CN1915986A - High purified tanshinone IIA sodium sulfonate, fabricating method, and preparation - Google Patents
High purified tanshinone IIA sodium sulfonate, fabricating method, and preparation Download PDFInfo
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Abstract
This invention relates to a method for preparing high-purity sodium tanshionone IIA sulfonate, and preparations containing the compound. Determined by HPLC, the content of sodium tanshionone IIA sulfonate is higher than 96%, the total content of the related materials is lower than 10%, and the content of individual impurities is lower than 4.0%. The injection of high-purity sodium tanshionone IIA sulfonate can avoid the problems of flotation and precipitation of components. Besides, the compounds can also be manufactured into large-volume infusion and freeze-dried powder injection.
Description
[technical field]
The invention belongs to medical technical field, relate to a kind of sodium tanshinone IIA sulfate, particularly relate to a kind of highly purified sodium tanshinone IIA sulfate, also relate to the preparation method of this sodium tanshinone IIA sulfate, and the preparation that uses this sodium tanshinone IIA sulfate to make.
[background technology]
The red sage root (RADIX ET RHIZOMA SALVIAE MILTIORRHIZAE) is as a kind of important Chinese medicinal materials, and " Chinese pharmacopoeia is recorded by many editions.The red sage root is the dry root and rhizome of labiate red sage root Salvia miltiorrhiza Bge..Spring, Qiu Erji excavate, and remove silt, and be dry and get.Red sage root hardship is slightly cold; The thoughts of returning home, Liver Channel.Has stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, the function of the relieving restlessness that clears away heart-fire.Be used for menoxenia, through closing dysmenorrhoea ， lumps in the chest and abdomen, chest ventral spine pain, hot numbness pain, sore swells and ache, dysphoria and insomnia; Hepatosplenomegaly, diseases such as stenocardia.The red sage root is because of the difference of extracting method, and the contained main chemical compositions of the red sage root mainly contains two big classes, promptly fat-soluble tanshinone compound and water-soluble phenolic acid compounds.The biological activity of this two classes chemical ingredients is confirmed by many medical literature and clinical application.Fat-soluble component in the red sage root mainly is that a class is the tanshinone analog that contains conjugation o-quinone structure of representative with the Tanshinone II A.Extract Tanshinone II A from the red sage root, the sodium tanshinone IIA sulfate that obtains after sulfonation has strengthened the water-soluble of medicine greatly, has obtained the novel drugs of higher curative effect.
Sodium tanshinone IIA sulfate is used for coronary heart disease and angina pectoris and myocardial infarction, cerebral arteries and arteria retina and the formation of peripheral vein thrombus, Behcet's syndrome, erythema nodosum.Coronary artery dilator, coronary blood flow increasing; Reducing heart rate increases myocardial contraction, improves the myocardial metabolism disorder and the heart function that cause after the anoxic; Anticoagulant; Promote tissue repair; Blood fat reducing; Protection red corpuscle and bacteria growing inhibiting.
At present sodium tanshinone IIA sulfate has only little aqueous injection in the formulation of China's listing, the loaded China national drug standard of its quality standard (product standard number: WS-10001-(HD-1014)-2002 is hereinafter to be referred as " standard-1014 ").The also loaded China national drug standard of the quality standard of its corresponding bulk drug (product standard number: WS-10001-(HD-0923)-2002 is hereinafter to be referred as " standard-0923 ").
In to the research of the little aqueous injection of sodium tanshinone IIA sulfate injection liquid, production process, the inventor finds to exist two serious technical problems, promptly (1) is 40 ℃ of accelerated test conditions after next month, the related substance amount of preparation raises fast (method by standard-0923 is measured), and (2) injection liquid is easy to generate precipitation after placing one month under 40 ℃ of accelerated test conditions.
Although the inventor has carried out comprehensive, deep research from methods such as the prescription of preparation, technologies, still do not solve this two problems.
In the quality standard of bulk drug, content assaying method adopts spectrophotometry to measure, and limit is decided to be 96%; And tlc is adopted in the control of related substance, limit is decided to be: for the test liquid of sodium tanshinone IIA sulfate 5mg/ml, Tanshinone I sodium sulfonate wherein must not be crossed 0.2mg/ml (＜4.0%), and Tanshinone II A wherein must not be crossed 0.2mg/ml (＜4.0%).
The inventor finds that the sodium tanshinone IIA sulfate bulk drug by current standards-0923 is carried out adopts high effective liquid chromatography for measuring, and its content is less than 94%, and the related substance total amount is up to more than 13%, and single impurity is up to more than 6%.
The inventor finds unexpectedly, behind the sodium tanshinone IIA sulfate purifying with conformance with standard-0923, adopt high effective liquid chromatography for measuring, the total amount of the related substance of bulk drug is below 10.0%, the amount of single impurity is below 4.0%, content adopts this highly purified sodium tanshinone IIA sulfate bulk drug to prepare the injection liquid of sodium tanshinone IIA sulfate more than 96.0%, the problem that exists in the time of can overcoming above-mentioned preparation aqueous injection significantly.And also can obtain good effect with the large capacity transfusion agent of this highly purified sodium tanshinone IIA sulfate preparation, lyophilized injectable powder etc.
Therefore, the objective of the invention is to the preparation that the preparation method of a kind of highly purified sodium tanshinone IIA sulfate, this highly purified sodium tanshinone IIA sulfate is provided and uses this highly purified sodium tanshinone IIA sulfate to make.
[summary of the invention]
Technical problem to be solved by this invention has provided the preparation method of a kind of highly purified sodium tanshinone IIA sulfate, this highly purified sodium tanshinone IIA sulfate and the preparation that uses this sodium tanshinone IIA sulfate to make.
As previously mentioned, prior art, in the promptly existing bulk drug national drug standards (standard-0923), content assaying method adopts spectrophotometry to measure, and limit is decided to be 96%; And tlc is adopted in the control of related substance, limit is decided to be: for the test liquid of sodium tanshinone IIA sulfate 5mg/ml, Tanshinone I sodium sulfonate wherein must not be crossed 0.2mg/ml (＜4.0%), and Tanshinone II A wherein must not be crossed 0.2mg/ml (＜4.0%).
