CN101461783B - Netilmicin sulphate nano micelle preparation for intravenous injection and preparation method thereof - Google Patents
Netilmicin sulphate nano micelle preparation for intravenous injection and preparation method thereof Download PDFInfo
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- CN101461783B CN101461783B CN2008101834132A CN200810183413A CN101461783B CN 101461783 B CN101461783 B CN 101461783B CN 2008101834132 A CN2008101834132 A CN 2008101834132A CN 200810183413 A CN200810183413 A CN 200810183413A CN 101461783 B CN101461783 B CN 101461783B
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Abstract
The invention provides a netilmicin sulfate nano-micelle preparation capable of being intravenously injected and a preparation method thereof. The netilmicin sulfate nano-micelle preparation is prepared from netilmicin sulfate, polyethylene glycol-phospholipid and an additive by the method comprising the following steps: the netilmicin sulfate and the polyethylene glycol-phospholipid are prepared into a polymer lipid membrane, and water or a buffer solution which is dissolved with the additive is added into the polymer lipid membrane for hydration to be prepared into the netilmicin sulfate nano-micelle preparation capable of being intravenously injected. The netilmicin sulfate nano-micelle preparation achieves the aim of long-acting circulation in blood, greatly improves the bioavailability, and also greatly increases the stability.
Description
Technical field
The present invention relates to a kind of can intravenous netilmicin sulfate nano-micelle preparations and preparation method thereof.Belong to field of pharmaceutical preparations.
Background technology
Netilmicin is a semisynthetic aminoglycoside broad-spectrum antibiotic.Its mechanism of action is to work by the normal protein matter that suppresses sensitive microbial is synthetic.Netilmicin has anti-microbial effect widely, be primarily aimed at gram negative bacilli and belong to and the minority gram positive bacteria, comprise citric acid bacterium genus, Enterobacter, escherichia coli, Klebsiella, bacterium morgani, bacillus pyocyaneus, Salmonella, Shigella and staphylococcus (penicillin resistant and methicillin bacterium).This product is external also to have activity to some isolating acinetobacter calcoaceticus, neisseria, the positive Bacillus proteus of indole, Rhodopseudomonas, Serratia.Be applicable to the treatment of responsive microbial complexity urinary tract infection, septicemia, skin soft-tissue infection, abdominal cavity infection and lower respiratory infection.
The sulfate of netilmicin, netilmicin sulfate have increased the widespread popularity of its preparation, but this product stability in aqueous solution is still very poor, and especially under heating condition, oxidation Decomposition is obvious, and the quality of the pharmaceutical preparations is difficult to ensure.
Summary of the invention
The object of the present invention is to provide a kind of can intravenous netilmicin sulfate nano-micelle preparations and preparation method thereof, have good quality stability.
For achieving the above object, technical solution of the present invention is as follows:
Provided by the invention can intravenous netilmicin sulfate nano-micelle preparations, make by the method that comprises following steps by netilmicin sulfate, polyglycol derivatization phospholipid and additives: netilmicin sulfate and polyglycol derivatization phospholipid are made the polymer adipose membrane, adding is dissolved with the water or the buffer solution aquation of additives, but makes the nano-micelle preparations of the netilmicin sulfate of injection for intravenous.
As preferably, in the above-mentioned described preparation wherein the weight ratio of netilmicin sulfate and polyglycol derivatization phospholipid be 1:(5～10).
Above-mentioned described can intravenous netilmicin sulfate nano-micelle preparations, wherein said additives, be not particularly limited, can select the proper drug adjuvant for use according to the preparation needs, the preferred described additives of the present invention comprise frozen-dried supporting agent, antioxidant or pH value regulator.
Further, the component of netilmicin sulfate nano-micelle preparations provided by the invention consists of: netilmicin sulfate 50～300mg, polyglycol derivatization phospholipid 250mg～3g, frozen-dried supporting agent 100mg～1g, antioxidant 2～10mg, pH value regulator adjust pH 4.5～7.0.
