CN101810610B - Amoxicillin sodium flucloxacillin sodium medicine compound liposome injection - Google Patents
Amoxicillin sodium flucloxacillin sodium medicine compound liposome injection Download PDFInfo
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- CN101810610B CN101810610B CN 201010149015 CN201010149015A CN101810610B CN 101810610 B CN101810610 B CN 101810610B CN 201010149015 CN201010149015 CN 201010149015 CN 201010149015 A CN201010149015 A CN 201010149015A CN 101810610 B CN101810610 B CN 101810610B
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Abstract
The invention provides an amoxicillin sodium flucloxacillin sodium medicine compound liposome injection which comprises amoxicillin sodium, flucloxacillin sodium, liposome carrier, lyoprotectant and optionally existing preservative, wherein the liposome carrier is soy lecithin and cholesterol. The liposome injection has good preparation stability, the liposome during freeze drying process does not crack caused by dehydration, fusion, ice crystal formation and the like; and likewise, the liposome keeps good encapsulation efficiency after hydration redissolution.
Description
Technical field
The present invention relates to a kind of antibiotic Liposomal formulation, relate in particular to a kind of amoxicillin sodium flucloxacillin sodium medicine compound liposome injection and method for making thereof, belong to medical technical field.
Background technology
The Amoxicillin Sodium flucloxacillin sodium is the composite antibiotic in 1: 1 ratio composition.The amoxicillin is semisynthetic penbritin, belongs to Aminopenicillin, and Grain-negative and positive bacteria are all had bactericidal action, is characterized in wide spectrum, not the penicillin resistant enzyme.The flucloxacillin is semisynthetic isoxazole class penicillin, is characterized in being difficult for being destroyed by penicillinase, and the drug resistance staphylococcus aureus that produces penicillinase is had bactericidal action.Be mainly used in the penicillin resistant staphy lococcus infection, but gram-negative bacteria is to the flucloxacillin drug resistance.Both antibacterial action mechanism is identical with penicillin, all is through combining with antibacterial penicillin-binding protein (PBPs), synthesizing of interfere with bacterial cell wall and an antibacterial action.After Amoxicillin Sodium and the flucloxacillin sodium associating, can play antibacterial action to staphylococcus bacterium producing multi enzyme preparation and some gram-negative bacteria sensitive strain.Be applicable to responsive microbial respiratory tract infection, digestive tract infection, urinary tract infection, skin soft-tissue infection, bone and the infection of joint, oral cavity and otorhinolaryngology infection etc.
The domestic existing sale at present of Amoxicillin Sodium flucloxacillin sodium compound preparation is the sterilized powder direct packaging and makes, and there is a common defective in it is exactly that preparation stabilization is poor, the prescription that can not satisfy the prescriptive period.Patent documentation CN101474176A has disclosed a kind of pharmaceutical composition of flucloxacillin sodium and amoxicillin sodium, comprises Amoxicillin Sodium and flucloxacillin sodium, and the two weight fraction is than being 5-1: 1-10, and direct packaging makes under aseptic condition.This method is just simply mixed packing with the two, active component Amoxicillin Sodium and flucloxacillin sodium is not carried out corresponding protection, causes product stability poor, has had a strong impact on clinical efficacy.
Summary of the invention
This injection that common process is prepared, physics and poor chemical stability, long-term storage drug quality can descend but also can generate some impurity, bring toxic and side effects, have stayed hidden danger for clinical use.If can screen some specific accessories and preparation technology, increase the stability of these article, bring very big safety will for clinical use.In line with this meaning, the inventor has finally accomplished the present invention through consulting a large amount of documents and materials and carrying out arduous experiment sieving demonstration.
