted for one week, the animals are randomly divided into three groups according to the weight, each group of male and female is 5, the animals are administrated by intraperitoneal injection at 9 am every day, and the dosage of ampicillin sodium/probenecid sodium is as follows: high dose 0.9 g/kg; low dose 0.4 g/kg; the administration volume was 0.5ml/100g body weight, and the control group was given the same volume of physiological saline. Observing the general state, behavior activity, diet and urine and feces of animals during administration, recording abnormal change at any time, weighing the body weight once a week, recording the food intake amount every day, recalculating the administration amount according to the body weight change, taking 5 animals from abdominal aorta on the next day of stopping administration to measure hematology and hematobiochemistry indexes, including red blood cell number, white blood cell number, platelet count, white blood cell classification and hemoglobin measurement; separating serum to perform liver and kidney function examination, taking out and weighing major mouse organs including heart, liver, spleen, lung, kidney, adrenal gland, pancreas, stomach, duodenum, colon, rectum, thyroid gland, thymus, brain, pituitary, eyeball, optic nerve, spinal cord, medulla oblongata, bladder, testis (epididymis), uterus (ovary), prostate, sternum handle, trachea and lymph node, calculating major organ coefficients according to body weight, performing naked eye and under-mirror pathological examination on each dose group, stopping feeding the rest animals continuously, and observing recovery period change.
5. Test results
(1) General observations were:
ampicillin sodium/probenecid sodium is injected into abdominal cavity of rat with high and low doses for three weeks continuously, the tested animals survive completely, before administration, during administration and in recovery period, the animals in each group move normally, act lively, grow normally, are straightened and smoothened, eat normally, urinate and defecate normally, and have no other abnormal physical signs. The test result shows that the ampicillin sodium/probenecid sodium continuously gives the intraperitoneal injection to the rats, and has no obvious influence on the behavior and the activity and the appearance physical signs of the rats.
(2) Influence on body weight and food intake
Before administration, during administration and in recovery period, rats in each dose group have normal drinking water and gain weight, and the administration group has no significant difference compared with a control group (see tables 1.1, 1.2 and 2.1).
TABLE 1.1 Effect of ampicillin sodium/probenecid subacute toxicity test on food intake during dosing in rats (g) (x. + -.s)
After administration
Before group administration
1W 2W 3W
Blank 15.1 + -1.4217 + -2.2417.0 + -2.8618.2 + -1.60
High dose group 15.9 + -1.3616.7 + -2.7617.8 + -1.9918.8 + -1.33
Low dose group 14.7 + -1.2416.9 + -3.6817.1 + -3.2118.1 + -1.76
P>0.05 compared with the control group
TABLE 1.2 Effect of ampicillin sodium/probenecid sodium subacute toxicity test on food intake (g) (x + -s) in convalescent rats
Group 1W 2W
Blank 20.97 + -1.0422.77 + -1.10
High dose group 20.17 + -1.1322.46 + -1.68
Low dose group 20.83 + -1.1322.00 + -1.63
P>0.05 compared with the control group
TABLE 2.1 Effect of ampicillin sodium/probenecid subacute toxicity test on weight gain (g) (x. + -.s) in rats
Group control group high dose group 0.9g/kg low dose group 0.4g/kg
112.3 +/-7.009113.3 +/-5.982107.3 +/-3.974 before administration
1W 151.6±12.05 143.7±19.18 140.4±15.39
2W 173.5±16.83 167.3±18.98 174.7±21.64
3W 210±23.68 197.1±26.78 196.4±23.65
Recovery period
1W 224±27.55 226±18.87 225.2±41.07
2W 247±17.77 248±22.97 249.8±20.41
P>0.05 compared with control group
6. And (3) clinical examination:
(1) hematology:
dosing phase each dose group was assayed for White Blood Cells (WBC), Red Blood Cells (RBC), Lymphocytes (LY), hemoglobin (Hb), and Platelet (PLT) neutral lobules (GRAN) using an american yapei cytometer.
And (3) detection results: all hematology indexes of the animals in the administration group are within normal range, and have no significant difference compared with the control group (see table 3)
TABLE 3 influence of ampicillin/probenecid on hematological indices in rats at the dosing period (n ═ 5 x. + -. s)
Grouped unit control group high dose group 0.9g/kg low dose group 0.4g/kg
WBC ×109/L 6.98±1.30 7.36±2.65 6.7±2.22
LY ％ 79.86±3.49 78.6±5.13 78.68±4.90
Plt ×109/L 710.6±103.67 661.8±117.29 664±123.77
GR ％ 12.4±3.48 14.06±6.21 13.96±5.00
RBC ×1012/L 6.98±0.30 6.71±0.18 6.99±0.26
HB (g/L) 136.4±5.13 134±5.43136.4±3.04
P>0.05 compared with the control group
(2) Blood biochemistry:
in the administration period, each dosage group is measured by aspartic acid amino converting enzyme (AST), alanine amino converting enzyme (ALT), alkaline phosphatase (ALP), UREA nitrogen (UREA), Total Protein (TP), Albumin (ALB), blood sugar (GLU), Total Bilirubin (TBIL), myoliver (CRE) and total Cholesterol (CHO) by a full-automatic biochemical analyzer (7150).
And (3) detection results: the UREA nitrogen (UREA) of the high-dose group administered with ampicillin sodium/probenecid is slightly increased and has difference with the group (P is less than 0.05 ═ and other biochemical indexes are in the normal range, and has no significant difference with the group (see table 4).
