CN111303473A - Preparation method of powder injection rubber plug - Google Patents
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- CN111303473A CN111303473A CN202010118166.9A CN202010118166A CN111303473A CN 111303473 A CN111303473 A CN 111303473A CN 202010118166 A CN202010118166 A CN 202010118166A CN 111303473 A CN111303473 A CN 111303473A
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Abstract
The invention belongs to the technical field of biological medicine, and particularly relates to a preparation method of a powder injection rubber plug, which comprises the following steps: soaking the rubber plug in a pH regulator solution, washing with water, drying, performing wet heat sterilization and drying; the rubber plug obtained by the preparation method is used for preparing the preparation after being used for packaging products such as somatostatin and the like, and the result of research of influencing factor tests and long-term stability tests shows that the preparation has better stability.
Description
Technical Field
The invention belongs to the technical field of biological medicines. In particular to a preparation method of a powder injection rubber plug.
Background
The medicine is prepared into a preparation of sterilized powder for injection by adopting an aseptic technique, which is called powder injection; the medicines which are sensitive to heat or unstable in aqueous solution, such as some antibiotics (penicillin G potassium, streptomycin and polymyxin) and enzyme preparations for medicine (trypsin, coenzyme A and the like), can not be prepared into general water-soluble injection, can not be heated and sterilized in aqueous solution, can only be prepared into powder injection by adopting an aseptic operation method, and can be used for clinical application after being dissolved by proper solvent for injection before use. The preparation method of the powder injection can be divided into two types according to different properties of the medicine: (1) refining the raw materials into sterile powder, and performing sterile subpackaging under sterile conditions. (2) Preparing the medicine into sterile aqueous solution, performing sterile filling according to a conventional method, freeze-drying, and sealing under a sterile condition to obtain the medicine.
The medicine is a special commodity, the medicine effect and the quality of the medicine are directly related to the health and the safety of human bodies, and the material and the structural form of medicine packaging, particularly the packaging material which is in direct contact with the medicine, play a decisive role in ensuring the stability of the medicine. Unsuitable packaging materials can cause exudation, adsorption, and even chemical reactions of the active pharmaceutical ingredient, leading to drug failure and sometimes serious toxic side effects. Therefore, whether the selection of the medicine packaging material is proper or not is an important index for evaluating the medicine quality, and the rubber plug is an important component of bottled sealing materials in medicine packaging; the development of rubber plugs is so far, and the safety in use possibly caused by the quality of the rubber plugs is always a focus of attention of products of the type. The medicinal butyl rubber plug is directly contacted with the medicament, and although the medicinal butyl rubber plug has good air tightness, heat resistance and acid and alkali resistance, the medicinal butyl rubber plug still has interaction with the medicament in the using process, and even influences the physicochemical properties of the medicament and the like.
With the increasingly accelerated process of the formation of the medicinal butyl rubber plug in China, the problem of compatibility between medicines and the rubber plug is seriously troubling medicine production enterprises and butyl rubber plug production enterprises. However, it is worth noting that the center of gravity of the quality of the medicine grabbed by pharmaceutical enterprises is always the production and processing process, and the packaging link is not paid enough attention, so that the research on a new preparation process method of the rubber plug is of great significance.
Disclosure of Invention
Based on the reasons, the applicant researches and obtains a novel preparation method of the rubber plug of the powder injection through multiple creative tests, the rubber plug obtained by the preparation method is used for preparing a preparation after being used for packaging products such as somatostatin and the like, and the result of the research of influencing factor tests and long-term stability tests shows that the preparation has better stability.
The invention is realized by the following technical scheme.
A preparation method of a rubber plug for powder injection comprises soaking rubber plug in pH regulator solution, washing with water, oven drying, heat-humid sterilizing, and oven drying.
The powder injection comprises: somatostatin and derivatives thereof.
Wherein the pH regulator is selected from: one or more of acetic acid, hydrochloric acid, phosphoric acid, sorbic acid, maleic acid, taurine, propionic acid, L-malic acid, DL-malic acid, citric acid, octanoic acid, succinic acid, DL-tartaric acid and sulfuric acid.