The commercially available prod sodium tanshinone IIA sulfate is (available from Shanghai No.1 Bio-Chemical Pharmacetical Industry Co., Ltd, lot identification mark is Y041120), measure by standard-0923, behind the deduction moisture, content is 96.3%, related substance calculates respectively by two kinds of impurity, all less than 4% (but all greater than 3%, with 4%, 3% contrast).
With above-mentioned bulk drug (lot number Y041120) preparation sodium tanshinone IIA sulfate injection liquid, after placing 3 months under 40 ℃ of accelerated test conditions, following problem appears:
(1) the related substance amount of preparation rising fast (method of pressing bulk drug standard-0923 is measured), two kinds of impurity calculate respectively, when initial all less than 4% (but all greater than 3%, with 4%, 3% contrast) when being increased to March all greater than 6% (but all less than 7%, with 6%, 7% contrast);
(2) injection liquid is easy to generate the block precipitation of white.
Based on these problems, the inventor finds, adopt high performance liquid chromatography, with the chromatographic condition of groping voluntarily, measure sodium tanshinone IIA sulfate (Y041120), its content snap-fastener calculates after removing moisture, only is 93.8%, and the related substance summation is up to 13.42% (maximum single impurity level reaches 6.11%).Causing this content and related substance is possible than big-difference, because spectrophotometry content in the current standards-0923, the tlc determination related substance, the specificity of its analytical procedure, accuracy, sensitivity etc. are all not as good as high performance liquid chromatography.
For this reason, (Y041120) carries out purifying to bulk drug, adopts high performance liquid chromatography to carry out quality control, and the content behind the purifying is more than 96.0% (HPLC), and the related substance total amount is below 10.0%, and the amount of single impurity is at (HPLC) below 4.0%.Adopt this through purifying, and after content and related substance reach above-mentioned requirements, compare (it is identical to write out a prescription) with the injection liquid made from unpurified bulk drug, the injection liquid made from purified feed stock 40 ℃ place 1 month after, the variation of related substance is little, and does not see have precipitation to occur.Here it is basis of the present invention.
Therefore, the present invention is achieved in that
(1) a kind of highly purified sodium tanshinone IIA sulfate: adopt high effective liquid chromatography for measuring content and related substance, the content of its sodium tanshinone IIA sulfate is more than 96.0%, and the related substance total amount is below 10.0%, and the amount of single impurity is below 4.0%.
(2) a kind of preparation method of highly purified sodium tanshinone IIA sulfate: the sodium tanshinone IIA sulfate bulk drug lower with purity is parent material, carries out recrystallization, obtains meeting the highly purified sodium tanshinone IIA sulfate of above (a 1) described specification of quality.
The sodium tanshinone IIA sulfate bulk drug that above-mentioned purity is lower can be commercially available sodium tanshinone IIA sulfate (for example, available from Shanghai No.1 Bio-Chemical Pharmacetical Industry Co., Ltd), measure by standard-0923, content is that 96.3%, two kind of impurity is all less than 4% (but greater than 3%, with 4%, 3% contrast).
The sodium tanshinone IIA sulfate bulk drug that above-mentioned purity is lower also can be the sodium tanshinone IIA sulfate of homemade low-purity, and its content can be lower than 96% of standard-0923 regulation, more than 90%, but is lower than 96% as content; And the amount of related substance is higher than the 4%+4% of standard-0923 regulation, as below 8%+8%, but more than 4%+4%.
(3) a kind of preparation that contains highly purified sodium tanshinone IIA sulfate: be pharmacological component promptly with the highly purified sodium tanshinone IIA sulfate of the present invention, make the preparation that contains sodium tanshinone IIA sulfate, as low capacity aqueous injection, lyophilized injectable powder, large capacity transfusion agent, oral solid formulation, oral liquid, external preparation etc.
Specifically, the present invention can realize by following scheme.
A kind of highly purified sodium tanshinone IIA sulfate is characterized in that,
(1) adopt high effective liquid chromatography for measuring content, the content of sodium tanshinone IIA sulfate wherein is more than 96.0%,
(2) adopt the high effective liquid chromatography for measuring related substance, wherein the total amount of related substance is below 10.0%, and the amount of single impurity is below 4.0%;
The method of described high effective liquid chromatography for measuring content and related substance, according to " two appendix VD of Chinese pharmacopoeia version in 2005 carry out, and may further comprise the steps:
(i) chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent, be 0.05mol/L with concentration and be that the volume ratio of 3.0 Spirit of Mindererus and methyl alcohol is that 35: 65 mixing solutions is a moving phase with the acetic acid adjust pH, the detection wavelength is 270nm, adjusting flow velocity to the retention time of sodium tanshinone IIA sulfate is about 8 minutes, number of theoretical plate calculates by the sodium tanshinone IIA sulfate peak should be not less than 2500, and the resolution at sodium tanshinone IIA sulfate peak and other peak should be greater than 1.2;
(ii) related substance inspection: it is an amount of to get sodium tanshinone IIA sulfate, adds the moving phase dissolving, makes the solution that concentration is about 100 μ g/ml, as need testing solution, precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, add moving phase and be diluted to scale, shake up, in contrast solution; Get contrast solution 20 μ l, inject liquid chromatograph, regulate detection sensitivity, make the peak height of main composition chromatographic peak be about 20% of full range; It is an amount of that other gets the Tanshinone II A reference substance, adds moving phase and make the solution that concentration is 10 μ g/ml, gets 20 μ l and inject liquid chromatograph, and the record color atlas is to 1.2 times of Tanshinone II A peak retention time; Precision is measured contrast solution and each 20 μ l of need testing solution again, injects liquid chromatograph respectively, and the record color atlas is to 1.2 times of Tanshinone II A peak retention time; Each impurity chromatographic peak area sum in the color atlas of need testing solution divided by contrast solution main peak area, is calculated the total amount of related substance; The chromatographic peak area of maximum single impurity calculates the amount of single impurity divided by contrast solution main peak area in the color atlas of need testing solution;
(iii) assay: precision takes by weighing the about 25mg of sodium tanshinone IIA sulfate, puts in the 100ml measuring bottle, adds the moving phase dissolving and is diluted to scale, shakes up, and the accurate again 5ml that draws puts in the measuring bottle of 50ml, adds moving phase and is diluted to scale, shakes up, as need testing solution; To meet China national drug standard WS-10001-(HD-0923)-2002, check that with (ii) item method the total amount of related substance is less than 2%, the amount of single impurity is below 1.0%, and be reference substance at 60 ℃ of following vacuum-dryings to the sodium tanshinone IIA sulfate of constant weight, it is an amount of that precision takes by weighing this sodium tanshinone IIA sulfate reference substance, with moving phase dissolving and make the reference substance solution that concentration is about 25 μ g/ml; Get each 20 μ l of need testing solution and reference substance solution, inject liquid chromatograph respectively, the record color atlas is pressed external standard method with calculated by peak area content.