TABLE 4 influence of ampicillin/probenecid on biochemical indices in rat blood (n ═ 5 x. + -. s)
Grouped unit control group high dose group 0.9g/kg low dose group 0.4g/kg
ALT U/L 73.46±17.87 69.58±13.78 64.38±9.44
TP g/L 63.26±3.46 63.18±2.90 64.78±2.33
ALB g/L 30.58±2.06 29.9±2.28 31.28±2.11
ALP U/L 251±38.63 266.5±31.37 261.36±2.65
AST U/L 232.82±8.70 235.72±34.77 223.18±9.07
UREA mmol/L 8.48±0.26 10.052±1.22*9.698±0.76
CR μmol/L 71.66±4.97 80.96±13.72 75.94±8.54
CHO mmol/L 2.146±0.23 2.184±0.28 2.174±0.26
GLU mmol/L 6.43±0.62 6.378±0.63 6.564±0.614
T-BIL μmol/L 7.54±0.56 7.42±0.63 7.36±0.50
Compared with the control group:*p＜0.05
7. histological examination
(1) And (4) visual observation: the rats were sacrificed after three weeks of ampicillin sodium/probenecid sodium intraperitoneal injection, and the main organs of each dose group were observed by naked eyes (including heart, liver, spleen, lung, kidney, stomach, adrenal gland, thyroid gland, brain, thymus, testis, prostate and uterus (ovary) without obvious changes, and the organ coefficients were not significantly different from those of the control group (see table 5).
TABLE 5 influence of ampicillin/probenecid sodium on organ coefficients in rats during dosing (x. + -. sn ═ 5g/100g)
Group control group high dose group and low dose group
The dosage is 0.9g/kg and 0.4g/kg
Heart 0.4957 + -0.08940.3985 + -0.07330.4813 + -0.0761
Liver 4.6767 + -1.06633.9651 + -0.52744.8682 + -1.2375
Spleen 0.2307 + -0.04460.2106 + -0.02760.2301 + -0.0392
Lung 0.7609 + -0.14480.6713 + -0.10520.7300 + -0.1329
Kidneys 0.9776 +/-0.18830.8948 +/-0.28780.9661 +/-0.2180
Adrenal gland 0.0190 +/-0.00980.0122 +/-0.00640.018 +/-0.0110
Thyroid gland 0.0076 + -0.00390.0071 + -0.00250.0112 + -0.0064
Brain 0.6864 + -0.12010.6438 + -0.11160.6926 + -0.1146
Thymus 0.3537 + -0.05470.3148 + -0.07290.3778 + -0.1226
Testis (epididymis) 1.30721.35621.2837
Prostate 0.13790.10910.1629
Uterus (ovary) 0.25570.19890.3036
P>0.05 compared with the control group
(2) And (4) observing under a mirror: after three weeks of intraperitoneal injection of ampicillin sodium/probenecid sodium in rats, specimens of main organs (same as above) of each dose group and a control group are subjected to conventional fixation, HE staining, tissue section and microscopic observation, no obvious pathological change is observed, and the results are reported as pathological reports.
8. Conclusion of the experiment
After three weeks of intraperitoneal injection of the rats in the two high and low ampicillin sodium/probenecid sodium dose groups, the UREA nitrogen (UREA) high dose group in the blood biochemical index has difference compared with the control group (P is less than 0.05), and the results show that: the change of renal function should be monitored after long-term administration, other indexes have no obvious difference compared with a control group, and the morphological change of each visceral organ has no obvious difference compared with the control group after pathological histological examination.
Ampicillin sodium/probenecid sodium vascular irritation test
1. And (3) abstract: the test shows that: ampicillin sodium/probenecid sodium intravenous drip has no obvious vascular irritation.
2. The purpose of the test is as follows: the existence of the vascular irritation of the ampicillin sodium/probenecid sodium is observed through tests.
3. Test drugs: ampicillin sodium/probenecid sodium (3: 1) was dissolved in physiological saline for use in the test. 4. Test animals: new Zealand big ear white rabbit, body weight 2.3-2.5 kg. Supplied by the department of laboratory animals of the university of Jilin. Certificate number: SCXK (Ger) 2003-0001.
5. The test method comprises the following steps: healthy rabbits were taken 4 times, half female and half male. The test pieces were divided into a 0.9% sodium chloride injection control group and ampicillin sodium/probenecid sodium, 2 pieces per group, according to body weight and sex. 10ml/kg of ampicillin sodium/probenecid sodium is slowly dripped into the auricular margin vein of the left ear of the rabbit 1 time a day for 7 consecutive days. The control group was treated by intravenous drip with 0.9% sodium chloride injection by the same method. Except for observing the local expression of the drug administration during and after each drug administration, the auricle at the drug side is cut off after the last intravenous drip, and after the routine fixation, 0.5cm wide specimens are cut at intervals of 1cm at the position 1cm away from the proximal end of the intravenous drip injection needle, and 3 specimens are taken in total. And (5) staining the section, and carrying out microscopic pathological observation.
6. As a result: no rabbit auricle vasodilation is observed by naked eyes, and no red swelling exists; the control group and the drug group have no inflammatory cell infiltration and have no obvious change after microscopic pathological examination.
7. And (4) conclusion: 10ml/kg of ampicillin sodium/probenecid sodium is instilled into ear margin vein of rabbit 1 time a day for 7 days continuously. The results of pathological examination under the naked eye and the microscope show that the ampicillin sodium/probenecid sodium intravenous drip has no local irritation.
Hemolysis test of ampicillin sodium/probenecid sodium
1. And (3) abstract: the test shows that: ampicillin sodium/probenecid sodiumhas no hemolysis and erythrocyte agglutination phenomenon.
2. The purpose of the test is as follows: and (5) observing whether the ampicillin sodium/probenecid sodium has hemolysis and erythrocyte agglutination phenomena.
3. Test drugs: ampicillin sodium/probenecid sodium was supplied from the consignor. The test was carried out after dissolving in physiological saline.
