CN103006676B - Novel piperacillin-tazobactam composition - Google Patents
Novel piperacillin-tazobactam composition Download PDFInfo
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- CN103006676B CN103006676B CN201210579845.1A CN201210579845A CN103006676B CN 103006676 B CN103006676 B CN 103006676B CN 201210579845 A CN201210579845 A CN 201210579845A CN 103006676 B CN103006676 B CN 103006676B
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Abstract
The invention discloses a novel piperacillin-tazobactam composition. Pegylation is performed on the piperacillin, so that the good stability is ensured simultaneously when the water-solubility of the drug is improved; the tazobactam is modified to be tazobactam glucuronate, therefore, the characteristic of high hygroscopicity is modified, problems of poor liquidity caused by easy absorption of moisture, non-uniform mixing with piperacillin, easiness in color change and metamorphic degradation and the like can be avoided, while the pototype drug is released after the drug enters human bodies, the antidote, i.e. glucuronic acid, is also released and can be used for treating drug cumulative poisoning and residue caused by large use amount of antibiotic in a long period; after being respectively subjected to molecular modification, the two active ingredients are modified in physicochemical property, greatly improved in stability, ensured in effective content after the drug enters the human bodies; and therefore, the problem of quality stability of the novel composition in production, storage, preparation and infusion processes is basically solved, and the dosage of tazobactam is greatly reduced.
Description
Technical field
The present invention relates to a kind of antibiotic medicine, particularly relate to a kind of novel piperacillin Tazobactam Sodium compositions.
Background technology
Piperacillin sodium and tazobactam sodium for injection is succeeded in developing by Wyeth of the U.S., and listing dosage form is injectable powder, and avocin and sodium-tazobactam proportioning are 8:1 and 4:1.Piperacillin is a kind of beta-lactam antibiotic of wide spectrum, the amino of ampicillin introduces the amide groups of heterocyclic substituted, due to can the cell membrane of the multiple gram positive bacteria of quick penetration, effect by force and rapidly, bacillus pyocyaneus being had to the effect of enhancing, is the penicillin derivative that antimicrobial spectrum is wider, but its have draw moist, very unstable in solution at room temperature, will cause forming particulate matter.Piperacillin is easily destroyed by beta-lactamase, and Tazobactam Sodium is a kind of irreversible competitive beta-lactamase inhibitor, and its inhibit activities is considerably beyond clavulanic acid and sulbactam.Tazobactam Sodium and piperacillin conbined usage can the beta-lactamases of deactivation lastingly, reduce beta-lactamase to the destruction of piperacillin, thus make piperacillin play antibacterial action to zymogenic bacteria.Piperacillin sodium and tazobactam sodium compound preparation quantity is large, determined curative effect, and market prospect is good, but the defect of formulation products existence and stability aspect.
Adopt process prepared by freeze-drying, avocin and sodium-tazobactam are in solution state in dosing and dry run thereof, degraded easily occur rotten, cause product quality defective; And the poor stability of the ordinary preparation that goes on the market, can not satisfy the prescriptive period interior prescription; Medicinal liquid is at room temperature unstable, easy formation granule, especially after the piperacillin sodium and tazobactam sodium solution of stored frozen melts again or when the product being prepared into freeze-dried powder is again mixed with solution, standing time more long grain generate more, granule in parenteral solutions is very large to patient's harm, and intravenous injection may be caused scorching.
Chinese patent CN1802179A discloses Wyeth of the U.S. by adding ion chelating agent disodium edta (EDTA) and buffer agent sodium citrate in avocin and sodium-tazobactam, and the ratio controlled between medicine and adjuvant, solve the problem forming microgranule in prior art when reconstructing and thawing in Pharmaceutical composition, parenteral can be used safely in, weak point is that the use of ion chelating agent particularly ethylenediaminetetraacetic acid (EDTA) easily makes the sodium in bone, potassium, calcium ion run off, and produces osteoporosis equivalent risk.
Chinese patent CN101890016A and CN101890015A individually discloses a kind of micro-balloon injection and lipidosome injection of pharmaceutical composition comprising piperacillin sodium and tazobactam sodium, the problem of the normal injection agent poor stability that can take on a new look to a certain extent.These novel ejection preparations (lipidosome injection, micro-balloon injection), have certain superiority compared with traditional drug administration by injection, but also also exist that low, the easy adhesion of envelop rate is assembled, easily broken, burst effect, may cause the problems such as immunoreation.In addition, the Maturity that these novel forms amplify production is at home still inadequate, and require very harsh to preparation process condition, production difficulty is large, and technique poor reproducibility, production cost is high, and this increases the financial burden of patient virtually, is not thus also optimal selection.
Polyethylene Glycol (PEG), with the advantage that its other macromolecules such as good water solublity, nontoxic, good biocompatibility are incomparable, become a kind of important bio-modification material, the only a few ratified by U.S. FDA can as one of synthetic polymer of injection drug in body.In the curative effect strengthening various medicine (protein, antineoplastic agent and antibiotic etc.) and expansion clinical application range, there is very tempting development prospect.
