CN1513456A - Eye drop contg. pazoxacin methanesulphonate, its prepn. method and its anti-infective function - Google Patents

Abstract

An eye drops of Pazhushaxing mesylate is prepared from Pazhushaxing mesylate as active component and additive through dissolving them in the water for injection, and forming liquid or solid.

Description

Pazufloxacin Mesilate eye drop and preparation technology thereof---infection

Technical field

The present invention relates to a kind of pharmaceutical product and preparation technology thereof, specifically a kind of quinolone antibiotic Pazufloxacin Mesilate eye drop and preparation technology thereof.

Technical background

Quinolones is the newer synthetic antibacterial drug of a class, the effect of it and other antimicrobial drug is different, it serves as the effect target with the DNA of antibacterial, play a role and make DNA of bacteria can't form superhelix by hindering DNA topoisomerase II and IV, further cause chromosomal irreversible lesion, cause the bacterial cell can't schizogamy.It has the selective toxicity effect to antibacterial.Antibacterial can not conducted chemical sproof influence but quinolones is not subject to plasmid because of plasmid conduction wide-scale distribution to many antibiotic drug resistance, thereby and many antibacterials between do not have cross resistance.The antimicrobial spectrum of quinolones is constantly being widened, develop into anti-Gram-negative and positive bacteria, anaerobe, mycobacterium, legionella, mycoplasma and chlamydial super wide spectrum from the narrow spectrum of single anti-gram negative bacteria, established their leading positions in anti-infectives.

On current international market, the share of quinolones in antibacterials market increases just with surprising rapidity.World's quinolones sales volume was only 1.04 hundred million dollars in 1985, rose to 1,000,000,000 dollars in 1988, reached 2,200,000,000 dollars in 1992, was raised to 6,000,000,000 dollars in 1996, made the insider regard with special esteem.Second filial generation fluoroquinolone representative products norfloxacin, ofloxacin, ciprofloxacin etc., its comprehensive clinical efficacy are to gram negative bacteria, have reached the effect of the first generation, second generation cephalosporin.Wherein the antibacterial activity of ciprofloxacin is the strongest, is subjected to clinical favor most, and nineteen ninety global marketing volume promptly reaches 800,000,000 dollars, occupies second of all anti-infectives, after in several years, ciprofloxacin still keeps being in great demand, annual sales amount reaches 1,500,000,000 dollars.The novel fluoroquinolone representative products of third generation Sparfloxacin, nadifloxacin, levofloxacin, grepafloxacin and the alafloxacin etc. of the listing nineties, its antimicrobial spectrum expands pathogenic bacterium in resisting gram-positive and negative bacterium, chlamydia, mycoplasma and the cell to, antibacterial activity also improves greatly, pharmacokinetics and safety simultaneously also has greatly improved, and comprehensive clinical efficacy meets or exceeds the effect of third generation cephalosporin.Levofloxacin optimum wherein, and obtained extensive use, according to statistics in Japan, levofloxacin year in 1988 was sold 24,000,000,000 yen, occupied the 4th of all prescription drugs, first of anti-infectives, this is a milestone on the quinolone medicine development history.

The statistical data of China 14 city sample in first half of the year calendar year 2001 hospitals shows: anti-infective accounts for purchases 29.54% of medicine total value, wherein quinolones accounts for 14.89% of anti-infective total value, occupy the 3rd, 2 cephalo-type and the penicillins downward trend of ranking forefront is obvious, and the growth trend of quinolones is powerful, approaches the share of penicillins medicine.Quinolones is the research and development focus of current anti-infective, and this type of medicine is not with having cross resistance between many antibacterials, and these characteristics have utilizes applying of it; Three quinolones-levofloxacins, ofloxacin, the ciprofloxacins that sales volume is the highest belong to the third generation in the market.

The 4th generation up-to-date quinolones such as Gatifloxacin (Gatifloxacin), clinafloxacin (Clinafloxacin), Pazufloxacin (Pazufloxacin) and sieve Flucloxacillin-(Noxlfloxacin) etc., its structure and pharmacological property have had very big improvement again.Pazufloxacin Mesilate (PazufloxacinMesilate, development T-3762) demonstrates following advantage:

1, very high blood drug level and dividing a word with a hyphen at the end of a line property of favorable tissue, also having to be clinical effectiveness and the safety that the class medicine is equal to mutually with beta-lactam, can be used as antibiotic medicine for injection and uses.

2, indication scope widely, to slightly～the superior clinical effectiveness of severe infection disease performance.Except that various infection diseases are shown the good clinical effectiveness, Pazufloxacin Mesilate also has lower nervus centralis effect, and the clinical side effects incidence rate is also lower.

3, various bacterial infection diseases once also there was curative effect preferably with other drug nonresponder Pazufloxacin Mesilate, have wide antimicrobial spectrum and powerful antibacterial efficacy, and because of different with the mechanism of action of beta-lactam and aminoglycoside medicaments, performance effect when all right these antibiotic are invalid.

