CN102993293A - Method for purifying teriparatide acetate - Google Patents
Method for purifying teriparatide acetate Download PDFInfo
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- CN102993293A CN102993293A CN2012105147573A CN201210514757A CN102993293A CN 102993293 A CN102993293 A CN 102993293A CN 2012105147573 A CN2012105147573 A CN 2012105147573A CN 201210514757 A CN201210514757 A CN 201210514757A CN 102993293 A CN102993293 A CN 102993293A
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Abstract
The invention provides a method for purifying teriparatide acetate, comprising the following steps: dissolving crude peptide by using the aqueous solution of 10-30% of acetic acid and 5-20% of acetonitrile in volume ratio; carrying out gradient elution and purification on a crude peptide solution; adjusting the pH value of the aqueous solution of 0.1-0.4% of sulfuric acid and 0.1-0.4% of acetic acid in volume ratio by using ammonia water to be 5.0-6.0; obtaining the solution as phase A and acetonitrile as phase B; eluting when the gradient of the phase B is 20-40%; salting out; washing by using an ammonium acetate solution containing 3-10% of acetonitrile; converting acetate by using the high performance liquid chromatography of the octadecylsilane chemically bonded silica gel; and eluting an acetic acid aqueous solution acetonitrile system. The invention aims to provide a method for purifying the teriparatide acetate, which is simple in operation, high in yield and purity, and favorably realizes industrialization.
Description
Technical field
The present invention relates to the purification process of a peptide species, relate in particular to the purification process of teriparatide acetate.
Background technology
Teriparatide, English name Teriparatide, molecular formula is C
181H
292N
55O
51S
2Teriparatide (pTH(1-34)) is 34 peptides, also claims human parathyroid hormone (1-34).Teriparatide is human parathyroid hormone (Parathyroid Hormone, human) N-terminal 1-34 polypeptide that amino acid forms, researched and developed by U.S. Eli Lilly company, use as medicine with teriparatide acetate, belong to the gene recombination medicine, gone on the market by drugs approved by FDA in 2002.It is the 1st bone formation-promoter that is approved for the treatment serious osteoporosis, and more widely market application foreground is arranged.
It is more to relate at present teriparatide synthetic document and patent; but relate to the less of purifying; the mass-producing purification (a collection of getting more than elaboration 200 grams) and the high purity that combine of reverse-phase chromatography of the present invention and saltouing and reach pharmaceutical grade (purity reaches more than 99.5%, maximum single mix 0.1%) and do not relate to especially particularly.
Prior art CN102731643A discloses a kind of purification process of teriparatide, adopt water as solvent, then adopt the C18 post to carry out purifying take the 0.2%TFA/ acetonitrile as moving phase, then turn salt with 0.2% acetic acid/acetonitrile C18 post, though can obtain the teriparatide acetate of higher degree, but total recovery only has about 20%, is unfavorable for industry production.
There is the low difficult problem of yield for solving prior art, improves the purification yield of teriparatide acetate, reduce production costs, also need purification process is further studied.
Summary of the invention
The present invention proposes a kind of purification process of teriparatide acetate, purity height and yield are good, reach industrialized requirement.
For achieving the above object, consider the character of teriparatide itself, the purification process of a kind of teriparatide acetate provided by the invention may further comprise the steps:
Step 1): dissolve thick peptide according to concentration 20g/L-50g/L with the acetic acid of volume ratio 10%-30% and 5%-20% acetonitrile solution; Water is diluted to 10%-30% with the volume ratio of the volume sum of the acetic acid in the thick peptide solution and acetonitrile.Step 1) hereinafter also is expressed as " pre-treatment ".
" thick peptide solution " refers to thick peptide through resulting solution after the pre-treatment, and employed water is pure water, and meets the water for injection standard, preferred ultrapure water; Employed acetic acid is analytically pure Glacial acetic acid, the preferred chromatographically pure of the purity grade of " acetonitrile " of the present invention.
Selecting the acetic acid of volume ratio 10%-30% and 5%-20% acetonitrile solution mixed solvent system is to consider that by simultaneous test the easy to operate of actual production process draws, can step-down in the concentration of the dissolution with solvents of this concentration, cause the sample dissolution volume excessive, be unfavorable for the processing (can cause the volume overload, purification efficiency is low) of reverse-phase chromatography.
