CN103709244B - The purification process of a kind of insulin crystals or insulin analog crystals - Google Patents
The purification process of a kind of insulin crystals or insulin analog crystals Download PDFInfo
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- CN103709244B CN103709244B CN201310455305.7A CN201310455305A CN103709244B CN 103709244 B CN103709244 B CN 103709244B CN 201310455305 A CN201310455305 A CN 201310455305A CN 103709244 B CN103709244 B CN 103709244B
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Abstract
The invention belongs to medicinal chemistry art, disclose the purification process of a kind of Regular Insulin and analog crystals thereof.Volatile, the hypotoxic organic solvent of purification process employing of the present invention rinses at short notice and adds drip washing insulin crystals or its analog crystals, with thoroughly except the volatility difference of trace residual in decrystallizing and the high organic solvent of toxicity, after drip washing terminates by dry remove up hill and dale to rinse add the good organic solvent of volatility that drip washing introduces, thus solve the problem of not volatile organic solvent residual in crystallization.Purification process of the present invention is simple and efficient to handle, the insulin crystals that purifying obtains or its analog crystals finished product higher than untreated crystallization purity, dissolvent residual is lower, and particle is more homogeneous, dispersed better, is convenient to preserve and packing.
Description
This application claims the right of priority on September 29th, 2012 submits that Patent Office of the People's Republic of China, application number are 201210380407.2 to, denomination of invention is the Chinese patent application of " a kind of insulin crystals and or the purification process of its analog crystals of Regular Insulin ", its full content combines in this application by reference.
Technical field
The invention belongs to medicinal chemistry art, relate to the purification process of a kind of insulin crystals or insulin analog crystals.
Background technology
Regular Insulin is a kind of proteohormone secreted as the stimulation of glucose, lactose, ribose, arginine, hyperglycemic-glycogenolytic factor etc. by endogenous or exogenous material by beta Cell of islet, Regular Insulin uniquely falls hypoglycemic hormone in body, promotes glycogen, fat, protein synthesis simultaneously.Regular Insulin is first found in nineteen twenty-one by the Canadian F.G. class court of a feudal ruler and C.H. bass the first chief executive of Special Administrative Region.Nineteen twenty-two starts for clinical, and the diabetic subject do not controlled of making over is saved.The Regular Insulin of current clinical application mainly all extracts from pig, Pancreas Bovis seu Bubali.But because insulinize still has limitation, a kind of novel insulin-insulin analog arises at the historic moment.Insulin analog refers to the secretion both can simulating Normal insulin, and simultaneously structurally also similar to Regular Insulin material, more traditional insulin human is more suitable for Human Physiology needs.Current insulin analog mainly comprises Lantus, insulin detemir, Insulin lispro, insulin aspart and moral paddy Regular Insulin.
In the preparation process of Regular Insulin and analogue thereof, generally all will carry out crystallisation step, due to the Regular Insulin after crystallization and analogue is convenient preserves, therefore crystallization is a requisite link in the preparation technology of existing Regular Insulin and analogue thereof.But mostly all need to add the organic solvents such as phenol derivatives in the crystallisation process of at present Regular Insulin and analogue thereof, these volatility differences and the residual meeting of the high organic solvent of toxicity have a strong impact on the quality of insulin product.Such as phenol is a kind of noxious solvent, and volatility is poor, has severe corrosive, has strong corrosive nature to skin, mucous membrane, also can suppress central nervous system or infringement Liver and kidney function simultaneously.Carrying out phenol analysis to current insulin analog-Lantus at two kinds of commercialized product of China, all find that there is the phenol of certain content.Regular Insulin and insulin analog market huge, there is not the reported in literature of insulin crystal or insulin analog crystals body Impurity removal aspect at present, therefore how to remove in insulin crystals or insulin analog crystals residual volatility difference and the high organic solvent of toxicity, the quality improving Regular Insulin and insulin analog medicine is a great problem that current technology faces.
Summary of the invention
In view of this, the object of the invention is for the problems of the prior art, the purification process of a kind of insulin crystals or insulin analog crystals be provided, the insulin crystals after purifying or insulin analog crystal purity high, dissolvent residual is low.
