CN114306568A - Preparation method of octreotide acetate freeze-dried powder injection for injection - Google Patents
Preparation method of octreotide acetate freeze-dried powder injection for injection Download PDFInfo
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Abstract
The invention discloses a preparation method of octreotide acetate freeze-dried powder injection for injection, which comprises the steps of adjusting the pH value of a mannitol lactic acid solution to 3.7-4.7 by a sodium bicarbonate solution, adding octreotide acetate to obtain an octreotide acetate solution, filtering by a filter, carrying out aseptic filling and half-top plugging, and then carrying out freeze-drying, wherein the freeze-drying process comprises the following steps: gradually cooling the freeze-drying box to below-40 ℃ within 3h to keep the temperature of the product at-40 ℃ for 2 h; then starting a vacuum pump, gradually heating the freeze-drying box to-15 ℃ within 3h, and maintaining the product temperature at-15 ℃ for 10 h; then the freeze-drying box is gradually heated to 0 ℃ within 2 hours, so that the temperature of the product is maintained at 0 ℃ and maintained for 2 hours; and finally, gradually heating the freeze-drying box to 26 ℃ within 2h, maintaining the product temperature at 26 ℃ for not less than 8h, fully plugging the freeze-drying box when freeze-drying is finished, and then performing capping, lamp inspection and packaging to obtain the octreotide acetate freeze-dried powder injection for injection without acetic acid, so that adverse reactions such as pain of injection parts caused by acetic acid are avoided.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of octreotide acetate freeze-dried powder injection for injection.
Background
Octreotide is an artificially synthesized octapeptide compound, is a human somatostatin analogue, has similar pharmacological action to natural hormone, but has stronger action of inhibiting growth hormone, glucagon and insulin. Similar to somatostatin, octreotide also inhibits the response of LH to GnRH, reduces visceral blood flow, inhibits the secretion of 5-HT, gastrin, vasoactive intestinal peptide, chymotrypsin, motilin, glucagon.
Octreotide acetate is a polypeptide preparation, so that the oral administration is poor in absorption and has strong first-pass effect, and subcutaneous and intravenous administration can achieve rapid and complete absorption.
Most products of octreotide acetate and octreotide acetate injection in the market at present have the acetic acid content of 3-12%, however, the component which actually plays the curative effect is octreotide, and the acetic acid does not participate in the treatment effect, but causes adverse reactions such as injection part pain and the like.
Disclosure of Invention
The invention aims to solve the problems that: acetic acid in octreotide acetate injection can cause adverse reactions such as injection site pain and the like. In order to improve the water solubility and stability of octreotide, it is usually in the form of acetate, acetic acid is somewhat bound to free amino groups and is present in a residual state, and the residual acetic acid can be present in a free state by adjusting the pH and then evaporated and removed during lyophilization. Therefore, the application provides a preparation method of octreotide acetate freeze-dried powder injection for injection, wherein the pH value of octreotide acetate solution is controlled to be 3.7-4.7, so that acetic acid mainly exists in a free state, and the acetic acid is removed by controlling the freeze-drying time and the freeze-drying temperature in the freeze-drying process, so that the octreotide acetate freeze-dried powder injection without the acetic acid is obtained.
