CN101224298B - Propofol compounds - Google Patents
Propofol compounds Download PDFInfo
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- CN101224298B CN101224298B CN2008100189516A CN200810018951A CN101224298B CN 101224298 B CN101224298 B CN 101224298B CN 2008100189516 A CN2008100189516 A CN 2008100189516A CN 200810018951 A CN200810018951 A CN 200810018951A CN 101224298 B CN101224298 B CN 101224298B
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- propofol
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Abstract
The invention belongs to the pharmaceutical field, which relates to a propofol combination. The weight proportion of the materials contained in the combination is: propofol: hydroxypropyl-B-cyclodextrin: albumin is equal to 0.1-2 : 1-35 : 1-35. The combination has good stability, simple production technique and low cost, and the injection pain is alleviated obviously. .
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of good stability, the simple propofol composition of production technology.
Background technology
Propofol (2, the 6-diisopropyl phenol) is the intravenous anesthesia agent that is widely used.Because the propofol water solublity is very poor, makes propofol be difficult to be formulated in the aqueous solution, the commercially available prod is the emulsion injection at present, is made up of soybean oil, egg phosphatide, glycerol etc.The weak point of propofol emulsion injection is: the physical and chemical stability of product is poor, pain during injection is bigger, bulky grain may make blood vessel blockage, emulsion preparation technology is complicated in addition, owing to do not contain antibacterial in the formula for a product, a large amount of fat encourages the generation of microorganism easily in the formula for a product simultaneously.So the propofol emulsion in use must be noted the sterile working, the propofol emulsion after once using last no matter what, all should abandon, must not give over to and use next time.
At PCT patent application WO9317711 (Australian Commercial Research﹠amp; Development) comprised in the prescription of Miao Shuing that propofol and 6A-amino-6A-N-(4-ammonia butyl)-6A-deoxidation-beta-schardinger dextrin-forms associated complex.
S.Arzneim.-Forsch.43:818-823 (1993), Vierstein et.al have described the prescription of propofol and 2-hydroxy-beta-cyclodextrin formation associated complex.
Eur.J.Pharmacol.238:75-80 (1993), Pedersen et.al have described the prescription that comprises 17.83mg/ml propofol and 400mg/ml 2-hydroxy-beta-cyclodextrin.
J.Pharm.Sci.87:514-518 (1998), Trapani et.al. have described the interactively between propofol and the 2-hydroxy-beta-cyclodextrin and the anesthesia characteristic of this system.
International patent application no PCT/GB/00737 (South African Druggist Limited) has described a prescription composition and has comprised propofol and 2-hydroxyl-2-beta-schardinger dextrin-.(1∶2mol/mol)。This system has adopted cosolvent.
Int.J.Pharm.139:215-218 (1996), Trapani et.al. have described two methods of preparing propofol and HPBCD associated complex: cosolvent evaporation method and lyophilization.This this preparation steps relates to propofol and needed in 40.5%HPBCD balance 4 days.
Anesth Analg 82:920-924 (1996), Bielsen, SJ et.al. have described a prescription and have comprised 20% (W/V) the HPBCD solution of 5mg/ml propofol and assessed its effect to mouse cardiovascular aspect.
International Patent Application Publication No. WO/2003/06324:(Shimoda Biotech Ltd) Penkler, LJ have described a medicament freeze-drying powder and have formed, and it has comprised propofol and water soluble Beta-cyclodextrin forms complex.
International Patent Application Publication No. W/O/2004/108113 has described the propofol solution formula of a stable clarifying direct use.
United States Patent (USP) 7034013 (April 25,2006) (Cydex Inc.) Thompson, D.et al. have described a clarification propofol aqueous formulation.This prescription has comprised propofol and sulfobutyl ether-beta-cyclodextrin.The shortcoming of this prescription is to use high concentration (30-60%w/v) thereby HPBCD has produced remarkable influence to security of products.Also increased simultaneously product cost.This prescription must be preserved down at 2-8 ℃, and this has brought inconvenience to transportation and storage.