Based on the above-mentioned high effective liquid chromatography for measuring content and the method for related substance, preferred, a kind of highly purified sodium tanshinone IIA sulfate provided by the invention is characterized in that,
(1) adopt high effective liquid chromatography for measuring content, the content of sodium tanshinone IIA sulfate wherein is more than 97.0%,
(2) adopt the high effective liquid chromatography for measuring related substance, wherein the total amount of related substance is below 8.0%, and the amount of single impurity is below 3.0%.
Based on the above-mentioned high effective liquid chromatography for measuring content and the method for related substance, preferred, a kind of highly purified sodium tanshinone IIA sulfate provided by the invention is characterized in that,
(1) adopt high effective liquid chromatography for measuring content, the content of sodium tanshinone IIA sulfate wherein is more than 98.0%,
(2) adopt the high effective liquid chromatography for measuring related substance, wherein the total amount of related substance is below 7.0%, and the amount of single impurity is below 2.5%.
A kind of preparation method of highly purified sodium tanshinone IIA sulfate:
(1) in 50～60 ℃ ethanol, the sodium tanshinone IIA sulfate powder than low-purity of adding, limit edged stir and make powder dissolution, obtain nearly saturated settled solution, add chloroform in liquor capacity than the ratio that is 3～7%, solution is heated to 70 ± 3 ℃, at room temperature leave standstill, slowly cool to room temperature, cool to 2～6 ℃ then, after to be crystallized the separating out, filter, vacuum-drying gets brick-red crystalline powder;
(2) measure content and related substance, content is more than 96.0% as a result, and the total amount of related substance is below 10.0%, and the amount of single impurity is below 4.0%.
Preferred scheme is a kind of preparation method of highly purified sodium tanshinone IIA sulfate:
(1) in 55～60 ℃ ethanol, add commercially available or homemade sodium tanshinone IIA sulfate powder than low-purity, the limit edged stirs and makes powder dissolution, obtains nearly saturated settled solution, add chloroform in liquor capacity than the ratio that is 5%, solution is heated to 70 ± 2 ℃, at room temperature leaves standstill, slowly cool to room temperature, cool to 2～6 ℃ then, after to be crystallized the separating out, filter vacuum-drying;
(2) measure content and related substance, content is more than 96.0% as a result, and the total amount of related substance is below 10.0%, and the amount of single impurity is below 4.0%.
Preferred scheme is a kind of preparation method of highly purified sodium tanshinone IIA sulfate:
(1) in 57～60 ℃ ethanol, add commercially available or homemade sodium tanshinone IIA sulfate powder than low-purity, the limit edged stirs and makes powder dissolution, obtains nearly saturated settled solution, add chloroform in liquor capacity than the ratio that is 5%, solution is heated to 70 ± 2 ℃, at room temperature leaves standstill, slowly cool to room temperature, cool to 2～4 ℃ then, after to be crystallized the separating out, filter vacuum-drying;
(2) repeat as stated above once again, get brick-red crystalline powder;
(3) measure content and related substance, content is more than 96.0% as a result, and the total amount of related substance is below 10.0%, and the amount of single impurity is below 4.0%.
The sodium tanshinone IIA sulfate that above-mentioned the present invention uses than low-purity, can be commercially available, as buying (is Y041120 as lot number) from Shanghai No.1 Bio-Chemical Pharmacetical Industry Co., Ltd, by quality standard-0923 check, content is 96.3%, related substance calculates respectively by two kinds of impurity, all less than 4% (but all greater than 3%, with 4%, 3% contrast); Also can be homemade, as make sodium tanshinone IIA sulfate with commercially available Tanshinone II A process sulfonation reaction than low-purity.
The sodium tanshinone IIA sulfate that above-mentioned the present invention uses than low-purity, its purity is not needed to carry out strict control, because can carry out multi-pass operations by above-mentioned purification process, can obtain highly purified sodium tanshinone IIA sulfate of the present invention, therefore, the sodium tanshinone IIA sulfate than low-purity that above-mentioned the present invention uses is measured by standard-0923, its content can be more than 90%, and two kinds of impurity is all less than 8% starting material.
Use the preparation of highly purified sodium tanshinone IIA sulfate preparation of the present invention, go up the sodium tanshinone IIA sulfate and the pharmaceutically acceptable auxiliary material of significant quantity comprising treatment.
Use the preparation of highly purified sodium tanshinone IIA sulfate preparation of the present invention, comprise low capacity aqueous injection, lyophilized injectable powder, large capacity transfusion agent, oral liquid, oral solid formulation etc.
Above-mentioned low capacity aqueous injection can be adorned 1～25ml for every, wherein contains highly purified sodium tanshinone IIA sulfate 1～200mg of the present invention, wherein also contains acceptable accessories.
Above-mentioned lyophilized injectable powder contains highly purified sodium tanshinone IIA sulfate 1～200mg of the present invention in every bottle, wherein also contains acceptable accessories.
Above-mentioned large capacity transfusion agent can be adorned 50～1000ml for every bottle, wherein contains highly purified sodium tanshinone IIA sulfate 1～500mg of the present invention, wherein also contains acceptable accessories.
Above-mentioned liquid oral medicament in every 10ml, wherein contains highly purified sodium tanshinone IIA sulfate 1～200mg of the present invention, wherein also contains acceptable accessories.
Use the preparation of highly purified sodium tanshinone IIA sulfate preparation of the present invention, adopt the high effective liquid chromatography for measuring related substance, the chromatographic peak of deduction solvent and/or auxiliary material, wherein the total amount of related substance is below 10.0%, and the amount of single impurity is below 4.0%.