Prior art CN102731643A adopts water as solvent, its can affect the purifying elution system concentration with an organic solvent, need elution system long period balance chromatographic column, adopting the thick peptide of other dissolution with solvents can introduce new solvent (causes finished product to introduce new organic solvent residual, affects final product quality.
The concentration of thick peptide of preparation is controlled at 20g/L-50g/L is conducive to purification efficiency, be higher than when 50g/L can cause follow-up reverse-phase chromatography purifying and do not hang chromatographic column, be lower than 20g/L and can make purification efficiency low.
Water is diluted to 10%-30% with the volume ratio of the volume sum of the acetic acid in the thick peptide solution and acetonitrile, when can causing follow-up reverse-phase chromatography purifying, do not hang by the solvent that is higher than 30% this scope when the ratio of acetic acid and acetonitrile chromatographic column, when the ratio of acetic acid and acetonitrile is lower than 10% sample is separated out, cause follow-up reverse-phase chromatography purifying to carry out.
Step 2): thick peptide solution is carried out the gradient elution purifying, and the sulfuric acid with 0.1%-0.4% and 0.1%-0.4% aqueous acetic acid (volume ratio is with ammoniacal liquor adjust pH 5.0-6.0, preferred 5.5) are the A phase, and acetonitrile is the B phase, gradient: B%:20%-40%; Step 2) hereinafter also is expressed as " purifying ".
The A that generates two kinds of buffering salts after two kinds of acid of sulfuric acid and 0.1%-0.4% acetic acid of selection 0.1%-0.4% are regulated with ammoniacal liquor is the result of optimized choice mutually, adopts 0.2%TFA to have better separating effect than prior art CN102731643A.The concentration of buffering salt is lower than limited range the moving phase surge capability is died down in the mobile phase A, and wash-out and spectrogram distortion do not reach the requirement of separation fully to cause sample.Greater than this scope, the excessive concentration of buffering salt is larger to the chromatographic system damage in the mobile phase A, even can the part generation saltout, and causing can't purifying.In addition, the pH value of mobile phase A is also extremely important, does not reach separating effect in 5.0-6.0 scopes.
The A phase preferably obtains by the great many of experiments sieve with B ratio mutually in the elution system, and B% is lower than 20% sample can not wash lower chromatographic column, and B% can go out in advance greater than 40% sample, all can not carry out purifying.Adopt this solvent systems purifying, separating effect can significantly improve than prior art, the yield about 90% in this step, and the purity of gained sample improves yield and purity greatly more than 95%, has reduced production cost.
Described " thick peptide " refers to adopt liquid phase synthesizing method or solid-phase synthesis to obtain, not yet pass through the teriparatide that the thick peptide of teriparatide of refinement treatment or purity can not fulfilling medicinals, the purity of teriparatide adopts the difficult purifying of realizing this concentration product of method of art methods CN102731643A more than 20% in the thick peptide.
Described step 2) use is with the chromatographic column of octadecylsilane chemically bonded silica as stationary phase in, and pillar diameter and length are preferably: 5 cm * 25 cm, 10 cm * 25 cm or 30 cm * 25 cm.
Step 3) adopts the method for saltouing that it is carried out further purifying, and its purity is reached more than 99%.Step 3) hereinafter also is expressed as " saltouing ".
Described " saltouing " refers to by control step 2) acetonitrile concentration of the qualified solution of gained and the pH value of solution, make the process that sample separates out (described qualified solution refers to that purity is greater than 95% sample).The preferred method of saltouing is: revolve the method for steaming with step 2 by normal temperature) ratio of acetonitrile is down to below 10% in the qualified solution of gained, is placed into 2-8 degree centigrade more than 2 hours after again its pH value being transferred to 5.5-7.0 with 20% weak ammonia, and it is separated out.Again turbid solution is carried out centrifugal treating, supernatant liquor is as liquid waste disposal; The lower floor solid with the phosphate aqueous solution of volume by volume concentration 50%-100% with its dissolving after, get final product with changing step 4) over to after one times of the water for injection dilution again.