The pH regulator solution is a pH regulator aqueous solution with the mass concentration of 1-100%.
The preferable pH regulator solution is a pH regulator aqueous solution with the mass concentration of 40-100%.
The preferable pH regulator solution is a pH regulator aqueous solution with the mass concentration of 60-100%.
The pH regulator solution is acetic acid water solution with the mass concentration of 1-100%.
Preferably, the pH regulator solution is an acetic acid aqueous solution with the mass concentration of 40-100%.
Preferably, the pH regulator solution is an acetic acid aqueous solution with the mass concentration of 60-100%.
The preparation method comprises the following steps: soaking the rubber plug in a pH regulator aqueous solution for 24-48h, washing with water, drying at 70-110 deg.C for 2 h, performing wet heat sterilization at 121 deg.C for 25-35 min, and drying at 110 deg.C for 60-90 min to obtain the rubber plug.
Wherein somatostatin (I) comprises: octreotide, somatostatin (II), somatostatin-14 and somatostatin-28.
The somatostatin (I) is a generalized somatostatin which comprises a general name of medicines such as octreotide, somatostatin acetate, somatostatin-14, somatostatin-28 and the like.
The above-mentioned somatostatin acetate is: somatostatin is a tetradecapeptide obtained by cracking a macromolecular peptide of 116 amino acids, the molecular structure of the tetradecapeptide is annular, a disulfide bond is arranged between cysteine at the 3 rd position and cysteine at the 14 th position, and the tetradecapeptide and acetic acid are used for synthesizing the somatostatin acetate. Somatostatin is a neurohormone with a wide range of actions, and has the main effects of inhibiting the basal secretion of pituitary Growth Hormone (GH) and inhibiting GH secretion response of adenohypophysis caused by various stimuli, including exercise, meal, stress, hypoglycemia and the like. Somatostatin has been developed for human use, and its indications include: (1) severe acute esophageal variceal bleeding; (2) bleeding from severe acute gastric or duodenal ulcers, or complicated acute erosive or hemorrhagic gastritis; (3) adjuvant treatment of pancreatic, biliary and intestinal fistulas; (4) prevention and treatment of pancreatic postoperative complications; (5) adjuvant treatment of diabetic ketoacidosis.
The somatostatin for injection produced by the Switzerland company, a foreign original product, has good stability, and is stored at the temperature of below 25 ℃. The somatostatin for injection produced at present in China has poor stability, and the somatostatin for injection produced in the year of Chinese pharmacopoeia 2015 is stored in a cold place (2-10 ℃), so that the storage condition is required to be harsh, the product storage is not facilitated, and the stability in the validity period is poorer. The glass ampoule is used as an inner packaging material of a foreign primary research product, the glass ampoule is used as an inner packaging material of a medicine, the phenomena of dissolution of components and glass flaking can occur, and fine glass flaking can block blood vessels to form thrombus or pulmonary granuloma, so that the safety risk exists. At present, somatostatin inner packing materials produced by some domestic enterprises are penicillin bottles and rubber plugs, although safety risks are avoided, after the penicillin bottles and the rubber plugs are used, the acidity change under a long-term storage condition is large and exceeds the acidity range (4.5-6.5) of somatostatin for injection in the 2015 edition of Chinese pharmacopoeia, related substances and high polymers are remarkably changed, and the medicine quality is adversely affected.
The rubber plug of the invention is as follows: butyl rubber stoppers, including but not limited to: chlorinated butyl rubber plug.
The octreotide is as follows: is an artificially synthesized octapeptide derivative of natural somatostatin, and has similar pharmacological action to somatostatin but longer action duration.
Somatostatin-14 and somatostatin-28 of the present invention: namely somatostatin-14 (SST-14) and somatostatin-28 (SST-28), wherein the C-terminal of the SST-14 and SST-28 has the same 14-amino acid polypeptide structure, 2 cysteines contained in the SST-14 and SST-28 form a 12-amino acid loop by disulfide bonds, and the formed loop structure forms the physiological active domain of the somatostatin.