The related substance inspection of preparation and assay also can adopt the high performance liquid chromatography of above-mentioned raw materials medicine quality control to carry out, as long as in the dosing process, do simple the adjustment, this is that those skilled in the art are easy to accomplish, such as, get an amount of preparation, with moving phase dissolving or be diluted to respective concentration, filter in case of necessity and get final product.
With the low capacity aqueous injection is example, with identical prescription, and the injection liquid made from low-purity and highly purified sodium tanshinone IIA sulfate bulk drug respectively.The result shows, 40 ℃ of accelerated test conditions after next month, the little aqueous injection that two kinds of raw materials are made forms in precipitation, evident difference is being arranged aspect the related substance variation:
(1) the little liquid drugs injection made of low-purity raw material has 20～30% sample to produce the block precipitation of white approximately, the related substance total amount by 0 month about 13.5% be increased to about 16.5% of March, the amount of maximum single impurity by 0 month about 6.1% be increased to the about 7.8% of March, increase about 3.0% and 1.7% respectively.
(2) the little liquid drugs injection sample made of high-purity raw is not seen and is produced precipitation, the related substance total amount by 0 month about 6.4%～9.8%, be increased to about 6.9%～10.4% of March, the amount of maximum single impurity by 0 month about 2.4%～3.8%, be increased to the about 2.6%～4.1% of March, increase about 0.5% and 0.25% respectively.
This beneficial effect produces owing to bulk drug purity improves.After bulk drug was purified, the quality of little liquid drugs injection was significantly improved.Those skilled in the art can easily accomplish, use this highly purified bulk drug to prepare other preparation, and the quality of preparation is improved.Be the preparation made from the high purity sodium tanshinone IIA sulfate of the present invention, not only comprise the low capacity aqueous injection, also comprise high-capacity injection,, also comprise powder injection, oral solution, oral solid formulation etc. as glucose injection, sodium chloride injection etc.
Therefore, the objective of the invention is to, the preparation method of a kind of highly purified sodium tanshinone IIA sulfate, this highly purified sodium tanshinone IIA sulfate and the preparation that uses this sodium tanshinone IIA sulfate to make are provided.
Basis of the present invention is: the sodium tanshinone IIA sulfate bulk drug is up to the standards by standard-0923, but by above-mentioned high performance liquid chromatography check, content is below 96.0%, the total amount of related substance is more than 10.0%, the amount of single impurity is more than 4.0%, when preparing injection liquid with this bulk drug, 40 ℃ of accelerated test conditions after next month, the related substance amount of preparation raises fast (pressing the HPLC method measures), and is easy to generate precipitation.But, at the sodium tanshinone IIA sulfate bulk drug process purifying that above-mentioned this purity is lower, make content more than 96.0%, the total amount of related substance is below 10.0%, the amount of single impurity is behind the highly purified sodium tanshinone IIA sulfate below 4.0%, bulk drug with this purifying prepares preparation, can overcome preparation significantly and be prone to precipitation and related substance increase defective faster under 40 ℃ of accelerated test conditions.
On this basis, the inventor has finished the present invention.
[embodiment]
Following embodiment further describes the present invention, but described embodiment only is used to illustrate the present invention rather than restriction the present invention.
Embodiment 1
(1) starting material are the sodium tanshinone IIA sulfate (lot number is Y041120) of low-purity, available from Shanghai No.1 Bio-Chemical Pharmacetical Industry Co., Ltd, measure by standard-0923, content is 96.3%, the related substance total amount is less than 8%, the amount of single impurity is less than 4%[but respectively greater than 6% and 3%, with 4%, 3% contrast], all the other projects are up to specification.After the assay was approved, with high effective liquid chromatography for measuring content of the present invention and related substance, content is 93.8%.The total amount of related substance is 13.42%, and the amount of single impurity is 6.11%.
(2) in 56 ℃ ethanol 1000ml, add sodium tanshinone IIA sulfate (lot number Y041120) powder 200g than low-purity;
(3) the limit edged stirs and makes powder dissolution, obtains nearly saturated settled solution;
(4) the chloroform 50ml of 5% ratio adding by volume stirs, and solution is heated to 72 ℃, stirring and dissolving;
(5) at room temperature leave standstill, slowly cool to room temperature, left standstill 12 hours, cool to 2～4 ℃ then, left standstill 12 hours;
(6) after to be crystallized the separating out, filter, vacuum-drying gets brick-red crystalline powder (lot number Y050415).
The highly purified sodium tanshinone IIA sulfate of making is measured according to China national drug standard WS-10001-(HD-0923)-2002, and every index is all up to specification.According to high performance liquid chromatography of the present invention, measure content and related substance again
Embodiment 2
(1) starting material are the highly purified sodium tanshinone IIA sulfate (lot number Y050415) that the foregoing description 1 is made, measure by standard-0923, content is 98.6%, the related substance total amount is less than 7%, the amount of single impurity is less than 4%[but respectively greater than 6% and 3%, with 4%, 3.5%, 3% contrast], all the other projects are up to specification.After the assay was approved, with high effective liquid chromatography for measuring content of the present invention and related substance, content is 97.4%, and the total amount of related substance is 7.73%, and the amount of single impurity is 2.97%.
(2) in 59 ℃ ethanol 1000ml, the sodium tanshinone IIA sulfate than low-purity of adding (lot number Y050415) powder 200g;
(3) the limit edged stirs and makes powder dissolution, obtains nearly saturated settled solution;
(4) the chloroform 50ml of 5% ratio adding by volume stirs, and solution is heated to 72 ℃, stirring and dissolving;
(5) at room temperature leave standstill, slowly cool to room temperature, left standstill 12 hours, cool to 2～3 ℃ then, left standstill 24 hours;
(6) after to be crystallized the separating out, filter, vacuum-drying gets brick-red crystalline powder [lot number Y050420].
The highly purified sodium tanshinone IIA sulfate of making is measured according to standard-0923, and every index is all up to specification.According to high performance liquid chromatography of the present invention, measure content and related substance again.