4. Test animals: new Zealand big ear white rabbit, body weight 2.3-2.5 kg. Supplied by the department of laboratory animals of the university of Jilin.
5. The test method comprises the following steps: taking blood of the new zealand big ear white rabbit without fibrin, adding physiological saline to shake the blood evenly, centrifuging the blood, then pouring the blood back to remove supernatant, and measuring red blood cells to obtain red blood cell suspension diluted to 2 percent for test. A plurality of test tubes are taken, numbered and shown in Table 1, added with various test solutions, shaken gently, placed in a water bath at 37 ℃, observed and recorded for 0.5, 1, 2, 3 and 4 hours respectively, and observed for hemolysis and erythrocyte agglutination, and placed at room temperature for 24 hours, and then the occurrence of hemolysis and erythrocyte agglutination is continuously observed.
6. And (3) test results: ampicillin sodium/probenecid sodium is observed in water bath at 37 ℃ for 4 hours, except hemolysis control 7 th tube shows obvious pink hemolysis, no erythrocyte sinks, other tubes do not show hemolysis and erythrocyte agglutination phenomenon in 0.5, 1, 2, 3 and 4 hours, so that erythrocyte sinks can be seen, and after the test tube is shaken, the sinking erythrocyte floats upwards without erythrocyte agglutination.
7. And (4) conclusion: ampicillin sodium/probenecid sodium was observed in waterbath at 37 ℃ for 4 hours at the concentrations shown in tables 2 and 3, and no hemolysis was observed, and no hemolysis or aggregation occurred even after the mixture was left at room temperature for 24 hours.
TABLE 1 sequence of hemolytic test operations for ampicillin sodium/probenecid sodium
| Test tube number | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Ampicillin sodium/probenecid sodium (ml) (concentration) See tables 2 and 3) | 0.1 | 0.2 | 0.3 | 0.4 | 0.5 | - | - |
| Physiological saline (ml) | 2.4 | 2.3 | 2.2 | 2.1 | 2.0 | 2.5 | - |
| Distilled water (ml) | - | - | - | - | - | - | 2.5 |
| 2% erythrocyte suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
TABLE 2 ampicillin sodium/probenecid sodium hemolytic test
| 10% mixing 22.5% mixing 45% mixing | Probenecid's sodium salt 1.11％ Corresponding to undissolved Probenecid's sodium salt 2.2％ Corresponding to the undissolved and undissolved propylene Sushu 5% Corresponding to the undissolved and undissolved propylene Sushu 10% |
TABLE 3 ampicillin sodium/probenecid sodium hemolytic test
Peng, pharmacokinetic test of ampicillin sodium/probenecid sodium in beagle dogs
1. The purpose is as follows: the experiment aims to observe the pharmacokinetic process of the ampicillin sodium after the single intravenous injection of the ampicillin and the combined administration of the ampicillin sodium/probenecid sodium for the dogs under the same dosage so as to confirm whether the intravenous administration route of the probenecid sodium can prolong the area under the curve (AUC) and the blood elimination half-life (t) of the ampicillin sodium1/2β) Lays a foundation for the modification of the dosage form of the compound preparation.
2. Test materials
2.1 drugs and reagents
Ampicillin sodium and ampicillin sodium/probenecid sodium; enalapril maleate (internal standard, purity provided by Beijing pharmaceutical biologicals assay: 99.8%); canine plasma blank(provided by the department of laboratory animals of the basic medical college of the university of Jilin).
The methanol is pure in chromatography, purchased from Tianjin Kancoded science and technology limited company, and other reagents are pure in analysis, and are products of Tianjin Fuchen chemical reagent factory and Beijing chemical factory.
2.2 test animals
6 adult beagle dogs with the weight range of 10.0 +/-1.6 kg, purchased from the experimental animals center of Sichuan academy of medical sciences, and the qualification number: the doctor's word No. 24103123.
2.3 protocol and mode of administration
The 6 dogs were randomized into two groups (control group R and test group T) and a two-cycle crossover test was performed with a 7-day interval between the two dosing weeks. The dose and mode of administration were as follows:
control group: ampicillin sodium controls were administered separately to each dog at 40, 80 and 160 mg-kg-1Dissolved in physiological saline, and then injected intravenously.
Experimental groups: ampicillin/probenecid 40/13.5, 80/27 and 160/54 mg/kg were administered to each dog-1Dissolved in physiological saline, and then injected intravenously.
2.4 sample Collection and processing
Intravenous blood sampling time points: 0.17, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0h (control group take 24.0, 36.0, 48.0h continuously)
About 1ml of blood is collected from the canine hind limb saphenous vein at the above blood collection time point. Immediately after blood sample removal, the cells were transferred to heparin tubes, centrifuged (3500rpm) for 10min, plasma was separated, frozen and stored in a-20 ℃ freezeruntil assayed.
2.5 plasma sample analysis method
Dog plasma samples were assayed using the LC/MS/MS method.
2.6 data processing
Listing the blood concentration data of each dog after intravenous injection of ampicillin sodium and ampicillin sodium// probenecid sodium, giving a blood concentration-time curve, and according to the blood concentration-timeInterval data, pharmacokinetic parameters after intravenous and oral administration of dogs were calculated using a non-compartmental model of Topfit 2.0 software (Thomae GmbH, Germany) and t-values for ampicillin in control and test groups1/2β，AUC0-tAnd AUC0-∞The results were compared and examined for statistical differences.
3. Results and discussion
3.1 plasma concentration and pharmacokinetic parameters after intravenous administration of beagle dogs
The mean plasma concentration-time curve of ampicillin sodium after intravenous injection of 6 beagle dogs in the low, medium and high three dose groups (control group) and ampicillin sodium/probenecid sodium (test group) is shown in figure 1. As can be seen from FIG. 1, the mean blood concentration of ampicillin at each blood sampling time point was higher than that of the control group after intravenous injection of ampicillin sodium/probenecid. The pharmacokinetic parameters of the control group and the test group are shown in tables 1 to 6, respectively.