For realizing object of the present invention, the present invention adopts following technical scheme:
A purification process for insulin crystals or insulin analog crystals, comprising:
Step 1, get insulin crystals to be purified or insulin analog crystals, add organic solvent and rinse crystal, be stirred to suction filtration after dispersion completely, collect gained crystal.
Step 2, collect step 1 gained crystal, use organic solvent drip washing, drip washing terminates to drain completely afterwards, is drying to obtain further;
Wherein, described insulin crystals to be purified or insulin analog crystals contain phenol derivatives; Described organic solvent is one or more in ethanol, acetonitrile, n-propyl alcohol, propyl carbinol, Virahol, acetone, or ethanol, acetonitrile, n-propyl alcohol, propyl carbinol, Virahol, one or more and water in acetone mixture, and in mixture, the content of water is less than 50v/v%; Time sum≤the 120min of described flushing crystal and drip washing crystal.
Regular Insulin and analogue thereof belong to proteohormone, and the sample of protein is different from general chemical example, because protein has certain space structure, strong acid, highly basic, heavy metallic salt, urea, guanidine, stain remover, trichoroacetic acid(TCA), organic solvent, high temperature, ray, ultrasonic wave, the factor such as thermal agitation or stirring all easily makes protein generation sex change, therefore conventional impurity elimination mode is adopted to remove volatility difference in insulin crystals or insulin analog crystals and while the high organic solvent of toxicity, to ensure the protein-active of insulin crystals or insulin analog crystals.
The present invention adopts volatile hypotoxic organic solvent to rinse insulin crystals to be purified or insulin analog crystals with except residual a large amount of volatility difference in decrystallizing and organic solvent impurity such as the relatively high phenol derivatives of toxicity, further with volatile hypotoxic organic solvent drip washing insulin crystals or insulin analog crystals, with thoroughly except the volatility difference of trace residual in decrystallizing and the high organic solvent of toxicity, drip washing terminate rear drain completely insulin crystals or insulin analog crystals then by dry remove up hill and dale to rinse add the good organic solvent of volatility that drip washing introduces, thus the problem of not volatile organic solvent residual in solution crystallization.The whole process of purification process of the present invention all operates under normal temperature or low temperature, and the time adding drip washing insulin crystals or insulin analog crystals with organic solvent flushing is shorter, volatile organic solvent removed finally by drying, haveing suffered journey effectively can prevent protein denaturation.The insulin crystals obtained by the present invention or insulin analog crystals finished product high compared to untreated crystallization purity, dissolvent residual is lower, and particle is more homogeneous, dispersed better, is convenient to preserve and packing.
As preferably, drip washing crystal described in step 2 is for organic solvent gradation rinse step 1 gained crystal.Described gradation is specially more than at least twice, can be three times, four times.Under the prerequisite that each organic solvent rinsing crystal is enough, the number of times of flushing is more, and it is more thorough that volatility difference residual in crystallization and the high organic solvent of toxicity are removed.
Further, in certain embodiments, then the concrete operations of described drip washing crystal rinse suction filtration after each flush for getting organic solvent gradation dropping on crystal, or drip suction filtration on crystal and while each flushing for getting organic solvent.
As preferably, the consumption of organic solvent of described flushing crystal be the 5-15 of crystal volume doubly, be more preferably 8-10 doubly.
As preferably, the consumption of organic solvent of described drip washing crystal be the 5-10 of crystal volume doubly, be more preferably 6-8 doubly.
The organic solvent that described in purification process of the present invention, volatility is good to be described organic solvent be in ethanol, acetonitrile, n-propyl alcohol, propyl carbinol, Virahol, acetone one or more, or ethanol, acetonitrile, n-propyl alcohol, propyl carbinol, Virahol, one or more and water in acetone mixture, and in mixture, the content of water is less than 50v/v%.As Virahol, acetone, 80% ethanol, 85% ethanol, 90% ethanol etc. all effectively can remove the residual of organic solvent in crystallization.
As preferably, described organic solvent is 80 ~ 100% acetonitriles, one or more of 80 ~ 100% ethanol or 80 ~ 100% n-propyl alcohols.