The powder injection is a generalized powder injection, and specifically comprises the following components: (1) refining the raw materials into sterile powder, and packaging under sterile condition to obtain powder for injection. (2) Preparing the medicine into sterile aqueous solution, performing sterile filling according to a conventional method, freeze-drying, and sealing under a sterile condition to obtain the freeze-dried powder injection.
Preparation examples
Example 1
Treatment method of somatostatin freeze-dried powder plug for injection
Adding a chlorinated butyl rubber plug into an acetic acid aqueous solution with the mass concentration of 90%, soaking for 24 hours, washing with water, drying for 2 hours at 80 ℃, performing moist heat sterilization for 30 minutes at 121 ℃, and drying for 80 minutes at 110 ℃. And (5) standby.
The prescription of the somatostatin freeze-dried powder injection is as follows:
the preparation process of the somatostatin freeze-dried powder injection for injection comprises the following steps:
(1) weighing somatostatin according to the prescription amount, adding the somatostatin into injection water with the prescription amount of 50%, stirring and dissolving, weighing mannitol according to the prescription amount, adding injection water with the prescription amount of 20% to dissolve, mixing the two solutions, rinsing a mannitol container with injection water with the prescription amount of 20% for three times, merging the rinsing solution into the mixed solution, and adding the injection water to the prescription volume.
(2) Filtering the medicinal liquid with 0.22 μm filter membrane, subpackaging in 2ml borosilicate glass injection bottles, each bottle is 0.5ml, and half pressing.
(3) Placing the sample in a freeze dryer, starting refrigeration to enable the temperature of the heat conduction oil to be lower than-40 ℃, keeping the temperature for more than 120 minutes, heating to-35 ℃, keeping the temperature for 120 minutes, cooling to-45 ℃, and keeping the temperature for 60 minutes; setting the vacuum degree to 10Pa, raising the temperature to enable the temperature of the heat-conducting oil to reach-15 ℃, keeping the temperature for 150 minutes, raising the temperature to enable the temperature of the heat-conducting oil to reach-5 ℃, keeping the temperature for 60 minutes, raising the temperature to enable the temperature of the heat-conducting oil to reach 0 ℃, and keeping the temperature for 60 minutes; setting the vacuum degree to 10Pa, raising the temperature to enable the temperature of the heat-conducting oil to reach 25 ℃, keeping the temperature for 60 minutes, stopping vacuum control (no aeration), and continuously keeping drying for 360 minutes; after the freeze-drying is finished, filling nitrogen, pressing a plug (a standby rubber plug) and rolling a cover.
Example 2
Treatment method of somatostatin freeze-dried powder plug for injection
Adding a chlorinated butyl rubber plug into an acetic acid aqueous solution with the mass concentration of 90%, soaking for 48 hours, washing with water, drying for 2 hours at 80 ℃, performing moist heat sterilization for 30 minutes at 121 ℃, and drying for 80 minutes at 110 ℃. And (5) standby.
Example 2 the formulation and preparation process were the same as in example 1 except that the stopper treatment was performed in a different manner.
Example 3
Method for processing octreotide acetate freeze-dried powder plug for injection
Adding chlorinated butyl rubber plugs into acetic acid water solution with the mass concentration of 70%, soaking for 24 hours, washing, drying for 2 hours at 80 ℃, performing moist heat sterilization for 30 minutes at 121 ℃, and drying for 90 minutes at 110 ℃. And (5) standby.
The prescription of the octreotide acetate freeze-dried powder for injection is as follows:
the preparation process of the octreotide acetate freeze-dried powder for injection comprises the following steps:
(1) weighing octreotide acetate and mannitol according to the prescription amount, adding injection water with the prescription amount of 50%, stirring and dissolving, weighing lactic acid according to the prescription amount, adding injection water with the prescription amount of 10%, dissolving, mixing the two solutions, rinsing a lactic acid container for three times by using injection water with the prescription amount of 10%, merging the rinsing solution into the mixed solution, adding 1mol/L sodium bicarbonate solution, adjusting the pH value to 4.2, and adding the injection water to the prescription volume.
(2) Filtering the liquid medicine with 0.22 μm filter membrane, subpackaging in 2ml borosilicate glass tube injection bottles, 1ml each, and half pressing.