Glucuronic acid is the intermediate of sugared biological metabolism, is human body bulk mass, and nonhazardous, can not have side effects.Hepatocyte is external through renal excretion after being combined with the bilirubin of glucuronic acid in liver, metabolic waste, medicine, toxin, thus has the liver protecting and Detoxication.
Summary of the invention
For solving the deficiencies in the prior art, the invention provides a kind of novel piperacillin Tazobactam Sodium compositions, raising medicine is water miscible while, ensure that medicine has good stability and enters the effective content after in body, not only increase drug effect, also reduce the consumption of Tazobactam Sodium, save cost.
For achieving the above object, novel piperacillin Tazobactam Sodium compositions provided by the present invention, it comprises piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate, and described piperacillin-mono methoxy polyethylene glycol and the molecular structural formula of Tazobactam Sodium-glucuronate are respectively:
The present invention carries out Pegylation to the carboxyl of piperacillin, improve medicine water miscible while, ensure that it has good stability, trim enters after in body, and decomposable asymmetric choice net discharges original shape medicine, plays drug effect.After listing product are made into medicinal liquid on request, start to occur the phenomenons such as variable color, precipitation and content overproof after at room temperature placing 24h, be only 46% to the content of piperacillin during 60h; And after the sample prepared in the present invention is made into medicinal liquid, under similarity condition, places 60h still stablize, do not occur variable color and precipitation, content is on 95%.After being mixed with injection after listing product are placed 3 years, piperacillin can degrade more than 50%; Product of the present invention only degrades about 6% after same situation is configured to injection.As can be seen here, the present invention substantially increases stability and the utilization rate of piperacillin, reduces its consumption.
In addition, antibiotic feature is that drug effect and dosage relation are little, as long as drug level just has drug effect on Mlc, but due to the antibiotic half-life shorter, therefore need multiple dosing, its blood drug level can be maintained.And in product of the present invention, because Polyethylene Glycol has slow release effect, piperacillin is released slowly, make it maintain for a long time on Mlc, thus administration number of times is reduced to 1-2 times/day by 3-4 times/day of common listing product.
The present invention is by carrying out structural modification to Tazobactam Sodium, improve its stability, it is made to obtain larger utilization rate, significantly reduce its dosage, by common listing product daily 1.0g-1.5g be down to 0.1g every day, decrease the untoward reaction caused because dosage is excessive, and reduce production and treatment cost to a great extent.Trim provided by the present invention plays its drug effect after entering and decompositing original shape medicine after in body; In addition, product provided by the present invention, while discharging original shape medicine, also discharges antidote glucuronic acid, can be used for because long-term a large amount of drug accumulation using antibiotic to cause is poisoning and residual.And after piperacillin and Tazobactam Sodium two kinds of active component are carried out molecular modification respectively, two kinds of active component are made to reach good releasing effect in vivo: medicine enters after in body, first Tazobactam Sodium is discharged, and make enzyme deactivation in vivo with after enzyme strong bonded, and play enzyme inhibition, release piperacillin again, thus ensure that it exempts from the destruction of enzyme, play antibacterial action to greatest extent.
As the restriction to foregoing invention, by the weight fraction of active component piperacillin and Tazobactam Sodium, the proportioning of described piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate is 4 ~ 32:1.Obtained injection is compared with listing product thus, and more stable, bacteriostasis significantly strengthens.
As the further restriction to foregoing invention, by the weight fraction of active component piperacillin and Tazobactam Sodium, the proportioning of described piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium is 20:1.Preferred proportion 20:1, best dosage regimen is specification is 1.050g(piperacillin 1.0g and Tazobactam Sodium 0.050g) invention product, daily twice, each 1.Scheme is treated thus, and the antibacterial effect of acquisition is best, and dosage is minimum, and administration number of times is few, and side reaction is few, and treatment cost is low.
As the restriction to foregoing invention, described novel piperacillin Tazobactam Sodium compositions is common flour injection or lyophilized injectable powder.
As the restriction to foregoing invention, described novel piperacillin Tazobactam Sodium compositions is lyophilized injectable powder, wherein with the addition of caffolding agent-mannitol.
As the restriction to foregoing invention, the ratio of the total amount of described mannitol and piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate is 0.088 ~ 0.178:1.
Concretely, through the lyophilized injectable powder of the novel piperacillin Tazobactam Sodium compositions of modification, its composition comprises: proportioning is the piperacillin-mono methoxy polyethylene glycol (mPEG) of 4:1-32:1 and Tazobactam Sodium-glucuronate and mannitol, before lyophilization, calculate with quality percent by volume (g/ml) in every 30000ml medicinal liquid, the content of each component is respectively: mannitol is 1.5%-2.5%, and piperacillin-mono methoxy polyethylene glycol (mPEG) and Tazobactam Sodium-glucuronate are 14%-17%.More specifically, above-mentioned lyophilized injectable powder, before lyophilization, containing mannitol 602g, piperacillin-mono methoxy polyethylene glycol (mPEG) 4440g and Tazobactam Sodium-glucuronate 79g in every 30000ml medicinal liquid.