In order to avoid long organic solvent process makes insulin crystals or insulin analog crystals sex change, described in purification process of the present invention, rinse the time sum≤120min of crystal and drip washing crystal, be preferably≤45min.Described flushing crystal time is 20min in certain embodiments, and the described drip washing time is 8min.Described flushing crystal time is 15min in further embodiments, and the drip washing time is 20min.
Preferred, the time sum≤15min of described flushing crystal and drip washing crystal.Described flushing crystal time is 10min in certain embodiments, and the described drip washing time is 5min.Described flushing crystal time is 5min in further embodiments, and the drip washing time is 10min.
Further, insulin analog crystals described in purification process of the present invention is insulin glargine crystals, insulin detemir crystallization, Insulin lispro crystallization, insulin aspart crystal or moral paddy insulin crystals.
Purification process of the present invention removes the good organic solvent of volatility rinsing and add drip washing and introduce up hill and dale after draining insulin crystals or insulin analog crystals completely further by drying.As preferably, described drying is vacuum-drying or lyophilize.
As preferably, described phenol derivatives is phenol, meta-cresol or Resorcinol.
Insulin crystals of the present invention or insulin analog crystals can for refining commercial products, also can be the insulin crystals prepared of method known to those skilled in the art or insulin analog crystals.
By high performance liquid chromatography (HPLC) and pharmacodynamics, the present invention proves that insulin crystals of the present invention or insulin analog crystals activity and purifying did not change in the past in a particular embodiment.
The invention provides the purification process of a kind of insulin crystals or insulin analog crystals, adopt volatile, hypotoxic organic solvent to rinse at short notice and add drip washing insulin crystals or insulin analog crystals, with thoroughly except the volatility difference of trace residual in decrystallizing and the high organic solvent of toxicity, after drip washing terminates by dry remove up hill and dale to rinse add the good organic solvent of volatility that drip washing introduces, thus solve the problem of not volatile organic solvent residual in crystallization.Purification process of the present invention is simple and efficient to handle, the insulin crystals that purifying obtains or insulin analog crystals finished product higher than untreated crystallization purity, dissolvent residual is lower, and particle is more homogeneous, dispersed better, is convenient to preserve and packing.
Accompanying drawing explanation
Fig. 1 shows the comparative result figure of Lantus crystal hypoglycemic effect before and after dehydrated alcohol process.
Embodiment
The embodiment of the invention discloses the purification process of a kind of insulin crystals or insulin analog crystals.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope method as herein described is changed or suitably change with combination, realize and apply the technology of the present invention.
For realizing object of the present invention, the present invention adopts following technical scheme:
Embodiment 1:
Take the insulin glargine crystals of the preparation such as phenol, zinc chloride, the acetonitrile adding about crystallization 10 times of volumes rinses crystal 10min, stirs after crystal is disperseed completely, opens vacuum pump suction filtration, uses the acetonitrile drip washing 5min of about 8 times of volumes more simultaneously.Drip washing terminates to drain completely afterwards, takes out crystallization, puts into lyophilized plate freeze-drying.Phenol content before and after the acetonitrile treatment that HPLC method detects in Lantus crystal, the results are shown in Table 1.And molten residual with reference to national standard employing gas chromatographic detection to acetonitrile in final Lantus crystal freeze-drying prods, the results are shown in Table 2.
Phenol content before and after table 1 acetonitrile treatment in Lantus crystal
The content of acetonitrile in table 2 Lantus crystal freeze-drying prods
From table 1 result, do not detect phenol and remain in the Lantus crystal after acetonitrile rinses, illustrates that acetonitrile can effectively removes the residual of organic solvent in crystallization, illustrate that the effect of phenol in acetonitrile removal crystallization is very significant.From table 2 result, in final Lantus crystal freeze-drying finished product, the residual of acetonitrile does not detect, far below national standard.
Embodiment 2:
Insulin glargine crystals described in Example 1, the dehydrated alcohol adding about crystallization 8 times of volumes rinses crystal 20min, after stirring makes to disperse completely, open vacuum pump suction filtration, use the dehydrated alcohol drip washing 8min of about 5 times of volumes more simultaneously, drip washing terminates to drain completely afterwards, takes out crystallization, puts into lyophilized plate freeze-drying.Phenol content before and after the dehydrated alcohol process that HPLC method detects in Lantus crystal, the results are shown in Table 3, and molten residual with reference to national standard employing gas chromatographic detection to ethanol in final Lantus crystal freeze-drying prods, the results are shown in Table 4.
