CN105168150A - Preparation method of isosorbide mononitrate freeze-dried powder for injection - Google Patents
Preparation method of isosorbide mononitrate freeze-dried powder for injection Download PDFInfo
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- CN105168150A CN105168150A CN201410238146.XA CN201410238146A CN105168150A CN 105168150 A CN105168150 A CN 105168150A CN 201410238146 A CN201410238146 A CN 201410238146A CN 105168150 A CN105168150 A CN 105168150A
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Abstract
The invention provides a preparation method of an isosorbide mononitrate freeze-dried powder for injection. The preparation method includes the steps: S1 formula preparation, S2 drug liquid preparation, S3 filling, S4 freeze drying and S5 packaging. Through adjustment of the processing steps, such as accurate control of the temperature rising rate, the heat preservation temperature, the heat preservation time and pressure and other parameters and control of multi-layer filtration, the obtained isosorbide mononitrate freeze-dried powder for injection has the advantages of being high in quality, good in stability, high in clinical use safety, more normative in preparation process, and suitable for popularization.
Description
Technical field
The present invention relates to pharmaceutical field, refer to a kind of preparation method of injection isosorbide mononitrate lyophilized powder especially.
Background technology
Isosorbide mononitrate is long acting nitrate class antianginal drug, and the sixties are found in the cylinder metabolism-ure of sorbide nitrate.First the eighties pushes market by German BochringerCnbh, thereafter in the successively listing of American-European more than ten countries, and is widely used in clinical.China, in this medicine of import in 1988, receives the popular welcome of extensive patients.Isosorbide mononitrate Elemental characters: white crystals or crystalline powder, odorless.Easily molten in acetone or chloroform, slightly molten in ethanol, slightly soluble in water.Isosorbide mononitrate is adapted to the long-term treatment of coronary heart disease; Anginal prevention; Anginal treatment is continued after myocardial infarction; With Folium Digitalis Purpureae and/or diuretic use in conjunction, treatment chronic heart failure; The long-term treatment of coronary heart disease and prevention angina pectoris attacks, be also applicable to the treatment after myocardial infarction.
Existing isosorbide mononitrate injectio is in long-term storage process in the market, isosorbide mononitrate is easily degraded, the decline of the content of preparation and related substance is caused to increase, the reason producing this phenomenon is that isosorbide mononitrate is easily hydrolyzed in acidity or alkaline environment, for suppressing the hydrolysis of isosorbide mononitrate, manufacturer with the addition of propylene glycol in injection, glycerol etc. are as stabilizing agent, but the drug safety of stabilizing agent does not ensure fully, simultaneously due to needs high temperature sterilize, the stability of product is bad, related substance increases obviously after sterilization, and in storage process, the hydrolysis of medicine is inevitable, cause the quality of isosorbide mononitrate very unstable thus, therefore pot-life has larger fluctuation scope, Clinical practice risk is larger.
Summary of the invention
Given this, the invention provides a kind of preparation method of injection isosorbide mononitrate lyophilized powder, preparation process is specification more, is suitable for promoting, and the injection isosorbide mononitrate lyophilized powder quality obtained is high, and good stability, Clinical practice safety is high.
For solving the problems of the technologies described above, technical scheme of the present invention is:
A preparation method for injection isosorbide mononitrate lyophilized powder, comprises step: the preparation of S1 formula, S2 drug solution preparing, S3 fill, S4 lyophilization and S5 packaging, and wherein step S4 lyophilization comprises:
Carry out first time cooling to medical liquid B, cooling rate is 0.4 ~ 0.6 DEG C/min for the first time, makes medical liquid B be down to-32 ~-38 DEG C from room temperature, and is incubated 2 ~ 4 hours;
Open vacuum pump evacuation, vacuum is 10 ~ 15 handkerchiefs;
Carry out first time intensification to medical liquid B, programming rate is 0.15 ~ 0.2 DEG C/min for the first time, makes medical liquid B be warming up to 0 DEG C gradually, and disappears latter 2 ~ 4 hours at 0 DEG C of insulation to ice crystal;
Carry out second time to medical liquid B to heat up, second time programming rate is 0.1 ~ 0.15 DEG C/min, makes medical liquid B be warming up to 22 ~ 28 DEG C gradually, and is incubated 2 ~ 4 hours.