Embodiment 3
(1) starting material are the sodium tanshinone IIA sulfate (lot number is Y050212) of low-purity, self-control, the self-control method is: by prior art, dna purity is 81% Tanshinone II A (HPLC method) from the red sage root, carry out sulfonation reaction with the vitriol oil then, make sodium tanshinone IIA sulfate (lot number Y050212).Measure by standard-0923, content is 93.3%, and the related substance total amount is less than 12%, and the amount of single impurity is less than 6%[but respectively greater than 10% and 5%, with 5%, 6% contrast], all the other projects are up to specification, after the assay was approved.With high effective liquid chromatography for measuring content of the present invention and related substance, content is 92.6%, and the total amount of related substance is 13.66%, and the amount of single impurity is 6.03%.
(2) in 53 ℃ ethanol 1000ml, the sodium tanshinone IIA sulfate than low-purity of adding (lot number 050212) powder 200g;
(3) the limit edged stirs and makes powder dissolution, obtains nearly saturated settled solution;
(4) the chloroform 70ml of 7% ratio adding by volume stirs, and solution is heated to 70 ℃, stirring and dissolving;
(5) at room temperature leave standstill, slowly cool to room temperature, left standstill 12 hours, cool to 4～6 ℃ then, left standstill 12 hours;
(6) after to be crystallized the separating out, filter, vacuum-drying gets brick-red crystalline powder;
(7) the gained powder repeats crystallization once by above (2)～(6) step again, gets brick-red crystalline powder (lot number Y050425).
The highly purified sodium tanshinone IIA sulfate of making is measured according to standard-0923, and every index is all up to specification.According to high performance liquid chromatography of the present invention, measure content and related substance again.
Embodiment 4
Measure the content of sodium tanshinone IIA sulfate and the high performance liquid chromatography of related substance
High effective liquid chromatography for measuring content and related substance are according to " two appendix VD of Chinese pharmacopoeia version in 2005 carry out.
(i) chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent, be 0.05mol/L with concentration and be that the volume ratio of 3.0 Spirit of Mindererus and methyl alcohol is that 35: 65 mixing solutions is a moving phase with the acetic acid adjust pH, the detection wavelength is 270nm, adjusting flow velocity to the retention time of sodium tanshinone IIA sulfate is about 8 minutes, number of theoretical plate calculates by the sodium tanshinone IIA sulfate peak should be not less than 2500, and the resolution at sodium tanshinone IIA sulfate peak and other peak should be greater than 1.2;
(ii) related substance inspection: the method by (i) determined chromatographic condition and system suitability test is measured.
It is an amount of to get sodium tanshinone IIA sulfate, adds the moving phase dissolving, makes the solution that concentration is about 100 μ g/ml, and as need testing solution, precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution; Get contrast solution 20 μ l, inject liquid chromatograph, regulate detection sensitivity, make the peak height of main composition chromatographic peak be about 20% of full range; It is an amount of that other gets the Tanshinone II A reference substance, adds moving phase and make the solution that concentration is 10 μ g/ml, gets 20 μ l and inject liquid chromatograph, and the record color atlas is to 1.2 times of Tanshinone II A peak retention time; Precision is measured contrast solution and each 20 μ l of need testing solution again, injects liquid chromatograph respectively, and the record color atlas is to 1.2 times of Tanshinone II A peak retention time; Each impurity chromatographic peak area sum in the color atlas of need testing solution divided by contrast solution main peak area, is calculated the total amount of related substance; The chromatographic peak area of maximum single impurity calculates the amount of single impurity divided by contrast solution main peak area in the color atlas of need testing solution;
(iii) assay: precision takes by weighing the about 25mg of sodium tanshinone IIA sulfate, puts in the 100ml measuring bottle, adds the moving phase dissolving and is diluted to scale, shakes up, and the accurate again 5ml that draws puts in the measuring bottle of 50ml, adds moving phase and is diluted to scale, shakes up, as need testing solution; To meet China national drug standard WS-10001-(HD-0923)-2002, check that with (ii) item method the total amount of related substance is less than 2%, the amount of single impurity is below 1.0%, and be reference substance at 60 ℃ of following vacuum-dryings to the sodium tanshinone IIA sulfate of constant weight, it is an amount of that precision takes by weighing this sodium tanshinone IIA sulfate reference substance, with moving phase dissolving and make the reference substance solution that concentration is about 25 μ g/ml; Get each 20 μ l of need testing solution and reference substance solution, inject liquid chromatograph respectively, the record color atlas is pressed external standard method with calculated by peak area content.
When the content of measuring preparation and related substance, get the preparation with the bulk drug a great deal of, prepare need testing solution with moving phase, to filter in case of necessity, all the other are operated with (ii) above-mentioned and (iii) identical.
Embodiment 5
The check of sodium tanshinone IIA sulfate bulk drug
(1) measures the sodium tanshinone IIA sulfate bulk drug (Y041120, Y050212) and the highly purified sodium tanshinone IIA sulfate bulk drug (Y050415, Y050420, Y050425) of the related low-purity of embodiment 1～3 with the method for standard-0923, the results are shown in Table 1.
(2) measure the sodium tanshinone IIA sulfate bulk drug and the highly purified sodium tanshinone IIA sulfate bulk drug of the related low-purity of embodiment 1～3 with the method for the embodiment of the invention 4, the results are shown in Table 1.
Assay is purified with the method that the check clone inventor presses embodiment 1, and lot number is C050110, checks by standard-0923, and is up to specification; With embodiment 4 (ii) item method check that the total amount of related substance is 1.17%, the amount of maximum single impurity is 0.62.
Table 1 is measured the assay of sodium tanshinone IIA sulfate bulk drug with the method for the national drug standards
| The method of inspection | Interventions Requested | Sample lot number and source | ||||
| The Y041120 outsourcing | The Y050212 self-control | Y050415 is by the Y041120 purifying | Y050420 is by the Y050415 purifying | Y050425 is by the Y050212 purifying | ||
| Standard-0923 | Content | 96.3％ | 93.3％ | 98.6％ | 99.1％ | 97.7％ |
| Total impurities | Less than 8% | Less than 12% | Less than 7% | Less than 6% | Less than 8% | |
| Single impurity level | Less than 4% | Less than 6% | Less than 4% | Less than 3% | Less than 4% | |
| Other project | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification | |
| Embodiment 4 | Content | 93.8％ | 92.6％ | 97.4％ | 98.8％ | 96.9％ |
| Total impurities | 13.42％ | 13.66％ | 7.73％ | 6.44％ | 9.81％ | |
| Single impurity level | 6.11％ | 6.03％ | 2.97％ | 2.38％ | 3.79％ | |
From last table as seen, adopt preparation method of the present invention, the highly purified sodium tanshinone IIA sulfate bulk drug of making is used high effective liquid chromatography for measuring, and content obviously raises, and related substance obviously reduces.But the method that adopts the national drug standards is measured and is not seen tangible raising.