1. antibacterial activity

(1) antibacterial activity in vitro

Pazufloxacin Mesilate is to the external activity of clinical isolates, and compares with ofloxacin, ciprofloxacin, IPM, CAZ, GM and MINO.In gram positive bacteria, Pazufloxacin Mesilate is to the MIC of golden Portugal bacterium and form staph ₉₀Be 0.25-4 μ g/ml, and to the activity (MIC of the golden Portugal bacterium of methicillin-resistant ₉₀: 16 μ g/ml) be better than all contrast medicines.Activity and ciprofloxacin to the gram negative bacteria of the bacillus pyocyaneus that comprises enterobacteriaceae and anti-IPM and anti-GM are suitable, are better than other contrast medicine.

Pazufloxacin Mesilate is to the external activity of clinical isolating anaerobe (1994-1997), and compares with tosufloxacin, ciprofloxacin, IPM and CAZ.The activity of Pazufloxacin Mesilate is weaker than tosufloxacin and IPM, and is suitable with ciprofloxacin and CAZ, wherein only the activity of some bacterium is better than CAZ.Pazufloxacin Mesilate is to Clostridium perfringens, Fusobaterium nucleatum and some peptostreptococcus, Porphyromonas spp., some Prevotella, propionibacterium acnes shows good antibacterial activity, when concentration is 1.56 μ g/ml, can suppress 90% of anaerobe, but to the activity of bacteroides fragilis and prevotella bivia a little less than, even concentration also only can suppress 50% of this 2 bacterium up to 6.25 μ g/ml.

Pazufloxacin Mesilate shows the external activity result of study of department of obstetrics and gynecology clinical isolates, to the MIC of streptococcus agalactiae, gardnerella Vaginalis, escherichia coli, bacillus pyocyaneus, Peptostreptococcusmagnus, bacteroides fragilis and prevotella bivia ₅₀Be respectively: 3.13,6.25,0.025,0.78,6.25,6.25 and 12.5 μ g/ml; MIC to streptococcus agalactiae, gardnerella Vaginalis, escherichia coli, bacillus pyocyaneus, Peptostreptococcus magnus, bacteroides fragilis and prevotellabivia ₉₀Be respectively: 3.13,6.25,0.10,12.5,25,12.5 and 25 μ g/ml.Explanation thus, Pazufloxacin Mesilate can be treated the department of obstetrics and gynecology infection with another kind to the antibacterial combination drug that anaerobe has relative activity.

The results of in vitro studies of Pazufloxacin Mesilate shows that also its external activity and ciprofloxacin and levofloxacin are almost suitable, with non-enterally administer beta-lactam antibacterial, IPM, flomoxef (FMOX) and the no cross resistance of ceftazidime (CAZ).

Pazufloxacin Mesilate and CAZ, IPM, GM and ciprofloxacin are carried out the antibacterial activity in vitro controlled trial, and the result shows that Pazufloxacin Mesilate is wideer than CAZ and GM to the antimicrobial spectrum of gram negative bacteria and positive bacteria, and is similar with ciprofloxacin to IPM.To the streptococcic MlC of clinical isolating Gram-positive ₉₀Be 3.13 μ g/ml, be weaker than IPM and ciprofloxacin, and to the streptococcus and the enterococcal MIC of quinolinones sensitivity ₉₀For 0.2-6.25 μ g/ml, be better than CAZ.Pazufloxacin Mesilate is to the MIC of the gram negative bacteria of the bacillus pyocyaneus of the enterobacteria that comprises anti-cephem and anti-CAZ, IPM, GM ₉₀Be 0.025-50 μ g/ml.Explanation thus, Pazufloxacin Mesilate is better than CAZ to the activity of nearly all gram negative bacteria, IPM and GM.

(2) antibacterial activity in vivo

One shows that to the protective effect of being infected by the gram positive bacteria of the bacillus pyocyaneus that comprises MRSA, anti-IPM and GM and negative microbial mice system Pazufloxacin Mesilate also can be used for treating pulmonary infection and the urinary tract infection of mice.

Table 1. Pazufloxacin Mesilate, ciprofloxacin and levofloxacin are external to clinical isolates

Antibacterial activity comparative test result (MlC ₉₀, μ g/ml)