Phenol content before and after the process of table 3 dehydrated alcohol in Lantus crystal
The content of acetonitrile in table 4 Lantus crystal freeze-drying prods
From table 3 result, do not detect phenol and remain in the Lantus crystal after dehydrated alcohol rinses, illustrates that dehydrated alcohol can effectively removes the residual of organic solvent in crystallization, illustrate that the effect of phenol in dehydrated alcohol removal crystallization is very significant.From table 4 result, the residual quantity of ethanol unusual pettiness in final Lantus crystal freeze-drying finished product, far below national standard.
Embodiment 3:
Take meta-cresol, insulin crystals prepared by zinc chloride, add 95% alcohol flushing crystal 15min of about crystallization 15 times of volumes, after stirring makes to disperse completely, open vacuum pump suction filtration, use 95% ethanol rinse 20min of about 10 times of volumes again, drip washing terminates to drain completely afterwards, takes out crystallization simultaneously, put into lyophilized plate, add a small amount of frozen water and soak.Meta-cresol content before and after 95% Ethanol Treatment that HPLC method detects in insulin crystal, the results are shown in Table 5.And molten residual with reference to national standard employing gas chromatographic detection to ethanol in final insulin crystal freeze-drying prods, the results are shown in Table 6.
Meta-cresol content before and after table 595% Ethanol Treatment in insulin crystal
The content of ethanol in table 6 insulin crystal freeze-drying prods
From table 5 result, do not detect phenol in the Lantus crystal after 95% alcohol flushing and remain, illustrate that 95% ethanol can effectively removes the residual of organic solvent in crystallization, illustrate that the effect that phenol in crystallization removed by 95% ethanol is very significant.From table 6 result, the residual quantity of ethanol unusual pettiness in final Lantus crystal freeze-drying finished product, far below national standard.
Embodiment 4:
Take Resorcinol, zinc chloride prepares insulin aspart crystal.The crystallization suction filtration obtained reclaims crystal, after draining, close vacuum pump, the n-propyl alcohol adding about crystallization 5 times of volumes rinses crystal 5min, stirs after making to disperse completely, open vacuum pump suction filtration, use the n-propyl alcohol drip washing 10min of about 6 times of volumes again, drip washing terminates to drain completely afterwards, takes out crystallization simultaneously, put into lyophilized plate, add a small amount of frozen water and soak.Resorcinol content in the n-propyl alcohol process front/rear door winter insulin crystal that HPLC method detects, the results are shown in Table 7.And molten residual with reference to national standard employing gas chromatographic detection to n-propyl alcohol in final insulin aspart crystal freeze-drying prods, the results are shown in Table 8.
Resorcinol content in table 7 n-propyl alcohol process front/rear door winter insulin crystal
The content of n-propyl alcohol in table 8 insulin aspart crystal freeze-drying prods
From table 7 result, do not detect Resorcinol and remain in the insulin aspart crystal after n-propyl alcohol rinses, illustrates that n-propyl alcohol effectively removes remaining of organic solvent in crystallization.From table 8 result, the residual quantity of n-propyl alcohol unusual pettiness in final insulin aspart crystal freeze-drying prods, far below national standard.
Embodiment 5
The insulin glargine crystals (sample B) of embodiment 1 after dehydrated alcohol insulin glargine crystals before treatment (sample A) and process is respectively taken 0.1mg, 2mL water dissolution is used after mixing, carry out HPLC detection, sample A is consistent with the color atlas of sample B, all obtains simple spike.
Embodiment 6
With reference to Chinese Pharmacopoeia. two [S] .2010: annex, the described method of 119-122.First the insulin glargine crystals (sample B) of embodiment 1 after dehydrated alcohol insulin glargine crystals before treatment (sample A) and process is prepared the sample becoming 2U/mL respectively.According to official method, rabbit is divided into saline control group, sample A group and sample B group, often organize each 10.