3.2 results
Ampicillin sodium alone (control group) was administered to beagle dogs at 40, 80 and 160 mg-kg doses-1T of ampicillin sodium in plasma1/2βRespectively for 0.70 +/-0.10, 0.92 +/-0.07 and 1.49 +/-0.13 h; AUC0-t129.8 +/-28.04, 142.8 +/-24.92 and 233.7 +/-48.71 mu g.h.mL respectively-1，AUC0-∞130.1 +/-28.07, 143.0 +/-24.94 and 234.0 +/-48.78 mu g.h.mL respectively-1(ii) a Ampicillin/probenecid sodium was administered intravenously to beagle dogs (test group) at 40/13.5, 80/27 and 160/54 mg-kg-1T of ampicillin sodium in plasma1/2βRespectively for 0.98 +/-0.09, 1.15 +/-0.11 and 1.75 +/-0.21 h; AUC0-t160.2 +/-16.27, 171.8 +/-41.79 and 275.5 +/-79.55 mu g.h.mL respectively-1，AUC0-∞160.5 +/-16.29, 172.1 +/-41.79 and 276.1 +/-79.77 mu g.h.mL respectively-1. It is particularly worth mentioning that the time for the blood concentration of ampicillin in the high, medium and low dose groups to exceed the Minimum Inhibitory Concentration (MIC) for a particular bacterium is two hours longer than that in the control group.
Table 1 pharmacokinetics of low dose control group ampicillin sodium table 2 pharmacokinetics of low dose test group ampicillin sodium
Parameter
t1/2AUC0-tAUC0-∞t1/2AUC0-tAUC0-∞
Low dose-R Low dose-T
(h) (μg·h·mL-1) (μg·h·mL-1) (h) (μg·h·mL-1) (μg·h·mL-1)
1 0.80 127.5 128.1 1 0.98 150.3 150.4
2 0.81 184.0 184.2 2 0.99 186.2 186.4
3 0.64 121.9 122.1 3 0.89 148.5 148.8
4 0.58 118.8 118.8 4 0.95 160.7 161.1
5 0.63 101.9 102.0 5 0.94 171.8 172.3
6 0.74 124.8 125.1 6 1.15 143.6 143.8
Mean 0.70 129.8 130.1 Mean 0.98 160.2 160.5
SD 0.10 28.04 28.07 SD 0.09 16.27 16.29
Pharmacokinetic parameters of dose-control ampicillin sodium in Table 3 Table 4
t1/2AUC0-tAUC0-∞t1/2AUC0-tAUC0-∞
Middle dose-R middle dose-T
(h) (μg·h·mL-1) (μg·h·mL-1) (h) (μg·h·mL-1) (μg·h·mL-1)
1 0.97 132.9 133.0 1 0.99 152.3 152.6
2 0.98 141.1 141.4 2 1.09 131.8 132.0
3 0.89 100.8 100.9 3 1.13 120.5 121.0
4 0.82 158.6 158.7 4 1.30 213.3 213.7
5 0.86 173.4 173.6 5 1.15 208.0 208.4
6 0.99 150.2 150.3 6 1.25 204.8 205.0
Mean 0.92 142.8 143.0 Mean 1.15 171.8 172.1
SD 0.07 24.92 24.94 SD 0.11 41.79 41.79
TABLE 3-11 pharmacokinetic parameters of high dose control group ampicillin 3-12 pharmacokinetic parameters of high dose test group ampicillin
t1/2AUC0-tAUC0-∞t1/2AUC0-tAUC0-∞
High dose-R high dose-T
(h) (μg·h·mL-1) (μg·h·mL-1) (h) (μg·h·mL-1) (μg·h·mL-1)
1 1.61 250.8 251.1 1 1.71 269.9 270.7
2 1.59 191.8 192.1 2 1.98 237.4 238.0
3 1.34 199.8 200.1 3 1.46 238.7 239.0
4 1.27 200.3 200.5 4 1.53 196.5 196.8
5 1.52 244 244.3 5 1.88 336.9 337.9
6 1.47 331.5 331.9 6 1.73 425.3 426.2
Mean 1.49 233.7 234 Mean 1.75 275.5 276.1
SD 0.13 48.71 48.78 SD 0.21 79.55 79.77
TABLE 3-1 blood concentration of ampicillin at different times in the Low dose control group (g. mL-1)
Animal numbering
Time(h)
1 2 3 4 56 Mean SD
0.17 115.2 161.0 122.0 121.0 108.0 125.0 125.4 18.47
0.50 78.70 92.9 67.9 69.6 61.3 68.30 73.1 11.18
1.00 35.60 53.3 40.9 36.7 31.9 35.30 39.0 7.60
1.50 26.40 37.5 22.5 21.9 16.8 29.60 25.8 7.19
2.00 18.10 24.3 12.6 11.4 9.23 15.00 15.1 5.44
3.00 5.65 12.8 5.24 5.17 3.82 4.30 6.16 3.32
4.00 2.25 5.65 1.77 1.88 1.31 1.56 2.40 1.62
6.00 0.54 0.99 0.18 0.10 0.12 0.33 0.38 0.34
8.00 n.d. 0.18 n.d. n.d. n.d. n.d. 0.03 0.07
n.d.: below the lower limit of quantitation
TABLE 3-2 blood concentration (μ g. multidot.mL) of ampicillin at different times in the low dose test group-1)
Animal numbering
Time(h)
1 2 3 4 5 6 Mean SD
0.17 123.0 152.0 124.0 133.0 143.0 142.0 136.2 11.51
0.50 76.6 85 68.9 78.4 74.7 63.7 74.6 7.46
1.00 44.3 50.8 45.8 49.3 55.9 36.9 47.2 6.47
1.50 32.9 33.3 29.6 28 33.4 25.1 30.4 3.41
2.00 18.2 25.820.0 24.8 23.8 14.4 21.2 4.42
3.00 7.86 16.0 10.7 11.8 13.7 10.2 11.71 2.85
4.00 7.06 8.00 5.75 5.50 5.90 4.66 6.15 1.19
6.00 1.44 2.45 1.18 1.24 1.36 1.59 1.54 0.47
8.00 0.37 0.55 0.23 0.30 0.34 0.58 0.40 0.14
10.0 0.10 0.12 n.d. n.d. n.d. 0.12 0.06 0.06
n.d.: below the lower limit of quantitation
Blood concentration of ampicillin (μ g/mL) at different times in the dose control group in Table 9-1)