Preparation lipidosome injection membrane material commonly used is phospholipid and additives; Wherein phospholipid can be selected natural phospholipid and synthetic phospholipid for use usually, and said natural phospholipid is one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine, the soybean phospholipid acyl inositol; Said synthetic phospholipid is one or more in dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, two Laurel phosphatidyl cholines, DOPG, distearyl acid phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, the two lauroyl phosphatidyl glycerols.The membrane material of additives commonly used has cholesterol, 18-amine., phosphatidic acid.The membrane material that is used to prepare lipidosome injection also has PHOSPHATIDYL ETHANOLAMINE, cholesterol second fat, paddy to carry alcohol, natrii tauroglycocholas, phosphatidyl silk amino acid, stearmide, single stearoyl phosphatidic acid, single stearoyl PHOSPHATIDYL ETHANOLAMINE, two cetyl phosphate (DCP), two palmityl PHOSPHATIDYL ETHANOLAMINEs, single palmityl PHOSPHATIDYL ETHANOLAMINE, two myristoyl PHOSPHATIDYL ETHANOLAMINEs.Additives generally are used for regulating membrane structure, change charged character, like cholesterol liposome bimolecular tunic are solidified, thereby reduce the generation of free radical, have reduced oxidation level, and liposome stability is significantly strengthened.
Bound by theory not; The inventor has found soybean lecithin, two kinds of materials of cholesterol are made up unexpectedly, has beyond thought effect, thereby has obtained the liposome of excellent in stability; It has good preparation stability; Liposome can not break because of dehydration, fusion, ice crystal generation etc. in the freeze-drying process, and after aquation was redissolved, liposome kept good envelop rate equally.
Technical scheme of the present invention is following:
A kind of amoxicillin sodium flucloxacillin sodium medicine compound liposome injection; Be made up of Amoxicillin Sodium, flucloxacillin sodium, liposome vectors, frozen-dried supporting agent and the optional antiseptic that exists, wherein said liposome vectors is soybean lecithin and cholesterol.
Amoxicillin sodium flucloxacillin sodium medicine compound liposome injection of the present invention, wherein Amoxicillin Sodium and flucloxacillin sodium are 1: 1 aseptic mixtures of weight ratio.
Amoxicillin sodium flucloxacillin sodium medicine compound liposome injection of the present invention, each composition weight umber is: 1 part of Amoxicillin Sodium, 1 part of flucloxacillin sodium; Soybean lecithin 2-10 part; Cholesterol 0.5-6 part, 2～20 parts of frozen-dried supporting agents, 0～2 part of antiseptic.
As the present invention's one preferred embodiment, above-mentioned each composition weight umber is: 1 part of Amoxicillin Sodium, 1 part of flucloxacillin sodium, soybean lecithin 4-6 part, cholesterol 0.8-1.5 part, 5～10 parts of frozen-dried supporting agents, 0～0.7 part of antiseptic.
Above-mentioned described amoxicillin sodium flucloxacillin sodium medicine compound liposome injection; Wherein said frozen-dried supporting agent is selected from one or more in sodium chloride, mannitol, glucose, lactose, polyvinylpyrrolidone, sucrose, glycine, sorbitol, trehalose, the dextran, is preferably 1: 1 the mixture of weight ratio of glucose and mannitol.
Above-mentioned described amoxicillin sodium flucloxacillin sodium medicine compound liposome injection, wherein said antiseptic are selected from one or more in phenol, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, the bromine alkanamine, are preferably sodium benzoate.
The present invention also provides a kind of method for preparing amoxicillin sodium flucloxacillin sodium medicine compound liposome injection, and concrete steps comprise:
(1) soybean lecithin and cholesterol are dissolved in the organic solvent, placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, has obtained immobilized artificial membrane, adds the buffer salt solution stirring and dissolving, obtains blank liposome solution;
(2) Amoxicillin Sodium and flucloxacillin sodium are dissolved in the water for injection,, are incubated under 50～70 ℃ of states supersound process 40-60 minute, add again after frozen-dried supporting agent, antiseptic fully dissolve, filter with prepared blank liposome solution mix homogeneously;
(3) above-mentioned steps (2) gained solution is carried out spray drying, carry out packing under the aseptic condition, make amoxicillin sodium flucloxacillin sodium medicine compound liposome injection.
In the above-mentioned described method for preparing, organic solvent is selected from one or more in ethanol, isopropyl alcohol, methanol, butanone, acetone, ethyl acetate, chloroform, dichloromethane or the ethyl acetate, is preferably volume ratio and is 3: 1 isopropyl alcohol and ethanol mixed solvent.