The technical scheme adopted by the invention is as follows:
the preparation method of the octreotide acetate freeze-dried powder injection for injection comprises the following steps:
step S1, accurately weighing octreotide acetate, mannitol, lactic acid and sodium bicarbonate for later use;
step S2, adding water for injection into sodium bicarbonate, stirring and dissolving to obtain 1mol/L sodium bicarbonate solution;
step S3, adding water for injection into mannitol, adding lactic acid after full dissolution, stirring and mixing, and adding a sodium bicarbonate solution to adjust the pH value to 3.7-4.7 to obtain a mixed solution;
step S4, adding octreotide acetate into the mixed solution, stirring for dissolving, uniformly mixing and fixing the volume to obtain octreotide acetate solution;
step S5, filtering the octreotide acetate solution through a filter, and performing aseptic filling and half-top plugging after filtering;
step S6, the qualified product is sent to a freeze-drying box for freeze-drying, and the freeze-drying process comprises the following steps: gradually cooling the freeze-drying box to below-40 ℃ within 3h to keep the temperature of the product at-40 ℃ for 2 h; then starting a vacuum pump, gradually heating the freeze-drying box to-15 ℃ within 3h, and maintaining the product temperature at-15 ℃ for 10 h; then the freeze-drying box is gradually heated to 0 ℃ within 2 hours, so that the temperature of the product is maintained at 0 ℃ and maintained for 2 hours; finally, the temperature of the freeze-drying box is gradually raised to 26 ℃ within 2h, so that the temperature of the product is maintained at 26 ℃ and is kept for not less than 8h, and after freeze-drying is finished, the isolating valve is closed;
step S7, performing full stoppering when the freeze-drying is finished; and then, rolling a cover, inspecting by a lamp, and packaging to obtain the octreotide acetate freeze-dried powder injection for injection.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, in the step S1, the mass ratio of octreotide acetate, mannitol and lactic acid is 1:350-450: 35-55.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, the mass ratio of the octreotide acetate, mannitol and lactic acid is 1:398: 45.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, in the step S3, water for injection is added into mannitol, lactic acid is added after full dissolution, stirring and mixing are carried out, and then sodium bicarbonate solution is added to adjust the pH value to 4.1-4.3, so as to obtain a mixed solution.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, the pH value of the mixed solution is 4.2.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, in the step S4, octreotide acetate is added into the mixed solution, stirred to dissolve, mixed uniformly and subjected to volume fixing to obtain an octreotide acetate solution with the octreotide content of 0.1 mg/mL.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, in the step S5, the specification of the filter is 0.22 μm.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, in the step S5, sterile filling and half stopper filling operations are performed under the protection of nitrogen.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, in the step S6, the end point of the freeze-drying process is that the difference between the vacuum degree of the freeze-drying box before 3 minutes and the vacuum degree after 3 minutes is less than 5 pa.
In the preparation method of the octreotide acetate freeze-dried powder injection for injection disclosed by the application, in the step S7, the capping operation is performed under the protection of nitrogen.
The invention has the beneficial effects that:
the invention provides a preparation method of octreotide acetate freeze-dried powder injection for injection, which is characterized in that the pH value of octreotide acetate solution is controlled to be 3.7-4.7, so that acetic acid mainly exists in a free state, and then the octreotide acetate solution is filtered, aseptically filled, half filled and freeze-dried, wherein the freeze-drying process is that a freeze-drying box is gradually cooled to below-40 ℃ within 3 hours, so that the temperature of a product is maintained at-40 ℃ and is kept for 2 hours; then starting a vacuum pump, gradually heating the freeze-drying box to-15 ℃ within 3h, and maintaining the product temperature at-15 ℃ for 10 h; then the freeze-drying box is gradually heated to 0 ℃ within 2 hours, so that the temperature of the product is maintained at 0 ℃ and maintained for 2 hours; and finally, gradually heating the freeze-drying box to 26 ℃ within 2h, maintaining the product temperature at 26 ℃ for not less than 8h, volatilizing free acetic acid in the octreotide acetate solution by controlling the freeze-drying time and the freeze-drying temperature in the freeze-drying process, and then performing full-capping, lamp inspection and packaging to obtain the octreotide acetate freeze-dried powder injection without acetic acid, so that adverse reactions of pain and the like caused by acetic acid components in the octreotide acetate powder injection for injection to patients are effectively solved, the curative effect is kept unchanged, and the product quality is improved.
Detailed Description
In the following, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.
Reference in the specification to "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment can be included in at least one embodiment of the specification. The appearances of the phrase in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. It is explicitly and implicitly understood by one skilled in the art that the embodiments described herein can be combined with other embodiments.
The embodiment of the application provides a preparation method of octreotide acetate freeze-dried powder injection for injection, which mainly aims to ensure that acetic acid mainly exists in a free state by controlling the pH value of octreotide acetate solution, and then remove the acetic acid by freeze-drying to obtain the octreotide acetate freeze-dried powder injection without the acetic acid.