Embodiment 6
Sodium tanshinone IIA sulfate with different purity prepares the low capacity aqueous injection
Reference standard-1014 with identical prescription and technology, adopts the sodium tanshinone IIA sulfate of different purity (different lot number) to prepare the low capacity aqueous injection, and it is as follows to write out a prescription:
| Component | Consumption | Remarks |
| Sodium tanshinone IIA sulfate EDTA-2Na water for injection | 5g 0.5g adds to 1000ml | Main ingredient, the metal chelating agent solvent |
Preparation method: get sodium tanshinone IIA sulfate, the EDTA-Na of recipe quantity, add 500ml water for injection, stirring and dissolving.Add 0.1% (w/v) gac, adding 1M hydrochloric acid soln or 1M sodium hydroxide solution adjusting pH value is 4.5 ± 0.2, is heated to 75～80 ℃, stirred 10 minutes, and be chilled to 45～50 ℃, coarse filtration is taken off charcoal, add water for injection to 1000ml, regulate pH value to 4.5 ± 0.2, with 0.22 μ m filtering with microporous membrane, can, every bottled 5ml, seal, sterilized 20 minutes, and promptly got the sodium tanshinone IIA sulfate injection with small volume for 115 ℃.
5 batches of used raw materials are respectively Y041120, Y050212, Y050415, Y050420, Y050425, and the lot number of the injection liquid of making by above prescription and technology is respectively Inj-1120, Inj-0212, Inj-0415, Inj-0420, Inj-0425.
Place 40 ℃ thermostat container to place 3 months the low capacity aqueous injection of making, sample precipitation production is measured content and related substance according to the method for embodiment 4 again when observing 0 month (promptly measuring without 40 ℃ of placements) and March.
Measure related substance by the method for standard-0923 in addition.
Sedimentary observational technique is: every batch sample is got 50 (bottle) and is observed, and accumulative total produces sedimentary ampoule (bottle) number.The results are shown in Table 2.
40 ℃ of quality change results that keep sample of table 2 sodium tanshinone IIA sulfate injection with small volume
| Project | Time | The sample lot number | |||||
| Inj-1120 | Inj-0212 | Inj-0415 | Inj-0420 | Inj-0425 | |||
| Precipitation (precipitation number/observed number) | 0 month | 0/50 | 0/50 | 0/50 | 0/50 | 0/50 | |
| March | 12/50 | 17/50 | 0/50 | 0/50 | 0/50 | ||
| High performance liquid chromatography | Content (mg/ml) | 0 month | 5.06 | 5.03 | 4.96 | 4.91 | 5.09 |
| March | 5.04 | 5.05 | 4.93 | 4.94 | 5.11 | ||
| Total impurities | 0 month | 13.47％ | 13.62％ | 7.84％ | 6.41％ | 9.86％ | |
| March | 16.31％ | 16.90％ | 8.34％ | 6.89％ | 10.42％ | ||
| Single impurity | 0 month | 6.23％ | 6.07％ | 2.96％ | 2.44％ | 3.77％ | |
| March | 7.87％ | 7.81％ | 3.17％ | 2.62％ | 4.05％ | ||
| Tlc | Impurity-I * | 0 month | ＜4％ | ＜4％ | ＜3％ | ＜2％ | ＜3％ |
| March | ＜6％ | ＜6％ | ＜4％ | ＜2％ | ＜3％ | ||
| Impurity-II ** | 0 month | ＜4％ | ＜4％ | ＜3％ | ＜3％ | ＜3％ | |
| March | ＜6％ | ＜6％ | ＜3％ | ＜3％ | ＜4％ | ||
Annotate:
*Impurity-I: be the Tanshinone I sodium sulfonate;
*Impurity-II: be Tanshinone II A.
From last table as seen, with identical prescription and technology, adopt the bulk drug of different purity, make the sodium tanshinone IIA sulfate injection with small volume, its stability difference is obvious: precipitation appears in preparation that the bulk drug of low-purity is made easily, and impurity increases very fast with the process that keeps sample; And the preparation that highly purified bulk drug is made is not seen the appearance precipitation, and impurity changes less with the process that keeps sample.
Embodiment 7
Sodium tanshinone IIA sulfate with different purity prepares large vol glucose injection, lyophilized injectable powder
With two crowdes of raw material Y050212, Y050420,, prepare the high-capacity injection and the lyophilized injectable powder of sodium tanshinone IIA sulfate respectively respectively with identical prescription.
The prescription of high-capacity injection is as follows:
| Component | Consumption | Remarks |
| Sodium tanshinone IIA sulfate glucose injection water | 200mg 50g adds to 1000ml | Main ingredient, the isotonic agent solvent |
Preparation method: get the sodium tanshinone IIA sulfate of recipe quantity, add 500ml water for injection, stirring and dissolving, the glucose of adding recipe quantity, stirring and dissolving.Add 0.1% (w/v) gac, adding hydrochloric acid soln adjusting pH value is 4.5 ± 0.2, is heated to and boils, boiled 10 minutes, and be chilled to 55～60 ℃, coarse filtration is taken off charcoal, add water for injection to 1000ml, regulate pH value to 4.5 ± 0.2, with 0.22 μ m filtering with microporous membrane, can, every bottled 250ml, seal, sterilized 20 minutes, and promptly got the large vol glucose injection that contains sodium tanshinone IIA sulfate for 115 ℃.Lot number is respectively P0212, P0420.
