CN103040838B - Drug composition and application thereof - Google Patents
Drug composition and application thereof Download PDFInfo
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- CN103040838B CN103040838B CN201310001296.4A CN201310001296A CN103040838B CN 103040838 B CN103040838 B CN 103040838B CN 201310001296 A CN201310001296 A CN 201310001296A CN 103040838 B CN103040838 B CN 103040838B
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Abstract
The invention relates to a drug composition and an application of the drug composition in preparing drugs for treating infection, especially moderate or severe infection.
Description
Technical field
The present invention relates to the application at preparation treatment urinary system infection, particularly moderate or severe urinary system infection medicine of a kind of composition product and said composition.
Background technology
Compound 1 (structure is such as formula shown in I) is a kind of second filial generation semisynthetic antibiotics, as a kind of broad-spectrum sterilization antibiotic usage.
Formula I
Compound 2 (structure is such as formula shown in II) is a kind of beta-lactamase inhibitor, and using with Antibiotic combination to increase antibiotic antibacterial activity.
Formula II
Along with compound 1 extensive use clinically, the original responsive bacterial strain of part creates drug resistance to compound 1, and its antibacterial effect is declined.The drug tolerance of strain in numerous area, the whole nation is researched and analysed result and is shown, has also occurred the phenomenon to compound 1 drug resistance in recent years to the sensitive organism such as escherichia coli, proteus mirabilis, hemophilus influenza of compound 1 sensitivity.
Such as: Dan Xiaomei etc. are to Tianjin institute 2001-2003 clinical separation pathogenic bacteria 772 strain drug resistance analysis, antibacterial is to the resistant rate of compound 1: S. aureus L-forms (MRSA) 100%, escherichia coli 51.06%, Klebsiella 18.07%, Pseudomonas aeruginosa 91.53%, Enterobacter 55.22%, acinetobacter 69.74%.
No.1 Hospital Affiliated to Zhongshan Univ. ten thousand builds new grade during year January in January, 2003 to 2004, from all kinds of specimen of this Out-patient Department and inpatient, culture of isolated goes out the strain of various common bacteria 1910, the display of drug resistance analysis result is carried out to it, produces beta-lactamase and the resistant rate of escherichia coli to compound 1 of not producing beta-lactamase is respectively 94%, 17%; Produce beta-lactamase and the resistant rate of Klebsiella Pneumoniae to compound 1 of not producing beta-lactamase is respectively 94%, 23%; The enterobacter cloacae not producing beta-lactamase is 76% to the resistant rate of compound 1.
Within 2003,11, Shanghai City hospital clinical Microbiological Lab collects 22158 strain antibacterials altogether, and wherein following antibacterial to the resistant rate of compound 1 is: escherichia coli (40.6%); Klebsiella Pneumoniae (49.2%); Enterobacter cloacae (58.2%); Citrobacter freundii (51.2%); Rub root fungus (72.1%); Proteus vulgaris (43.4%); Serratia marcesens (66.2%); Hemophilus influenza (adult: 22.3%; Child: 10.1%).It is worth noting, produce beta-lactamase and the resistant rate of escherichia coli to compound 1 of not producing beta-lactamase is respectively 94.9%, 12.4%, produce beta-lactamase and the resistant rate of Klebsiella Pneumoniae to compound 1 of not producing beta-lactamase is respectively 93.9%, 13.7%, identical with the trend that the beta-lactamase-producing strain more non-beta-lactamase-producing strain resistant rate that In Guangzhou Area is reported significantly raises.
Therefore, improve the drug resistance of patient to antibiotic medicine such as compound 1 grade, particularly providing producing the good novel drugs of beta-lactamase bacterial drug resistance is the technical barrier that this area needs to solve at present.
Clinical observation finds, often there is some difference on General Symptoms and local symptom for culture of patients with urinary system infection, and according to General Symptoms (as the mental status, shiver with cold, gastrointestinal reaction, heating, blood leukocytes raises or neutral classification raises) with coincident with severity degree of condition can be divided into slightly by local symptom (as frequent micturition, urgent micturition, dysurea, urine color, lumbago, percussion tenderness over kidney region, urine microscopy etc.), moderate and severe.
For patients with mild, cured by multi-medicament screening, but needed longer treatment time; And for moderate or severe patient, because of state of an illness possibility threat to life at any time, any later treatment must not be had, need to select eutherapeutic medicine be treated in time.At present, alignment degree or severe state of an illness patient safety, effectively medicine is clinically provided also to be the technical barriers that this area needs to solve at present.