Above-mentioned lyophilized injectable powder, if do not add caffolding agent, directly piperacillin-the mono methoxy polyethylene glycol (mPEG) of proportioning 4:1-32:1 and the aqueous solution of Tazobactam Sodium-glucuronate are carried out lyophilization, obtained freeze-drying finished product easily forms cavity and atrophy, medicated powder is sticky wall easily, has a strong impact on product quality.So must add caffolding agent, attempt multiple caffolding agent: glucose, lactose, dextran etc., the appearance character of gained preparation and water solublity fail to reach requirement, only have and select mannitol as caffolding agent, obtained finished product good moldability, good water solubility, concrete outcome is as shown in the table:
Lyophilizing caffolding agent kind is screened
| Caffolding agent kind | Mouldability | Water solublity |
| Mannitol | Loose powdery | Good |
| Glucose | Non-molding | Good |
| Lactose | Non-molding | Generally |
| Dextran | Block | Generally |
| Mannitol+dextran | Non-molding | Good |
In above-mentioned lyophilized injectable powder, the consumption of mannitol is most important, need strict control, elect as and calculate with quality percent by volume (g/mL) in every 30000mL medicinal liquid before lyophilization, mannitol is 1.5%-2.5%, if lower than lower limit, mannitol concentration is inadequate, can product appearance be affected, occur atrophy phenomenon; If higher than the upper limit, surprisingly found by great many of experiments, bad stability, analysis may be due in dry run, mannitol concentration is too high, and system eutectic point can be made to raise, and causes the destroyed decomposition of piperacillin-mono methoxy polyethylene glycol (mPEG) molecule.
Novel piperacillin Tazobactam Sodium compositions is prepared into lyophilized injectable powder, and its preparation method comprises the following steps:
Step one: the mannitol of the described amount weighed up is joined in sterile water for injection to dissolving completely, then limit adds piperacillin-mono methoxy polyethylene glycol (mPEG) and the Tazobactam Sodium-glucuronate of described amount, while add sterile water for injection to be stirred to dissolving, solution is settled to 30000mL, add active carbon, after fine straining, obtain filtrate;
Step 2: be filled in cillin bottle by filtrate the dividing of step one gained, partly jump a queue, puts into freeze dryer and carries out lyophilization, obtained novel piperacillin Tazobactam Sodium freeze-dried powder;
In above-mentioned steps two, lyophilization is divided into pre-freeze, once distillation and secondary distillation three phases, and wherein the pre-freeze stage will repeat to complete for twice: quick freezing, to temperature-50 DEG C, is warming up to-40 DEG C, maintains 2.5h, so repeats twice; Evacuation 2Pa, is slowly warming up to sublimation temperature-12 DEG C with 16h by pre-freezing temperature-40 DEG C, continues dry 2h; Maintain vacuum 2Pa, slowly rise to secondary sublimation temperature 25 DEG C, drying time 6-8h.
The pre-freeze stage will repeat to complete for twice, is in order to medicinal liquid is fully frozen reality, is conducive to carrying out forming open structure in dry run.
The time that in once distillation, temperature raises is extended in preparation process, it is made fully to remove solid ice, otherwise, after heating up, steam is assembled under duricrust, the result of partial vacuum is exactly that bubbling and profile are not full, so imposing a condition of once distilling is evacuation 2Pa, is slowly warming up to sublimation temperature-12 DEG C with 16h by pre-freezing temperature-40 DEG C, continue dry 2h, effect is fine.
In sum, the therapeutic effect of product of the present invention in infection is remarkable, the glucuronic acid simultaneously discharged in vivo has detoxicating functions, in a word, the present invention not only ensure that product quality and stability thereof, improves antibacterial efficacy, also reduces the toxic and side effects of medicine, decrease frequency and the dosage of administration, have clinical value.Therefore, comprehensively, improve physicochemical property, substantially increase stability, ensure that and enter the effective content after in body, solve the ordinary preparation product that the gone on the market problems such as content declines to a great extent, relevant thing obviously increases after being configured to infuse, fundamentally solve this compound preparation producing, store, steady quality sex chromosome mosaicism in preparation and infusion process, also greatly reduce the consumption of Tazobactam Sodium; Tazobactam Sodium, by modifying with glucuronic acid, improves bibulous characteristic, avoids the poor fluidity caused due to easy moisture absorption, mixes uneven with piperacillin, the problems such as easy to change and rotten degraded.
Detailed description of the invention
Embodiment 1 piperacillin-mono methoxy polyethylene glycol Tazobactam Sodium compositions
One, the preparation of piperacillin-mono methoxy polyethylene glycol
The reaction scheme of piperacillin-mono methoxy polyethylene glycol:
(1) amination mono methoxy polyethylene glycol (mPEG-NH is prepared
2)
The dichloromethane solution of 3 times of mole hydrazoic acid is joined in the tetrahydrofuran solution of 1 times of mole mono methoxy polyethylene glycol (mPEG), then the tetrahydrofuran solution of 3 times of mole diisopropyl azodiformates (DIAD) is added, add the tetrahydrofuran solution of 6 times of mole triphenylphosphines in gained mixture again, carry out stirring reaction.