In the described step 3), the ratio of acetonitrile is down to below 10% in the qualified solution of gained, again its pH value is preferably transferred to 6.5 with 20% weak ammonia; Be placed into 2-8 degree centigrade more than 2 hours, it is separated out; Again turbid solution is carried out centrifugal treating, supernatant liquor is as liquid waste disposal; Lower floor's solid preferably with 60% phosphate aqueous solution with its dissolving after, change step 4) over to after one times of the water for injection dilution again.Adopt the phosphate aqueous solution of this pH value and respective concentration to have the effect of better saltouing.
This step improves the purity of sample, with the purity of teriparatide from greater than 95% to greater than 99.0%.In addition, use the salt analysis method to have very large cost advantage than CN102731643A, the cost that the cost of saltouing is processed well below reverse-phase chromatography, particularly particularly evident when large-scale production.
Step 4) adopts reversed-phased high performace liquid chromatographic that the vitriol of teriparatide is changed into acetate.Step 4) hereinafter also is expressed as " turning salt ".
The stationary phase of described " RPLC " is eight alkyl silane bonded silica gels, and the method that turns salt is preferably: with the Spirit of Mindererus flushing 15-30min that contains 3%-10% acetonitrile, the concentration of Spirit of Mindererus is 0.1%-0.8%, preferred 0.3%; Then use aqueous acetic acid acetonitrile system wash-out, the concentration of described aqueous acetic acid is 0.1%-0.4%, is preferably 0.2%.The acetonitrile concentration that this elution step adopts is more than 40%, collects teriparatide solutions, and is concentrated, gets teriparatide acetate after the lyophilize.
Use is with the chromatographic column of eight alkyl silane bonded silica gels as stationary phase in the described step 4), and pillar diameter and length are preferably: 5 cm * 25 cm, 10 cm * 25 cm or 30 cm * 25 cm.
Purifying teriparatide method operation feasible provided by the invention, purity high (can reach more than 99.0% and maximum single mixing less than 0.1%), yield high (purification yield can reach more than 80%) reach industrialized requirement (a batch can obtain the above smart peptide of 200 grams).
The present invention adopts reverse-phase chromatography and the way of the combination of saltouing is carried out purification process; the purifying that is conducive to the thick peptide sample of concentration about 20%; have very large cost advantage (cost that the cost of saltouing is processed well below reverse-phase chromatography) than CN102731643A, particularly particularly evident when large-scale production.The teriparatide purity that obtains of the present invention is than Gao Keda more than 99.5% in addition, and arbitrary list is assorted all less than 0.1%, meets the requirements of customs declaration of the standards country pharmaceutical chemicalss such as the U.S. and European Union fully.Purification process of the present invention has significantly improved the quality of product, and greatly reduces than the purifying cost of prior art, and yield also significantly improves.
Description of drawings
Fig. 1: adopt embodiment 1 to obtain the HPLC spectrogram of teriparatide acetate.
Embodiment
Embodiment one:
1. sample preparation:
Dissolve thick peptide with 10%-30% acetic acid and 5%-20% acetonitrile solution according to the concentration that is not more than 50g/L with volume ratio; Water is following for subsequent use with the organic phase dilution proportion to 30% in the thick peptide solution.
2. purifying:
Purification condition: chromatographic column: the chromatographic column take octadecylsilane chemically bonded silica as stationary phase, pillar diameter and length are: 5 cm * 25 cm.Moving phase: A phase: 0.3% sulfuric acid and 0.2% aqueous acetic acid (v/v), with ammonia soln adjust pH 6.0; The B phase: acetonitrile, flow velocity: 50-80 ml/min, gradient B%:20%-40% detects wavelength: 280 nm.Sample size is 2.5g.
Purge process: rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 2.5g.Linear gradient elution 60min collects the purpose peak, the teriparatide solutions purity of collecting is no more than in water temperature greater than 95% part vacuum rotary steam is concentrated into acetonitrile concentration less than for subsequent use afterwards 10% below under 35 ℃ the condition.