The prescription of lyophilized injectable powder is as follows:
| Component | Consumption | Remarks |
| Sodium tanshinone IIA sulfate N.F,USP MANNITOL water for injection | 5g 150g adds to 1000ml | Main ingredient, the balustrade solvent |
Preparation method: get the sodium tanshinone IIA sulfate of recipe quantity, add 500ml water for injection, stirring and dissolving, the N.F,USP MANNITOL of adding recipe quantity, stirring and dissolving.Add 0.1% (w/v) gac, regulating the pH value is 4.5 ± 0.2, is heated to and boils, and boils 10 minutes, is chilled to 50～60 ℃, coarse filtration is taken off charcoal, adds water for injection to 1000ml, regulates pH value to 4.5 ± 0.2, with 0.22 μ m filtering with microporous membrane, can, every bottle of 2ml, false add plug, lyophilize.Promptly get the lyophilized injectable powder that contains sodium tanshinone IIA sulfate.Lot number is respectively D0212, D0420.
Freeze-drying method can be with reference to relevant textbook, and those skilled in the art can realize at an easy rate.
The thermostat container that the large vol glucose injection made and lyophilized injectable powder place 40 ℃ was placed 3 months, observe glucose injection sample precipitation production when 0 month and March, measure the content and the related substance of glucose injection and lyophilized injectable powder again according to the method for embodiment 4.The results are shown in Table 3.
40 ℃ of quality change results that keep sample of large capacity transfusion agent of table 3 sodium tanshinone IIA sulfate and lyophilized injectable powder
| Project | Time | The sample lot number | |||
| P0212 | P0420 | D0212 | D0420 | ||
| Precipitation | 0 month | 0/50 | 0/50 | - | - |
| (precipitation number/observed number) | March | 6/50 | 0/50 | - | - |
| Content | 0 month | 0.207mg/ml | 0.203mg/ml | 10.11mg/ bottle | 10.06mg/ bottle |
| March | 0.206mg/ml | 0.201mg/ml | 10.04mg/ bottle | 10.03mg/ bottle | |
| Total impurities | 0 month | 13.52％ | 6.44％ | 13.46％ | 6.46％ |
| March | 16.47％ | 6.97％ | 16.31％ | 6.94％ | |
| Single impurity | 0 month | 6.21％ | 2.41％ | 6.26％ | 2.38％ |
| March | 7.94％ | 2.66％ | 7.85％ | 2.62％ |
From last table as seen, with identical prescription and technology, adopt the bulk drug of different purity, make sodium tanshinone IIA sulfate large vol glucose injection and lyophilize injection, its stability difference is obvious: precipitation appears in the preparation that the bulk drug of low-purity is made, and impurity increases very fast with the process that keeps sample; And the preparation that highly purified bulk drug is made is not seen the appearance precipitation, and impurity changes less with the process that keeps sample.
Highly purified sodium tanshinone IIA sulfate of the present invention can also be used for other preparation, and as liquid oral medicament, oral solid formulation etc., self-evident, the present invention prolongs and these formulation products.
Claims (9)
1. a highly purified sodium tanshinone IIA sulfate is characterized in that,
(1) adopt high effective liquid chromatography for measuring content, the content of sodium tanshinone IIA sulfate wherein is more than 96.0%,
(2) adopt the high effective liquid chromatography for measuring related substance, wherein the total amount of related substance is below 10.0%, and the amount of single impurity is below 4.0%;
The method of described high effective liquid chromatography for measuring content and related substance, according to " two appendix VD of Chinese pharmacopoeia version in 2005 carry out, and may further comprise the steps:
(i) chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent, be 0.05mol/L with concentration and be that the volume ratio of 3.0 Spirit of Mindererus and methyl alcohol is that 35: 65 mixing solutions is a moving phase with the acetic acid adjust pH, the detection wavelength is 270nm, adjusting flow velocity to the retention time of sodium tanshinone IIA sulfate is about 8 minutes, number of theoretical plate calculates by the sodium tanshinone IIA sulfate peak should be not less than 2500, and the resolution at sodium tanshinone IIA sulfate peak and other peak should be greater than 1.2;
(ii) related substance inspection: it is an amount of to get sodium tanshinone IIA sulfate, adds the moving phase dissolving, makes the solution that concentration is about 100 μ g/ml, as need testing solution, precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, add moving phase and be diluted to scale, shake up, in contrast solution; Get contrast solution 20 μ l, inject liquid chromatograph, regulate detection sensitivity, make the peak height of main composition chromatographic peak be about 20% of full range; It is an amount of that other gets the Tanshinone II A reference substance, adds moving phase and make the solution that concentration is 10 μ g/ml, gets 20 μ l and inject liquid chromatograph, and the record color atlas is to 1.2 times of Tanshinone II A peak retention time; Precision is measured contrast solution and each 20 μ l of need testing solution again, injects liquid chromatograph respectively, and the record color atlas is to 1.2 times of Tanshinone II A peak retention time; Each impurity chromatographic peak area sum in the color atlas of need testing solution divided by contrast solution main peak area, is calculated the total amount of related substance; The chromatographic peak area of maximum single impurity calculates the amount of single impurity divided by contrast solution main peak area in the color atlas of need testing solution;
(iii) assay: precision takes by weighing the about 25mg of sodium tanshinone IIA sulfate, puts in the 100ml measuring bottle, adds the moving phase dissolving and is diluted to scale, shakes up, and the accurate again 5ml that draws puts in the measuring bottle of 50ml, adds moving phase and is diluted to scale, shakes up, as need testing solution; To meet China national drug standard WS-10001-(HD-0923)-2002, check that with (ii) item method the total amount of related substance is less than 2%, the amount of single impurity is below 1.0%, and be reference substance at 60 ℃ of following vacuum-dryings to the sodium tanshinone IIA sulfate of constant weight, it is an amount of that precision takes by weighing this sodium tanshinone IIA sulfate reference substance, with moving phase dissolving and make the reference substance solution that concentration is about 25 μ g/ml; Get each 20 μ l of need testing solution and reference substance solution, inject liquid chromatograph respectively, the record color atlas is pressed external standard method with calculated by peak area content.
2. by the sodium tanshinone IIA sulfate of claim 1, it is characterized in that,
(1) adopt high effective liquid chromatography for measuring content, the content of sodium tanshinone IIA sulfate wherein is more than 97.0%,
(2) adopt the high effective liquid chromatography for measuring related substance, wherein the total amount of related substance is below 8.0%, and the amount of single impurity is below 3.0%.