Antibacterial (strain) ciprofloxacin Pazufloxacin Mesilate levofloxacin

Gold Portugal bacterium (64) 12.5 25＞100

Gold Portugal bacterium (37) 3.13 3.13 6.25

Gold Portugal bacterium (21) 25 50＞100

Form staph (45) 3.13 3.13

3.13

Form staph (32) 25 25 50

Micrococcus scarlatinae (34) 3.13 0.78

0.78

Streptococcus pneumoniae (26) 3.13 1.56

1.56

Enterococcus faecalis (27) 3.13 1.56

1.56

E.faecalis(27)????????????????????6.25???????????????????25

1.56

E.avium(27)???????????????????????6.25???????????????????3.13

1.56

Escherichia coli 0.20 0.20

0.10

Fei Shi citric acid bacillus (34) 0.20 0.39

0.10

Pneumobacillus (39) 0.05 0.10

0.10

Intestinal bacillus cloacae (38) 0.10 0.20

0.10

Intestinal produces bacillus (36) 0.05 0.10

0.05

Grain matter Serratieae (37) 6.25 12.5

12.5

Proteus mirabilis (33) 0.05 0.20

0.10

Proteus vulgaris (36) 0.025 0.10

0.05

Morganella morganii (36) 0.013 0.10

0.013

Thunder Ji Shi family name Bacillus proteus (27) 3.13 12.5

25

Bacillus pyocyaneus (57) 100＞100

100

Bacillus pyocyaneus (30) 6.25 25

6.25

Acinetobacter calcoaceticus (28) 0.78 0.78

0.78

Hemophilus influenza (47) 0.025 0.05

0.05

Micrococcus catarrhalis (36) 0.10 0.10

0.10

Gonococcus (24) 0.025 0.05

0.013

(3) antibiotic after effect

Pazufloxacin Mesilate, ciprofloxacin, GM, IPM and CAZ are respectively 2.96h to the PAE of pneumobacillus 3K-25,1.73h, 1.23h, 0.380h and 0.103h are respectively 2.85h, 2.09h, 1.731.83h and 0.0286h to the PAE of bacillus pyocyaneus KU-1.This shows that the PAE of Pazufloxacin Mesilate is better than all contrast medicines.

Pazufloxacin Mesilate depends on concentration and processing time to the PAE of escherichia coli and bacillus pyocyaneus, and the concentration factor is even more important.In general, the processing time, concentration was big more when identical, and its PAE is long more.

2. pharmacokinetics

(1) animal pharmacokinetics

The pharmacokinetic study result of mice, rat, rabbit and the quiet notes Pazufloxacin Mesilate of Canis familiaris L. single shows that blood drug level is 4.77-6.83 μ g/ml during as the quiet notes this product of single 5min, explanation thus, and its blood drug level does not have obvious species variation.Rat test shows, Pazufloxacin Mesilate can be distributed in rapidly except that cerebral tissue each organize in (mainly be distributed in the kidney, concentration and blood drug level in other tissue are suitable).Mainly by draining with former medicine in the urine, as the 24h urine response rate after the quiet notes this product of mice, rat, rabbit and Canis familiaris L. single is respectively 44.7%, 74.3%, 54.9% and 56.6%.And the 24h rat bile Central Plains medicine response rate only 2.2%.Dosage (5-100mg/kg) the correlation test explanation that rat is carried out, its AUC and dosage are linear, and the response rate and dosage size almost have nothing to do in the urine.Response rate no significant difference in blood drug level when repeatedly medication (2 times/day, 6 days) and single medication and the urine.Its main pharmacokinetic parameter sees Table 2.

Main pharmacokinetic parameter (the dosage: 5mg/kg) of the quiet notes Pazufloxacin Mesilate of table 2. animal

Animal (only)	Route of administration	C 5min(μg/ml)	Cmax (μg/ml)	????T 1/2(h)	????AUC ????(μg.h/ml)
						Mice (5)	Quiet notes	5.39±0.42	---	????0.23	????2.4
Rat (10)	Quiet notes	5.20±1.34	---	????0.88	????5.2
						Rabbit (5)	Quiet notes	6.83±1.10	---	????1.0±0.2	????6.0±1.4
Canis familiaris L. (4)	Quiet notes	4.77±1.04	---	????4.5±1.0	????20±4
						Canis familiaris L. (4)	Intravenous drip (30min)	---	5.61±1.29	????5.2±2.3	????21±11

Rat, mice are given ¹⁴C labelling Pazufloxacin Mesilate 5mg/kg single and its blood concentration of quiet repeatedly notes back, distribution and drainage result: rat, the quiet notes whole body of mice single total body clearance are respectively 1.03,1.211/h/kg, distribution volume is respectively 1.25,0.991/kg, the radiation concentration change is the two-phase variation in the blood, and the half-life of disappearance phase was respectively 1.49 hours, 1.91 hours; Rat, the main excretion pathway of mice all are kidneys, and rat is about 77%, mice about 68% is discharged through urine, and residue is discharged by feces, and the rat bile excretion rate is about 18%; Internal organs and the tissue in concentration be kidney, liver for the highest, other then whole body extensively distribute, but transfer to brain, the spinal cord person is very few; After the administration of suckling female rats, shift the radiation (being 1.5-3.2) of finding to have higher concentration in its milk with the blood level ratio; After the gestation female rats administration on the the 20th, 21 radiation by Placenta Hominis shift in the fetus body (with the parent plasma concentration than being 0.2-0.8), fetal drug concentration ratio parent blood level changes more a little later; Rat 1 quiet repeatedly notes every day are the not variation of drainage situation after 10 days, and medicine is not seen residual rapidly in the drainage body; Rat 1 repetitively administered every day distributed and single-dose internal organs, the tissue of not seeing drug accumulation about the same in the body after 10 days.Mice is given ¹⁴Mostly be glucuronide conjugate in the urine after C label (Pazufloxacin the is 5mg/kg) administration; Rat almost major part directly drains in urine for not metabolic former medicine; The former medicine of not variation that rat drains in bile is considerably less; Animal also has glucose adduct-Pazufloxacin M1 except that main metabolites is glucuronide conjugate, rabbit, monkey also detect the Pazufloxacin M2 and the Pazufloxacin M3 of oxidation, and these oxides are more in the monkey; The quiet notes Pazufloxacin Mesilate of people (containing Pazufloxacin is 400mg) back is most of drains in the urine, and dosage about 94% is not for changing former medicine, and residue 5.7% is a glucuronide conjugate, also has the Pazufloxacin M2 and the Pazufloxacin M3 of trace in addition; The quiet repeatedly notes Pazufloxacin Mesilate of people (containing Pazufloxacin 300mg, every day 2 times, continuous 5 days) major metabolite is that the excretion rate and the single-dose of glucuronide conjugate do not have difference.