Above-mentioned described netilmicin sulfate nano-micelle preparations, wherein said polyglycol derivatization phospholipid are that peg molecule is by the active group be combined on covalent bond and the phospholipid molecule, active group such as nitrogenous base or hydroxyl.
Further, the molecular weight polyethylene glycol scope in the wherein said polyglycol derivatization phospholipid structure is 200～20000, and is preferred 1000～10000, and more preferably molecular weight polyethylene glycol is 2000.
Further, phospholipid is phosphatidyl ethanolamine, phosphatldylcholine, phosphinositides, phosphatidyl serine, two phosphatidyl glycerol, the sour phospholipid that contracts, haemolysis cholinphospholipide, haemolysis ethanolamine phospholipid, distearyl phosphatidyl ethanolamine, dipalmitoylphosphatidylethanoiamine or DOPE in the wherein said polyglycol derivatization phospholipid.
As most preferably, above-mentioned described netilmicin sulfate nano-micelle preparations, wherein said polyglycol derivatization phospholipid are Macrogol 2000 DSPE (PEG2000-DSPE).
Above-mentioned described netilmicin sulfate nano-micelle preparations, wherein said antioxidant is selected from one or more in sodium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite, thiourea, dibenzylatiooluene, ascorbic acid, the Butylated hydroxyanisole; Described frozen-dried supporting agent is selected from one or more in mannitol, lactose, glucose, sucrose, sorbitol, xylitol, maltose, glycine, the sodium chloride; Described pH value regulator is selected from one or more in hydrochloric acid, lactic acid, sodium hydroxide, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, sodium dihydrogen phosphate, the sodium hydrogen phosphate.
The preparation method of netilmicin sulfate nano-micelle preparations provided by the invention may further comprise the steps:
(1) netilmicin sulfate and polyglycol derivatization phospholipid are dissolved in an amount of organic solvent or its mixture, mixing is uniformly dispersed, and organic solvent is removed in decompression, gets the polymer adipose membrane of netilmicin sulfate;
(2). in the polymer adipose membrane of gained, add the aqueous solution that is dissolved with frozen-dried supporting agent and antioxidant, adding pH value regulator buffer solution adjusting pH value again is 4.5～7.0, heating in water bath to 50～70 ℃ aquation 1～3 hour, the polyglycol derivatization phospholipid bag that obtains netilmicin sulfate carries nano-micelle;
(3), obtain the lyophilized formulations of netilmicin sulfate with the micellar solution lyophilization that obtains.
Organic solvent is one or more in methanol, ethanol, chloroform, dichloromethane, normal hexane, the n-butyl alcohol in the wherein above-mentioned preparation process (1).
Antioxidant is preferably sodium sulfite or sodium pyrosulfite in the above-mentioned preparation process (2), and frozen-dried supporting agent is preferably mannitol or glucose, and the pH value regulator is preferably citric acid and sodium citrate buffer or phosphate buffer.
Beneficial effect below by description of test technical scheme provided by the present invention.The prepared netilmicin sulfate nano-micelle preparations of each embodiment and the powder pin of list marketing are carried out quality testing.Respectively the powder pin of the netilmicin sulfate nano-micelle preparations that makes and list marketing is placed under 60 ℃ of high temperature, illumination 4500Lx condition and carried out the influence factor in 10 days and test investigation; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 18 months, carry out long term test and investigate, detect the variation of every quality index, the gained data are shown in table 1-3:
Table 1 influence factor result
Table 2 accelerated test result
Table 3 long-term test results
By above data result as can be seen, the sample that the embodiment of the invention makes influence factor 10 days, quicken June and long-term 18 months after every quality index do not have significant change, all meet quality standard; The injectable powder influence factor of list marketing 10 days, quicken June and long-term 18 months after every quality index change greatly, exceed the quality standard requirement.Proved absolutely that the netilmicin sulfate injectable powder stability for preparing is fine in the technology of the present invention scope, had fine preparation superiority.
Compared with prior art, the preparation method of netilmicin sulfate nano-micelle preparations provided by the invention has following advantage:
1, nano-micelle of the present invention is wrapped in netilmicin sulfate in the hydrophobic core, has not only reached long-acting circulation purpose in blood, has greatly improved bioavailability, but also has increased stability of formulation greatly.