The application discloses a preparation method of octreotide acetate freeze-dried powder injection for injection, which comprises the following steps:
step S1, accurately weighing octreotide acetate, mannitol, lactic acid and sodium bicarbonate for later use;
step S2, adding water for injection into sodium bicarbonate, stirring and dissolving to obtain 1mol/L sodium bicarbonate solution;
step S3, adding water for injection into lactic acid, stirring and mixing, adding a sodium bicarbonate solution to adjust the pH value to 3.7-4.7 to obtain a mixed solution;
step S4, adding octreotide acetate into the mixed solution, stirring for dissolving, uniformly mixing and fixing the volume to obtain octreotide acetate solution;
step S5, filtering the octreotide acetate solution through a filter, and performing aseptic filling and half-top plugging after filtering;
step S6, the qualified product is sent to a freeze-drying box for freeze-drying, and the freeze-drying process comprises the following steps: gradually cooling the freeze-drying box to below-40 ℃ within 3h to keep the temperature of the product at-40 ℃ for 2 h; then starting a vacuum pump, gradually heating the freeze-drying box to-15 ℃ within 3h, and maintaining the product temperature at-15 ℃ for 10 h; then the freeze-drying box is gradually heated to 0 ℃ within 2 hours, so that the temperature of the product is maintained at 0 ℃ and maintained for 2 hours; finally, the temperature of the freeze-drying box is gradually raised to 26 ℃ within 2h, so that the temperature of the product is maintained at 26 ℃ and is kept for not less than 8h, and after freeze-drying is finished, the isolating valve is closed;
step S7, performing full stoppering when the freeze-drying is finished; and then, rolling a cover, inspecting by a lamp, and packaging to obtain the octreotide acetate freeze-dried powder injection for injection.
In order to improve the water solubility and stability of octreotide, it is usually in the form of acetate, with acetic acid being somewhat bound to free amino groups and somewhat in a residual state. Most products of octreotide acetate and octreotide acetate injection in the market at present have the acetic acid content of 3-12%, however, the component which actually plays the curative effect is octreotide, and the acetic acid does not participate in the treatment effect, but causes adverse reactions such as injection part pain and the like. Based on the above, the application provides a preparation method of octreotide acetate freeze-dried powder injection for injection, wherein the pKa of acetic acid is 4.75, so that the pH value of octreotide acetate solution is controlled to be 3.7-4.7, acetic acid mainly exists in a free state, and then the octreotide acetate solution is filtered, aseptically filled, half-stoppered and then freeze-dried, wherein the freeze-drying process is that a freeze-drying box is gradually cooled to below-40 ℃ within 3 hours, so that the product temperature is maintained at-40 ℃ and kept for 2 hours; then starting a vacuum pump, gradually heating the freeze-drying box to-15 ℃ within 3h, and maintaining the product temperature at-15 ℃ for 10 h; then the freeze-drying box is gradually heated to 0 ℃ within 2 hours, so that the temperature of the product is maintained at 0 ℃ and maintained for 2 hours; and finally, the temperature of the freeze-drying box is gradually raised to 26 ℃ within 2h, so that the product temperature is maintained at 26 ℃ and is kept for no less than 8h, free acetic acid in the octreotide acetate solution can be volatilized and removed by controlling the freeze-drying time and the freeze-drying temperature in the freeze-drying process, the acetic acid content in the octreotide acetate powder injection for injection is reduced to the maximum extent, the effect that the finished product does not contain acetic acid is achieved, the adverse reactions of pain and the like caused by acetic acid components in the octreotide acetate preparation for injection to patients are effectively solved, the curative effect is kept unchanged, and the product quality is improved.
Specifically, in step S1, the mass ratio of octreotide acetate, mannitol and lactic acid is 1:350-450: 35-55. Wherein, the mass ratio of octreotide acetate, mannitol and lactic acid can be 1:350:35, 1:370:40, 1:398:45, 1:420:50, 1:450:55, and preferably is 1:398: 45.
Specifically, in step S2, a 1mol/L sodium bicarbonate solution is prepared: weighing NaHCO3(molecular weight: 84.01) 16.802g, adding water for injection, stirring to dissolve, and diluting to 200ml for use.