Find in clinical practice, the state of an illness of patient shows as the patient of moderate or severe, part delays caused by the state of an illness, this some patients is due to the complexity of its mechanism of causing a disease and state of an illness situation, more difficultly to be cured by conventional medicine, therefore, provide good to bacterial drug resistance and to the effective medicine of the patient that is in a bad way, this area needs the technical barrier that solves at present most especially.
In view of above problems of the prior art, the research of related drugs is constantly being groped and is verifying, good, effective or drug resistance good and to the effective Clinical practice medicine of serious illness to serious illness to obtaining drug resistance.Relevant gropes research such as:
Chinese patent literature CN1513457A discloses a kind of free acid of compound 1 or the free acid of its salt and compound 2 or its salt pharmaceutical composition by weight 2: 1 to 8: 1 composition, it tentatively finds from antibacterial experiment in vitro, and this pharmaceutical composition has certain inhibit activities to being separated the bacterial strain such as the staphylococcus aureus of product beta-lactamase, staphylococcus epidermidis, streptococcus pneumoniae, colon bacillus, Klebsiella pneumonia, Pseudomonas aeruginosa, acinetobacter calcoaceticus, generation bacillus, shigella flexneri and enterobacter cloacae obtained.
China's antibiotic magazine, 2009,34 (10): 621-631, have studied the acute toxicity LD50>7.50g/g of compound formulation in Mice Body of injection compound 1 and compound 2 (2:1), the gavage fatal dose of Beagle dog is 3.0g/kg, its toxicity is similar to the toxicity of compound alone 1, and animal experiment shows that injection compound 1 is good with compound formulation toleration in experimental animals of compound 2.
Analytical chemistry research notes, 2010,38 (6): 864-868, have studied 24 health volunteer's single dose intravenous are instiled low (1.5g), in (2.25g), the compound 1 of high (4.5g) dosage or continuous 7 days of compound 2, the pharmacokinetics of (2:1) compound injection of doses of compound 1 and compound 2 in 3 intravenous drips every day, found that, compound 1 and compound 2 blood drug level increase with dosage and increase, single and continuous several times administration concentration without significant difference, peak shape and peak time basically identical.
China's antibiotic magazine, 2009,34 (11): 699-702, have studied the compositions to 66 routine health volunteers single quiet 0.75g, 1.5g, 3.0g, 4.5g, 6.0g, 7.5g, 9.0g or quiet 7.5g, 9.0g injection compound 1 and compound 2 continuously respectively, carry out clinical observation to experimenter after medication, lab testing and Electrocardioscopy, found that, the safety of the compositions of single and continuous application injection compound 1 and compound 2, toleration is good.
Though above-mentioned research confirms that compound 1 and the compositions of compound 2 have safety and toleration in external activity, animal and human's body body definitely.But these documents all do not report whether said composition is effective in vivo, and whether can be prepared into the disease at which kind of position of Drug therapy, treat the disease of which kind of degree, which kind of disease to have better therapeutic effect to, this has technical problem to be solved.
In fact, infer that in body, effectiveness is very insecure according to external activity.According to " drug registration management method " (version in 2007), new drug registration declares listing except needing the experimental studies such as study of pharmacy, external activity research, the anxious poison of animal, long malicious, carcinogenic, mutagenesis, also need to carry out clinical human's safety and efficiency evaluation test, observe human body for the tolerance degree of medicine, untoward reaction, pharmacokinetics, and medicine is on the impact of routine blood test, routine urinalysis, blood biochemistry etc., guaranteeing Clinical efficacy that is rear safely and drugs further.Wherein, clinical safety, particularly Clinical efficacy research are only the stage the most key in this complexity research.The compound that the research of many external activities, animal experiment result of study well enter clinical research fails to be developed to medicine because of factor safe, effective etc. in body, even if clinical research proves the compound of safety in body, also for want of effectively fail to be developed to medicine in body.Illustrate that in the external activity of compound or compositions, body, whether safety is effectively not directly related with in body, do not have predictability.
As pharmacy progress, 2004, report in 28 (4): 163-168: at present, new drug comes into the market not to be a highly effective process, and wherein more than 90% medicine having entered clinical research is finally fallen short of success for lack of final effort due to factors such as safety, pharmacokinetics, drug effects.