Animal numbering
Time(h)
1 2 3 4 5 6 Mean SD
0.17 134.6 127.6 89.00 149.8 188.6 144.8 139.1 32.43
0.50 80.20 73.20 60.80 73.20 98.00 98.40 80.6 14.98
1.00 42.40 42.20 34.60 61.80 54.00 53.80 48.1 10.05
1.50 24.60 28.80 22.40 33.60 29.40 28.60 27.9 3.93
2.00 12.78 18.10 11.90 18.04 15.72 12.76 14.9 2.79
3.00 3.40 6.66 2.40 5.50 4.30 2.80 4.20 1.65
4.00 2.33 4.31 2.25 2.83 2.95 2.35 2.80 0.78
6.00 0.46 0.97 0.42 0.64 0.43 0.47 0.60 0.21
8.00 0.11 0.21 0.10 n.d. n.d.n.d. 0.07 0.09
n.d.: below the lower limit of quantitation
The blood concentration (. mu.g. mL) of ampicillin at different times in the dose test group in Table 10-1)
Time (h) animal numbering
1 2 3 4 5 6 Mean SD
0.17 151.2 106.4 98.20 182.6 181.4 161.4 146.9 36.62
0.50 81.00 57.00 54.60 115.8 100.4 95.60 84.07 24.56
1.00 45.80 39.40 37.00 75.00 63.00 66.80 54.50 15.84
1.50 29.20 28.00 28.20 46.40 40.80 42.00 35.77 8.22
2.00 17.20 18.50 18.06 24.80 27.20 26.40 22.03 4.58
3.00 5.92 7.0 6.1 9.18 9.92 11.4 8.25 2.24
4.00 3.43 6.53 4.68 5.16 8.16 9.36 6.22 2.24
6.00 0.76 1.68 1.21 1.35 2.00 2.52 1.59 0.62
8.00 0.19 0.59 0.31 0.41 0.72 0.81 0.51 0.24
10.0 n.d. 0.13 n.d. 0.22 0.21 0.22 0.13 0.11
n.d.: below the lower limit of quantitation
TABLE 11 blood concentration of ampicillin (μ g/mL) at various times in the high dose control group-1)
Animal numbering
Time(h)
1 2 3 4 5 6 Mean SD
0.17 197.6 179.6 193.6 188.4 225.2 287.6 212.0 40.11
0.50 126.4 94.4 130.8 117.2 138.8 174 130.3 26.30
1.00 79.20 63.20 49.20 67.60 78.40 98.40 72.67 16.76
1.50 54.40 38.00 39.68 41.20 47.20 72.00 48.75 12.88
2.00 33.92 21.04 24.68 20.72 26.96 46.00 28.89 9.67
3.00 19.16 11.40 8.70 8.07 12.40 19.50 13.21 5.01
4.00 7.64 3.99 2.65 3.00 4.73 7.89 4.98 2.28
6.00 1.76 0.86 0.45 0.52 0.93 1.43 0.99 0.51
8.00 0.44 0.25 0.19 0.20 0.34 0.55 0.33 0.15
10.0 0.21 0.16 0.11 0.11 0.17 0.26 0.17 0.06
12.0 0.13 0.12 n.d. n.d. 0.12 0.17 0.09 0.07
n.d.: below the lower limit of quantitation
TABLE 12 blood concentration of ampicillin (μ g. multidot.mL) at different times in the high dose test group-1)
Animal numbering
Time(h)
1 2 3 4 5 6 Mean SD
0.17 210.4 194.8 176.4 169.2 266 337.6 225.7 64.74
0.50 120.4 127.2 142.0 78.80 164.4 200.8 138.9 41.43
1.00 97.20 66.40 64.40 60.80 107.2 134.0 88.33 29.43
1.50 54.40 43.20 48.40 33.88 72.00 90.00 56.98 20.59
2.00 35.04 34.80 35.40 27.16 33.96 52.80 36.53 8.55
3.00 11.72 14.80 15.32 15.30 26.12 30.32 18.93 7.44
4.00 11.88 8.28 8.84 7.06 14.16 17.00 11.20 3.85
6.00 3.18 1.93 2.64 2.10 3.36 3.99 2.87 0.79
8.00 2.07 1.03 0.69 0.78 1.24 1.49 1.22 0.51
10.0 0.50 0.48 0.26 0.36 0.59 0.66 0.47 0.15
12.0 0.34 0.24 0.15 0.13 0.37 0.36 0.27 0.11
n.d.: below the lower limit of quantitation
4. Discussion of the related Art
The study finds that the blood elimination half-life t of the test group is low, medium and high dosage level ampicillin1/2βThe total length is prolonged compared with the control group, and the total length is respectively prolonged by 0.28, 0.23 and 0.26 h; AUC of test group ampicillin0-tAnd AUC0-Also has an improvement over the control group, which is respectively increased by 23.4%, 20.3% and 17.9%. The data are statistically processed, and the difference is significant (P is less than 0.05). AUC in 3 dose groups0-tAnd AUC0-∞Linearly related to the dose administered (r>0.9708, P<0.05). Therefore, the probenecid sodium (potassium) can obviously prolong the half-life period of ampicillin sodium and improve the blood concentration, so that the total amount of the drug in the body in unit time of ampicillin is correspondingly increased, and the drug effect is obviously improved. Of particular importance, probenecid can significantly prolong the time that ampicillin sodium exceeds the MIC of the corresponding bacteria, which is beneficial to killing the bacteria and reducing the occurrence and development of drug resistance, because the concentration of the drug below the MIC is very easy to cause the generation of drug-resistant strains.