United States Patent (USP) 7138387 (NOV21,2006) (Bharat Serums﹠amp; Vaccines Limited) Pai, S et al. described-aqueous formulation of clarifying propofol and HPBCD, and the same with United States Patent (USP) 7034013, it has used the HPBCD of 30-60%W/V and product to preserve down at 2-8 ℃.
International Patent Application Publication No. is WO/2007/052295 (Bharat Serum﹠amp; Vaccine Limited) Daftary, GV et al. have described one and have been suitable for intravenous anesthetis solvent formula.This prescription has comprised propofol, HPBCD and local anesthetic lignocaine.
The albumen and the propofol that all do not relate to utilization in the patent of all references associate.
Summary of the invention
The purpose of this invention is to provide a kind of good stability, produce simple, easy to use and effective propofol composition.
The objective of the invention is to realize by following technical measures:
A kind of propofol composition is characterized in that said composition contains following weight ratio:
Propofol: hydroxypropyl-B-cyclodextrin: albumin is 0.1～2: 1～35: 1～35
Wherein albumin is human serum albumin or bovine serum albumin, and further albumin is preferably the human serum albumin.
Described compositions, its dosage form are injection solution.
Described compositions is also including but not limited to following one or more adjuvants: buffer solution, antioxidant, osmotic pressure regulator, pH regulator agent, antiseptic.
Wherein:
Buffer solution consists of: one or more of phosphate, citrate, glycine, histidine etc., and its concentration 1～150mM, pH are 4～8.5;
Antioxidant is: editic acid (EDTA), edetate, sodium pyrosulfite, acetylcysteine, ascorbic acid usp/bp, consumption are 0.01%～1.0% of composition total weight;
Osmotic pressure regulator is: one or more in glycerol, mannitol, sucrose, glucose, the sodium oxide, consumption are 0.1%～20% of composition total weight;
Antiseptic is: benzoic acid, benzyl alcohol, methaform, phenethanol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristyl 4-methyl pyridine chloride (myristylgammapicolinium chloride), sodium benzoate, sorbic acid, thymol, methyl parahydroxybenzoate, nipagin A, nipasol, butoben, ethylenediaminetetraacetic acid, edetate, and the antiseptic consumption is 0.005%～2.0% of a composition total weight;
The pH regulator agent is: HCL or NaOH etc.
The concentration of propofol can be 1mg/ml to 20mg/ml, and its solution pH value is 4～8.5.
Preparation of compositions method provided by the invention treats that for hydroxypropyl-B-cyclodextrin, albumin, antioxidant, antiseptic and osmotic pressure regulator etc. are dissolved in the suitable buffer solution thoroughly pH value is regulated after adding propofol and being stirred to thorough dissolving in the dissolving back.Aseptic filtration sterilization back envelope is filled in and promptly gets final products in vial or the plastic bag behind the standardize solution.
Clearly, can carry out some changes or improvement to the technology of the present invention, as raw material, additive and preparation method, but this and do not mean that these changes exceed the category of disclosure invention.
Beneficial effect of the present invention:
Propofol composition provided by the invention contains hydroxypropyl-B-cyclodextrin and albumin.Behind the said composition wiring solution-forming, good stability, injection pain obviously reduces, this is because the albumin in the prescription forms conjugate with propofol, thereby reduced free propofol when injection so pain.The propofol solution process that the present invention in addition studied is simple, greatly reduces production cost.This prescription has all shown suitable stability in 12 months that are tested under 2 ℃～35 ℃ preservation condition.
The specific embodiment
The invention will be further elaborated by the following examples.