In the research history of antibiotic medicine, good and the clinical safety that the antibacterial Antibiotique composition presenting wide spectrum is for want of enough of multiple external activity and effectiveness and stop research: such as Chinese antibiotic magazine, 2010, report in 35 (12): 881-910, DQ-2556, CB-181963, FK-041, E1101, FR192752, S-3578 etc., wherein, CB-181963 is owing to only having very short post antibiotic effect (PAE), its administration frequency must higher than the administration frequency of remaining beta-lactam (lacking enough effectiveness), S-3578 stops clinical research because there is erythra side-effect problem (lacking enough safeties).
As can be seen here, carry out the research of sufficient activity in vivo confirm whether it still has or have what kind of pharmaceutically acceptable activity to embodying the medicine of antibacterial activity in vitro, remaining those skilled in the art needs to pay the work that creative work just can complete.
Complexity urinary tract infection belongs to one of common cause of intractable urinary tract infection, refer to companion's urogenital tract structure or dysfunction, or urinary tract infection when having kidney outer concomitant disease (as diabetes, sickle-cell disease etc.), often there is urinary tract infection recurrence or re-infection in complexity patients of urinary tract infection.The treatment of complexity urinary tract infection seems to be easier in the control in actute infection stage, and often ignores the inspection of the treatment course for the treatment of and complicated factor, and many patient Chang Yin exist complicated factor, cause urinary system infection recurrent exerbation, even finally cause impaired renal function.At present, for complexity urinary tract infection mainly with selecting antibiotic, improve the immunity of patient, and the mode being aided with tcm treatment according to syndrome differentiation is treated.But, for the urinary system infection showing as complexity urinary tract infection by bacterial antibiotic list medicine drug resistance, particularly cause because producing beta-lactamase, the state of an illness shows as the complexity urinary tract infection of moderate or severe, there are no the comparatively effective medicine of bibliographical information.
The applicant, from prior art Problems existing, has carried out a large amount of experimentatioies, and this completes the present invention.
Summary of the invention
When carrying out In vivo study to the described compositions of prior art, the present inventor finds, although embody more superior antibacterial activity in described compositions antibacterial experiment in vitro compared with compound alone 1, because external antibacterial experiment does not consider any organic factor, effect when infecting for interior therapeutic is unpredicted, and effect during moderate or severe infection especially to complexity is difficult to calculate especially.For the reason of result in unpredictable this body, may be because medicine must through complicated transhipment, metabolic process in human body, medicine can be made to differ etc. at the aggregation extent of human body different parts, but real concrete reason the present inventor also fail to understand completely.But, be not subject in the restriction of theory, pass through a large amount of antibacterial research of various antibacterial at infection site, the present inventor have been surprisingly found that, described compositions is for because producing beta-lactamase and/or causing compositions sensitive bacterial, and especially the urinary system infection of moderate or severe complexity urinary tract infection has very outstanding effect.This point clearly will show in test below.
The object of the present invention is to provide a kind of medicinal application in treatment be the urinary system infection of complexity urinary tract infection by the clinical manifestation of the single medicine drug resistance of bacterial compound 1.Particularly be applied to because producing beta-lactamase and/or cause compositions sensitive bacterial, especially moderate or severe urinary system infection.
In the present invention, the free acid structure of compound 1 is such as formula shown in IB, and the free acid structure of compound 2 is such as formula shown in IIB:
(formula IB) (formula IIB).
In order to solve the technical barrier that prior art exists, research worker of the present invention is to this has been a large amount of systematicness work:
1, Pharmacodynamics in vitro experiment
Plate doubling dilution is adopted to measure compositions In Vitro Bacteriostasis/antibacterial activity, experimental result shows: compound 1 is (with free acid, structure is such as formula IB) and compound 2 (with free acid, structure is such as formula IIB) weight ratio is that the compositions of 2:1 ~ 4:1 is to multiple beta-lactamase-producing strain, such as staphylococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, colon bacillus, Klebsiella pneumonia, Pseudomonas aeruginosa, acinetobacter calcoaceticus, aerobacteria, the In Vitro Bacteriostasis of shigella flexneri and enterobacter cloacae etc. is respond well, fungistatic effect is better than compound alone 1 or compound 2.