3. saltout:
Salting-out process: with step 2) after the sample solution that obtains transfers to 5.5 with 20% ammoniacal liquor with its pH value, be placed into again in the 2-8 degree centigrade of refrigerator and take out after 3 hours, carry out centrifugal treating with 3 minutes methods of 3000 rev/mins, supernatant liquor is as liquid waste disposal, lower floor's solid with 50% phosphate aqueous solution with its dissolving after, get final product with changing step 4) over to after one times of the water for injection dilution again.
4. turn salt:
Chromatographic column: the chromatographic column take eight alkyl silane bonded silica gels as stationary phase, pillar diameter and length are: 5 cm * 25 cm.Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50%, applied sample amount 2g, with 0.3% the ammonium acetate aqueous solution flushing 15-30min that contains 5% acetonitrile, then with 0.2% the aqueous acetic acid wash-out that contains 50% acetonitrile, collect the purpose peak, the teriparatide solutions of collecting is no more than in water temperature goes to suitable big or small cillin bottle after vacuum rotary steam is concentrated into about 100 mg/mL under 35 ℃ of conditions.Can obtain purity after the lyophilize greater than 99.5% teriparatide acetate.
Embodiment two:
1. sample preparation:
Dissolve thick peptide with 10%-30% acetic acid and 5%-20% acetonitrile solution according to the concentration that is not more than 50g/L with volume ratio; Water is following for subsequent use with the organic phase dilution proportion to 30% in the thick peptide solution.
2. purifying:
Purification condition: chromatographic column: the chromatographic column take octadecylsilane chemically bonded silica as stationary phase, pillar diameter and length are: 10 cm * 25 cm.Moving phase: A phase: 0.3% sulfuric acid and 0.2% aqueous acetic acid (v/v), with ammonia soln adjust pH 5.5; The B phase: acetonitrile, flow velocity: 150-250 ml/min, gradient B%:20%-40% detects wavelength: 280 nm.Sample size is 10g.
Purge process: rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 10g.Linear gradient elution 60min collects the purpose peak, the teriparatide solutions purity of collecting is no more than in water temperature greater than 95% part vacuum rotary steam is concentrated into acetonitrile concentration less than for subsequent use afterwards 10% below under 35 ℃ the condition.
3. saltout:
Salting-out process: with step 2) after the sample solution that obtains transfers to 6.0 with 20% ammoniacal liquor with its pH value, be placed into again in the 2-8 degree centigrade of refrigerator and take out after 3 hours, carry out centrifugal treating with 3 minutes methods of 3000 rev/mins, supernatant liquor is as liquid waste disposal, lower floor's solid with 80% phosphate aqueous solution with its dissolving after, get final product with changing step 4) over to after one times of the water for injection dilution again.
4. turn salt:
Chromatographic column: the chromatographic column take eight alkyl silane bonded silica gels as stationary phase, pillar diameter and length are: 10 cm * 25 cm.Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50%, applied sample amount 10g, with 0.3% the ammonium acetate aqueous solution flushing 15-30min that contains 5% acetonitrile, then with 0.2% the aqueous acetic acid wash-out that contains 50% acetonitrile, collect the purpose peak, the teriparatide solutions of collecting is no more than in water temperature goes to suitable big or small cillin bottle after vacuum rotary steam is concentrated into about 100 mg/mL under 35 ℃ of conditions.Can obtain purity after the lyophilize greater than 99.5% teriparatide acetate.
Embodiment three:
1. sample preparation:
Dissolve thick peptide with 10%-30% acetic acid and 5%-20% acetonitrile solution according to the concentration that is not more than 50g/L with volume ratio; Water is following for subsequent use with the organic phase dilution proportion to 30% in the thick peptide solution.
2. purifying:
Purification condition: chromatographic column: the chromatographic column take octadecylsilane chemically bonded silica as stationary phase, pillar diameter and length are: 15 cm * 25 cm.Moving phase: A phase: 0.3% sulfuric acid and 0.2% aqueous acetic acid (v/v), with ammonia soln adjust pH 5.0; The B phase: acetonitrile, flow velocity: 350-600 ml/min, gradient B%:20%-40% detects wavelength: 280 nm.Sample size is 25g.