Sodium (potassium) probenecid, sodium penicillin G, cefazolin, cefuroxime and cefotaximeBlood elimination half-life (t) of sodium oxime and cefoxitin sodium1/2β) Influence of (2)
1. The purpose is as follows: the experiment aims at observing the blood elimination half-life (t-half-life) of probenecid sodium (potassium) to penicillin G sodium salt, cefazolin sodium, cefuroxime sodium, cefotaxime sodium and cefoxitin sodium1/2β) The influence of (2) lays a foundation for the research and development of series compound injections.
2. Test materials
2.1 drugs and reagents
Probenecid sodium (potassium)/penicillin G sodium salt, probenecid sodium (potassium)/cefazolin sodium, probenecid sodium (potassium)/cefuroxime sodium, probenecid sodium (potassium)/cefotaxime sodium and probenecid sodium (potassium)/cefoxitin sodium compound injection powder (penicillin bottles) and corresponding antibiotic reference substances; enalapril maleate (internal standard, purity provided by Beijing pharmaceutical biologicals assay: 99.8%); canine plasma blank (provided by the department of laboratory animals of the basic medical college of the university of Jilin).
The methanol is pure in chromatography, purchased from Tianjin Kancoded science and technology limited company, and other reagents are pure in analysis, and are products of Tianjin Fuchen chemical reagent factory and Beijingchemical factory.
2.2 test animals
Adult beagle dogs, having a weight range of 10.50 + -1.3 kg, were purchased from the laboratory animals center of Sichuan academy of medical sciences.
2.3 protocol and mode of administration
Beagle dogs were randomly grouped (control group R and test group T) and a two-cycle crossover test was performed with a 7-day interval between the two dosing weeks. The dose and mode of administration were as follows:
control group: each dog in each control group was given the corresponding antibiotic control alone, dissolved in saline, and then injected intravenously. The specific dosage is as follows: penicillin G: 80.65mg/kg, cefazolin: 53.76mg/kg, cefuroxime: 40.32mg/kg, cefotaxime: 40.32mg/kg, cefoxitin: 53.76 mg/kg.
Experimental groups: each dog in each test group was given the corresponding antibiotic and probenecid sodium (potassium) cocktail, dissolved in normal saline, and then injected intravenously. The specific dosage is as follows: each dog was given probenecid 26.88mg/kg intravenously, except for the same antibiotics as in the control group.
2.4 sample Collection and processing
About 1ml of blood was collected from the canine hind limb venule. Immediately after blood sample removal, the cells were transferred to heparin tubes, centrifuged (3500rpm) for 10min, plasma was separated, frozen and stored in a-20 ℃ freezer until assayed.
2.5 plasma sample analysis method
Dog plasma samples were assayed using the LC/MS/MS method.
2.6 data processing
The blood elimination half-lives (t) of the experimental group and the control group were compared and examined1/2β) Whether there was a statistical difference in the results.
3. Results
TABLE 1 Effect of probenecid sodium (Potassium) on the blood elimination half-life of various β -lactam antibiotics
| Blood elimination half-life (hour, probenecid sodium group) blood elimination half-life (hour, probenecid potassium group) Control group test group |
| Penicillin G0.481.260.511.22 Cefazolin 1.362.231.322.31 Cefuroxime 0.721.210.681.28 Cefotaxime 1.482.131.42 2.26 Cefoxitin 0.681.360.711.31 |
Note: there was no statistical difference between the probenecid sodium group and probenecid potassium group, but both the control and test groups differed significantly by P<0.05.
4. Discussion of the related Art
The research finds that probenecid sodium (potassium) remarkably prolongs the blood elimination half-life period (t1/2 β) of antibiotics in a test group, and since the β -lactam antibiotics belong to time-dependent antibiotics, the most critical factor of the antibacterial effect of the time-dependent antibiotics does not lie in the peak concentration of blood drugs, but whether the blood concentration exceeds the MIC of corresponding pathogenic bacteria or not, and the probenecid sodium (potassium) prolongs the half-life period of the antibiotics, so that the probenecidsodium (potassium) can obviously prolong the time that the blood concentration of the antibiotics exceeds the MIC of corresponding pathogenic bacteria.
The invention has the advantages that the probenecid sodium (potassium) and the β -lactam antibiotics are simultaneously injected or instilled in an intravenous way, the total amount of the medicines in the body in unit time of the β -lactam antibiotics is increased, the medicine effect can be obviously improved, the dosage of the antibiotics can be reduced and the medicine feeding interval can be prolonged, thereby saving resources and bringing convenience to patients
The specific implementation mode is as follows:
the invention is further described with reference to the following examples:
example 1: dissolving 22 kg of sodium hydroxide in 200L of purified water, adding 142 kg of probenecid after all the sodium hydroxide is dissolved, heating to 60 ℃, adjusting the pH value to be more than 7.5, and continuously stirring until the pH value is basically constant. Filtering and sterilizing with 0.45 μm filter membrane at 60 deg.C, fine filtering with 0.22 μm filter membrane to remove pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid sodium meeting human injection standard.