2, pharmacological toxicology research
General pharmacology result of the test shows: for the compound 1 of free acid and the compositions that is 2:1 with the weight ratio of the compound 2 of free acid, under the dosage of mouse mainline 240mg/kg, 480mg/g, 960mg/kg, compositions all had no significant effect mice autonomic movement, balance ability and the length of one's sleep to pentobarbital sodium induction; Under the dosage of anesthetized dog venoclysis 120mg/g, 240mg/kg, 480mg/kg, compositions is to amplitude of respiration, respiratory frequency, heart rate, mean arterial pressure are showed no obvious impact, to electrocardio S-T section, P ripple, QRS wave group, P-R interval, Q-T interval each administration group and matched group administration before and after be showed no obvious change.Can find out in animal experiment, injection compound 1 has no significant effect central nervous system, respiratory system, cardiovascular system with the compositions of compound 2.
Acute toxicity test adopts tail vein injection single-dose, and carrying out maximum dosage-feeding experiment: compound 1 reaches 5.00g/kg, is the maximum dosage under this medicine maximum dissolvable concentration 125.0mg/mL and maximum administration volume 40mL/kg; Compound 2 reaches 2.50g/kg, and compound 1 reaches 7.50g/kg with the compositions of compound 2 (2:1).Result of the test shows in animal acute toxicity test, and the compositions of compound 1 and compound 2 and single medicine, to no significant difference in the influence degree of animal, meet preliminary security requirement.
Long term toxicity test result shows: the compositions of compound 1 and compound 2 (2:1) and single medicine, to no significant difference in the influence degree of animal, meet preliminary security requirement.Compound 1 and the compositions 300mg/kg dosage of compound 2 (2:1) are the safety non-toxic dosage of this medicine, and this dosage is about 2.5 times that estimate people's maximal dose.
Experiment shows, has consistent pharmacological toxicology result with the compound 1 of free acid with the compositions being 3:1 or 4:1 with the weight ratio of the compound 2 of free acid with the compound 1 of free acid with the compositions that the weight ratio of the compound 2 of free acid is 2:1.
In above-mentioned experiment, compound 1 and the compositions of compound 2 (2:1) refer to the compound 1 of free acid and the compositions that is 2:1 with the weight ratio of the compound 2 of free acid.
3, biopharmaceutics research
Due to the toxicity of the compositions of acute toxicity, long term toxicity test result display compound 1 and compound 2 (2:1), with single dose than no significant difference, toxicity does not increase.According to the regulations of drug registration management, preclinical animal pharmacokinetic trial can be removed from.The intravenous injection peaking concentration-time, half-life etc. of the compositions of compound 1 and compound 2 (2:1) and compound 1, compound 2 single dose are close, and metabolic chart is similar, meets the condition making compound preparation.
In above-mentioned experiment, compound 1 and the compositions of compound 2 (2:1) refer to the compound 1 of free acid and the compositions that is 2:1 with the weight ratio of the compound 2 of free acid.
4, the compositions I phase clinical human tolerance test of compound 1 and compound 2
Tolerance test result shows, with the compound 1 of free acid and with the maximum tolerated dose of the weight ratio of the compound 2 of the free acid compositions single-dose that is 2:1 for 9.0g; Multiple dosing 2.25-3.0g, every 8 hours once, intravenous drip, and continuous 7 days also safer, better tolerance.
Same experiment shows, show as safety in human body equally with the compound 1 of free acid with the compositions that the weight ratio of the compound 2 of free acid is 3:1 and 4:1, toleration is good.
As can be seen from above-mentioned Pharmacodynamics in vitro experiment, pharmacological toxicology research, biopharmaceutics research, toleration, with the compound 1 of free acid with the compositions performance In Vitro Bacteriostatic that the weight ratio of the compound 2 of free acid is 2:1 ~ 4:1, show as good safety, toleration at animal and human's body.But because medicine must through complicated transhipment, metabolic process in human body, medicine can be made to differ at the aggregation extent of human body different parts, different therapeutic effect can be there is in corresponding medicine for different parts disease, with the compositions of compound 2, curative effect situation is infected to partes corporis humani position by further human trial research compound 1, find the indication with optimum therapeuticing effect.
Toleration is because being carry out in healthy population, comparatively simple and easy to the selection of tested crowd in experimentation, the Human Tolerance implementations of its paper examines, overall merit use the safety of drug dose in human body, but this experiment has which kind of purposes and effect situation without any enlightenment and help to medicine in human body.