In reactant liquor, add 1M hydrochloric acid 1L, heat 2 hours again, be cooled to room temperature at 65 DEG C, filter, vacuum drying, obtains amination mono methoxy polyethylene glycol (mPEG-NH
2).
When small-molecule drug carries out PEG modification, there is the problem that drug loading is too little, need as far as possible with the PEG that molecular weight is little, the PEG of molecular weight more than 1000 is usually nontoxic.Therefore mono methoxy polyethylene glycol (mPEG) molecular weight selected in reaction is 1500-2000.
In the step of more than reacting, the stirring reaction condition after triphenylphosphine that adds is very important, is specially and first at room temperature stirs 30 minutes, then at 65 DEG C, heat reaction in 2 hours.This main because this step reaction be in order to by the conversion of hydroxyl of mono methoxy polyethylene glycol for amino, only have and just can reach high amino conversion ratio in such a situa-tion, the stirred at ambient temperature started is to allow the abundant mix homogeneously of all substances, and then at high temperature can accelerated reaction carry out, Reaction time shorten, but temperature is moderate, and the too high reaction of temperature is too violent, reaction can be insufficient, also affects conversion ratio.So this reaction condition is the key point concerning product yield, hydroxyl nearly 100% can be made to convert amido to.Amino amount is determined by trinitrophenol titration.
(2) piperacillin-mono methoxy polyethylene glycol is prepared
The piperacillin of 2 times of moles is dissolved in dimethyl formamide (DMF) solution of 3 times of mole diisopropyl ethyl amines (DIEA), under stirring, adds 1 times of mole mPEG-NH
2dMF solution, reaction at room temperature carry out 3.5h.
Add 1M HCl in reactant liquor, to there being solid to separate out, leave standstill, filter, solid water dissolution, then uses petroleum ether precipitation, obtains white solid piperacillin-mono methoxy polyethylene glycol, and productive rate is 60%, and purity is 94% ~ 98%, and fusing point is 165 ~ 168 DEG C.
More than react in the step of two, in order to allow mPEG-NH
2react completely, add excessive piperacillin, be conducive to end product like this and be separated.Because piperacillin dissolubility in water is low, and the dissolubility of end-product piperacillin-mono methoxy polyethylene glycol is high, so select water to be extracted by end-product in the step of reaction two, and then precipitate further with petroleum ether, separation method is simple, and purity is high.
The preparation of two, piperacillin-mono methoxy polyethylene glycol Tazobactam Sodium common flour injection
In the preparation process of this injectable powder, Tazobactam Sodium adopts sodium-tazobactam, and namely finally make piperacillin-mono methoxy polyethylene glycol sodium-tazobactam common flour injection, its preparation method is as follows:
Piperacillin-mono methoxy polyethylene glycol (mPEG) and the sodium-tazobactam of recipe quantity is taken respectively by described proportioning, mix homogeneously, by the powder that mixes aseptically quantitative separating in sterile glass vials, with aseptic plug and the sealing of button plug, then carrying out with aseptic aluminium lid rolling lid sealing, labeling, mounted box.
Embodiment 1-1 ~ 1-8 lists respectively in preparation process, the Different Weight ratio of piperacillin-mono methoxy polyethylene glycol (mPEG) and sodium-tazobactam, as shown in the table:
Embodiment 2 piperacillin sodium and tazobactams-glucuronic acid ester composition
The compositions related in the present embodiment is that wherein, the piperacillin as active component adopts avocin by not forming through the piperacillin of modification and the Tazobactam Sodium through modifying.
Because Tazobactam Sodium is by the impact of the factors such as pH, temperature, oxidation, the easy open loop of its beta-lactam structure, causes whole molecule to be destroyed, thus also there is instable problem.We are by carrying out structural modification to it, and by Tazobactam Sodium and glucuronic acid bonding, the compound obtained has special spatial configuration, can significantly improve its stability, and good water solubility, enter after in body and can decompose rapidly, discharge original shape medicine Tazobactam Sodium, and play drug effect.
Select to modify the carboxyl of Tazobactam Sodium, make the hydroxyl in itself and glucuronic acid carry out esterification.Sterically hindered larger due to Tazobactam Sodium isomerization carboxyl, thus esterification to only occur in glucuronic acid carboxyl connect on the hydroxyl of the para-position carbon of carbon.In addition, in order to improve the esterification activity of Tazobactam Sodium, being first acyl chlorides by its converting carboxylate groups, then carrying out esterification with the hydroxyl in glucuronic acid structure, and then obtained Tazobactam Sodium-glucuronate.Its method is as follows:
One, the preparation of Tazobactam Sodium-glucuronate
Tazobactam Sodium-glucuronate reaction scheme is as follows:
(1) Tazobactam Sodium acyl chlorides is prepared
Get a certain amount of Tazobactam Sodium and be placed in flask, add the thionyl chloride (SOCl of corresponding amount
2), the mol ratio of Tazobactam Sodium and thionyl chloride is 4:3, reaction backflow 4h at 85 DEG C.