Mixing probenecid sodium and penicillin G sodium at a weight ratio of 1: 3 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Example 2: 28 kg of sodium hydroxide is dissolved in 280 l of purified water, 143 kg of probenecid is added after all the sodium hydroxide is dissolved, the temperature is heated to 65 ℃, the PH value is adjusted to be more than 8, and the stirring is carried out continuously until the PH value is basically constant. Filtering with 0.45 μm filter membrane at 65 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid sodium meeting human injection standard.
Mixing probenecid sodium and ampicillin sodium according to the weight ratio of 1: 2.8 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Example 3: 40 kg of sodium hydroxide is dissolved in 300 l of purified water, 150 kg of probenecid is added after all the sodium hydroxide is dissolved, the temperature is heated to 70 ℃, the pH value is adjusted to 10, and the mixture is continuously stirred until the pH value is basically constant. Filtering with 0.45 μm filter membrane at 70 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid sodium meeting human injection standard.
Mixing probenecid sodium and cefazolin sodium at a weight ratio of 1: 2 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Example 4: firstly, dissolving 102 sodium hydroxide in 1308 purified water (or water for injection) to completely dissolve, adding 663 probenecid, heating to 68 ℃, adjusting the pH value to 9, and continuously stirring until the pH value is basically constant; filtering with 0.45 μm filter membrane at 68 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid sodium meeting human injection standard;
mixing probenecid sodiumand cefuroxime sodium according to the weight ratio of 1: 1.5 under aseptic condition, subpackaging under aseptic condition, and finally preparing into powder injection.
Example 5: firstly, dissolving 0.17 potassium hydroxide in 11.5 purified water (or water for injection) completely, adding 0.88 probenecid, heating to 60 ℃, adjusting the pH value to 7.5, and continuously stirring until the pH value is basically constant; filtering with 0.45 μm filter membrane at 60 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid potassium material meeting human injection standard; mixing probenecid potassium and cefotaxime sodium according to the weight ratio of 1: 1.5 under aseptic condition, subpackaging under aseptic condition, and finally preparing into powder injection.
Example 6: firstly, 173.44 potassium hydroxide is dissolved in 1308 purified water (or water for injection) and is completely dissolved, 885.75 probenecid is added, the temperature is heated to 70 ℃, the PH value is adjusted to 10, and the mixture is continuously stirred until the PH value is basically constant; filtering with 0.45 μm filter membrane at 70 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid potassium material meeting human injection standard; mixing probenecid potassium and cefoxitin sodium at a weight ratio of 1: 2 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Example 7: dissolving 22 kg of potassium hydroxide in 200L of purified water, adding 142 kg of probenecid after all the potassium hydroxide is dissolved, heating to 60 ℃, adjusting the pH value to be more than 7.5, and continuously stirring until the pH value is basically constant. Filtering and sterilizing with 0.45 μm filter membrane at 60 deg.C, fine filtering with 0.22 μm filter membrane to remove pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid potassium meeting human injection standard.
Mixing probenecid potassium and penicillin G sodium at a weight ratio of 1: 3 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Example 8: 28 kg of potassium hydroxide is dissolved in 280 l of purified water, 143 kg of probenecid is added after all the potassium hydroxide is dissolved, the temperature is heated to 65 ℃, the PH value is adjusted to be more than 8, and the mixture is continuously stirred until the PH value is basically constant. Filtering with 0.45 μm filter membrane at 65 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid potassium meeting human injection standard.
Mixing probenecid potassium and ampicillin sodium at a weight ratio of 1: 2.8 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Example 9: 40 kg of potassium hydroxide is dissolved in 300 l of purified water, 150 kg of probenecid is added after all the potassium hydroxide is dissolved, the temperature is heated to 70 ℃, the pH value is adjusted to 10, and the mixture is continuously stirred until the pH value is basically constant. Filtering with 0.45 μm filter membrane at 70 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid potassium meeting human injection standard.
Mixing probenecid potassium and cefazolin sodium at a weight ratio of 1: 2 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Example 10: firstly, dissolving 102 potassium hydroxide in 1308 purified water (or water for injection) to completely dissolve, adding 663 probenecid, heating to 68 ℃, adjusting the pH value to 9, and continuously stirring until the pH value is basically constant; filtering with 0.45 μm filter membrane at 68 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid potassium material meeting human injection standard;
mixing probenecid potassium and cefuroxime sodium according to the weight ratio of 1: 1.5 under aseptic condition, subpackaging under aseptic condition, and finally preparing into powder injection.
Example 11: firstly, dissolving 0.17 sodium hydroxide in 11.5 purified water (or water for injection) to be completely dissolved, adding 0.88 probenecid, heating to 60 ℃, adjusting the pH value to 7.5, and continuously stirring until the pH value is basically constant; filtering with 0.45 μm filter membrane at 60 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid sodium meeting human injection standard; mixing probenecid sodium and cefotaxime sodium according to the weight ratio of 1: 1.5 under aseptic condition, subpackaging under aseptic condition, and finally preparing into powder injection.
Example 12: firstly, 173.44 sodium hydroxide is dissolved in 1308 purified water (or water for injection) and is completely dissolved, 885.75 probenecid is added, the temperature is heated to 70 ℃, the PH value is adjusted to 10, and the stirring is continuously carried out until the PH value is basically constant; filtering with 0.45 μm filter membrane at 70 deg.C for sterilization, fine filtering with 0.22 μm filter membrane for removing pyrogen, and drying under aseptic condition to obtain white or quasi-white crystalline powder of probenecid sodium meeting human injection standard; mixing probenecid sodium and cefoxitin sodium at a weight ratio of 1: 2 under aseptic condition, packaging under aseptic condition, and making into powder for injection.