5, human body pharmacodynamics clinical trial
In order to determine that medicine has which kind of purposes and effect situation in human body, need carry out loaded down with trivial details and the human body pharmacodynamics clinical trial of complexity finally could determine whether medicine has therapeutic effect to disease, this process of the test relates to the formulation of clinical trial protocol, the selection of indication, the selection of case, the formulation of dosage regimen, test grouping and method, test rating, therapeutic evaluation, the concrete enforcement of clinical trial protocol, statistical evaluation, the problems such as adverse reaction monitoring and strick precaution, the defect of arbitrary link will cause the inefficacy of evaluating drug effect, therefore, human body effect experiment is the most key link determining drug effectiveness.
Research staff of the present invention, by a large amount of early-stage preparations and Preliminary experiment results analysis and summary, final formulation science, reasonable, effective clinical trial protocol, finally found by the complex clinical trial of several years: compound 1 and the compositions of compound 2 being used for further is the culture of patients with urinary system infection of complexity urinary tract infection by the clinical manifestation of the single medicine drug resistance of bacterial compound 1, particularly because producing beta-lactamase and/or causing compositions sensitive bacterial, especially the patient of moderate or severe urinary system infection, tool has an unexpected effect.
Wherein, the order of severity of the state of an illness, can according to the General Symptoms of patient (as the mental status, shiver with cold, gastrointestinal reaction, heating, blood leukocytes raises or neutral classification raises) and local symptom (as frequent micturition, urgent micturition, dysurea, urine color, lumbago, percussion tenderness over kidney region, urine microscopy etc.) etc., give a mark by the order of severity and/or with or without corresponding performance, moderate or severe is judged to be so that comprehensive scores is higher, this standard comparatively science, both can be used for just checking the patient not carrying out treating, also may be used for the patient through Drug therapy.In clinical practice, when as long as doctor finds the above-mentioned General Symptoms of patient and/or local symptom wherein have one, to show comparatively ordinary circumstance serious or outstandingly namely judge that the state of an illness is as moderate or severe, moderate of the present invention or severe had both comprised this type of patient, also the patient judged by above-mentioned scoring criterion is comprised, also comprise patient after receiving antibiotic or the treatment of other antimicrobials, the situation that the state of an illness does not take a favorable turn or increases the weight of further.
Technical scheme of the present invention screens patient's compositions in the following manner, to study compositions of the present invention in its whether body effectively:
(1), inclusion criteria: 1. agree to participate in this clinical trial and the patient signing Informed Consent Form; 2. one full year of life one full year of life to 70 age 18, being in hospital or out-patient of male or female; 3. be the patient of complexity urinary tract infection to clinical manifestation, the General Symptoms showed by it and local symptom carry out adding up and giving a mark, and screening coincident with severity degree of condition is the patient of moderate or severe, and concrete evaluation criteria is as following table:
If patient exists one of following situation, will be excluded, and not enter group and test:
1, allergies and allergic constitution person is had to cephalo-type and beta-lactam antibacterials.
2, severe infections etc. need antibacterials use in conjunction person.
3, severe cardiac, liver, kidney diaseases, or ALT, AST, BUN exceed Upper Limit of Normal Value 1.5 times, Cr exceedes Upper Limit of Normal Value person.
4, the serious or PD person of hematopathy, late tumor and central nervous system disease (as epilepsy) or other system.
5, spiritedness illness can not partner.
6, the women of gestation or preparation gestation, women breast-feeding their children.
7, the patient of any other trial drug has been accepted in selected first 3 months.
(2), select (1) middle cumulative score result to be that moderate or the unification of severe culture of patients with urinary system infection accept injection compound 1 single therapy 72 hours, usage and dosage is specific as follows:
Grade and moderate infection--injection compound 1 (1.0g), after dissolving, adds normal saline 100ml angular vein and instils, 30 minutes time, every 8 hours 1 time with normal saline 10mL.
Severe infection--injection compound 1 (1.5g), after dissolving, adds normal saline 100ml angular vein and instils, 30 minutes time, every 8 hours 1 time with normal saline 10mL.
Whether effectively to patient judge by injection compound 1 single therapy 72 hours, to judging that invalid patient gives the compositions of compound 1 of the present invention and compound 2 further.
(3) cumulative score result in (1), is selected to be moderate or severe culture of patients with urinary system infection, within 0 ~ 1 day before compound 1 single therapy, gather mud-stream urine specimen and carry out antibacterial culturing, beta-lactamase detection and drug sensitive test, screening antibacterial culturing be the patient of " positive and to the single medicine drug resistance of compound 1, the antibacterial to the product beta-lactamase of the compositions sensitivity of compound 1 and compound 2 ".