2, preparation process of the present invention is simple than liposome, is fit to large-scale production more.
3, with the mode intravenously administrable of netilmicin sulfate, be a kind of new trial, have very big novelty, domestic discovery as yet at present with the nano-micelle lyophilized formulations.
The specific embodiment
Embodiment 1
Netilmicin sulfate 50g
Macrogol 2000 DSPE 250g
Sodium sulfite 2g
Mannitol 100g
Phosphate buffer is regulated pH value 4.5～7.0
Preparation technology
(1) take by weighing netilmicin sulfate 50g and Macrogol 2000 DSPE 250g is dissolved in the 500ml normal hexane, mixing is uniformly dispersed, and normal hexane is removed in decompression, the polymer adipose membrane of netilmicin sulfate;
(2) 100g mannitol and 2g sodium bisulfate is water-soluble, add in the polymer adipose membrane of gained, adding phosphate buffered solution adjusting pH value again is 5.8, heating in water bath to 70 ℃ aquation 1 hour, and the Macrogol 2000 DSPE bag that obtains netilmicin sulfate carries nano-micelle;
(3), obtain the lyophilized formulations of netilmicin sulfate with the micellar solution lyophilization that obtains.
Embodiment 2
Netilmicin sulfate 300g
Macrogol 2000 dipalmitoylphosphatidylethanoiamine 3000g
Sodium pyrosulfite 10g
Glucose 1000g
Citrate buffer is regulated pH value 4.5～7.0
Preparation technology
(1) take by weighing netilmicin sulfate 300g and Macrogol 2000 dipalmitoylphosphatidylethanoiamine 3000g is dissolved in the 6000ml dehydrated alcohol, mixing is uniformly dispersed, and dehydrated alcohol is removed in decompression, the polymer adipose membrane of netilmicin sulfate;
(2) 1000g glucose and 10g sodium pyrosulfite is water-soluble, add in the polymer adipose membrane of gained, adding citrate buffer solution adjusting pH value again is 5.6, heating in water bath to 50 ℃ aquation 3 hours, the Macrogol 2000 dipalmitoylphosphatidylethanoiamine bag that obtains netilmicin sulfate carries nano-micelle;
(3), obtain the lyophilized formulations of netilmicin sulfate with the micellar solution lyophilization that obtains.
Embodiment 3
Netilmicin sulfate 100g
Macrogol 2000 DOPE 800g
Sodium thiosulfate 5g
Lactose 500g
Citrate buffer is regulated pH value 4.5～7.0
Preparation method makes netilmicin sulfate nano-micelle lyophilized formulations with embodiment 1.
Embodiment 4
Netilmicin sulfate 200g
Macrogol 2000 phosphatidyl ethanolamine 1500g
Sodium sulfite 8g
Sorbitol 900g
Phosphate buffer is regulated pH value 4.5～7.0
Preparation method makes netilmicin sulfate nano-micelle lyophilized formulations with embodiment 1.
According to the above embodiments the present invention has been made detailed description.It should be noted that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (3)
- One kind can intravenous netilmicin sulfate nano-micelle preparations, by netilmicin sulfate, polyglycol derivatization phospholipid and additives are made by the method that comprises following steps: netilmicin sulfate and polyglycol derivatization phospholipid are made the polymer adipose membrane, add the water or the buffer solution aquation that are dissolved with additives, but make the nano-micelle of the netilmicin sulfate of injection for intravenous, with the micellar solution lyophilization that obtains, obtain the lyophilized formulations of netilmicin sulfate, wherein, described additives are frozen-dried supporting agent, antioxidant and pH value regulator, and, netilmicin sulfate 50～300mg, polyglycol derivatization phospholipid 250mg～3g, frozen-dried supporting agent 100mg～1g, antioxidant 2～10mg, pH value regulator adjust pH 4.5～7.0, wherein, by weight netilmicin sulfate: polyglycol derivatization phospholipid is 1: (5～10), described polyglycol derivatization phospholipid is the Macrogol 2000 DSPE, the Macrogol 2000 dipalmitoylphosphatidylethanoiamine, Macrogol 2000 DOPE or Macrogol 2000 phosphatidyl ethanolamine, described frozen-dried supporting agent is a mannitol, glucose, lactose or sorbitol, described antioxidant is a sodium sulfite, sodium pyrosulfite, sodium thiosulfate or sodium sulfite, described pH value regulator is phosphate buffer or citrate buffer.
