CN102119929B - Medicinal composition of sulbenicillin sodium for injection and preparation method thereof - Google Patents
Medicinal composition of sulbenicillin sodium for injection and preparation method thereof Download PDFInfo
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- CN102119929B CN102119929B CN201110009465XA CN201110009465A CN102119929B CN 102119929 B CN102119929 B CN 102119929B CN 201110009465X A CN201110009465X A CN 201110009465XA CN 201110009465 A CN201110009465 A CN 201110009465A CN 102119929 B CN102119929 B CN 102119929B
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Abstract
The invention discloses a medicinal composition of sulbenicillin sodium, in particular sulbenicillin sodium nano particle injection. The sulbenicillin sodium nano particle injection consists of sulbenicillin sodium, a carrier material, a stabilizer and an excipient, wherein the effective mean particle size of nano particles is 10 to 200nm. The invention also discloses the preparation method of the injection. The preparation method comprises the following steps of: mixing the sulbenicillin sodium and the stabilizer in water for injection, regulating a pH value, adding the carrier material and the excipient to obtain solution of sulbenicillin sodium nano particles, and freeze-drying to obtain the nano particle injection. The sulbenicillin sodium nano particle injection has the advantages of high resolubility, high stability, high loading rate, high clinical experiment safety and the like, and the process is suitable for industrialized mass production.
Description
Technical field
The invention belongs to medical technical field, relate to pharmaceutical composition of a kind of sulbenicillin sodium for injection and preparation method thereof, in particular, relate to a kind of sulbenicillin disodium nanoparticle injection and preparation method thereof.
Background technology
Sulbenicillin disodium, and its chemical being called (2S, 5R, 6R)-3, and 3-dimethyl-6-(2-phenyl-2-sulfo group acetamido)-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid disodium salt, molecular formula is C
16H
16N
2Na
2O
7S
2, molecular weight 458.42, structural formula is:
The sulbenicillin belongs to wide spectrum semi-synthetic penicillins antibiotic, through suppressing the synthetic performance of bacteria cell wall bactericidal action.These article are also had an antibacterial activity to Hemolytic streptococcus, streptococcus pneumoniae and the staphylococcus of not producing penicillinase; And peptostreptococcus, clostridium also there are certain effect in interior anaerobe, mainly are applicable to pneumonia, urinary tract infection, complexity skin soft-tissue infection and septicemia etc. due to the responsive Pseudomonas aeruginosa of these article, some distortion stalk Pseudomonas and other the responsive gram negative bacterias.Because these article have advantages such as drug resistance is low, has a broad antifungal spectrum, so it is evident in efficacy, is a clinical line medication.Be put into national medical insurance medicine at present, this has proved that also its effectiveness and safety have obtained approval significantly.The sulbenicillin disodium of current listing is an injection, and specification is 1.0g, 2.0g and 4.0g.
Chinese patent CN1732931A discloses a kind of antibacterial combination of sulbenicillin sodium for injection, and it contains sulbenicillin disodium and sulbactam sodium, and the two weight ratio is 1～32: 1.Chinese patent CN1732929A discloses a kind of sulbenicillin sodium for injection and preparation process thereof thereof, it is characterized in that components by weight is: sulbenicillin: sodium bicarbonate: activated carbon: water=1: 0.17～0.35: 0.01: 3.This patent is prescription and the production technology of sulbenicillin sodium for injection in conventional field, and made medicine solubility and stability are more relatively poor, has influenced the safety and the effectiveness of drug use greatly.
Chinese patent CN101301269A discloses a kind of slow releasing agent that contains the sulbenicillin; Form by sustained-release micro-spheres and solvent; Sustained-release micro-spheres contains slow-release auxiliary material and PCs, and solvent is the special solvent that contains suspending agents such as sodium carboxymethyl cellulose, and viscosity is 100cp-3000cp (20 ℃-30 ℃ time); Slow-release auxiliary material is selected from EVAc, polifeprosan, PLA, PLGA, decanedioic acid copolymer, albumin glue, gelatin etc.; Sustained-release micro-spheres also can be made into sustained-release implant.Sustained-release implant and slow releasing injection are placed in bacterium kitchen range part or injection can slowly discharge medicine more than 5 to 30 days in local lesion, obvious its general toxicity that reduces when effectively obtaining and keeping local kitchen range active drug concentration.But the sustained-release micro-spheres particle diameter is big, belongs to the equal time-dependent system of thermodynamics and kinetics, adopts conventional sterilization method filtration sterilization or heat sterilization, all is difficult to realize, and because of its preparation technology's difficulty, is not easy to promote.