(2) human pharmacokinetics

Single agent intravenous drip Pazufloxacin Mesilate 50,100,200,400 of healthy volunteer and 500mg, multi-agent intravenous drip 300 and 500mg/2 the day/sky and 500mg/3 the day/sky, lasting: 5 days.

When single agent administration, the Cmax of 5 kinds of dosage (when 30min has instiled) is respectively 1.28,2.68,4.61,9.93 and 11.0 μ g/ml, T _1/2Be 1.74-1.88h, Cmax and AUC and dosage are linear.Mainly by draining in the urine, it is almost irrelevant to drain the 89.5-93.3% excretion rate and the dosage that are about dosage among the 24h.During the multi-agent medication, the blood drug level maximum appears at first day, and the homaluria rate is not seen increase.The intravenous drip time is that the Cmax of 60min is to be 80% of 30min the intravenous drip time.Safety issue does not appear in single agent 1000mg.During with the probenecid combination drug, its plasma half-life prolongs, and the homaluria rate reduces.The pharmacokinetics of Pazufloxacin Mesilate, antibacterial activity and clinical trial prove that there is not safety issue in Pazufloxacin Mesilate.

The pharmacokinetic parameter of the quiet notes of the single agent of table 3 Pazufloxacin Mesilate healthy volunteer

Application method		Dosage (mg)	??Vd ??(1)	??T 1/2α ??(h -1)	??T 1/2β ??(h -1)	??Tmax ??(h)	????Cmax ????(μg/ml)	???AUC ???(μg·h/ml)
									The intravenous drip time is 30min		??50	??18.1 ??72	??0.09 ??6	??1.76 ??9	??0.50 ??0	????1.278	???2.232
??100	??21.9 ??30	??0.13 ??4	??1.83 ??1	??0.50 ??0	????2.677	???4.216
							??200	??21.3 ??95			??0.12 ??5	??1.81 ??0	??0.50 ??0	????4.610	???8.046
??400	??20.0 ??24	??0.09 ??6	??1.74 ??0	??0.50 ??0	????9.928	???18.510
							??500	??24.5 ??96			??0.11 ??6	??1.88 ??1	??0.50 ??0	????11.029	???21.679
The intravenous drip time is 60min		??500	??17.6 ??91	??0.11 ??6	??1.89 ??1	??1.00 ??0										????8.573	???20.415
							??1000	??26.1 ??31	??0.35 ??7	??2.26 ??2	??1.00 ??0	????18.353	???50.990
		With the probenecid combination drug	????+	??200	??26.9 ??52	??0.11 ??5								??3.74 ??5	??0.50 ??0	????4.695	???19.237
????-	??200						??19.7 ??24	??0.11 ??9	??1.88 ??9	??0.50 ??0	????4.661	???8.023

(3) advanced age renal dysfunction patient pharmacokinetics

To having studied the pharmacokinetics of Pazufloxacin Mesilate among 7 gerontal patients (71-88 year), clearance rate (Ccr) according to the creatine liver is divided into three groups with the patient, point is annotated Pazufloxacin Mesilate (30min drips off), and the result shows (table 3), and point is annotated to finish and promptly reached Cmax; Underspeeding of severe renal dysfunction patient's blood drug level less than moderate renal function patient; There is the T relevant with the renal dysfunction degree _1/2Prolong excretory minimizing in AUC minimizing and the urine.

Patient's Pazufloxacin Mesilate clearance rate that renal function goes down descends, and eliminates the half-life prolongation, for avoiding drug accumulation, should carry out dose titration.Hemodialysis and continuous peritoneal dialysis can not be got rid of Pazufloxacin Mesilate in body.

Table 4. Pazufloxacin Mesilate renal dysfunction at advanced age patient single dose point is annotated (300mg)

Pharmacokinetic parameter

Group (number)	Numbering	??????Ccr ??????(ml/min)		????Cmax ????(μg/ml)	??T 1/2??(h)	???AUC ???(μg·h/ml)	24h urinates the response rate (%)
								??I(2)	??1 ??2	????≥ ????60	??84. ??0 ??63. ??6	????6.4 ????7.1	??2.4 ??2.3	???12.3 ???17.8	???92.75 ???80.71
??II(2)	??3 ??4	????20- ????60	??59. ??7 ??33. ??1	????10.5 ????21.1	??4.7 ??4.6	???38.5 ???53.7	???60.85 ???63.63
								??III(3)	??5 ??6 ??7	????20	??11. ??6 ??9.8 ??6.6	????8.4 ????7.8 ????8.2	??12. ??1 ??16. ??7 ??18. ??3	???100.6 ???94.2 ???148.2	???28.63 ???12.21 ???21.34

3. toxicology

(1) acute toxicity

The quiet notes Pazufloxacin Mesilate of the single agent of rat, Canis familiaris L. and monkey, the result shows, its LD ₅₀Be respectively 260-391,260-521 and 260-520mg/kg.