In the above-mentioned described method for preparing, what buffer salt solution can be in phosphate buffer, citrate buffer, carbonate buffer solution, the borate buffer solution is a kind of, is preferably pH value and is citric acid-sodium citrate buffer of 5.6.
Amoxicillin sodium flucloxacillin sodium medicine compound liposome injection advantage provided by the invention is following:
(1) stability is high: active component Amoxicillin Sodium and flucloxacillin sodium are wrapped in the liposome, and each item detects index after long-term the placement does not all have significant change, has greatly improved stability;
(2) envelop rate is high: the envelop rate of Liposomal formulation of the present invention is generally 83%-90%, can reach 93%, is higher than other Liposomal formulations according to the conventional method preparation significantly, and long-term placement the seepage phenomenon can not take place, and has guaranteed product quality;
(3) side effect is little: liposome vectors vivo degradation, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(4) preparation is simple: the present invention selects mixed organic solvents for use, compares with using single organic solvent, and solubility property is better, dissolve sooner, and easier reduction vaporization is removed.
The specific embodiment
Following examples all are further to explain for what the superiority to preparation technology of the present invention and prepared sample carried out, and are unintelligible for the present invention has been done further claim limitation.
The preparation of embodiment 1 amoxicillin sodium flucloxacillin sodium medicine compound liposome injection
Prescription (specification 0.5g)
Amoxicillin Sodium 25g
Flucloxacillin sodium 25g
Soybean lecithin 100g
Cholesterol 20g
Glucose 62.5g
Mannitol 62.5g
Sodium benzoate 2.5g
The preparation process
(1) 100g soybean lecithin and 20g cholesterol being dissolved in the 800ml volume ratio is in 3: 1 the isopropyl alcohol and ethanol mixed solvent; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent; Obtained immobilized artificial membrane; Add pH value 5.6 citric acid-sodium citrate buffer solution 500ml stirring and dissolving, obtain blank liposome solution;
(2) 25g Amoxicillin Sodium and 25g flucloxacillin sodium are dissolved in the 300ml water for injection; With prepared blank liposome solution mix homogeneously; Be incubated under 70 ℃ of states supersound process 40 minutes; Add again after 62.5g glucose and 62.5g mannitol, 2.5g sodium benzoate fully dissolve, with 0.45 μ m filtering with microporous membrane;
(3) above-mentioned steps (2) gained solution is carried out spray drying, be distributed into 100 bottles under the aseptic condition, make amoxicillin sodium flucloxacillin sodium medicine compound liposome injection.
The preparation of embodiment 2 amoxicillin sodium flucloxacillin sodium medicine compound liposome injections
Prescription (specification 1.0g)
Amoxicillin Sodium 50g
Flucloxacillin sodium 50g
Soybean lecithin 300g
Cholesterol 75g
Glucose 250g
Mannitol 250g
Sodium benzoate 35g
The preparation process
(1) 300g soybean lecithin and 75g cholesterol being dissolved in the 1500ml volume ratio is in 3: 1 the isopropyl alcohol and ethanol mixed solvent; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent; Obtained immobilized artificial membrane; Add pH value 5.6 citric acid-sodium citrate buffer solution 800ml stirring and dissolving, obtain blank liposome solution;
(2) 50g Amoxicillin Sodium and 50g flucloxacillin sodium are dissolved in the 500ml water for injection; With prepared blank liposome solution mix homogeneously; Be incubated under 50 ℃ of states supersound process 60 minutes; Add again after 250g glucose and 250g mannitol, 35g sodium benzoate fully dissolve, with 0.45 μ m filtering with microporous membrane;
(3) above-mentioned steps (2) gained solution is carried out spray drying, be distributed into 100 bottles under the aseptic condition, make amoxicillin sodium flucloxacillin sodium medicine compound liposome injection.
The preparation of embodiment 3 amoxicillin sodium flucloxacillin sodium medicine compound liposome injections
Prescription (specification 2.0g)
Amoxicillin Sodium 100g
Flucloxacillin sodium 100g
Soybean lecithin 500g
Cholesterol 120g
Glucose 350g
Mannitol 350g
Sodium benzoate 30g
The preparation process makes amoxicillin sodium flucloxacillin sodium medicine compound liposome injection with embodiment 2.