Chinese patent CN101822640A discloses a kind of sulbenicillin sodium liposome injection; It is characterized in that being made up of sulbenicillin disodium, soybean lecithin, cholesterol, two palmityl PHOSPHATIDYL ETHANOLAMINEs, antioxidant and excipient, wherein each composition weight umber is preferably: 1 part of sulbenicillin disodium, 3～5 parts of soybean lecithins, 0.8～2 part of cholesterol, 0.2～1 part of two palmityl PHOSPHATIDYL ETHANOLAMINE, 0.1～0.5 part of antioxidant and 5～10 parts of excipient.The lipidosome injection that makes with this technology has significant advantage, as: solubility and stability are all relatively good, and envelop rate is high.But its preparation technology is too complicated, and uses poisonous, inflammable and explosive organic solvent in a large number, has bigger potential safety hazard.
Summary of the invention
The invention provides a kind of sulbenicillin sodium for injection pharmaceutical composition; It is sulbenicillin disodium nanoparticle injection; This injection has characteristics such as solubility is good, and stability is excellent, drug loading is high, safety of clinical trials is good, has overcome the deficiency that exists in the prior art.
The purpose of this invention is to provide a kind of sulbenicillin disodium nanoparticle injection.
Another object of the present invention provides the method for preparing of above-mentioned injection.
Specifically, the invention provides a kind of sulbenicillin sodium injection, this injection is made up of sulbenicillin disodium, nanoparticulate carriers material, surface stabilizer, excipient; Wherein, each composition weight umber is:
1 part of sulbenicillin disodium
3～10 parts of carrier materials
0.03～0.1 part of surface stabilizer
2～8 parts of excipient
In a preferred embodiment of the invention, the invention provides a kind of sulbenicillin sodium injection, wherein, each composition weight umber is:
1 part of sulbenicillin disodium
4～6 parts of carrier materials
0.04～0.06 part of surface stabilizer
4～6 parts of excipient
In most preferred embodiment of the present invention, the invention provides a kind of sulbenicillin sodium injection, wherein, each composition weight umber is:
1 part of sulbenicillin disodium
5 parts of carrier materials
0.05 part of surface stabilizer
5 parts of excipient
In the sodium injection of sulbenicillin provided by the invention; Wherein, Carrier material is selected from alpha-cyanoacrylate alkane ester or methyl methacrylate, preferably, is selected from a kind of in methyl 2-cyanoacrylate, cyanacrylate, alpha-cyanoacrylate propyl ester, the positive butyl ester of alpha-cyanoacrylate, the isobutylcyanoacrylate; Most preferably, be selected from cyanacrylate.
In the sodium injection of sulbenicillin provided by the invention, wherein, surface stabilizer is selected from anionic surface stabilizing agent, cationic surface stabilizing agent, amphion surface stabilizer and nonionic surface stabilizer.Preferably, described anionic surface stabilizing agent is selected from sodium lauryl sulphate, sodium hexadecyl sulfate, dodecyl sodium sulfate, sodium stearyl sulfate, dihexyl sodium sulfosuccinate, liver sodium cholate, sodium taurocholate; Described cationic surfactant is selected from benzalkonium bromide, benzalkonium chloride, gathers peaceful amine, bromination polybutene acid methyl ester trimethyl ammonium bromide, bromination hexyl desyl,a-phenyl phenacyl trimethyl ammonium, methyl tricaprylammonium chloride, dimethylammonium chloride, Tetrabutylammonium bromide; Described amphion surface stabilizer is selected from cephalin, phosphatidylcholine, serinephosphatide, lipositol, glycolipid, neutral esters, cholesterol; Described nonionic surface stabilizer is selected from polyvinyl alcohol, Polyethylene Glycol, Arlacel-20, sorbitan palmitate, sorbitan monostearate, Arlacel-80, sorbitan trioleate, dextran, polysorbate 20, polysorbate 40, polysorbate 60, polyoxyethylene sorbitan monoleate, polysorbate 85, Brij30, Brij35, poloxamer; Most preferably, described surface stabilizer is selected from dextran, polysorbate 40, poloxamer.