(2) long term toxicity

Rat quiet notes Pazufloxacin Mesilate in continuous March, every day 1 time, dosage is respectively 4,, 13,, 39 and the long term toxicity test result of 130mg/kg show that Pazufloxacin Mesilate is 13mg/kg to nonhazardous (articular cartilage the is no abnormal) dosage of rat.

Female, male cynomolgus monkey continuous 13 all quiet notes Pazufloxacin Mesilates, every day 1 time, dosage be respectively 26,52 and long term toxicity and the 4 all recovery result of the tests of 104mg/kg show that Pazufloxacin Mesilate is to nonhazardous dosage＞104mg/kg of female, male cynomolgus monkey.

(3) genotoxicity

Rat shows in the result of study of allelotaxis's phase (during pregnant 7-17 days) quiet notes Pazufloxacin Mesilate to its reproductive development influence, and Pazufloxacin Mesilate is 156mg/kg to the general toxicity of parental generation rat, genotoxicity with to the nonhazardous dosage of fetal development.

4. clinical research

Pazufloxacin Mesilate shows in the clinical efficacy in internal medicine field and bacteriology's curative effect and safety evaluatio result, clinical total effective rate 75.1% (181/241) to respiratory tract infection, the antibacterial total body clearance is respectively 69.2% (72/104), wherein the effective percentage to chronic respiratory tract infection is 76.1% (67/88), effective percentage to pneumonia/pulmonary suppuration is 75.7% (109/144), adverse reaction rate is 4.0%, and the unusual rate of lab testing is 14.3%.

The clinical total effective rate of Pazufloxacin Mesilate treatment complexity urinary tract infection is 78.7%, and the total body clearance of gram negative bacteria and positive bacteria is respectively 79.3%85.9%, and adverse reaction rate is 1.1%, and the unusual rate of lab testing is 8.0%.

The surgery field shows the curative effect and the tissue concentration distribution result of study of Pazufloxacin Mesilate, Pazufloxacin Mesilate is respectively 78.3% (18/23), 86.7% (13/15), 73.7% (14/19) and 86.7% (13/15) to the clinical effective rate of intra-abdominal infection, biliary tract infection, traumatic infection and postoperative pneumonia, septicemia (2 example), cellulitis (1 example), osteomyelitis (1 example) and perianal abscess (1 example) are produce effects, and total effective rate is 81.8% (63/77).The effective percentage that mixed vaccine (containing bacillus pyocyaneus) is infected is 80.0% (12/15).Untoward reaction do not occur, the unusual rate of lab testing is 12.5% (10/80).

The department of obstetrics and gynecology field shows the curative effect of Pazufloxacin Mesilate and the CONCENTRATION DISTRIBUTION result of study in the retroperitoneum transudate, the women is extractd in 5 uterus put notes Pazufloxacin Mesilate (the some notes time: 30min), the result shows, Pazufloxacin Mesilate peak time in serum and retroperitoneum transudate is respectively has annotated back 15-30min and 1.5-2.5h, and the highest mean concentration in the two is respectively 20.89 and 6.98 μ g/ml.Pazufloxacin Mesilate is 100% (5/5: produce effects 1 example wherein, effective 4 examples) to the effective percentage of retroperitonitis, and the clearance rate of clinical isolates is 87.5% (7/8), untoward reaction do not occur, the lab testing no abnormality seen.Result of study shows that every day, dosage 600mg or 1000mg can effectively treat the department of obstetrics and gynecology infection.

Quiet notes Pazufloxacin Mesilate is to the clinical efficacy and the safety of complexity urinary tract infection.Sum 179 examples can be estimated curative effect 150 examples, 300mg wherein, every day secondary, 49 examples; A 500mg, a twice-daily, 100 examples; A 500mg, three times on the one, 1 example, be 5 days the course of treatment.Therapeutic outcome shows, obvious effective rate 37.3% (56/150), effective percentage 41.3% (62/150), total effective rate 78.7% (118/150).The effective percentage that divides by the disease kind is respectively pyelonephritis 75.9% (44/58), cystitis 80.4% (74/92).The effective percentage that divides by dosage is respectively a twice-daily, a 300mg person, 81.6% (40/49); One twice-daily, a 500mg person, 77.0% (77/100); A 500mg, three times on the one persons 100% (1/1).Its bacteriology's curative effect is as follows: antibacterial total body clearance 85.9% (201/234), and wherein to G ⁺Bacterium is 79.3% (88/111), to G ^-Bacterium is 91.9% (113/123).179 examples that are used for estimating side effect have the 2 routine appearance may the side effect relevant with medicine, 1 example is moderate diarrhoea, other 1 example is that the diarrhoea of slight vomiting and nauseating and moderate has it concurrently, and 2 examples are elderly patient (71 years old and 81 years old), side effect incidence rate 1.1% (2/179).The unusual occurrence rate 8% (13/163) of test chamber inspection mainly is that the transaminase who gently arrives moderate raises and oxyphil cell's increase, and this rising or increase and dosage have dependency trend.