Compound 1 and the compositions of compound 2 are applied to the patient of the urinary system infection screened by the way, being surprised to find said composition has extraordinary effect for the culture of patients with urinary system infection that the clinical manifestation of the compound 1 single medicine drug resistance being caused (antibacterial culturing becomes positive) by antibacterial is complexity urinary tract infection.
Find antibacterial further investigation, compositions of the present invention particularly has extraordinary effect to the urinary system infection because producing the complexity urinary tract infection that beta-lactamase causes.Antibacterial Species estimation: described antibacterial includes but not limited to Acinetobacter bauamnnii, staphylococcus epidermidis, escherichia coli, klebsiella pneumoniae, enterobacter cloacae.
In experimentation of the present invention, follow-up investigation is carried out to culture of patients with urinary system infection, and the record of General Symptoms and local symptom and statistics, compositions of the present invention is effective to the patient of various coincident with severity degree of condition, and particularly the patient of moderate or severe is still effective.
Find antibacterial further investigation further, particularly the urinary system infection that causes compositions sensitive bacterial of drug sensitive test is more effective for the compositions of compound 1 and compound 2.
Wherein, be moderate or the severe patient of complexity urinary tract infection to the clinical manifestation by the single medicine drug resistance of bacterial compound 1, described Production by Bacteria beta-lactamase and responsive to compositions, give the compositions of compound of the present invention 1 with compound 2 (with the compound 1 of free acid and with the weight ratio of the compound 2 of free acid for 2:1) after, antibacterial and whole body sign and local sign etc. are observed, study and are added up, unexpected and surprised discovery:
Compound 1 is 83.3% with the bacteria clearance of compositions to the patient of described complexity urinary tract infection of compound 2, clinical effective rate is 66.7%, comprehensive therapeutic effect cure rate is 66.7%, in bacteriological identification-clearance rate, clinical efficacy-effective percentage, comprehensive therapeutic effect-cure rate aspect all has better effect.
Described " removing ", for after treatment, the specimen of former infection site does not turn out the pathogen of original sense dye again.
Described " effectively " is at least showing one of clinical cure or antibacterial removing after treatment.
Described " recovery from illness " is clinical cure when patient follows up a case by regular visits to after treatment is finished, and antibacterial is removed.
So-called clinical cure: when patient follows up a case by regular visits to after treatment is finished all selected time symptom, sign all disappeared or recovered normal completely, the non-microorganism indexs such as lab testing have recovered normal all, and imaging examination result has been recovered normal or reached the degree that can judge to cure; In some indication, still may can observe some clinical symptoms or sign when following up a case by regular visits to after treatment terminates, or still there is the exception of some non-microorganism indexs.If above-mentioned situation only points out postinfectious state or underlying diseases, and inactive infection, then also can think clinical cure.
Same experiment shows, uses with the compound 1 of free acid and the compositions that is 3:1 or 4:1 with the weight ratio of the compound 2 of free acid, has consistent experimental result.
According to above-mentioned a large amount of systematic experimental studies results, propose following technical scheme and realize the object of the invention: a kind of compound 1 is preparing the application for the treatment of by the urinary system infection medicine of the single medicine drug resistance of bacterial compound 1 with the compositions of compound 2, and described urinary system infection clinical manifestation is complexity urinary tract infection.
Described Production by Bacteria beta-lactamase, includes but not limited to Acinetobacter bauamnnii, staphylococcus epidermidis, escherichia coli, klebsiella pneumoniae, enterobacter cloacae.The compositions of described antibacterial drug sensitivity testing in vitro to compound 1 and compound 2 is responsive.
Described urinary system infection coincident with severity degree of condition is moderate or severe.
Find in a large amount of experimentatioies, compositions of the present invention is given for above-mentioned patient, drug dose and corresponding form of medication can be selected according to injection routine dose and administering mode according to practical situation, wherein, in compositions with the compound 1 of free acid and with the weight ratio of the compound 2 of free acid for 2:1 ~ 4:1, preferred weight ratio 2:1 or 3:1 or 4:1.
Compound of the present invention 1 and the compositions of compound 2, record its ratio if clear, all refers to that preferred weight ratio is 2:1,3:1 or 4:1 with the compound 1 of free acid and the compositions that is 2:1 ~ 4:1 with the weight ratio of the compound 2 of free acid.