In the sodium injection of sulbenicillin provided by the invention, wherein, excipient is selected from one or more in gelatin, trehalose, lactose, glucose, sorbitol, mannitol, the xylitol, preferably, is selected from mannitol or lactose.
Sulbenicillin provided by the invention sodium injection is measured through the light dispersion method, and its effective particle mean size is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm.Here; Said effective particle mean size is represented based on the weight meter; The particulate granularity of at least 50% sulbenicillin disodium through above-mentioned commercial measurement, is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc. promptly less than effective meansigma methods.In embodiments of the invention, the granularity of at least 80%, at least 90%, at least 95% sulbenicillin disodium is less than effective meansigma methods, i.e. 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc.
The invention provides a kind of sulbenicillin disodium nanoparticle injection, this injection is made up of sulbenicillin disodium, nanoparticulate carriers material, surface stabilizer, excipient; Wherein, each composition weight umber is:
1 part of sulbenicillin disodium
3～10 parts of carrier materials
0.03～0.1 part of surface stabilizer
2～8 parts of excipient
And, described sulbenicillin disodium nanoparticle injection, through the light dispersion method, its effective size of grain is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm.Here; Said effective particle mean size is represented based on the weight meter; The particulate granularity of at least 50% sulbenicillin disodium through above-mentioned commercial measurement, is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc. promptly less than effective meansigma methods.In embodiments of the invention, the granularity of at least 80%, at least 90%, at least 95% sulbenicillin disodium is less than effective meansigma methods, i.e. 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc.
The present invention a kind of sulbenicillin disodium nanoparticle injection, this injection is made up of sulbenicillin disodium, nanoparticulate carriers material, surface stabilizer, excipient; Wherein, each composition weight umber is:
1 part of sulbenicillin disodium
4～6 parts of carrier materials
0.04～0.06 part of surface stabilizer
4～6 parts of excipient
And, described sulbenicillin disodium nanoparticle injection, through the light dispersion method, its effective size of grain is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm.Here; Said effective particle mean size is represented based on the weight meter; The particulate granularity of at least 50% sulbenicillin disodium through above-mentioned commercial measurement, is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc. promptly less than effective meansigma methods.In embodiments of the invention, the granularity of at least 80%, at least 90%, at least 95% sulbenicillin disodium is less than effective meansigma methods, i.e. 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc.
In most preferred embodiment of the present invention, the invention provides a kind of sulbenicillin sodium injection, wherein, each composition weight umber is:
1 part of sulbenicillin disodium
5 parts of carrier materials
0.05 part of surface stabilizer
5 parts of excipient
And, described sulbenicillin disodium nanoparticle injection, through the light dispersion method, its effective size of grain is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm.Here; Said effective particle mean size is represented based on the weight meter; The particulate granularity of at least 50% sulbenicillin disodium through above-mentioned commercial measurement, is 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc. promptly less than effective meansigma methods.In embodiments of the invention, the granularity of at least 80%, at least 90%, at least 95% sulbenicillin disodium is less than effective meansigma methods, i.e. 10～1800nm, 10～1200nm, 10～800nm, 10～400nm, 10～200nm etc.
On the other hand; The invention provides the method for preparing of above-mentioned sulbenicillin sodium injection, sulbenicillin disodium, stabilizing agent are mixed in water for injection, regulate pH value; The back adds carrier material and excipient dissolving; Get sulbenicillin disodium nanoparticle solution, it is sub-packed in the cillin bottle, adopt freeze drying process to make the nanoparticle injection again.