3. by the sodium tanshinone IIA sulfate of claim 2, it is characterized in that,
(1) adopt high effective liquid chromatography for measuring content, the content of sodium tanshinone IIA sulfate wherein is more than 98.0%,
(2) adopt the high effective liquid chromatography for measuring related substance, wherein the total amount of related substance is below 7.0%, and the amount of single impurity is below 2.5%.
4. press the preparation method of the highly purified sodium tanshinone IIA sulfate of claim 1, it is characterized in that, comprising following steps: in 50～60 ℃ ethanol, adding is than the sodium tanshinone IIA sulfate powder of low-purity, the limit edged stirs and makes powder dissolution, obtain nearly saturated settled solution, add chloroform in liquor capacity than the ratio that is 3～7%, solution is heated to 70 ± 3 ℃, at room temperature leave standstill, slowly cool to room temperature, cool to 2～6 ℃ then, after to be crystallized the separating out, filter, vacuum-drying gets brick-red crystalline powder.
5. press the preparation method of claim 4, it is characterized in that, comprising following steps: in 55～60 ℃ ethanol, add commercially available or homemade sodium tanshinone IIA sulfate powder than low-purity, the limit edged stirs and makes powder dissolution, obtain nearly saturated settled solution, add chloroform in liquor capacity than the ratio that is 5%, solution is heated to 70 ± 2 ℃, at room temperature leave standstill, slowly cool to room temperature, cool to 2～6 ℃ then, after to be crystallized the separating out, filter, vacuum-drying gets brick-red crystalline powder.
6. by the preparation method of claim 5, it is characterized in that, comprising following steps: in 57～60 ℃ ethanol, add commercially available or homemade sodium tanshinone IIA sulfate powder than low-purity, the limit edged stirs and makes powder dissolution, obtains nearly saturated settled solution, add chloroform in liquor capacity than the ratio that is 5%, solution is heated to 70 ± 2 ℃, at room temperature leaves standstill, slowly cool to room temperature, cool to 2～4 ℃ then, after to be crystallized the separating out, filter vacuum-drying; Repeat as stated above once again, get brick-red crystalline powder.
7. the highly purified sodium tanshinone IIA sulfate by claim 1 is the preparation that physiologically active ingredient is made, and it is characterized in that, comprises the treatment upward sodium tanshinone IIA sulfate and the pharmaceutically acceptable auxiliary material of significant quantity in the said preparation.
8. by the preparation of claim 7, it is characterized in that said preparation is injection with small volume, lyophilized injectable powder, large capacity transfusion agent, oral liquid or oral solid formulation.
9. press the preparation of claim 7 or 8, it is characterized in that, by the related substance in the high effective liquid chromatography for measuring said preparation of claim 1, the chromatographic peak of deduction solvent and/or auxiliary material, wherein the total amount of related substance is below 10.0%, and the amount of single impurity is below 4.0%.
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| CN101805391A (en) * | 2010-04-09 | 2010-08-18 | 上海第一生化药业有限公司 | Preparation method of sodium tanshinone IIA for injection |
| CN101863894A (en) * | 2010-06-01 | 2010-10-20 | 广东药学院 | Tanshinone II A derivative and preparation method and application thereof |
| CN102690318A (en) * | 2012-05-30 | 2012-09-26 | 海南合瑞制药股份有限公司 | Tanshinone II A sodium sulfonate crystal compound, preparation method thereof and medicine composition containing tanshinone II A sodium sulfonate crystal compound |
| JP2013510097A (en) * | 2009-11-03 | 2013-03-21 | リウ、リー | Tanshinone IIA sodium sulfonate hydrate and its preparation and use |
| CN103006549A (en) * | 2012-12-05 | 2013-04-03 | 广东宏远集团药业有限公司 | Method for preparing tanshinone IIA sodium sulfonate preparation by using hydrotropic defoaming solvent |
| CN105301155A (en) * | 2015-07-31 | 2016-02-03 | 复旦大学附属华山医院 | Method for measuring concentration of Sodium Tanshinone IIA Sulfonate (STS) in human plasma |
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| JP2013510097A (en) * | 2009-11-03 | 2013-03-21 | リウ、リー | Tanshinone IIA sodium sulfonate hydrate and its preparation and use |
| CN101805391A (en) * | 2010-04-09 | 2010-08-18 | 上海第一生化药业有限公司 | Preparation method of sodium tanshinone IIA for injection |
| CN101805391B (en) * | 2010-04-09 | 2014-12-03 | 上海第一生化药业有限公司 | Preparation method of sodium tanshinone IIA for injection |
| CN101863894A (en) * | 2010-06-01 | 2010-10-20 | 广东药学院 | Tanshinone II A derivative and preparation method and application thereof |
| CN101863894B (en) * | 2010-06-01 | 2012-07-18 | 广东药学院 | Tanshinone II A derivative and preparation method and application thereof |
| CN102690318A (en) * | 2012-05-30 | 2012-09-26 | 海南合瑞制药股份有限公司 | Tanshinone II A sodium sulfonate crystal compound, preparation method thereof and medicine composition containing tanshinone II A sodium sulfonate crystal compound |
| CN102690318B (en) * | 2012-05-30 | 2014-03-19 | 海南合瑞制药股份有限公司 | Tanshinone II A sodium sulfonate crystal compound, preparation method thereof and medicine composition containing tanshinone II A sodium sulfonate crystal compound |
| CN103006549A (en) * | 2012-12-05 | 2013-04-03 | 广东宏远集团药业有限公司 | Method for preparing tanshinone IIA sodium sulfonate preparation by using hydrotropic defoaming solvent |
| CN103006549B (en) * | 2012-12-05 | 2015-04-15 | 广东宏远集团药业有限公司 | Method for preparing tanshinone IIA sodium sulfonate preparation by using hydrotropic defoaming solvent |
| CN105301155A (en) * | 2015-07-31 | 2016-02-03 | 复旦大学附属华山医院 | Method for measuring concentration of Sodium Tanshinone IIA Sulfonate (STS) in human plasma |
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