Preparation embodiment 1:
Prescription:
Propofol 10g
Hydroxypropyl-B-cyclodextrin 100g
Human serum albumin 100g
Glycerol 1.8g
Ethylenediaminetetraacetic acid two is received 0.05g
Sodium hydrogen phosphate 12g
NaOH/HCL is an amount of
Water is an amount of
Preparation method: sodium hydrogen phosphate is dissolved in the injection water, be prepared into 1000ml buffer solution after regulating pH to 7.5 (with HCL or NaOH), hydroxypropyl-B-cyclodextrin, human serum albumin, glycerol, disodiumedetate are added 500ml buffer solution, after dissolving back adding propofol is stirred to thorough dissolving fully, regulate pH value to 7.5, the buffer solution that reuse has prepared is settled to 1000ml, behind the filtration sterilization filled with solution is become final products in type I vial.
Preparation embodiment 2:
Prescription:
Propofol 10g
Hydroxypropyl-B-cyclodextrin 100g
Bovine serum albumin 100g
Mannitol 5g
Acetylcysteine 0.01g
Glycine 1.5g
NaOH/HCL is an amount of
Water is an amount of
Preparation method: glycine is dissolved in the injection water, be prepared into 1000ml buffer solution after regulating pH to 7.0 (with HCL or NaOH), hydroxypropyl-B-cyclodextrin, bovine serum albumin, mannitol, acetylcysteine are added 500ml buffer solution, after dissolving back adding propofol is stirred to thorough dissolving fully, regulate pH value to 7.0, the buffer solution that reuse has prepared is settled to 1000ml, behind the filtration sterilization filled with solution is become final products in type I vial.
Preparation embodiment 3:
Prescription:
Propofol 10g
Hydroxypropyl-B-cyclodextrin 100g
Human serum albumin 100g
Sodium chloride 7g
Ethylenediaminetetraacetic acid two is received 0.05g
Sodium citrate 5g
NaOH/HCL is an amount of
Water is an amount of
Preparation method: sodium citrate is dissolved in the injection water, be prepared into 1000ml buffer solution after regulating pH to 7.0 (with HCL or NaOH), hydroxypropyl-B-cyclodextrin, human serum albumin, sodium chloride, ethylenediaminetetraacetic acid two received add 500ml buffer solution, after dissolving back adding propofol is stirred to thorough dissolving fully, regulate pH value to 7.0, the buffer solution that reuse has prepared is settled to 1000ml, behind the filtration sterilization filled with solution is become final products in type I vial.
Preparation embodiment 4:
Prescription:
Propofol 2g
Hydroxypropyl-B-cyclodextrin 20g
Human serum albumin 20g
Glucose 5g
Benzyl alcohol 0.1g
Histidine 10g
NaOH/HCL is an amount of
Water is an amount of
Preparation method: histidine is dissolved in the injection water, be prepared into 1000ml buffer solution after regulating pH to 6.5 (with HCL or NaOH), hydroxypropyl-B-cyclodextrin, human serum albumin, glucose, benzyl alcohol are added 500ml buffer solution, after dissolving back adding propofol is stirred to thorough dissolving fully, regulate pH value to 6.5, the buffer solution that reuse has prepared is settled to 1000ml, behind the filtration sterilization filled with solution is become final products in plastic bag.
Effect embodiment 1: the stability test of propofol solution:
Leave propofol solution (by embodiment 1 preparation) in 2～8 ℃, 25 ℃ and 35 ℃, at different measuring points liquid chromatography (analytical column: Hypersil ODS, 25cm*4.6mm, 5 μ m, detect wavelength: 270nm, mobile phase: the 600ml acetonitrile adds the mixed liquor that 150 methanol add the 250ml potassium phosphate solution, with analysis such as method such as degree such as grades), analyze its propofol content, data see the following form.The propofol solution that data show is prepared has shown suitable stability in 2 ℃～35 ℃ investigation scopes.