After reactant liquor is cooled to room temperature, first decompression steams unnecessary thionyl chloride, then decompression steams light yellow liquid Tazobactam Sodium acyl chlorides.
(2) Tazobactam Sodium-glucuronate is prepared
Glucuronic acid is dissolved in dichloromethane, adds the pyridine of corresponding amount, mix the Tazobactam Sodium acyl chlorides that limit drips corresponding amount under room temperature, the mol ratio of Tazobactam Sodium acyl chlorides, glucuronic acid and pyridine is 1:1.6:1.4.Acyl chlorides rate of addition controls at 1h, continues stirring reaction 3h at such a temperature afterwards.
By reactant liquor decompression and solvent recovery and unnecessary pyridine, then add water and chloroform (volume ratio 1:5) extracts, get organic facies anhydrous sodium sulfate drying, after reclaim under reduced pressure chloroform, obtain white solid Tazobactam Sodium-glucuronate, yield is 69%, and purity is 95% ~ 97%.
More than in reaction, the mol ratio 1:1.6 of Tazobactam Sodium acyl chlorides and glucuronic acid, glucal excessive acid, can ensure carboxyl in Tazobactam Sodium acyl chlorides and glucuronic acid connect the hydroxyl reaction of the para-position carbon of carbon, make product single, be easy to separation and purification.
And more than in reaction, add alkali as acid binding agent, be due to acyl chlorides and alcohol esterification after by-product be hydrochloric acid, adding alkali by acid and salify, can promote that reaction forward is carried out.Acid binding agent elects pyridine as, because of its action temperature and, can ensure product yield, reduce by-product, the molar ratio of Tazobactam Sodium acyl chlorides and pyridine is 1:1.4.Byproduct of reaction pyridine hydrochloride is soluble in water, can be removed by the method for extraction from aqueous phase, thus end-product of having purified, lock out operation is easy.
Two, the preparation of piperacillin sodium and tazobactam glucuronate common flour injection
Take avocin and the Tazobactam Sodium glucuronate of recipe quantity respectively by described proportioning, mix homogeneously, by the powder that mixes aseptically quantitative separating in sterile glass vials, with aseptic plug and the sealing of button plug, then carrying out with aseptic aluminium lid rolling lid sealing, labeling, mounted box.
Embodiment 2-1 ~ 2-3 is respectively the preparation method of a kind of avocin and Tazobactam Sodium-glucuronate common flour injection, and difference part is only that involved raw material parameter is different, shown in table specific as follows:
The preparation of embodiment 3 piperacillins-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate
In ingredient involved by the present embodiment, active component is the form that piperacillin and Tazobactam Sodium all adopt through modifying.
One, the preparation of piperacillin-mono methoxy polyethylene glycol
The method in embodiment 1 is adopted to complete the preparation of piperacillin-mono methoxy polyethylene glycol.
Two, the preparation of Tazobactam Sodium-glucuronate
The method in embodiment 2 is adopted to complete the preparation of Tazobactam Sodium-glucuronate.
Wherein, involved reaction is carried out all in anhydrous conditions, and agents useful for same has also done Non-aqueous processing all in advance.
The preparation of embodiment 4 piperacillins-mono methoxy polyethylene glycol (mPEG) and Tazobactam Sodium-glucuronic acid ester composition common flour injection
Piperacillin-mono methoxy polyethylene glycol prepared in embodiment 3 and Tazobactam Sodium-glucuronate are as crude drug, and the preparation method of its compositions common flour injection is as follows:
Piperacillin-mono methoxy polyethylene glycol (mPEG) and the Tazobactam Sodium-glucuronate of recipe quantity is taken respectively by described proportioning, mix homogeneously, by the powder that mixes aseptically quantitative separating in sterile glass vials, with aseptic plug and the sealing of button plug, then carrying out with aseptic aluminium lid rolling lid sealing, labeling, mounted box.
Embodiment 4-1 ~ 4-8 is respectively the preparation method of a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and Tazobactam Sodium-glucuronate common point of injection, and difference part is only that involved raw material parameter is different, and concrete mode is as shown in the table:
The preparation of embodiment 5 piperacillins-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate composite freeze-dried powder agent
Through the lyophilized injectable powder of the novel piperacillin Tazobactam Sodium compositions of modification, its composition comprises: proportioning is the piperacillin-mono methoxy polyethylene glycol (mPEG) of 4 ~ 32:1 and Tazobactam Sodium-glucuronate and mannitol, before lyophilization, calculate with quality percent by volume (g/mL) in every 30000mL medicinal liquid, the content of each component is respectively: mannitol is 1.5%-2.5%, and piperacillin-mono methoxy polyethylene glycol (n1PEG) and Tazobactam Sodium-glucuronate are 14%-17%.
More particularly, above-mentioned lyophilized injectable powder, before lyophilization, containing mannitol 602g, piperacillin-mono methoxy polyethylene glycol (mPEG) 4440g and Tazobactam Sodium-glucuronate 79g in every 30000ml medicinal liquid.