Further, during described S1 formula prepares, every 1000 described injection isosorbide mononitrate lyophilized powder pharmaceutical compositions, its formula consists of:
Further, step S2 drug solution preparing comprises:
S2-1: take appropriate water for injection and to add in Agitation Tank and to be cooled to room temperature;
S2-2: the isosorbide mononitrate and the mannitol that add configuration amount, is stirred to dissolving completely and obtains medicinal liquid A;
S2-3, regulate the pH value of medicinal liquid A with sodium hydroxide solution, benefit adds to the full amount of water for injection, and stirs;
S2-4: the active carbon adding configuration amount, stirs;
S2-5: filtering decarbonization;
S2-6: again filter after the assay was approved and obtain qualified medical liquid B.
Further, in described step S2-1,50 ~ 80% waters for injection taking configuration amount to add in Agitation Tank and are cooled to room temperature.
Further, in described step S2-3, regulate pH value to 5.8 ~ 6.2 of medicinal liquid A with 0.5mol/L sodium hydroxide solution.
Further, in described step S2-5, successively carry out filtering decarbonization through 0.45 μm of micropore filter element successively, and carry out fine straining through 0.22 μm of microporous filter membrane and take off charcoal.
Further, in described step S2-6, carry out fine straining through 0.22 μm of microporous filter membrane more after the assay was approved, obtain qualified medical liquid B.
Further, described step S3 fill comprises: adjustment racking machine, to specifying scale, by medicinal liquid A fill in vial, presses half plug.
Further, described step S4 lyophilization also comprises carries out the full plug outlet of the qualified rear pressure of pressure test to freezer dryer, and lyophilizing terminates.
Further, described step S5 comprises: put in storage after pricking aluminium lid, lamp inspection, packaging.
Compared with prior art, the invention has the beneficial effects as follows:
The invention provides a kind of preparation method of injection isosorbide mononitrate lyophilized powder, by the adjustment to processing step, as the accurate control of programming rate, holding temperature, temperature retention time and pressure and other parameters, and the control etc. of multiple filtration, make the injection isosorbide mononitrate lyophilized powder quality that obtains high, good stability, Clinical practice safety is high, preparation process is specification more, is suitable for promoting.In addition, formula of the present invention is simple, and adjuvant is less, avoids because adjuvant adds the too much side effect caused, improves Clinical practice safety.
Accompanying drawing explanation
Fig. 1 is the preparation method flow chart of a kind of injection isosorbide mononitrate of the present invention lyophilized powder;
Fig. 2 is the preparation method embodiment one step S2 flow chart of a kind of injection isosorbide mononitrate of the present invention lyophilized powder;
Fig. 3 is the preparation method embodiment one step S4 flow chart of a kind of injection isosorbide mononitrate of the present invention lyophilized powder.
Detailed description of the invention
For understanding the present invention better; below by following examples, elaboration concrete is further done to the present invention; but unintelligible is limitation of the invention; for some nonessential improvement and adjustment that those skilled in the art does according to foregoing invention content, be also considered as dropping in protection scope of the present invention.
Embodiment one
As shown in Fig. 1 flow chart, according to method provided by the invention, a kind of preparation method of injection isosorbide mononitrate lyophilized powder, comprises step: the preparation of S1 formula, S2 drug solution preparing, S3 fill, S4 lyophilization and S5 packaging, wherein,
S1 formula prepares:
Every 1000 described injection isosorbide mononitrate lyophilized powder pharmaceutical compositions, its formula consists of:
Formula of the present invention is simple, and adjuvant is less, avoids because adjuvant adds the too much side effect caused, improves Clinical practice safety.
S2 drug solution preparing:
As shown in Fig. 2 flow chart, comprise the following steps
S2-1, take appropriate water for injection and to add in Agitation Tank and to be cooled to room temperature, the injection water yield that first time adds is 50% of configuration amount;
S2-2, the isosorbide mononitrate adding configuration amount and mannitol, be stirred to dissolving completely and obtain medicinal liquid A;
S2-3, use 0.5mol/L sodium hydroxide solution adjust ph to 5.8, benefit adds to the full amount of water for injection, and stirs, and effectively inhibits the hydrolysis of formula, improves the stability of medicine;
S2-4, add the active carbon of configuration amount, stir and make it dispersed in 30 minutes;
S2-5, priority are carried out filtering decarbonization through 0.45 μm of micropore filter element successively, and are carried out fine straining through 0.22 μm of microporous filter membrane, can be improved the quality of goods by multiple filtration;
S2-6, sampling censorship, carry out fine straining through 0.22 μm of microporous filter membrane more after the assay was approved, obtain qualified medical liquid B.