Table 1:
| The stability test of propofol solution | ||
| Detect the date (moon) | Storage requirement (℃) | Concentration (%) |
| 0 | 100.0 | |
| 0.25 | 35 | 99.8 |
| 0.5 | 35 | 100.1 |
| 25 | 100.2 | |
| The stability test of propofol solution | ||
| 0.75 | 35 | 100.5 |
| 1.0 | 35 | 100.0 |
| 25 | 99.9 | |
| 2～8 | 100.2 | |
| 1.25 | 35 | 99.7 |
| 1.5 | 35 | 99.8 |
| 2.0 | 35 | 100.4 |
| 25 | 100.2 | |
| 2～8 | 100.2 | |
| 3.0 | 35 | 99.6 |
| 25 | 101.2 | |
| 2～8 | 101.9 | |
| 6.0 | 35 | 100.0 |
| 25 | 102.3 | |
| 2～8 | 101.7 | |
| 9.0 | 35 | 99.8 |
| 25 | 100.2 | |
| 2～8 | 100.2 | |
| 12.0 | 35 | 99.4 |
| 25 | 101.3 | |
| 2～8 | 100.8 | |
Claims (3)
1. propofol composition is characterized in that said composition contains the material of following weight ratio:
Propofol: hydroxypropyl-B-cyclodextrin: albumin is 0.1～2: 1～35: 1～35;
And the dosage form of said composition is an injection solution.
2. compositions according to claim 1 is characterized in that albumin is human serum albumin or bovine serum albumin.
3. compositions according to claim 1 is characterized in that said composition also comprises following one or more adjuvants: buffer solution, antioxidant, osmotic pressure regulator, pH regulator agent, antiseptic;
Wherein:
Buffer solution consists of: one or more of phosphate, citrate, glycine, histidine etc., and its concentration is 1～150mM, pH is 4～8.5;
Antioxidant is: editic acid, edetate, sodium pyrosulfite, acetylcysteine, ascorbic acid usp/bp, consumption are 0.01～1.0% of composition total weight;
Osmotic pressure regulator is: one or more in glycerol, mannitol, sucrose, glucose, the sodium oxide, consumption are 0.1～20% of composition total weight;
Antiseptic is: benzoic acid, benzyl alcohol, methaform, phenethanol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristyl 4-methyl pyridine chloride, sodium benzoate, sorbic acid, thymol, methyl parahydroxybenzoate, nipagin A, nipasol, butoben, ethylenediaminetetraacetic acid, edetate, and the antiseptic consumption is 0.005～2.0% of a composition total weight;
The pH regulator agent is: HCL or NaOH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100189516A CN101224298B (en) | 2008-02-01 | 2008-02-01 | Propofol compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100189516A CN101224298B (en) | 2008-02-01 | 2008-02-01 | Propofol compounds |
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| CN101224298A CN101224298A (en) | 2008-07-23 |
| CN101224298B true CN101224298B (en) | 2010-06-23 |
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| CN2008100189516A Expired - Fee Related CN101224298B (en) | 2008-02-01 | 2008-02-01 | Propofol compounds |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103263404B (en) * | 2012-04-28 | 2017-12-01 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | A kind of composite anaesthetic |
| CN102973722B (en) * | 2012-11-28 | 2014-12-17 | 赵作君 | Novel anesthetic |
| CN104161040A (en) * | 2014-06-27 | 2014-11-26 | 中国人民解放军第三军医大学第一附属医院 | Hydroxypropyl-beta-cyclodextrin supermolecule clathrate compound of butyl p-hydroxybenzoate, and preparing method and using method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005007131A2 (en) * | 2003-07-10 | 2005-01-27 | American Bioscience, Inc. | Propofol formulations with non-reactive container closures |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005007131A2 (en) * | 2003-07-10 | 2005-01-27 | American Bioscience, Inc. | Propofol formulations with non-reactive container closures |
Non-Patent Citations (2)
| Title |
|---|
| Pedersen et al..Smooth muscle relaxant effects of propofol and ketamine inisolated guinea-pig trachea,.European Journal of Pharmacology238.1993,238第2页. * |
| Pedersenetal..Smoothmusclerelaxanteffectsofpropofolandketamineinisolatedguinea-pigtrachea .European Journal of Pharmacology238.1993 |
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