Rabbit fasting, after 18 ~ 20 hours, gets blood from the auricular vein of each group of rabbit respectively, measures basal plasma glucose.Respectively organize rabbit afterwards and inject Lantus sample A, sample B respectively from the subcutaneous dosage by 0.25ml/kg of same area, control group insulin injection diluent, in injection after 0.25,0.5,1,1.5,2,2.5,3,3.5,4,5,6,8,10,24h, respectively from each rabbit ear edge venous blood sampling sample, blood sugar is detected with blood sugar instrument, and close observation rabbit action change.Calculate the mean value often organizing each time each rabbit blood glucose per-cent.Statistics is shown in Fig. 1.
From Fig. 1 result, compared to control group, use Lantus sample A and Lantus sample B all to have significant hypoglycemic effect, and retarding action continue for 8 hours.Lantus sample A and Lantus sample B hypoglycemic effect no significant difference, B group average hypoglycemic result is more better than A group effect, is estimated as caused by animal model subjects difference and error.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.
Claims (7)
1. a purification process for insulin crystals or insulin analog crystals, is characterized in that, comprising:
Step 1, get insulin crystals to be purified or insulin analog crystals, add organic solvent and rinse crystal, be stirred to suction filtration after dispersion completely, collect gained crystal;
Step 2, collect step 1 gained crystal, use organic solvent drip washing, drip washing terminates to drain completely afterwards, is drying to obtain further;
Wherein, described insulin crystals to be purified or insulin analog crystals contain phenol derivatives; Described organic solvent is one or more in ethanol, acetonitrile, n-propyl alcohol, or ethanol, acetonitrile, one or more and water in n-propyl alcohol mixture, and in mixture, the content of water is less than 50v/v%; Time sum≤the 45min of described flushing crystal and drip washing crystal; The consumption of organic solvent of described flushing crystal is 5-15 times of crystal volume, and the consumption of organic solvent of described drip washing crystal is 5-10 times of crystal volume.
2. purification process according to claim 1, is characterized in that, drip washing crystal described in step 2 is for organic solvent gradation rinse step 1 gained crystal.
3. purification process according to claim 1, it is characterized in that, then the concrete operations of drip washing crystal described in step 2 rinse suction filtration after each flush for getting organic solvent gradation dropping on crystal, or drip suction filtration on crystal and while each flushing for getting organic solvent.
4. purification process according to claim 1, is characterized in that, the consumption of organic solvent of described flushing crystal be the 8-10 of crystal volume doubly.
5. purification process according to claim 1, is characterized in that, the consumption of organic solvent of described drip washing crystal be the 6-8 of crystal volume doubly.
6. purification process according to claim 1, it is characterized in that, described organic solvent is 80 ~ 100% acetonitriles, one or more of 80 ~ 100% ethanol or 80 ~ 100% n-propyl alcohols.
7. purification process according to claim 1, it is characterized in that, described phenol derivatives is phenol, meta-cresol or Resorcinol.
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| CN201310455305.7A CN103709244B (en) | 2012-09-29 | 2013-09-29 | The purification process of a kind of insulin crystals or insulin analog crystals |
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| CN106117345B (en) * | 2015-05-05 | 2020-11-24 | 宜昌东阳光长江药业股份有限公司 | Method for preparing insulin glargine crystal |
| CN107118270B (en) * | 2017-04-12 | 2021-06-18 | 华润昂德生物药业有限公司 | Washing method of insulin detemir crystals |
| CN108929376B (en) * | 2017-05-23 | 2021-05-14 | 鲁南制药集团股份有限公司 | Washing method of insulin crystal or insulin analogue crystal |
| CN111386281B (en) * | 2017-09-26 | 2024-03-19 | 拜康生物制品印度有限公司 | Integrated automated filtration for separation, washing and drying of peptide crystals |
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| DE3511269A1 (en) * | 1985-04-12 | 1986-10-09 | Veb Berlin-Chemie, Ddr 1199 Berlin | METHOD FOR PURIFYING INSULIN |
| CN1340549A (en) * | 2000-08-26 | 2002-03-20 | 徐州万邦生化制药有限公司 | Process for preparing glucagon |
| CN1165549C (en) * | 2002-06-15 | 2004-09-08 | 江苏万邦生化医药股份有限公司 | Process for rourifying insuline |
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