The method for preparing of sulbenicillin disodium nano injection provided by the invention agent comprises the steps:
(1) sulbenicillin disodium, stabilizing agent are added in the water for injection, stir and make dissolving, regulate pH value to 1.0～3.0 with acid.
(2) in above-mentioned solution, add carrier material, stirring at room 4～6h adds the excipient stirring and makes dissolving, regulates pH value to 5.0～7.0 with alkali.
(3) adopt 0.22 μ m filtering with microporous membrane, obtain sulbenicillin disodium nanoparticle solution.
(4) above-mentioned solution branch is filled in the cillin bottle after the sterilization, uses the freezer dryer lyophilizing, the aseptic plug of reuse seals, and the last aseptic aluminium lid of reuse carries out the Zha Gai sealing, obtains sulbenicillin disodium nanoparticle injection.
The method for preparing of a kind of sulbenicillin disodium nanoparticle injection provided by the invention, wherein, step
(1) described acid is selected from hydrochloric acid, sulphuric acid, carbonic acid, nitric acid, phosphoric acid, formic acid, acetic acid, ethanedioic acid, citric acid; Be preferably hydrochloric acid, sulphuric acid, carbonic acid.
The method for preparing of a kind of sulbenicillin disodium nanoparticle injection provided by the invention, wherein, step
(2) described alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate; Be preferably sodium carbonate, sodium hydroxide.
With the prior art ratio, sulbenicillin disodium nano particle preparations provided by the invention and preparation method thereof has the following advantages:
1, good stability: sulbenicillin disodium provided by the invention is with its parcel and be adsorbed in the nanoparticulate carriers material, and its active component is effectively protected, so the more excellent commercially available article of stability are more excellent.Quicken June and long-time stability investigation result and show that also solution colour, pH value, related substance, content all do not have significant change, envelop rate is little, has greatly improved medicine stability.
2, antibacterial activity is high, and safety of clinical trials is good: nano particle preparations carrier material antibacterial activity in vitro of the present invention is high, and its stability all is superior to commercially available article under the different pH value, and the clinical trial anaphylaxis is few, antibacterial activity is strong.
3, preparation is simple: nanoparticle formulations prepared from solutions technology of the present invention is simple, need not add any organic solvent, in normal temperature condition injected water, can accomplish, and more is adapted to industrialized great production.
4, solubility is good; Save Range is wide: the employing of Freeze Drying Technique has effectively avoided the degraded of polymeric material, medicine to reveal or drug degradation; Make the medicine preservation condition wider; And add excipient before the lyophilization and make the solubility of these article good, basic identical before various physicochemical properties of medicine and the lyophilizing after redissolving.
The specific embodiment
Further specify the present invention through following specific embodiment, but do not receive the restriction of following examples
The preparation of embodiment 1 sulbenicillin disodium nanoparticle injection
Write out a prescription 100 bottles
Sulbenicillin disodium 100g
Methyl 2-cyanoacrylate 500g
Dextran 5g
Mannitol 500g
Preparation technology:
(1) 100g sulbenicillin disodium, 5g dextran are joined in the 2L water for injection, stir and make dissolving, regulate pH value to 1.0～2.0 with hydrochloric acid.
(2) under agitation,, behind the stirring at room 4h, add mannitol 500g, continue to be stirred to dissolving fully again, regulate pH value to 5.0～7.0 with sodium hydroxide to wherein adding the 500g methyl 2-cyanoacrylate with above-mentioned solution.
(3) above-mentioned solution is adopted the 0.22um filtering with microporous membrane, obtain sulbenicillin disodium nanoparticle solution.
(4) above-mentioned solution branch is filled in the cillin bottle after the sterilization, behind-45 ℃～-55 ℃ pre-freeze 3h, uses the freezer dryer lyophilizing, seal with aseptic plug the back, and the aseptic aluminium lid of reuse carries out the Zha Gai sealing, obtains sulbenicillin disodium nanoparticle injection.