Specifically, in step S3, the pH of the mixed solution is adjusted by sodium bicarbonate solution, and the content of acetic acid in the finally obtained octreotide acetate freeze-dried powder for injection is detected by controlling the pH, and the results are shown in table 1:
TABLE 1 content of acetic acid in octreotide acetate lyophilized powder for injection at different pH
| Adjusting the pH | Batch number | pH of the final product | Acetic acid content (%) |
| 4.8 | S200908 | 4.79 | Not detected out |
| 5.0 | S200905 | 5.01 | 0.88 |
| 5.0 | S200906 | 5.01 | 0.74 |
| 5.0 | S200907 | 5.00 | 0.68 |
| 5.5 | S210101 | 5.48 | 4.97 |
| 5.6 | S210102 | 5.54 | 5.24 |
| 5.7 | S210103 | 5.62 | 8.08 |
| 5.8 | S210104 | 5.59 | 6.69 |
| 5.9 | S210105 | 5.67 | 10.03 |
| Products on the market | - | - | 1.7-4.2 |
| 4.1-4.3 | Products of the present application | 4.1-4.3 | Not detected out |
As shown in table 1, the pH of the mixed solution was adjusted to 5.0 to 5.9, and acetic acid was detected in the obtained octreotide acetate lyophilized powder for injection, and the acetic acid content increased with the increase of pH. The pH value has obvious influence on the acetic acid content in the octreotide acetate finished product for injection, the number of lactic acid molecules in the product far exceeds the number of acetic acid molecules, the pKa of the acetic acid is 4.75, the pH value of the mixed solution is adjusted to 4.8, the acetic acid mainly exists in a free state, the acetic acid is volatilized and removed during freeze-drying, and no acetic acid is detected in the obtained octreotide acetate freeze-dried powder injection. In consideration of stability of octreotide acetate and complete removal of free acetic acid, the pH of the mixed solution may be adjusted to 4.1 to 4.3, and further, the pH of the mixed solution may be 4.1, 4.2, 4.3, preferably 4.2. The pH value of the octreotide acetate solution is controlled to be 4.1-4.2, so that most of acetic acid exists in a free state, and the acetic acid can be completely removed by freeze-drying to obtain the stable octreotide acetate freeze-dried powder injection without the acetic acid, thereby effectively solving the adverse reactions of pain and the like caused by acetic acid components in the octreotide acetate powder injection for injection to patients, simultaneously keeping the curative effect unchanged and improving the product quality.
Specifically, in step S4, the weighed octreotide acetate is added to the mixed solution, and the solution is stirred to dissolve, mixed uniformly and subjected to volume fixing to obtain 0.1mg/mL octreotide acetate solution.
Specifically, in step S5, the octreotide acetate solution is filtered through a 0.22 μm end filter, and then transferred to a filling machine for filling and half plugging. The filter is used for filtering the octreotide acetate solution, and the 0.22 mu m filter can filter impurities and bacteria in the octreotide acetate solution.
Specifically, in step S5, the filtration, filling and half-top-filling of the octreotide acetate solution are all performed under the protection of nitrogen, so as to ensure a sterile environment.
Specifically, in step S6, a differential pressure test is performed to confirm that the freeze-drying process is finished, i.e., the isolation valve is closed, the variation of the vacuum degree of the freeze-drying chamber is observed, and when the difference between the vacuum degree of the freeze-drying chamber before 3 minutes and the vacuum degree after 3 minutes is less than 5pa, the freeze-drying process is finished.
Specifically, in step S7, the capping operation is performed under a nitrogen blanket. The lamp detection temperature is below 26 ℃, a 20W (or 40W) fluorescent lamp is used as a light source (the optical density is 1000-1500 LX) under a dark background, and the distance between the light source and a detected product is 20-50 cm.
Based on the above embodiments, the preparation method of the octreotide acetate freeze-dried powder injection for injection provided by the embodiment of the invention has the following advantages: the preparation method comprises the steps of controlling the pH value of an octreotide acetate solution to be 3.7-4.7, enabling acetic acid to exist in a free state, filtering the octreotide acetate solution, carrying out aseptic filling, half plugging and freeze-drying, wherein the freeze-drying process is that a freeze-drying box is gradually cooled to be below-40 ℃ within 3 hours, and the temperature of a product is maintained at-40 ℃ and is kept for 2 hours; then starting a vacuum pump, gradually heating the freeze-drying box to-15 ℃ within 3h, and maintaining the product temperature at-15 ℃ for 10 h; then the freeze-drying box is gradually heated to 0 ℃ within 2 hours, so that the temperature of the product is maintained at 0 ℃ and maintained for 2 hours; and finally, gradually heating the freeze-drying box to 26 ℃ within 2h, maintaining the product temperature at 26 ℃ for not less than 8h, volatilizing free acetic acid in the octreotide acetate solution by controlling the freeze-drying time and the freeze-drying temperature in the freeze-drying process, and then performing full-capping, lamp inspection and packaging to obtain the octreotide acetate freeze-dried powder injection without acetic acid, so that adverse reactions of pain and the like caused by acetic acid components in the octreotide acetate powder injection for injection to patients are effectively solved, the curative effect is kept unchanged, and the product quality is improved.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The preparation method of the octreotide acetate freeze-dried powder injection for injection is characterized by comprising the following steps:
step S1, accurately weighing octreotide acetate, mannitol, lactic acid and sodium bicarbonate for later use;
step S2, adding water for injection into sodium bicarbonate, stirring and dissolving to obtain 1mol/L sodium bicarbonate solution;
step S3, adding water for injection into mannitol, adding lactic acid after full dissolution, stirring and mixing, and adding a sodium bicarbonate solution to adjust the pH value to 3.7-4.7 to obtain a mixed solution;
step S4, adding octreotide acetate into the mixed solution, stirring for dissolving, uniformly mixing and fixing the volume to obtain octreotide acetate solution;
step S5, filtering the octreotide acetate solution through a filter, and performing aseptic filling and half-top plugging after filtering;
step S6, the qualified product is sent to a freeze-drying box for freeze-drying, and the freeze-drying process comprises the following steps: gradually cooling the freeze-drying box to below-40 ℃ within 3h to keep the temperature of the product at-40 ℃ for 2 h; then starting a vacuum pump, gradually heating the freeze-drying box to-15 ℃ within 3h, and maintaining the product temperature at-15 ℃ for 10 h; then the freeze-drying box is gradually heated to 0 ℃ within 2 hours, so that the temperature of the product is maintained at 0 ℃ and maintained for 2 hours; finally, the temperature of the freeze-drying box is gradually raised to 26 ℃ within 2h, so that the temperature of the product is maintained at 26 ℃ and is kept for not less than 8h, and after freeze-drying is finished, the isolating valve is closed;
step S7, performing full stoppering when the freeze-drying is finished; and then, rolling a cover, inspecting by a lamp, and packaging to obtain the octreotide acetate freeze-dried powder injection for injection.
2. The method for preparing the octreotide acetate freeze-dried powder injection for injection according to claim 1, wherein the mass ratio of octreotide acetate, mannitol and lactic acid in step S1 is 1:350-450: 35-55.
3. The preparation method of the octreotide acetate freeze-dried powder injection for injection as claimed in claim 2, wherein the mass ratio of octreotide acetate, mannitol and lactic acid is 1:398: 45.
4. The preparation method of the octreotide acetate freeze-dried powder injection for injection according to claim 1, wherein in the step S3, water for injection is added into mannitol, lactic acid is added after full dissolution, stirring and mixing are carried out, and sodium bicarbonate solution is added to adjust the pH value to 4.1-4.3, so as to obtain a mixed solution.
5. The method for preparing the octreotide acetate freeze-dried powder injection for injection according to claim 4, wherein the pH of the mixed solution is 4.2.
6. The method for preparing the octreotide acetate freeze-dried powder injection for injection according to claim 1, wherein in the step S4, octreotide acetate is added into the mixed solution, and the solution is stirred, dissolved, mixed and subjected to volume fixing to obtain an octreotide acetate solution with the octreotide content of 0.1 mg/mL.
7. The method for preparing the octreotide acetate freeze-dried powder injection for injection according to claim 1, wherein in the step S5, the specification of the filter is 0.22 μm.
8. The method for preparing the octreotide acetate freeze-dried powder injection for injection according to claim 1, wherein in the step S5, sterile filling and half stopper filling operations are performed under the protection of nitrogen.
9. The method for preparing the octreotide acetate freeze-dried powder injection for injection according to claim 1, wherein in the step S6, the end point of the freeze-drying process is that the difference between the vacuum degree before 3 minutes and the vacuum degree after 3 minutes in the freeze-drying box is less than 5 pa.
10. The method for preparing the octreotide acetate freeze-dried powder injection for injection according to claim 1, wherein in the step S7, the capping operation is performed under the protection of nitrogen.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102526700A (en) * | 2011-12-31 | 2012-07-04 | 江苏奥赛康药业股份有限公司 | Octreotide acetate freeze-dried combination for injection and preparation method thereof |
| CN107510837A (en) * | 2017-09-12 | 2017-12-26 | 国药集团成都信立邦生物制药有限公司 | A kind of freeze drying powder injection of injection octreotide acetate and preparation method thereof |
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- 2022-01-18 CN CN202210055995.6A patent/CN114306568A/en active Pending
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| CN102526700A (en) * | 2011-12-31 | 2012-07-04 | 江苏奥赛康药业股份有限公司 | Octreotide acetate freeze-dried combination for injection and preparation method thereof |
| CN107510837A (en) * | 2017-09-12 | 2017-12-26 | 国药集团成都信立邦生物制药有限公司 | A kind of freeze drying powder injection of injection octreotide acetate and preparation method thereof |
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