Curative effect and the safety of quiet notes Pazufloxacin Mesilate aspect the treatment respiratory tract infection.Sum 278 examples, can be used for therapeutic evaluation 241 examples, the dosage overwhelming majority is 600mg (branch secondary) on the one and 1000mg (branch secondary) on the one, both amount to 232 examples, account for 96.3% (232/241), indivedual cases are 900mg (dividing three times) on the one or 1500mg (dividing three times), or once-a-day 300mg or once-a-day 500mg, the 3-14 days course of treatment.Therapeutic outcome shows, obvious effective rate 17.8% (43/241), effective percentage 57.3% (138/241), total effective rate are 75.1% (181/241), wherein the chronic respiratory tract infection effective percentage is 76.1% (67/88), and pneumonia and pulmonary suppuration effective percentage are 75.7% (109/144).In 241 examples, 60 examples are arranged for using the case of other antibacterial (comprising beta-lactam and quinolones) treatment failure, after using Pazufloxacin Mesilate, obvious effective rate is 10.0% (6/60), effective percentage is 53.3% (32/60), and total effective rate is 63.3% (38/60).Press the using dosage branch, 600mg (branch secondary) on the one, total effective rate is 74.2% (49/66); 1000mg (branch secondary) on the one, total effective rate is 74.7% (124/166), the two there was no significant difference.Bacteriology's efficacy result is as follows: negative conversion rate is 69.2% (72/104), wherein G ⁺The negative conversion rate that bacterium infects separately is 82.9% (29/35), G ^-The negative conversion rate that bacterium infects separately is 67.3% (37/55), and the negative conversion rate of MOI is 42.9% (6/14).G ⁺The clearance rate of bacterium is 77.6% (38/49), G ^-The clearance rate of bacterium is 68.6% (48/70).The side effect incidence rate is 4% (11/276), is mainly mild to moderate headache, dizziness, drug eruption, diarrhoea, stomach discomfort sense etc.The unusual incidence rate of test chamber inspection is 14.3% (36/252), mainly be transaminase's (comprising GOT and GPT) raise account for 6.3% (16/252) and the Eosinophilia account for 4.8% (12/252).

Quiet notes Pazufloxacin Mesilate is to the curative effect and the safety of surgical infection.Sum 83 examples can be used for estimating curative effect 77 examples, dosage 600mg (branch secondary) on the one 19 examples, and 1000mg (branch secondary) 50 examples on the one, both account for 89.6% (69/77), 1500mg (dividing three times) 5 examples, middle change dosage 3 examples, the 5-14 day course of treatment.The result shows, obvious effective rate 37.7% (29/77), effective percentage 44.2% (34/77), total effective rate 81.8% (63/77).Wherein, intra-abdominal infection effective percentage 78.3% (18/23), biliary tract infection effective percentage 86.7% (13/15), wound superinfection effective percentage 73.7% (14/19), postoperative pneumonia effective percentage 86.7% (13/15), septicemia, cellulitis, osteomyelitis and perianal abscess 5 examples are produce effects all.According to dosage divide, 600mg (branch secondary) effective percentage 73.7% (14/19) on the one, 1000mg (branch secondary) effective percentage 84.0% (42/50) on the one, the latter is higher than the former.40 examples are arranged for using the case of other antibiotic (comprising beta-lactam and quinolones) treatment failure in 77 examples, after this product treatment, obvious effective rate 37.5% (15/40), effective percentage 32.5% (13/40), total effective rate 70% (28/40).Bacteriology's effect is as follows: G ⁺Bacterium clearance rate 45% (5/11), G ^-Bacterium clearance rate 84.6% (11/13), anaerobe clearance rate 66.7% (2/3).In 77 examples, do not find side effect.The unusual occurrence rate 12.5% (10/80) of test chamber inspection mainly is that transaminase's (comprising GOT and GPT) raises, the oxyphil cell increases and leukopenia.

Curative effect and safety that quiet notes Pazufloxacin Mesilate infects 5 routine department of obstetrics and gynecology.5 examples be in to the peritonaeum pelvicum inflammation of severe, 600mg (branch secondary) 1 example on the one, 1000mg (branch secondary) 4 examples on the one, the 4-11 days course of treatment.Therapeutic outcome is produce effects 1 example, effective 4 examples, clinical total effective rate 100% (5/5).Bacteria clearance 87.5% (7/8), a strain of Qing Chuing not is an enterococcus faecalis, does not find side effect, the test chamber inspection does not occur unusual yet.

In sum, Pazufloxacin Mesilate is that a new generation is efficient, wide spectrum, the good quinolone antibiotic of safety, develops its preparation and will obtain huge social benefit and economic benefit.

Goal of the invention

The present invention is by prepare the method for Pazufloxacin Mesilate eye drop, reaches to treat the ophthalmology purpose safe and effective, that constant product quality is controlled that catches.