The preparation of embodiment 4 amoxicillin sodium flucloxacillin sodium medicine compound liposome injections
Prescription (specification 3.0g)
Amoxicillin Sodium 200g
Flucloxacillin sodium 200g
Soybean lecithin 800g
Cholesterol 300g
Glucose 500g
Mannitol 500g
The preparation process makes amoxicillin sodium flucloxacillin sodium medicine compound liposome injection with embodiment 2.Comparative example 1-4 respectively write out a prescription component and parts by weight such as table 1.
Table 1 Comparative Examples prescription is formed
| Component | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 | Comparative Examples 4 |
| Amoxicillin Sodium | 25g | 50g | 100g | 200g |
| Flucloxacillin sodium | 25g | 50g | 100g | 200g |
| Soybean lecithin | / | 300g | 500g | 800g |
| Hydrogenated yolk lecithin | 100g | / | / | / |
| Cholesterol | 20g | / | 120g | 300g |
| 18-amine. | / | 75g | / | / |
| Glucose | 62.5g | 250g | 700g | / |
| Mannitol | 62.5g | 250g | / | 750g |
| Lactose | / | / | / | 250g |
| Sodium benzoate | 2.5g | 35g | / | / |
| Potassium sorbate | / | / | 30g | 20g |
Prepare amoxicillin sodium flucloxacillin sodium medicine compound liposome injection by above prescription component, method for preparing is with embodiment 1.
The investigation of Test Example 1 liposome
Sample prepared among embodiment 1-4 and the Comparative Examples 1-4 is carried out quality investigation, mainly carry out liposome morphologic observation, particle size determination and liposome encapsulation and measure.
Wherein liposome form and particle size determination adopt optical microscopy and the computing of statistica5.0 statistical software to observe about 2000 to average.Entrapment efficiency determination adopts column chromatography for separation to combine spectrophotometry; This method operating procedure is: use column chromatography the liposome in the drug solution is separated; Utilize surfactant to destroy the liposome bilayer, calculate envelop rate with ultraviolet spectrophotometry and standard control again after medicine is discharged.
Each item result adds up like following table 2:
The investigation of table 2 liposome
| The liposome form | Mean diameter (nm) | Envelop rate (%) | |
| Embodiment 1 | Spherical or oval entity | 220 | 87.8 |
| Embodiment 2 | Spherical or oval entity | 250 | 86.9 |
| Embodiment 3 | Spherical or oval entity | 260 | 88.2 |
| Embodiment 4 | Spherical or oval entity | 230 | 87.1 |
| Comparative Examples 1 | Irregular shape | 1200 | 11.3 |
| Comparative Examples 2 | Irregular shape | 980 | 22.0 |
| Comparative Examples 3 | Spherical or oval entity | 530 | 64.2 |
| Comparative Examples 4 | Spherical or oval entity | 480 | 58.1 |
Above result has proved absolutely that the liposome effect of embodiment of the invention 1-4 preparation is fine, the form rule, and size is suitable for injection, and envelop rate is higher, has proved practical feasibility of the present invention.
Test Example 2 study on the stability
The amoxicillin sodium for injection flucloxacillin sodium that sample and Tianjin Huajin Pharmaceutical Co., Ltd. of embodiment of the invention 1-4, Comparative Examples 1-4 preparation produced was respectively at accelerated test under 40 ℃ of high temperature, relative humidity 75% condition 6 months; Respectively the 0th, 1,2,3,6 sampling at the end of month; Detect the variation of each item index; Sample each item of embodiment of the invention preparation as a result detects index and has no significant change; And Comparative Examples 1-4 and listing preparation quicken that related substance obviously increases after 6 months, and content obviously reduces, and the back clarity of redissolving is against regulation.The superiority of the present invention aspect the increase product stability has been described.
Foregoing description of the present invention is intended to as explanation, rather than restriction.Concerning the art technology people, can carry out multiple variation or modification in the embodiment described herein.Do not depart from the scope of the present invention or spirit in can obtain these variations.