The preparation of embodiment 2 sulbenicillin disodium nanoparticle injections
Write out a prescription 100 bottles
Sulbenicillin disodium 100g
Alpha-cyanoacrylate propyl ester 500g
Dextran 5g
Glucose 500g
Preparation technology:
(1) 100g sulbenicillin disodium, 5g dextran are joined in the 2L water for injection, stir and make dissolving, regulate pH value to 2.0～3.0 with formic acid.
(2) under agitation,, behind the stirring at room 5h, add glucose 500g again, continue to be stirred to dissolving fully again, regulate pH value to 5.0～7.0 with sodium bicarbonate to wherein adding 500g alpha-cyanoacrylate propyl ester with above-mentioned solution.
(3) above-mentioned solution is adopted the 0.22um filtering with microporous membrane, obtain sulbenicillin disodium nanoparticle solution.
(4) above-mentioned solution branch is filled in the cillin bottle after the sterilization, behind-45 ℃～-55 ℃ pre-freeze 3h, uses the freezer dryer lyophilizing, seal with aseptic plug the back, and the aseptic aluminium lid of reuse carries out the Zha Gai sealing, obtains sulbenicillin disodium nanoparticle injection.
The preparation of embodiment 3 sulbenicillin disodium nanoparticle injections
Write out a prescription 100 bottles
Sulbenicillin disodium 100g
The positive butyl ester 500g of alpha-cyanoacrylate
Poloxamer 5g
Mannitol 500g
Preparation technology:
(1) 100g sulbenicillin disodium, 5g dextran are joined in the 2L water for injection, stir and make dissolving, regulate pH value to 1.0～2.0 with hydrochloric acid.
(2) under agitation,, behind the stirring at room 5h, add mannitol 500g again, continue to be stirred to dissolving fully again, regulate pH value to 5.0～7.0 with sodium hydroxide to wherein adding the positive butyl ester of 500g alpha-cyanoacrylate with above-mentioned solution.
(3) above-mentioned solution is adopted the 0.22um filtering with microporous membrane, obtain sulbenicillin disodium nanoparticle solution.
(4) above-mentioned solution branch is filled in the cillin bottle after the sterilization, behind-45 ℃～-55 ℃ pre-freeze 3h, uses the freezer dryer lyophilizing, seal with aseptic plug the back, and the aseptic aluminium lid of reuse carries out the Zha Gai sealing, obtains sulbenicillin disodium nanoparticle injection.
The preparation of embodiment 4 sulbenicillin disodium nanoparticle injections
Write out a prescription 100 bottles
Sulbenicillin disodium 100g
The positive butyl ester 600g of alpha-cyanoacrylate
Dextran 6g
Lactose 600g
Preparation technology:
(1) 100g sulbenicillin disodium, 6g dextran are joined in the 2.4L water for injection, stir and make dissolving, regulate pH value to 2.0～3.0 with sulphuric acid.
(2) under agitation,, behind the stirring at room 6h, add lactose 600g again, continue to be stirred to dissolving fully again, regulate pH value to 5.0～7.0 with sodium hydroxide to wherein adding the positive butyl ester of 600g alpha-cyanoacrylate with above-mentioned solution.
(3) above-mentioned solution is adopted the 0.22um filtering with microporous membrane, obtain sulbenicillin disodium nanoparticle solution.
(4) above-mentioned solution branch is filled in the cillin bottle after the sterilization, behind-45 ℃～-55 ℃ pre-freeze 3h, uses the freezer dryer lyophilizing, seal with aseptic plug the back, and the aseptic aluminium lid of reuse carries out the Zha Gai sealing, obtains sulbenicillin disodium nanoparticle injection.
The preparation of embodiment 5 sulbenicillin disodium nanoparticle injections
Write out a prescription 100 bottles
Sulbenicillin disodium 100g
Isobutylcyanoacrylate 400g
Dextran 4g
Glucose 400g
Preparation technology:
(1) 100g sulbenicillin disodium, 4g dextran are joined in the 2L water for injection, stir and make dissolving, regulate pH value to 2.0～3.0 with hydrochloric acid.