Above-mentioned lyophilized injectable powder, if do not add caffolding agent, be directly that the piperacillin-mono methoxy polyethylene glycol (mPEG) of 4 ~ 32:1 carries out lyophilization with the aqueous solution of Tazobactam Sodium-glucuronate by proportioning, obtained freeze-drying finished product easily forms cavity and atrophy, medicated powder is sticky wall easily, has a strong impact on product quality.So must add caffolding agent, attempt multiple caffolding agent: glucose, lactose, dextran etc., the appearance character of gained preparation and water solublity fail to reach requirement, only have and select mannitol as caffolding agent, obtained finished product good moldability, good water solubility, result is as shown in the table:
Lyophilizing caffolding agent kind is screened
| Caffolding agent kind | Mouldability | Water solublity |
| Mannitol | Loose powdery | Good |
| Glucose | Non-molding | Good |
| Lactose | Non-molding | Generally |
| Dextran | Block | Generally |
| Mannitol+dextran | Non-molding | Good |
Above-mentioned lyophilized injectable powder, the consumption of mannitol is most important, need strict control, elect as and calculate with quality percent by volume (g/mL) in every 30000mL medicinal liquid before lyophilization, mannitol is 1.5%-2.5%, if lower than lower limit, mannitol concentration is inadequate, can product appearance be affected, occur atrophy phenomenon; If higher than the upper limit, surprisingly found by great many of experiments, bad stability, analysis may be due in dry run, mannitol concentration is too high, and system eutectic point can be made to raise, and causes the destroyed decomposition of piperacillin-mono methoxy polyethylene glycol (mPEG) molecule.
Therefore, select to add caffolding agent-mannitol in above-mentioned lyophilized injectable powder, to make it possible to the better lyophilized injectable powder of obtained effect, concrete preparation method is as follows:
Step one: the mannitol of the described amount weighed up is joined in sterile water for injection to dissolving completely, then limit adds piperacillin-mono methoxy polyethylene glycol (mPEG) and the Tazobactam Sodium-glucuronate of described amount, while add sterile water for injection to be stirred to dissolving, solution is settled to 30000ml, add active carbon, after fine straining, obtain filtrate;
Step 2: be filled in cillin bottle by filtrate the dividing of step one gained, partly jump a queue, puts into freeze dryer and carries out lyophilization, obtained novel piperacillin Tazobactam Sodium freeze-dried powder;
In above-mentioned steps two, lyophilization is divided into pre-freeze, once distillation and secondary distillation three phases, and wherein the pre-freeze stage will repeat to complete for twice: quick freezing, to temperature-50 DEG C, is warming up to-40 DEG C, maintains 2.5h, so repeats twice; Evacuation 2Pa, is slowly warming up to sublimation temperature-12 DEG C with 16h by pre-freezing temperature-40 DEG C, continues dry 2h; Maintain vacuum 2Pa, slowly rise to secondary sublimation temperature 25 DEG C, drying time 6-8h.
Before the compound medicine lyophilized injectable powder difference part of embodiment 5-1-1 ~ 5-1-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and Tazobactam Sodium-glucuronate to be effective ingredient weight ratio be 20:1 is only involved lyophilization, in every 30000mL medicinal liquid, mannitol content is different, specifically sees table:
Embodiment 5-2-1 ~ 5-2-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and is only that in the front every 30000mL medicinal liquid of involved lyophilization, mannitol content is different, specifically sees table with the compound medicine lyophilized injectable powder difference part that Tazobactam Sodium-glucuronate effective ingredient weight ratio is 4:1:
Embodiment 5-3-1 ~ 5-3-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and is only that in the front every 30000mL medicinal liquid of involved lyophilization, mannitol content is different, specifically sees table with the compound medicine lyophilized injectable powder difference part that Tazobactam Sodium-glucuronate effective ingredient weight ratio is 32:1:
Embodiment 5-4-1 ~ 5-4-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and is only that in the front every 30000mL medicinal liquid of involved lyophilization, mannitol content is different, specifically sees table with the compound medicine lyophilized injectable powder difference part that Tazobactam Sodium-glucuronate effective ingredient weight ratio is 8:1:
Embodiment 5-5-1 ~ 5-5-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and is only that in the front every 30000mL medicinal liquid of involved lyophilization, mannitol content is different, specifically sees table with the compound medicine lyophilized injectable powder difference part that Tazobactam Sodium-glucuronate effective ingredient weight ratio is 12:1:
Embodiment 5-6-1 ~ 5-6-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and is only that in the front every 30000mL medicinal liquid of involved lyophilization, mannitol content is different, specifically sees table with the compound medicine lyophilized injectable powder difference part that Tazobactam Sodium-glucuronate effective ingredient weight ratio is 16:1:
Embodiment 5-7-1 ~ 5-7-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and is only that in the front every 30000mL medicinal liquid of involved lyophilization, mannitol content is different, specifically sees table with the compound medicine lyophilized injectable powder difference part that Tazobactam Sodium-glucuronate effective ingredient weight ratio is 24:1:
Embodiment 5-8-1 ~ 5-8-5 is respectively a kind of piperacillin-mono methoxy polyethylene glycol (mPEG) and is only that in the front every 30000mL medicinal liquid of involved lyophilization, mannitol content is different, specifically sees table with the compound medicine lyophilized injectable powder difference part that Tazobactam Sodium-glucuronate effective ingredient weight ratio is 28:1:
All different ratio product antibacterial effect research in embodiment 6 embodiment 1-5
Test method is carried out with reference to the method in following journal article:
The people such as Zhao Fengqin. the comparitive study of piperacillin with tazobactam and Cefoperazone-sulbactam treatment respiratory tract bacterial infection. Chinese Journal of New Drugs and Clinical Remedies, the 22nd volume the 10th phase in 2003,583-586 page.