Claims (7)
1. The structural formula of probenecid sodium is as follows:
the molecular formula is: c13H18NO4The molecular weight of SNa is: 307.34
The structural formula of probenecid potassium:
the molecular formula is: c13H18NO4The molecular weight of K is: 323.45
2. The process for preparing probenecid according to claim 1, wherein the process comprises the following steps: firstly, dissolving 0.9-102 sodium hydroxide in 11.5-1308 purified water, adding 6.5-663 probenecid after all the sodium hydroxide is dissolved, heating to 60 +/-10 ℃ to ensure that the probenecid completely reacts; adjusting the pH value to 7.5-10, filtering and sterilizing through a 0.45 mu m filter membrane at the temperature of 60 +/-10 ℃, then performing fine filtration through a 0.22 mu m filter membrane to remove pyrogen, and drying under the aseptic condition to obtain the probenecid sodium raw material which is white or white-like crystalline powder and meets the human injection standard. The probenecid content of the product is not lower than 88.50% calculated on a dry product.
3. The process for preparing probenecid potassium according to claim 1, characterized in that: firstly, dissolving 0.17-173.44 potassium hydroxide in 11.5-1308 purified water, adding 0.88-885.75 probenecid after all the potassium hydroxide is dissolved, heating to 60 +/-10 ℃ to ensure that the probenecid completely reacts; adjusting the pH value to 7.5-10, filtering and sterilizing through a 0.45 mu m filter membrane at the temperature of 60 +/-10 ℃, then carrying out fine filtration through a 0.22 mu m filter membrane to remove pyrogen, and drying under the aseptic condition to obtain the probenecid potassium raw material which is white or white-like crystalline powder and meets the human injection standard. The probenecid content of the product is not lower than 86.25 percent calculated on a dry product.
4. The compound injection of claim 1, wherein the injection comprises probenecid sodium, probenecid potassium and β -lactam antibiotics, and is prepared by mixing probenecid sodium, probenecid potassium and β -lactam antibiotics at a ratio of 1: 1-3, packaging under aseptic condition, and making into powder for injection and lyophilized powder for injection.
5. The compound injection of probenecid sodium, probenecid potassium and β -lactam antibiotics of claim 4, wherein the powder for injection and the lyophilized powder for injection are simultaneously injected or instilled intravenously with β -lactam antibiotics.
6. The compound injection of claim 4, wherein the probenecid sodium and probenecid potassium and the β -lactam antibiotics comprise penicillin antibiotics and cephalosporin antibiotics, the penicillin antibiotics comprise penicillin G and ampicillin, and the cephalosporin antibiotics comprise cefazolin, cefuroxime, cefotaxime and cefoxitin.
7. Compound injection composed of probenecid sodium (potassium) and β -lactam antibiotics and its useUse for prolonging the blood elimination half-life (t) of β -lactam antibiotics1/2β) Increasing the area under the curve (AUC) and significantly prolonging the time during which the blood concentration of β -lactam antibiotic exceeds the MIC of the corresponding bacterium.
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| CN102924344A (en) * | 2012-10-10 | 2013-02-13 | 北京康正康仁生物科技有限公司 | Synthesis and preparation method for probenecid sodium and probenecid potassium |
| CN102976980A (en) * | 2012-12-07 | 2013-03-20 | 山东省化工研究院 | Probenecid purification method |
| CN102976979A (en) * | 2012-12-07 | 2013-03-20 | 山东省化工研究院 | Preparation method of water-soluble probenecid salt |
| CN111704562A (en) * | 2020-08-07 | 2020-09-25 | 安徽康正康仁药业有限公司 | Freeze-drying process for disc-loaded sterile bulk pharmaceutical chemicals of probenecid |
| CN111840236A (en) * | 2020-08-07 | 2020-10-30 | 安徽康正康仁药业有限公司 | Meropenem probenecid compound freeze-dried preparation for injection |
| CN112076161A (en) * | 2020-08-07 | 2020-12-15 | 安徽康正康仁药业有限公司 | Compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium |
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| IL31760A (en) * | 1968-04-17 | 1972-01-27 | Merck & Co Inc | A probenecid derivative and tablets containing it |
| JPS6055486B2 (en) * | 1976-02-28 | 1985-12-05 | 富山化学工業株式会社 | Composition for rectal administration of a compound having a β-lactam ring |
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2004
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| CN102924344A (en) * | 2012-10-10 | 2013-02-13 | 北京康正康仁生物科技有限公司 | Synthesis and preparation method for probenecid sodium and probenecid potassium |
| CN102976980A (en) * | 2012-12-07 | 2013-03-20 | 山东省化工研究院 | Probenecid purification method |
| CN102976979A (en) * | 2012-12-07 | 2013-03-20 | 山东省化工研究院 | Preparation method of water-soluble probenecid salt |
| CN102976980B (en) * | 2012-12-07 | 2014-06-25 | 山东省化工研究院 | Probenecid purification method |
| CN102976979B (en) * | 2012-12-07 | 2014-08-20 | 山东省化工研究院 | Preparation method of water-soluble probenecid salt |
| CN111704562A (en) * | 2020-08-07 | 2020-09-25 | 安徽康正康仁药业有限公司 | Freeze-drying process for disc-loaded sterile bulk pharmaceutical chemicals of probenecid |
| CN111840236A (en) * | 2020-08-07 | 2020-10-30 | 安徽康正康仁药业有限公司 | Meropenem probenecid compound freeze-dried preparation for injection |
| CN112076161A (en) * | 2020-08-07 | 2020-12-15 | 安徽康正康仁药业有限公司 | Compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium |
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| Publication number | Publication date |
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| CN100387574C (en) | 2008-05-14 |
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