(2) under agitation,, behind the stirring at room 5h, add glucose 400g again, continue to be stirred to dissolving fully again, regulate pH value to 5.0～7.0 with sodium carbonate to wherein adding the positive butyl ester of 400g alpha-cyanoacrylate with above-mentioned solution.
(3) above-mentioned solution is adopted the 0.22um filtering with microporous membrane, obtain sulbenicillin disodium nanoparticle solution.
(4) above-mentioned solution branch is filled in the cillin bottle after the sterilization, behind-45 ℃～-55 ℃ pre-freeze 3h, uses the freezer dryer lyophilizing, seal with aseptic plug the back, and the aseptic aluminium lid of reuse carries out the Zha Gai sealing, obtains sulbenicillin disodium nanoparticle injection.
Embodiment 6 sulbenicillin disodium nanoparticle injection particle diameters detect
Method: get the nano particle preparations of the present invention's preparation, be dissolved in water into the solution that every 1ml contains 1mg, use the laser light scattering particle size analyzer determination.The sulbenicillin disodium nano particle preparations of acetonideexample 1～5 preparation is a spherical shape, and particle size distribution is even, and the result sees table 1:
Table 1, sulbenicillin disodium nanoparticle injection particle diameter detect
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| d(0.1) | 30nm | 30nm | 50nm | 70nm | 30nm |
| d(0.5) | 80nm | 100nm | 110nm | 130nm | 80nm |
| d(0.9) | 130nm | 150nm | 150nm | 180nm | 140nm |
The result shows, gained of the present invention gets sulbenicillin disodium nanoparticle particle size distribution range all between 10～200nm, and particle size distribution is even.
Embodiment 7 sulbenicillin disodium nanoparticle injection envelop rates and drug loading detect
Method: sulbenicillin disodium nanoparticle injection is dissolved in water or is diluted to the solution that every 1ml contains sulbenicillin disodium 1mg, high speed centrifugation, 5000r/min; Centrifugal 30min gets clear liquid 1ml, uses dissolve with methanol; With the content of high effective liquid chromatography for measuring sulbenicillin, confirm entrapped content M
1, the sulbenicillin disodium total amount is M in the nano particle preparations
0, nano particle preparations gross weight M
2
Envelop rate=M
1/ M
0* 100%.
Drug loading=M
1/ M
2* 100%.
The sulbenicillin disodium nano particle preparations of acetonideexample 1～5 preparation is that envelop rate and drug loading result see table 2:
The envelop rate of table 2, sulbenicillin disodium nanoparticle injection and drug loading detect
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| Envelop rate | 86.4％ | 88.0％ | 90.2％ | 94.4％ | 87.5％ |
| Drug loading | 17.2％ | 17.3％ | 18.0％ | 15.6％ | 21.1％ |
The result shows that the sulbenicillin disodium nanoparticle injection of gained of the present invention is sealed rate all more than 85%, and the limit that also meets 2010 editions guidelines of Chinese Pharmacopoeia requires (envelop rate must not be lower than 80%).The dissolution velocity of embodiment 8 products is investigated
Embodiment 2, embodiment 3 and physical mixed are obtained sulbenicillin sodium for injection wait quality to get 5 bottles respectively, be designated as No. 1, No. 2, No. 3, No. 4, No. 5 with embodiment 2 gained samples; Be designated as No. 6, No. 7, No. 8, No. 9, No. 10 with embodiment 3 gained samples; Be designated as No. 11, No. 12, No. 13, No. 14, No. 15 with direct mixing gained sample; Dissolving method by clinical application injects 10ml water for injection respectively, and it is jolted on eddy mixer; To dissolve clear and bright fully is index, calculates dissolution velocity (seeing shown in the table 3)
The rate of dissolution of table 3, sulbenicillin disodium nanoparticle injection and direct packaging gained injection is investigated
The result shows that the rate of dissolution of sulbenicillin disodium nanoparticle injection provided by the invention obviously is superior to the injection of direct packaging gained.