Purge process: rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 25g.Linear gradient elution 60min collects the purpose peak, the teriparatide solutions purity of collecting is no more than in water temperature greater than 95% part vacuum rotary steam is concentrated into acetonitrile concentration less than for subsequent use afterwards 10% below under 35 ℃ the condition.
3. saltout:
Salting-out process: with step 2) after the sample solution that obtains transfers to 6.5 with 20% ammoniacal liquor with its pH value, be placed into again in the 2-8 degree centigrade of refrigerator and take out after 3 hours, carry out centrifugal treating with 3 minutes methods of 3000 rev/mins, supernatant liquor is as liquid waste disposal, lower floor's solid with 100% phosphate aqueous solution with its dissolving after, get final product with changing step 4) over to after one times of the water for injection dilution again.
4. turn salt:
Chromatographic column: the chromatographic column take eight alkyl silane bonded silica gels as stationary phase, pillar diameter and length are: 15 cm * 25 cm.Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50%, applied sample amount 25g, with 0.3% the ammonium acetate aqueous solution flushing 15-30min that contains 5% acetonitrile, then with 0.2% the aqueous acetic acid wash-out that contains 50% acetonitrile, collect the purpose peak, the teriparatide solutions of collecting is no more than in water temperature goes to suitable big or small cillin bottle after vacuum rotary steam is concentrated into about 100 mg/mL under 35 ℃ of conditions.Can obtain purity after the lyophilize greater than 99.5% teriparatide acetate.
Embodiment four:
1. sample preparation:
Dissolve thick peptide with 10%-30% acetic acid and 5%-20% acetonitrile solution according to the concentration that is not more than 50g/L with volume ratio; Water is following for subsequent use with the organic phase dilution proportion to 30% in the thick peptide solution.
2. purifying:
Purification condition: chromatographic column: the chromatographic column take octadecylsilane chemically bonded silica as stationary phase, pillar diameter and length are: 30 cm * 25 cm.Moving phase: A phase: 0.3% sulfuric acid and 0.2% aqueous acetic acid (v/v), with ammonia soln adjust pH 5.5; The B phase: acetonitrile, flow velocity: 50-80 ml/min, gradient B%:20%-40% detects wavelength: 280 nm.Sample size is 100g.
Purge process: rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 100g.Linear gradient elution 60min collects the purpose peak, the teriparatide solutions purity of collecting is no more than in water temperature greater than 95% part vacuum rotary steam is concentrated into acetonitrile concentration less than for subsequent use afterwards 10% below under 35 ℃ the condition.
3. saltout:
Salting-out process: with step 2) after the sample solution that obtains transfers to 6.5 with 20% ammoniacal liquor with its pH value, be placed into again in the 2-8 degree centigrade of refrigerator and take out after 3 hours, carry out centrifugal treating with 3 minutes methods of 3000 rev/mins, supernatant liquor is as liquid waste disposal, lower floor's solid with 60% phosphate aqueous solution with its dissolving after, get final product with changing step 4) over to after one times of the water for injection dilution again.
4. turn salt:
Chromatographic column: the chromatographic column take eight alkyl silane bonded silica gels as stationary phase, pillar diameter and length are: 30 cm * 25 cm.Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50%, applied sample amount 100g, with 0.3% the ammonium acetate aqueous solution flushing 15-30min that contains 5% acetonitrile, then with 0.2% the aqueous acetic acid wash-out that contains 50% acetonitrile, collect the purpose peak, the teriparatide solutions of collecting is no more than in water temperature goes to suitable big or small cillin bottle after vacuum rotary steam is concentrated into about 100 mg/mL under 35 ℃ of conditions.Can obtain purity after the lyophilize greater than 99.5% teriparatide acetate.