S3 fill:
Adjustment racking machine, to specifying scale, by above-mentioned qualified medical liquid B fill in vial, presses half plug.
S4 lyophilization:
As described in the flow chart of figure 3, comprise the following steps
S4-1, the vial that qualified medical liquid B is housed is placed on the laminate of lyophilization mechanical goods room, open drying baker refrigeration machine, first time cooling is carried out to medical liquid B, cooling rate is 0.5 DEG C/min for the first time, make medical liquid B be down to-32 DEG C from room temperature, and be incubated 2 hours, treat that medical liquid B fully charge is real, pre-freeze-drying process terminates, and improves the content of medicine and the stability of each component materials;
S4-2, unlatching vacuum pump evacuation carry out lyophilizing, and vacuum is 15 handkerchiefs;
S4-3, the first intensification is carried out to medical liquid B, programming rate is 0.15 DEG C/min for the first time, medical liquid B is made to be warming up to 0 DEG C gradually, and be retained to latter 2 hours of ice crystal disappearance at 0 DEG C, make the complete lyophilizing of the moisture in medical liquid B, the vial swelling fracture caused because of temperature shock when not only avoid direct outlet and product destroy, and further improve the content of medicine and the stability of each component materials;
S4-4, carry out the second intensification to medical liquid B, second time programming rate is 0.1 DEG C/min, makes medical liquid B be warming up to 25 DEG C gradually, be incubated 2 hours, the stability before guarantee medicine outlet and the adaptability after outlet;
S4-5, carry out the full plug outlet of the qualified rear pressure of pressure test to freezer dryer, lyophilizing terminates.
In freeze-drying process, to the accurate control of each temperature, and the control of insulation duration, the stability of process Chinese medicine can be ensured, improve the quality of finished product.
S5 packs:
Put in storage after pricking aluminium lid, lamp inspection, packaging.
In addition, the interior packaging material used in the preparation process of injection isosorbide mononitrate lyophilized powder adopts following technological parameter sterilizing:
Plug: in 121 DEG C of moist heat sterilizations 40 minutes; Vial: be no less than 6 minutes in 350 DEG C of insulations; Aluminium lid: in 110 DEG C of insulations 120 minutes.
Embodiment two and three
By in step S2-1 first time the injection water yield, pH value in S2-3, first time cooling in S4-1 to S4-4 step, first time heats up, the programming rate that second time heats up, holding temperature, temperature retention time and vacuum replace with as shown in table 1 in numerical value, at ambient temperature stability study is proceeded to gained finished product, result is as shown in table 1, compared with prior art, the inventive method adopts vacuum freeze-drying at lower temperature technology, medicine is produced at hermetic container, ensure medicine not easily oxidation deterioration, overcome Yin Gaowen in production process and cause the problem of medicament decomposes, gained injection isosorbide mononitrate lyophilized powder quality is high, good stability, finished product water content is low, extend the pot-life.
Table 1 different condition obtains the pot-life of injection isosorbide mononitrate lyophilized powder
Should be appreciated that and above describe for the present invention to be as set forth in the claims only example and illustrative, not to be limited it.Content of the present invention disclosed by this paper, other embodiment of the present invention is apparent for a person skilled in the art.It should be noted that the present invention and embodiment only should be seen as example; those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. a preparation method for injection isosorbide mononitrate lyophilized powder, is characterized in that, comprises step: the preparation of S1 formula, S2 drug solution preparing, S3 fill, S4 lyophilization and S5 packaging, and wherein step S4 lyophilization comprises:
Carry out first time cooling to medical liquid B, cooling rate is 0.4 ~ 0.6 DEG C/min for the first time, makes medical liquid B be down to-32 ~-38 DEG C from room temperature, and is incubated 2 ~ 4 hours;
Open vacuum pump evacuation, vacuum is 10 ~ 15 handkerchiefs;
Carry out first time intensification to medical liquid B, programming rate is 0.15 ~ 0.2 DEG C/min for the first time, makes medical liquid B be warming up to 0 DEG C gradually, and disappears latter 2 ~ 4 hours at 0 DEG C of insulation to ice crystal;
Carry out second time to medical liquid B to heat up, second time programming rate is 0.1 ~ 0.15 DEG C/min, makes medical liquid B be warming up to 22 ~ 28 DEG C gradually, and is incubated 2 ~ 4 hours.
2. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as described in the appended claim 1, is characterized in that, during described S1 formula prepares, and every 1000 described injection isosorbide mononitrate lyophilized powder pharmaceutical compositions, its formula consists of:
3. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as described in the appended claim 1, it is characterized in that, step S2 drug solution preparing comprises:
S2-1: take appropriate water for injection and to add in Agitation Tank and to be cooled to room temperature;
S2-2: the isosorbide mononitrate and the mannitol that add configuration amount, is stirred to dissolving completely and obtains medicinal liquid A;
S2-3, regulate the pH value of medicinal liquid A with sodium hydroxide solution, benefit adds to the full amount of water for injection, and stirs;
S2-4: the active carbon adding configuration amount, stirs;
S2-5: filtering decarbonization;
S2-6: again filter after the assay was approved and obtain qualified medical liquid B.
4. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as claimed in claim 3, is characterized in that, in described step S2-1,50 ~ 80% waters for injection taking configuration amount to add in Agitation Tank and are cooled to room temperature.
5. the preparation method of a kind of injection vinpocetine lyophilized powder as claimed in claim 3, is characterized in that, in described step S2-3, regulates pH value to 5.8 ~ 6.2 of medicinal liquid A with 0.5mol/L sodium hydroxide solution.
6. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as claimed in claim 3, it is characterized in that, in described step S2-5, successively carry out filtering decarbonization through 0.45 μm of micropore filter element successively, and carry out fine straining through 0.22 μm of microporous filter membrane and take off charcoal.
7. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as claimed in claim 3, is characterized in that, in described step S2-6, carry out fine straining more after the assay was approved, obtain qualified medical liquid B through 0.22 μm of microporous filter membrane.
8. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as described in the appended claim 1, it is characterized in that, described step S3 fill comprises: adjustment racking machine, to specifying scale, by medicinal liquid A fill in vial, presses half plug.
9. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as described in the appended claim 1, it is characterized in that, described step S4 lyophilization also comprises carries out the full plug outlet of the qualified rear pressure of pressure test to freezer dryer, and lyophilizing terminates.
10. the preparation method of a kind of injection isosorbide mononitrate lyophilized powder as described in the appended claim 1, it is characterized in that, described step S5 comprises: put in storage after pricking aluminium lid, lamp inspection, packaging.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410238146.XA CN105168150A (en) | 2014-05-30 | 2014-05-30 | Preparation method of isosorbide mononitrate freeze-dried powder for injection |
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| CN201410238146.XA CN105168150A (en) | 2014-05-30 | 2014-05-30 | Preparation method of isosorbide mononitrate freeze-dried powder for injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106619499A (en) * | 2016-12-22 | 2017-05-10 | 扬子江药业集团南京海陵药业有限公司 | Preparation method of isosorbide mononitrate injection |
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| CN1611214A (en) * | 2003-10-30 | 2005-05-04 | 王玫 | medicinal preparation of isosorbide dinitrate for injection and its preparing method |
| CN101816636A (en) * | 2010-03-20 | 2010-09-01 | 山东新时代药业有限公司 | Isosorbide mononitrate freeze-dried power injection and preparation method thereof |
| CN103239416A (en) * | 2013-05-13 | 2013-08-14 | 江苏奥赛康药业股份有限公司 | Injection composition with isosorbide mononitrate and preparation method for injection composition |
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- 2014-05-30 CN CN201410238146.XA patent/CN105168150A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1611214A (en) * | 2003-10-30 | 2005-05-04 | 王玫 | medicinal preparation of isosorbide dinitrate for injection and its preparing method |
| CN101816636A (en) * | 2010-03-20 | 2010-09-01 | 山东新时代药业有限公司 | Isosorbide mononitrate freeze-dried power injection and preparation method thereof |
| CN103239416A (en) * | 2013-05-13 | 2013-08-14 | 江苏奥赛康药业股份有限公司 | Injection composition with isosorbide mononitrate and preparation method for injection composition |
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| 姚日生等: "《制药工程原理与设备》", 31 January 2007, 高等教育出版社 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106619499A (en) * | 2016-12-22 | 2017-05-10 | 扬子江药业集团南京海陵药业有限公司 | Preparation method of isosorbide mononitrate injection |
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