Summary of the invention

For achieving the above object, the present invention adopts following technical scheme: Pazufloxacin Mesilate and additives are dissolved in make aqueous solution in the water for injection or Pazufloxacin Mesilate and additives are made packaged with powder, granule, block or tablet, water penetrated in remarks in addition, faces with preceding with the lysigenous clear and bright solution of water for injection.

Active component in the eye drop of the present invention is a Pazufloxacin Mesilate, and its chemical name is (S)-(-)-10-(the amino cyclopropyl of 1--9-fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid mesylate, structural formula is: Molecular formula is C ₁₆H ₁₅FN ₂O ₄CH ₄SO ₃, molecular weight is 414.41.

Additives in the eye drop of the present invention have osmotic pressure regulator, pH regulator agent, antibacterial, antioxidant, metal chelating agent, surfactant and extender etc.

Osmotic pressure regulator in the eye drop of the present invention includes but not limited to sodium chloride, boric acid, glucose, Borax, Chile saltpeter etc.

PH regulator agent in the eye drop of the present invention includes but not limited to Sha Shi phosphate buffer, Palitzsch, lucky Fei Shi buffer, borate buffer, methanesulfonic acid, sodium hydroxide etc.

Antibacterial in the eye drop of the present invention includes but not limited to: methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, benzyl alcohol, phenethanol etc.

Antioxidant in the eye drop of the present invention comprises but is not limited to sodium sulfite, sodium pyrosulfite, sodium thiosulfate etc.

Metal chelating agent in the eye drop of the present invention includes but not limited to ethylenediamine tetraacetic sodium oxalate etc.

Surfactant in the eye drop of the present invention comprises but is not limited to geramine, polyvinyl alcohol, polyoxyethylene sorbitan monoleate etc.

Extender in the eye drop of the present invention includes but not limited to mannitol, sorbitol, xylitol etc.

The preparation technology of eye drop of the present invention is: get Pazufloxacin Mesilate 0.1g to 10g, methanesulfonic acid, with an amount of water for injection dissolving.Taking ethylparaben, polyoxyethylene sorbitan monoleate add sodium chloride saturated solution with an amount of hot water for injection dissolving and make dissolving in addition.With above-mentioned two solution mixings, with adding the injection water to 1000ml behind sodium hydroxide solution (0.1mol/L) the adjusting pH value, stir evenly, aseptic subpackaged with 0.45 μ m filtering with microporous membrane, flowing steam high temperature pressure sterilizing, promptly.

The preparation technology of eye drop of the present invention is: get Pazufloxacin Mesilate, methanesulfonic acid, sodium chloride, mannitol, add the injection water and make dissolving, regulate pH value with sodium hydroxide solution (0.1mol/L), stir evenly, aseptic filtration is carried out lyophilization with sterile working's fill, promptly in sterilization container, water penetrated in remarks in addition, faces with preceding with using after the water for injection dissolving.

Result of study shows that Pazufloxacin Mesilate eye drop of the present invention is stable and controllable for quality, safe and effective.

Below through detecting explanation beneficial effect of the present invention

Detect index and method

1. dextroisomer detects according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000) and measures.

Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-chirality solution (get L-Phenylalanine 1.32g, copper sulfate 1g, add water 1000ml dissolving after, regulate pH value to 3.5 with sodium hydroxide test solution, shake up, promptly) (25: 75) are mobile phase, flow velocity is per minute 1ml, the detection wavelength is 322nm.Number of theoretical plate should be not less than 1500 by Pazufloxacin Mesilate, and left and right separating degree of revolving between the isomer should be greater than 1.5.

It is an amount of that the algoscopy precision is measured sample of the present invention, puts in the 10ml measuring bottle, adds mobile phase to scale, shakes up, and precision is measured in above-mentioned solution 1ml to the 25ml measuring bottle and added mobile phase to scale, as need testing solution; Precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, adds mobile phase to scale, shakes up, in contrast solution; Pazufloxacin Mesilate is revolved in cancellation in addition, adds mobile phase and makes the solution that contains 0.2mg among the 1ml, as prerun solution.Get prerun solution 20 μ l and inject chromatograph of liquid, each component peak sequence is followed successively by the laevoisomer and the dextroisomer of Pazufloxacin Mesilate.Get contrast solution 20 μ l, inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 10%～20% of a full scale; Get need testing solution 20 μ l again and inject chromatograph of liquid, the record chromatogram is to 2 times of main constituent peak retention time, and if any dextrorotation Pazufloxacin Mesilate peak, its peak area must not be greater than contrast solution main peak area in the need testing solution chromatogram.

2. related substance detects according to the chromatographic condition under the assay item and measures, and it is an amount of that precision is measured sample of the present invention, puts in the 100ml measuring bottle, add water to scale, shake up, precision is measured and is added mobile phase in above-mentioned solution 2ml to the 25ml measuring bottle and be diluted to scale, as need testing solution; Measure need testing solution 1ml and put in the 100ml measuring bottle, add mobile phase, shake up, in contrast solution to scale.Get contrast solution 20 μ l, inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 10%～20% of a full scale; Get need testing solution 20 μ l again and inject chromatograph of liquid, the record chromatogram, desolventizes outside the peak as showing impurity peaks to 4 times of main constituent chromatographic peak retention time, and each impurity peak area summation must not be greater than 1.5 times of contrast solution main peak area.