- 2. method for preparing the described netilmicin sulfate nano-micelle preparations of claim 1, it may further comprise the steps:(1) netilmicin sulfate and polyglycol derivatization phospholipid are dissolved in an amount of organic solvent, mixing is uniformly dispersed, and organic solvent is removed in decompression, gets the polymer adipose membrane of netilmicin sulfate;(2) in the polymer adipose membrane of gained, add the aqueous solution that is dissolved with frozen-dried supporting agent and antioxidant, adding pH value regulator buffer solution adjusting pH value again is 4.5～7.0, heating in water bath to 50～70 ℃ aquation 1～3 hour, the polyglycol derivatization phospholipid bag that obtains netilmicin sulfate carries nano-micelle;(3), obtain the lyophilized formulations of netilmicin sulfate with the micellar solution lyophilization that obtains.
- 3. the preparation method of netilmicin sulfate nano-micelle preparations according to claim 2, wherein said organic solvent is selected from one or more in methanol, ethanol, chloroform, dichloromethane, normal hexane, the n-butyl alcohol.
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| CN2008101834132A CN101461783B (en) | 2008-12-16 | 2008-12-16 | Netilmicin sulphate nano micelle preparation for intravenous injection and preparation method thereof |
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| CN2008101834132A CN101461783B (en) | 2008-12-16 | 2008-12-16 | Netilmicin sulphate nano micelle preparation for intravenous injection and preparation method thereof |
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| CN102451154A (en) * | 2010-10-14 | 2012-05-16 | 山东方明药业股份有限公司 | Netilmicin sulfate injection and preparation method thereof |
| CN102512365A (en) * | 2011-12-21 | 2012-06-27 | 无锡济民可信山禾药业股份有限公司 | Etimicin sulfate micelle freeze-dried powder injection and its preparation method |
| CN103610653B (en) * | 2013-11-27 | 2016-05-11 | 海南通用康力制药有限公司 | A kind of preparation method of injection netilmicin sulfate freeze-dried powder |
| CN109771371B (en) * | 2019-03-19 | 2020-03-20 | 安徽联谊药业股份有限公司 | Clindamycin phosphate injection and preparation method thereof |
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Non-Patent Citations (4)
| Title |
|---|
| 国家药典委员会.中华人民共和国药典 2 2005年版.化学工业出版社,2005,739-740. * |
| 国家药典委员会.中华人民共和国药典2 2005年版.化学工业出版社,2005,739-740. |
| 林宏英，陆晓燕，唐宁，梁伟.长春新碱PEG-PE胶束的制备及其对乳腺癌细胞生长的抑制.生物化学与生物物理进展33 8.2006,33(8),769-774. |
| 林宏英,陆晓燕,唐宁,梁伟.长春新碱PEG-PE胶束的制备及其对乳腺癌细胞生长的抑制.生物化学与生物物理进展33 8.2006,33(8),769-774. * |
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Owner name: HAINAN YONGTIAN PHARMACEUTICAL INSTITUTE CO., LTD. Free format text: FORMER OWNER: HAINAN MEIDA PHARMACEUTICAL CO., LTD. Effective date: 20130723 |
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Effective date of registration: 20130723 Address after: 570216 C03, Haikou Free Trade Zone, Hainan, China Patentee after: Hainan Yongtian Pharmaceutical Institute Co., Ltd. Address before: Room 416, Yu Cheng Building, science and technology Avenue, national hi tech Zone, Haikou, Hainan Patentee before: Hainan Meida Pharmaceutical Co., Ltd. |
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