(3) Placing the sample in a freeze dryer, starting refrigeration to make the temperature of the heat conducting oil reach below-40 ℃, keeping the temperature for more than 120 minutes, heating to-20 ℃, keeping the temperature for 120 minutes, cooling to-40 ℃, and keeping the temperature for 60 minutes; setting the vacuum degree to 10Pa, raising the temperature to enable the temperature of the heat-conducting oil to reach-15 ℃, keeping the temperature for 150 minutes, raising the temperature to enable the temperature of the heat-conducting oil to reach-5 ℃, keeping the temperature for 60 minutes, raising the temperature to enable the temperature of the heat-conducting oil to reach 0 ℃, and keeping the temperature for 60 minutes; setting the vacuum degree to 10Pa, raising the temperature to enable the temperature of the heat-conducting oil to reach 25 ℃, keeping the temperature for 60 minutes, stopping vacuum control (no aeration), and continuously keeping drying for 420 minutes; after the freeze-drying is finished, the plug (the standby rubber plug) is pressed and the cover is rolled.
Example 4
Method for processing octreotide acetate freeze-dried powder plug for injection
Adding chlorinated butyl rubber plugs into acetic acid, soaking for 24 hours, washing, drying for 2 hours at 80 ℃, carrying out moist heat sterilization for 30 minutes at 121 ℃, and drying for 90 minutes at 110 ℃. And (5) standby.
Example 4 the formulation and preparation process were the same as in example 3, except that the stopper treatment was performed in a different manner.
Comparative example 1
The plug used was untreated.
Comparative example 1 the formulation and preparation process were the same as in example 1 except that the stopper treatment was different.
Comparative example 2
The plug used was untreated.
Comparative example 2 the formulation and preparation process were the same as in example 1 except that the stopper treatment was performed in a different manner.
Comparative example 3
The plug used was untreated.
Comparative example 3 the formulation and preparation process were the same as in example 3 except that the stopper treatment was different.
Comparative example 4
The plug used was untreated.
Comparative example 4 the formulation and preparation process were the same as in example 3 except that the stopper treatment was different.
Verification examples
The following assay methods were used: chinese pharmacopoeia 2015 year edition: growth hormone for injection.
The detection method of the somatostatin polymer comprises the following steps: chromatographic conditions are as follows: the instrument comprises the following steps: a high performance liquid chromatograph; a chromatographic column: TosohTSKGel G2000SWXL (7.8 mm. times.300 mm, 5 μm)
) (ii) a Mobile phase: 30% isopropanol-40% glacial acetic acid water solution (150 mL isopropanol, 200mL glacial acetic acid, adding water to 500mL, and mixing well); flow rate: 0.5 mL/min; sample introduction amount: 20 mu L of the solution; detection wavelength: 276 nm; the operation mode is as follows: isocratic elution; operating time: 30 min; blank solution: a mobile phase; column temperature: 25 deg.C
The determination method comprises the following steps: test solution: taking a proper amount of somatostatin for injection, and preparing a solution of 1.0mg/mL by using a mobile phase.
Control solution: the test solution was diluted 100 times.
System applicability solution: taking appropriate amount of somatostatin acetate reference substance and dimer reference substance, adding mobile phase for dissolving, and making into mixed solution containing 1.0mg of somatostatin acetate and 0.1mg of dimer impurity per 1 mL.
System applicability requirements: the theoretical plate number of the acetic somatostatin peak is not lower than 2000, and the separation degree of the dimer and the acetic somatostatin is more than 1.5.
(1) The placing conditions are as follows: influential factor test high temperature 60 ℃. The changes of acidity, related substances and polymers under the condition of 60 ℃ high temperature of the influence factors of the standing of example 1, example 2, comparative example 1 and comparative example 2 are examined, and the results are shown in Table 1.
TABLE 1 comparative test of influencing factors of different somatostatin formulations
(2) The placing conditions are as follows: the long-term test is carried out at 25 +/-2 ℃ and the relative humidity is 65 +/-5%. The changes of acidity, related substances and polymers under the standing condition of the long-term test of example 1, example 2, comparative example 1 and comparative example 2 were examined, and the results are shown in Table 2.