3. assay is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).

Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, and (transferring pH to 4.0 with triethylamine)-methanol (62: 38) is mobile phase with (0.05mol/L) citric acid solution, and flow velocity is per minute 1ml, and the detection wavelength is 247nm.Number of theoretical plate should be not less than 2000 by the Pazufloxacin Mesilate peak.

It is an amount of that the algoscopy precision is measured sample of the present invention, puts in the 200ml measuring bottle, and thin up shakes up to scale, and precision is measured above-mentioned solution 2ml and put in the 100ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, and gets 20 μ l and inject chromatograph of liquid, the record chromatogram; Other learns from else's experience 105 ℃ in about 20mg to the 25ml measuring bottle of Pazufloxacin Mesilate reference substance that is dried to constant weight, be dissolved in water and be diluted to scale, shake up, precision is measured above-mentioned solution 2ml and is put in the 100ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, measure with method, with calculated by peak area, multiply by 0.7683, promptly by external standard method.Contain Pazufloxacin and should be 90.0%～110.0% of labelled amount.

Testing result

One, example 1 sample detection result

1. dextroisomer: 0.12%.

2. related substance: 0.20%.

3. content: 100.7%.

Two, example 2 sample detection results

1. dextroisomer: 0.16%.

2. related substance: 0.19%.

3. content: 101.3%.

The specific embodiment

One, example 1

Prescription:

Pazufloxacin Mesilate 6.51g (counting 5g) with Pazufloxacin

Sodium chloride 8.5g

Ethyl hydroxybenzoate 0.3g

Polyoxyethylene sorbitan monoleate is an amount of

Methanesulfonic acid is an amount of

Sodium hydroxide solution (0.1mol/L) is an amount of

Water for injection adds to 1000ml

Preparation technology:

Get Pazufloxacin Mesilate, methanesulfonic acid, with an amount of water for injection dissolving.Taking ethylparaben, polyoxyethylene sorbitan monoleate add sodium chloride saturated solution with an amount of hot water for injection dissolving and make dissolving in addition.With above-mentioned two solution mixings, with adding injection water 1000ml behind sodium hydroxide solution (0.1mol/L) the adjusting pH value, stir evenly, aseptic subpackaged with 0.45 μ m filtering with microporous membrane, flowing steam high temperature pressure sterilizing, promptly.

Two, example 2

Prescription:

Pazufloxacin Mesilate 6.51g (counting 5g) with Pazufloxacin

Sodium chloride 8.5g

Mannitol is an amount of

Methanesulfonic acid is an amount of

Sodium hydroxide solution (0.1mol/L) is an amount of

Water for injection is an amount of

Preparation technology:

Get Pazufloxacin Mesilate, methanesulfonic acid, sodium chloride, mannitol, add the injection water and make dissolving, regulate pH value with sodium hydroxide solution (0.1mol/L), stir evenly, aseptic filtration is carried out lyophilization with sterile working's fill, promptly in sterilization container.Water penetrated in remarks in addition, faces with preceding with using after the water for injection dissolving.

Claims (10)

1. Pazufloxacin Mesilate eye drop and preparation technology thereof, it is characterized in that: it is the packaged with powder, granule, block or tablet that is dissolved in the aqueous solution made in the water for injection or Pazufloxacin Mesilate and additives are made with Pazufloxacin Mesilate and additives, water penetrated in remarks in addition, faces with preceding with the lysigenous clear and bright solution of water for injection.

2. Pazufloxacin Mesilate eye drop according to claim 1 and preparation technology thereof, it is characterized in that: the chemical name of Pazufloxacin Mesilate is (S)-(-)-10-(the amino cyclopropyl of 1-)-9-fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid mesylate, structural formula is

Molecular formula is C ₁₆H ₁₅FN ₂O ₄CH ₄SO ₃, molecular weight is 414.41.

3. Pazufloxacin Mesilate eye drop according to claim 1 and preparation technology thereof are it is characterized in that: additives are osmotic pressure regulator, pH regulator agent, antibacterial, antioxidant, metal chelating agent, surfactant and extender.

4. the described osmotic pressure regulator of claim 3 includes but not limited to sodium chloride, boric acid, glucose, Borax, Chile saltpeter etc.

5. the described pH regulator agent of claim 3 includes but not limited to Sha Shi phosphate buffer, Palitzsch, lucky Fei Shi buffer, borate buffer, methanesulfonic acid, sodium hydroxide etc.

6. the described antibacterial of claim 3 includes but not limited to: methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, benzyl alcohol, phenethanol etc.

7. the described antioxidant of claim 3 comprises but is not limited to sodium sulfite, sodium pyrosulfite, sodium thiosulfate etc.

8. the described metal chelating agent of claim 3 includes but not limited to ethylenediamine tetraacetic sodium oxalate etc.

9. the described surfactant of claim 3 comprises but is not limited to geramine, polyvinyl alcohol, polyoxyethylene sorbitan monoleate etc.

10. the described extender of claim 3 includes but not limited to mannitol, sorbitol, xylitol etc.