Claims (2)
1. amoxicillin sodium flucloxacillin sodium medicine compound liposome injection is characterized in that:
And process 100 bottles through the method for following steps:
(1) 100g soybean lecithin and 20g cholesterol being dissolved in the 800ml volume ratio is in 3: 1 the isopropyl alcohol and ethanol mixed solvent; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent; Obtained immobilized artificial membrane; Add pH value 5.6 citric acid-sodium citrate buffer solution 500ml stirring and dissolving, obtain blank liposome solution;
(2) 25g Amoxicillin Sodium and 25g flucloxacillin sodium are dissolved in the 300ml water for injection; With prepared blank liposome solution mix homogeneously; Be incubated under 70 ℃ of states supersound process 40 minutes; Add again after 62.5g glucose and 62.5g mannitol, 2.5g sodium benzoate fully dissolve, with 0.45 μ m filtering with microporous membrane;
(3) above-mentioned steps (2) gained solution is carried out spray drying, be distributed into 100 bottles under the aseptic condition, make amoxicillin sodium flucloxacillin sodium medicine compound liposome injection.
2. amoxicillin sodium flucloxacillin sodium medicine compound liposome injection is characterized in that:
And process 100 bottles through the method for following steps:
(1) 300g soybean lecithin and 75g cholesterol being dissolved in the 1500ml volume ratio is in 3: 1 the isopropyl alcohol and ethanol mixed solvent; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent; Obtained immobilized artificial membrane; Add pH value 5.6 citric acid-sodium citrate buffer solution 800ml stirring and dissolving, obtain blank liposome solution;
(2) 50g Amoxicillin Sodium and 50g flucloxacillin sodium are dissolved in the 500ml water for injection; With prepared blank liposome solution mix homogeneously; Be incubated under 50 ℃ of states supersound process 60 minutes; Add again after 250g glucose and 250g mannitol, 35g sodium benzoate fully dissolve, with 0.45 μ m filtering with microporous membrane;
(3) above-mentioned steps (2) gained solution is carried out spray drying, be distributed into 100 bottles under the aseptic condition, make amoxicillin sodium flucloxacillin sodium medicine compound liposome injection.
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| CN102327224A (en) * | 2011-08-11 | 2012-01-25 | 傅苗青 | Adenosine cyclophosphate liposome injection and preparation method thereof |
| CN103040752B (en) * | 2012-12-20 | 2015-01-07 | 海南圣欣医药科技有限公司 | Shuxuening lipidosome injection |
| CN103330711B (en) * | 2013-07-11 | 2014-08-06 | 广州安健实业发展有限公司 | Flucloxacillin sodium and amoxicillin sodium for injection |
| CN113876713B (en) * | 2021-11-23 | 2023-02-03 | 河南省儿童医院郑州儿童医院 | Amoxicillin sodium and clavulanate potassium liposome and preparation method thereof |
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| CN1255331A (en) * | 1998-11-30 | 2000-06-07 | 王弘 | Hollow prosomatic liposome, its preparing process and clinical application of its encapsulated matter |
| EA004875B1 (en) * | 2000-06-28 | 2004-08-26 | Хамар Бакулиш Мафатлал | Use an agent for reversal of drug resistance in mycobacterium tuberculosis |
| CN1290511C (en) * | 2004-04-13 | 2006-12-20 | 南京易川药物研究所 | Doxorubicin liposome hydrochloride preparation and its preparing method |
| WO2006016468A1 (en) * | 2004-08-11 | 2006-02-16 | Konica Minolta Medical & Graphic, Inc. | Method of producing liposome-containing preparation |
| CN100490807C (en) * | 2006-10-23 | 2009-05-27 | 石药集团欧意药业有限公司 | Cephalofruxin ester liposome, its preparation and medicinal composition containing it |
| CN100548298C (en) * | 2008-04-09 | 2009-10-14 | 海南本创医药科技有限公司 | Pantoprazole sodium liposomes freeze-dry preparations and preparation method thereof |
| CN101518530B (en) * | 2009-03-12 | 2012-08-22 | 广州安健实业发展有限公司 | Stable solid composite medicament of compound penicillin |
| CN101623263B (en) * | 2009-08-24 | 2010-08-18 | 海南美大制药有限公司 | Cefminox sodium liposome preparation |
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