In a preferred version of the present invention, have with the compound 1 of free acid with the dosage form that the compositions that the weight ratio of the compound 2 of free acid is 2:1 includes but not limited to: 0.75g, 1.5g, 2.25g, 3.0g or 4.5g etc., wherein, 1.5g refers to that compositions is by taking free acid as the compound 1 of 1.0g and taking free acid as the forming of compound 2 of 0.5g, and the composition of other dosage forms can carry out corresponding calculating in this way.In addition, other compositionss if weight ratio is 3:1 or 4:1 contain identical or close dosage form.
Medicine of the present invention can by including but not limited to intravenous, subcutaneous, muscle, lumbar injection, or the mode of intravenous drip gives patient, water for injection or injection normal saline etc. can be selected before injection by composition dissolves and be adjusted to patient's acceptable drug level.
The present invention comprises the product form of said composition further, product is the solidapowder form such as powder pin or lyophilizing, in the ampuliform being stored in sealing or bag-like container, such as cillin bottle, ampoule bottle, transfusion bag etc., product records the carrier of said composition composition and uses thereof with one in addition, such as, the label carrier such as pharmaceutical packing box and/or paper description.
Preferably but be not limited to following drug products form:
A kind of composition product, it comprises:
(a), with the compound 1 of free acid and the compositions that is 2:1 ~ 4:1 with the weight ratio of the compound 2 of free acid, preferred weight ratio is 2:1,3:1 or 4:1;
The container of (b), dress compositions;
C (), label, label character is recorded or is illustrated that described compositions is suffered from by the application of bacterial compound 1 single medicine drug resistance urinary system infection medicine in preparation treatment.
The present invention relates to a kind of novelty teabag of compositions and the product containing this novelty teabag; as long as any mode describes and/or employs this purposes and has the product of this purposes; all should be understood to identical with spirit of the present invention, all belong within protection scope of the present invention.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but working of an invention mode is not limited thereto.
Embodiment 1
Screen patient in such a way:
(1), inclusion criteria: 1. agree to participate in this clinical trial and the patient signing Informed Consent Form; 2. one full year of life one full year of life to 70 age 18, being in hospital or out-patient of male or female; 3. be the patient of complexity urinary tract infection to clinical manifestation, the General Symptoms showed by it and local symptom carry out adding up and giving a mark, and screening coincident with severity degree of condition is the patient of moderate or severe, and concrete evaluation criteria is as following table:
If patient exists one of following situation, will be excluded, and not enter group and test:
1, allergies and allergic constitution person is had to cephalo-type and beta-lactam antibacterials.
2, severe infections etc. need antibacterials use in conjunction person.
3, severe cardiac, liver, kidney diaseases, or ALT, AST, BUN exceed Upper Limit of Normal Value 1.5 times, Cr exceedes Upper Limit of Normal Value person.
4, the serious or PD person of hematopathy, late tumor and central nervous system disease (as epilepsy) or other system.
5, spiritedness illness can not partner.
6, the women of gestation or preparation gestation, women breast-feeding their children.
7, the patient of any other trial drug has been accepted in selected first 3 months.
(2), select (1) middle cumulative score result to be that moderate or the unification of severe culture of patients with urinary system infection accept injection compound 1 single therapy 72 hours, usage and dosage is specific as follows:
Grade and moderate infection--injection compound 1 (1.0g), after dissolving, adds normal saline 100ml angular vein and instils, 30 minutes time, every 8 hours 1 time with normal saline 10ml.
Severe infection--injection compound 1 (1.5g), after dissolving, adds normal saline 100ml angular vein and instils, 30 minutes time, every 8 hours 1 time with normal saline 10ml.
(3) cumulative score result in (1), is selected to be moderate or severe culture of patients with urinary system infection, within 0 ~ 1 day before compound 1 single therapy, gather mud-stream urine specimen and carry out antibacterial culturing, beta-lactamase detection and drug sensitive test, screening antibacterial culturing be the patient of " positive and to the single medicine drug resistance of compound 1, the antibacterial to the product beta-lactamase of the compositions sensitivity of compound 1 and compound 2 ".
To select in (2) compound 1 single therapy 72 hours invalid, antibacterial culturing be " positive to free acid list medicine drug resistance; the antibacterial to the product beta-lactamase of the compositions sensitivity of compound 1 and compound 2 " patient in (3) simultaneously, screens 6 examples altogether and meets patient.