Adopt method of the prior art, carry out clinical trial for Patients With Respiratory Tract Infection, using cure rate as evaluation index, obtain following antibacterial action intensity table, "+" more multilist shows that antibacterial action is stronger.
Inclusion criteria: age 18-65 year inpatient, through clinical and Laboratory Diagnosed be, severe bacterial infection person that final selected 250 routine patients, are divided into 50 groups at random in respiratory tract.
Treat 50 groups of patients by dosage described in table 1 and frequency, treatment cycle is 14 days.
Compared by the antibacterial effect that listing product, piperacillin-mono methoxy polyethylene glycol (mPEG) are made common flour injection and the common flour injection prepared by avocin and Tazobactam Sodium-glucuronate prepared by common flour injection and lyophilized injectable powder, piperacillin-mono methoxy polyethylene glycol (mPEG) and sodium-tazobactam from Tazobactam Sodium-glucuronate according to different proportionings, comparative result is as shown in the table, and described proportioning take active component as piperacillin (C
23h
27n
5o
7and Tazobactam Sodium (C S)
10h
12n
4o
5s) Weight computation.
Table 1 injection antibacterial effect compares
As shown in Table 1, the common flour injection that the present embodiment provides and lyophilized injectable powder product, the proportioning of piperacillin and Tazobactam Sodium is 4 ~ 32:1, its antibacterial action is all better than listing product, the antibacterial action that ratio is " 24:1-32:1 " invention product weakens to some extent, be because the quantity not sufficient of Tazobactam Sodium causes, make enzyme destroy the piperacillin of part, thus affect antibacterial effect; Ratio is that the antibacterial action of " 4:1-16:1 " invention product is very strong, but Tazobactam Sodium consumption crosses Sheng, increases cost, improves rate of side effects.Therefore, most preferably dosage regimen is ratio is 20:1, specification 1.050g(piperacillin 1.0g and Tazobactam Sodium 0.050g) invention product, daily twice, each 1, with " product ratio of going on the market is 4:1, specification 1.25g(piperacillin 1.0g and Tazobactam Sodium 0.25g) daily twice, each 1-2 props up " or " listing product ratio is 8:1, specification 1.125g(piperacillin 1.0g and Tazobactam Sodium 0.125g) daily 3-4 time, each 3-4 props up " compare, antibacterial effect is best, dosage is minimum, administration number of times is few, side reaction is few, treatment cost is low.
The product that the present invention studies a kind ofly reduces Tazobactam Sodium proportion and produce the piperacillin Tazobactam Sodium ejection preparation of good clinical efficacy, should reduce costs, also to ensure Tazobactam Sodium consumption, it is made to give full play to enzyme inhibitor effect, piperacillin can not be made excessive, and this is only best proportioning.
The product usage and dosage of gained of the present invention is 1/time, and 1-2 times/day, all can reach good antibacterial effect.But the therapeutic effect of administration is at twice better than administration once a day, mainly due to administration once a day, phase Tazobactam Sodium is very weak to the inhibitory action of enzyme after the treatment, and at this moment piperacillin may be destroyed by enzyme, and weakens antibacterial action.
From data in table 1, the single trim that the present embodiment provides: the antibacterial action of piperacillin-mono methoxy polyethylene glycol (mPEG) sodium-tazobactam or piperacillin sodium and tazobactam-glucuronate is far away not as good as two trim, but slightly more better than listing product, not very not obviously.
Embodiment 7 quality investigation is studied
One, liquid medicine stability is investigated
Sample prepared in embodiment 4-1, embodiment 5-1-1 ~ 5-1-5 and listing product are diluted to 100ml medicinal liquid with 0.9% sodium chloride injection respectively, and measure it under room temperature (20-25 DEG C), place stability data in 60 hours.The detection method of " color ", " visible foreign matters ", " content ", " about thing " item is official method (2010 editions Chinese Pharmacopoeias), and the stability data result obtained is as shown in the table:
Medicinal liquid stability contrast table at room temperature
After listing product are made into medicinal liquid on request; within at room temperature (20-25 DEG C) places 24h; quality conforms with the regulations (content 90.0% ~ 110.0%; relevant thing is not more than 4.0%); after 24h, indices starts to exceed prescribed limit gradually, and occur the phenomenons such as variable color, formation granule or precipitation and content and relevant thing exceed standard, quality obviously starts to decline; be only about 46% to the content of piperacillin during 60h, relevant thing is also up to about 10%.And after sample various embodiments of the present invention prepared is made into medicinal liquid, placing 60h and still stablize under similarity condition, there is not variable color and precipitation in medicine, and content is also all on 95%, and relevant thing meets the requirements.