Claims (7)
1. the purification process of a teriparatide acetate may further comprise the steps:
Step 1): dissolve thick peptide according to concentration 20g/L-50g/L with the acetic acid of volume ratio 10%-30% and 5%-20% acetonitrile solution; Water is diluted to 10%-30% with the volume ratio of the volume sum of the acetic acid in the thick peptide solution and acetonitrile;
Step 2): the chromatographic column of thick peptide solution take octadecylsilane chemically bonded silica as stationary phase carried out the gradient elution purifying, with the aqueous solution of the sulfuric acid of volume ratio 0.1%-0.4% and volume ratio 0.1%-0.4% acetic acid solution after with ammoniacal liquor adjust pH 5.0-6.0 be A mutually, acetonitrile is the B phase, gradient: B%:20%-40%;
Step 3): with step 2) ratio of acetonitrile is down to below 10% in the qualified solution of gained, be placed into 2-8 degrees centigrade more than 2 hours after again its pH value being transferred to 5.5-7.0 with 20% weak ammonia, it is separated out, again turbid solution is carried out centrifugal treating, supernatant liquor is as liquid waste disposal; Lower floor's solid with 50%-100% phosphate aqueous solution with its dissolving after, again with one times of water for injection dilution;
Step 4): carry out high performance liquid phase with eight alkyl silane bonded silica gels and turn salt, step 3) gained solution is washed 15-30min with the Spirit of Mindererus that contains 3%-10% acetonitrile, the concentration of Spirit of Mindererus is 0.1%-0.8%, then use aqueous acetic acid acetonitrile system wash-out, collect teriparatide solutions, the volume by volume concentration of the acetic acid in the described aqueous acetic acid is 0.1%-0.4%, and the acetonitrile concentration that this elution step adopts is more than 40%.
2. described method according to claim 1 is characterized in that: is the A phase with the solution behind the ammoniacal liquor adjust pH 5.5 described step 2).
3. described method according to claim 1 is characterized in that: the pH value transfers to 6.5 with 20% weak ammonia in the described step 3).
4. described method according to claim 2 is characterized in that: the pH value transfers to 6.5 with 20% weak ammonia in the described step 3).
5. according to claim 1 to the described method of 4 arbitrary claims, it is characterized in that: in the described step 3) lower floor's solid with 60% phosphate aqueous solution with its dissolving after, again with one times of water for injection dilution.
6. according to claim 1 to the described method of 4 arbitrary claims, it is characterized in that: the concentration of Spirit of Mindererus is 0.3% in the described step 4), and the volume by volume concentration of the acetic acid in the aqueous acetic acid is 0.2%.
7. described method according to claim 5, it is characterized in that: the concentration of Spirit of Mindererus is 0.3% in the described step 4), the volume by volume concentration of the acetic acid in the aqueous acetic acid is 0.2%.
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| CN103694338A (en) * | 2013-12-20 | 2014-04-02 | 深圳翰宇药业股份有限公司 | Purification method of glucagon hydrochloride |
| CN106167522A (en) * | 2016-08-29 | 2016-11-30 | 杭州湃肽生化科技有限公司 | A kind of method of extensive isolated and purified teriparatide (Teriparatide) |
| CN108101959A (en) * | 2016-11-24 | 2018-06-01 | 四川科伦药物研究院有限公司 | A kind of method for preparing high-purity polypeptide or its analog |
| CN108373499A (en) * | 2018-02-06 | 2018-08-07 | 美药星（南京）制药有限公司 | A kind of purifying of Teriparatide acetate and ionic control method |
| CN111057140A (en) * | 2018-10-17 | 2020-04-24 | 深圳市健元医药科技有限公司 | Selepressin purification method |
| CN114316021A (en) * | 2021-12-29 | 2022-04-12 | 江苏诺泰澳赛诺生物制药股份有限公司 | Teriparatide and purification method thereof |
| CN114478750A (en) * | 2021-12-28 | 2022-05-13 | 深圳翰宇药业股份有限公司 | Purification method of teriparatide |
| CN115656391A (en) * | 2022-12-12 | 2023-01-31 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting impurities contained in teriparatide |
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| CN103694338A (en) * | 2013-12-20 | 2014-04-02 | 深圳翰宇药业股份有限公司 | Purification method of glucagon hydrochloride |
| CN103694338B (en) * | 2013-12-20 | 2018-04-06 | 深圳翰宇药业股份有限公司 | A kind of purification process of glucagon hydrochloride |
| CN106167522A (en) * | 2016-08-29 | 2016-11-30 | 杭州湃肽生化科技有限公司 | A kind of method of extensive isolated and purified teriparatide (Teriparatide) |
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