Embodiment 2
By with the compound 1 of free acid and the compositions that is 2:1 with the weight ratio of the compound 2 of free acid, give 6 routine patients of screening in above-described embodiment 1, carry out the treatment of 14 days by a definite date, wherein, the dosage of medicine and to give mode as follows:
Grade and moderate infection---injection compound 1 and the compositions (1.5g) of compound 2, after dissolving, add normal saline 100mL angular vein and instil, 30 minutes time, every 8 hours 1 time with normal saline 10mL.
Severe infection---injection compound 1 and the compositions (2.25g) of compound 2, after dissolving, add normal saline 100mL angular vein and instil, 30 minutes time, every 8 hours 1 time with normal saline 10mL.
After treatment terminates, to above-mentioned patient census's therapeutic effect: bacteriological identification-clearance rate, clinical efficacy-effective percentage, and comprehensive therapeutic effect-cure rate.Concrete outcome is as follows:
From upper table, described compound 1 is that the patient of complexity urinary tract infection is in bacteriological identification-clearance rate to clinical manifestation with the compositions of compound 2, clinical efficacy-effective percentage, and comprehensive therapeutic effect-cure rate aspect all improves significantly, show extraordinary Endophytic bacteria clearance rate, effectively clinical and effect of comprehensively fully recovering, can preferably for clinical practice.
Wherein, injection compound 1 and the compositions (1.5g) of compound 2 refer to containing taking free acid as the compound 1 of 1.0g and taking free acid as the compound 2 of 0.5g; Injection compound 1 and the compositions (2.25g) of compound 2 refer to containing taking free acid as the compound 1 of 1.5g and taking free acid as the compound 2 of 0.75g.
Same experiment shows, uses with the compound 1 of free acid and the compositions that is 3:1 or 4:1 with the weight ratio of the compound 2 of free acid, has consistent experimental result.
Weight ratio of the present invention is that the compound 1 of 2:1 ~ 4:1 is treating the culture of patients with urinary system infection by the complexity urinary tract infection of the single medicine drug resistance of bacterial compound 1 with the compositions of compound 2, particularly because producing beta-lactamase and/or causing compositions sensitive bacterial, especially the patient of moderate or severe urinary system infection, has good effect.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (3)
1. compound 1 is preparing the application for the treatment of by the urinary system infection medicine of the single medicine drug resistance of bacterial compound 1 with the compositions of compound 2, described antibacterial is for producing beta-lactamase antibacterial, described urinary system infection clinical manifestation is complexity urinary tract infection, described urinary system infection is moderate or severe urinary system infection, in compositions with the compound 1 of free acid and with the weight ratio of the compound 2 of free acid for 2:1 ~ 4:1, wherein, compound 1 and compound 2 are respectively such as formula shown in (I) and formula (II):
2. apply as claimed in claim 1, it is characterized in that: described antibacterial is responsive to described compositions.
3. the application as described in claim as arbitrary in claim 1 to 2, is characterized in that: in compositions with the compound 1 of free acid and with the weight ratio of the compound 2 of free acid for 2:1,3:1 or 4:1.
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| CN1543958A (en) * | 2003-11-25 | 2004-11-10 | 郭东宇 | Antibiotic action enhancing medicinal composition |
| CN1729987A (en) * | 2005-08-19 | 2006-02-08 | 夏中宁 | Cefuroxime sodium and sulbactam sodium composition for injection |
| CN1850047A (en) * | 2006-06-01 | 2006-10-25 | 济南帅华医药科技有限公司 | Slow-release preparation containing beta-lactamase inhibitor and cephalosporin and its use |
| CN101648016A (en) * | 2008-08-11 | 2010-02-17 | 广州威尔曼新药开发中心有限公司 | Medicinal composition with high stability |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543958A (en) * | 2003-11-25 | 2004-11-10 | 郭东宇 | Antibiotic action enhancing medicinal composition |
| CN1729987A (en) * | 2005-08-19 | 2006-02-08 | 夏中宁 | Cefuroxime sodium and sulbactam sodium composition for injection |
| CN1850047A (en) * | 2006-06-01 | 2006-10-25 | 济南帅华医药科技有限公司 | Slow-release preparation containing beta-lactamase inhibitor and cephalosporin and its use |
| CN101648016A (en) * | 2008-08-11 | 2010-02-17 | 广州威尔曼新药开发中心有限公司 | Medicinal composition with high stability |
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