After the sample prepared by embodiment 5-1-4 is made into medicinal liquid, places 36h and still stablize under similarity condition, indices starts undesirable afterwards.After the sample prepared by embodiment 5-1-5 is made into medicinal liquid, under similarity condition, place 60h still stablize, indices all meets the requirements.
From above data, the more common listing product of piperacillin Tazobactam Sodium injection prepared by the present invention program are after being configured to transfusion, and the stability of at room temperature placing obtains and improves widely, has apparent effect, for Clinical practice is provided convenience.
Two, long-time stability are investigated
By going on the market, powder ampoule agent for injection and embodiment 4-1 ~ 4-3, embodiment 5-1-1 ~ 5-1-5, embodiment 5-2-1 ~ 5-2-5 and embodiment 5-3-1 ~ 5-3-5 carry out quality comparation, by States Pharmacopoeia specifications temperature 25 DEG C ± 2 DEG C, under the condition of relative humidity 60% ± 10%, carry out long-term stable experiment 36 months.The detection method of the test item such as " color ", " visible foreign matters ", " content ", " about thing " and " moisture " is official method (2010 editions Chinese Pharmacopoeias), and the stability data result obtained is as follows:
Injection long-term stable experiment contrast table
Listing powder ampoule agent for injection is in the long-term stable experiment of 12 months, quality conforms with the regulations (content 90.0% ~ 110.0%, relevant thing is not more than 4.0%, moisture must not cross 2.5%), 18 months time, occur that variable color, precipitation and content and relevant thing exceed standard phenomenon, quality obviously starts to decline, and is only about 50%, about thing and moisture are then up to 10% and about 5.5% to the content of piperacillin when 36 months.And each embodiment prepared by the present invention, long-term placement is still stablized for 36 months, and variable color and precipitation do not occur medicine, content also all on 98%, about thing and moisture also all meet the requirements.
In the prescription of embodiment 5-1-4,5-2-4 and 5-3-4, mannitol content is higher than 2.5%, obtained freeze-dried powder outward appearance is good, but bad stability, piperacillin-mono methoxy polyethylene glycol (mPEG) content obviously declines, when 24 months, content starts undesirable, occur precipitation, relevant thing also exceeds standard, and when 36 months, piperacillin-mono methoxy polyethylene glycol (mPEG) content is down to about 67%.But the content of Tazobactam Sodium-glucuronate does not have significant change, to when 36 months also higher than 98%.Expectation is that the mannitol of high concentration can destroy piperacillin-mono methoxy polyethylene glycol (mPEG) molecule.
In the prescription of embodiment 5-1-5,5-2-5 and 5-3-5, mannitol content is lower than 1.5%, and concentration is inadequate, makes freeze-dried powder outward appearance bad, the quality problems such as occur atrophy, subside, and affect later phase clinical use.
Learn thus, the present invention program provides a kind of novel piperacillin Tazobactam Sodium compositions, and it is that 4:1-32:1(is by active component piperacillin (C that described compositions comprises proportioning
23h
27n
5o
7and Tazobactam Sodium (C S)
10h
12n
4o
5s) weighing scale) piperacillin-mono methoxy polyethylene glycol (mPEG) and Tazobactam Sodium-glucuronate, obtained injection is compared with listing product thus, stability is significantly improved, and antibacterial action obviously strengthens, solve clinical in practical difficulty.As made freeze-dried powder, need add caffolding agent mannitol, content controls at 1.5%-2.5%.
Claims (5)
1. a piperacillin Tazobactam Sodium compositions, it is characterized in that: it comprises piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate, described piperacillin-mono methoxy polyethylene glycol and the molecular structural formula of Tazobactam Sodium-glucuronate are respectively:
with
by the weight fraction that active component is piperacillin and Tazobactam Sodium, the proportioning of described piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate is 4 ~ 32:1.
2. piperacillin Tazobactam Sodium compositions according to claim 1, it is characterized in that: the weight fraction by active component being piperacillin and Tazobactam Sodium, the proportioning of described piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate is 20:1.
3. the piperacillin Tazobactam Sodium compositions according to any one of claim 1 ~ 2, is characterized in that: described piperacillin Tazobactam Sodium compositions is common flour injection or lyophilized injectable powder.
4. piperacillin Tazobactam Sodium compositions according to claim 3, is characterized in that: described piperacillin Tazobactam Sodium compositions is lyophilized injectable powder, wherein with the addition of caffolding agent-mannitol.
5. piperacillin Tazobactam Sodium compositions according to claim 4, is characterized in that: the ratio of the total amount of described mannitol and piperacillin-mono methoxy polyethylene glycol and Tazobactam Sodium-glucuronate is 0.088 ~ 0.178:1.
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