Embodiment 8 sulbenicillin disodium nanoparticle injection study on the stability
1) accelerated test is investigated
The sample of the embodiment of the invention 1～5 preparation and the sulbenicillin sodium injection of raw material direct packaging preparation are placed at 40 ℃ of high temperature, following 6 months of relative humidity 75% ± 5% condition respectively, quicken to investigate, the result sees table 4:
The study on the stability of table 4, sulbenicillin disodium nanoparticle injection and direct packaging gained injection
Experiment shows that the injection character of sulbenicillin sodium raw materials direct packaging preparation becomes pale yellow powder when quickening June, and pH descends bigger, and content reduces obviously, and related substance significantly raises; Sample appearance character, visible foreign matters, pH value, content and the related substance of the embodiment of the invention 1～5 preparation have no significant change, and solubility is very fast, and envelop rate descends all in 3%; Prove that fully product of the present invention is superior to the listing article aspect stable, have gratifying technique effect.
2) stability study under the different pH value
Embodiment 1 gained sulbenicillin disodium nanoparticle injection and commercially available article are dissolved in pH=2.0 (glycine-HCl buffer), pH=4.0 (glycine-HCl buffer), pH=7.0 (phosphate buffer) and pH=9.0 (glycine-NaOH buffer) respectively; Place under 100 ℃, measure its antibacterial activity 3 strain staphylococcus aureuses.
The result shows, at 100 ℃, and under the pH=2.0 condition, sulbenicillin disodium nanoparticle injection 10min inactivation, pH=4.0～9.0 o'clock, 30min still keeps excellent antibiotic active; Commercially available article injection is at 100 ℃, and 5min is an inactivation under the pH=2.0 condition, and pH=4.0～9.0 o'clock can keep reasonable antibacterial activity in the 20min, inactivation during 30min.Shown in table 5, table 6:
Table 5, the antibacterial activity of sulbenicillin disodium nanoparticle injection under 100 ℃
The antibacterial activity of the commercially available article of table 6 under 100 ℃
The vitro antibacterial activity research of embodiment 9 sulbenicillin sodium for injection
Get embodiment 1 and conventional sulbenicillin sodium injection, adopt the agar doubling dilution to study with regard to its antibacterial activity in vitro with the clinical isolates strain, and comparison, shown in 7:
The antibacterial activity of table 7 sulbenicillin disodium nanoparticle injection and conventional injection is (MIC.mg/ml) relatively
Above experimental result shows that sulbenicillin disodium nanoparticle injection is compared with conventional injection, and its vitro antibacterial activity is obviously stronger.
Embodiment 10, safety research
Whole body is sensitivity test initiatively
Purpose: repeat to inject body through sulbenicillin sodium for injection.Observe the body immune system response situation, to judge the safety of this clinical drug injection.
The sulbenicillin disodium nanoparticle injection of material: embodiment 1 gained, specification: 1.0g faces the time spent to be dissolved in 0.9% sodium chloride injection.
Listing reference substance: specification 1.0g faces the time spent to be dissolved in 0.9% sodium chloride injection.
Positive control: egg protein, face the time spent is mixed with 2mg/ml with normal saline solution.
Animal: 150～250g healthy guinea pig, provide by Animal Experimental Study chamber, Chongqing Institute of Chinese Medicine, the quality certification number is: SCXK (Chongqing) 2007-0006 number.Conformed in three days in the Animal House raising, room temperature 20-25 ℃, relative humidity 55-70%.Animal House uses the quality certification number to be: SYXK (Chongqing) 2007-0004 number.
The result: listing article low dose group does not have animal dead during sensitization, have 3 animals to observe after exciting and scratch nose or sneeze phenomenon; Listing article high dose group has 4 animal deads during sensitization, have 1 nose and sneeze phenomenon to occur scratching after the residue animal excites.The test sample low dose group does not have animal dead during sensitization, have 1 animal to observe after exciting and scratch the nose phenomenon; The test sample high dose group has 2 animal deads during sensitization, have 1 the nose phenomenon to occur scratching after the residue animal excites.After attacking injection, dyspnea and dead phenomenon all appear in egg protein group Cavia porcellus.No matter the animal of 0.9% sodium chloride injection group is during the sensitization or after the booster injection, allergic phenomena all do not occur.The result shows: sulbenicillin disodium nanoparticle injection fluid power causes the Cavia porcellus systemic anaphylaxis, should note anaphylaxis during clinical practice, and the safety of its preparation is superior to the listing article.
Claims (9)
1. sulbenicillin sodium pharmaceutical composition, it is a sulbenicillin disodium nanoparticle injection, and wherein, described injection is made up of sulbenicillin disodium, nanoparticulate carriers material, surface stabilizer, excipient, and wherein, each composition weight umber is:
Here, said carrier material is an alpha-cyanoacrylate alkane ester; Described alpha-cyanoacrylate alkane ester is selected from a kind of in methyl 2-cyanoacrylate, cyanacrylate, alpha-cyanoacrylate propyl ester, the positive butyl ester of alpha-cyanoacrylate, the isobutylcyanoacrylate;
Said surface stabilizer is the nonionic surface stabilizer; Described nonionic surface stabilizer is selected from dextran or poloxamer.
2. sulbenicillin according to claim 1 sodium pharmaceutical composition, wherein, each composition weight umber is:
3. sulbenicillin according to claim 2 sodium pharmaceutical composition, wherein, each composition weight umber is:
4. according to the described sulbenicillin of arbitrary claim sodium pharmaceutical composition in the claim 1 to 3, wherein, said excipient is selected from one or more in gelatin, trehalose, lactose, glucose, sorbitol, mannitol, the xylitol.
5. sulbenicillin according to claim 4 sodium pharmaceutical composition, wherein, described excipient is selected from mannitol or lactose.
6. according to the described sulbenicillin of arbitrary claim sodium pharmaceutical composition in the claim 1 to 3, wherein, measure through the light dispersion method, its effective particle mean size is 10～200nm.
7. sulbenicillin according to claim 6 sodium pharmaceutical composition, wherein, the granularity of at least 80% sulbenicillin disodium is less than effective meansigma methods.
8. according to the said sulbenicillin of claim 7 sodium pharmaceutical composition, wherein the granularity of at least 95% sulbenicillin disodium is less than effective meansigma methods.
9. the said sulbenicillin disodium preparation of drug combination of arbitrary claim method in the claim 1 to 8 comprises the steps:
(1) sulbenicillin disodium, stabilizing agent are added in the water for injection, stir and make dissolving, with acid for adjusting pH value to 1.0～3.0;
(2) in above-mentioned solution, add carrier material, stirring at room 4～6h adds the excipient stirring and makes dissolving, regulates pH value to 5.0～7.0 with alkali;
(3) adopt 0.22 μ m filtering with microporous membrane, obtain sulbenicillin disodium nanoparticle solution;
(4) above-mentioned solution branch is filled in the cillin bottle after the sterilization, uses the freezer dryer lyophilizing, aseptic plug seals, and the last aseptic aluminium lid of reuse carries out the Zha Gai sealing, obtains sulbenicillin disodium nanoparticle injection.
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| CN1732929A (en) * | 2005-08-18 | 2006-02-15 | 张舰 | Sulbenicillin sodium for injection and process for preparing its formulation |
| CN101805356A (en) * | 2010-04-27 | 2010-08-18 | 湖南湘药制药有限公司 | Preparation methods of sulbenicillin sodium and injection thereof |
| CN101912370A (en) * | 2010-08-17 | 2010-12-15 | 湖南三清药业有限公司 | D(-)-sulbenicillin disodium powder for injection and preparation process thereof |
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| CN1732929A (en) * | 2005-08-18 | 2006-02-15 | 张舰 | Sulbenicillin sodium for injection and process for preparing its formulation |
| CN101805356A (en) * | 2010-04-27 | 2010-08-18 | 湖南湘药制药有限公司 | Preparation methods of sulbenicillin sodium and injection thereof |
| CN101912370A (en) * | 2010-08-17 | 2010-12-15 | 湖南三清药业有限公司 | D(-)-sulbenicillin disodium powder for injection and preparation process thereof |
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