TABLE 2 Long-term test comparison of different somatostatin formulations
The following assay methods were used: chinese pharmacopoeia 2015 year edition: under the term of octreotide acetate for injection.
The detection method of the octreotide polymer comprises the following steps: chromatographic conditions are as follows: the instrument comprises the following steps: a high performance liquid chromatograph; a chromatographic column: tosoh TSKgelG2000SWXL (7.8 mm. times.300 mm, 5 μm)
) (ii) a Mobile phase: 30% isopropanol-40% glacial acetic acid water solution (150 mL isopropanol, 200mL glacial acetic acid, adding water to 500mL, and mixing well); flow rate: 0.5 mL/min; sample introduction amount: 20 mu L of the solution; detection wavelength: 276 nm; the operation mode is as follows: isocratic elution; operating time: 30 min; blank solution: a mobile phase; column temperature: 25 deg.C
The determination method comprises the following steps: test solution: taking a proper amount of octreotide for injection, and preparing a solution of 0.1mg/mL by using mobile phase.
Control solution: the test solution was diluted 100 times.
System applicability solution: dissolving octreotide acetate control and dimer control with mobile phase to obtain mixed solution containing octreotide acetate 0.1mg and dimer impurity 0.01mg per 1 mL.
System applicability requirements: the theoretical plate number of the octreotide acetate peak is not less than 2000, and the separation degree of the dimer and the octreotide acetate is more than 1.5.
(1) The placing conditions are as follows: influential factor test high temperature 40 ℃. The changes of acidity, related substances and polymers at 40 ℃ after the exposure of the influencing factors of example 3, example 4, comparative example 3 and comparative example 4 were examined, and the results are shown in Table 3.
Table 3 comparative testing of the influencing factors of different octreotide formulations
(2) The placing conditions are as follows: long-term test 5 + -3 deg.C. The changes of acidity, related substances and polymers under the standing condition of the long-term test of example 3, example 4, comparative example 3 and comparative example 4 were examined, and the results are shown in Table 4.
Table 4 long-term experimental comparison of different octreotide formulations
And (4) test conclusion: as can be seen from tables 1, 2, 3 and 4, after using the present invention to treat the injection somatostatin and the injection octreotide acetate lyophilized powder plug, the acidity changes slightly in the examples and significantly changes in the comparative examples; the growth of the examples is smaller than that of the comparative examples in terms of substances and high polymers. The invention effectively improves the stability of the somatostatin for injection and the octreotide acetate freeze-dried powder injection for injection, and is suitable for long-term storage of medicaments.
The raw material (acetic acid somatostatin) is replaced by somatostatin-14 and somatostatin-28, and the test conclusion is the same.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. It is intended that the present invention be understood and implemented by those skilled in the art, and not limited thereto. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (7)
1. A preparation method of a powder injection rubber plug is characterized in that: soaking the rubber plug in a pH regulator solution, washing with water, drying, performing wet heat sterilization, and drying.
2. The preparation method of the rubber plug of the powder injection according to claim 1, wherein the powder injection comprises: somatostatin and derivatives thereof.
3. The preparation method of the rubber plug of the powder injection according to claim 1 or 2, wherein the pH regulator is selected from the following components: one or more of acetic acid, hydrochloric acid, phosphoric acid, sorbic acid, maleic acid, taurine, propionic acid, L-malic acid, DL-malic acid, citric acid, octanoic acid, succinic acid, DL-tartaric acid and sulfuric acid.
4. The preparation method of the rubber plug of the powder injection according to claim 1 or 2, wherein the pH regulator solution is a pH regulator aqueous solution with a mass concentration of 1-100%.
5. The preparation method of the rubber plug of the powder injection according to claim 1 or 2, wherein the pH regulator solution is acetic acid aqueous solution with the mass concentration of 1-100%.
6. The preparation method of the rubber plug of the powder injection according to claim 1 or 2, which comprises the following steps: soaking the rubber plug in a pH regulator aqueous solution for 24-48h, washing with water, drying at 70-110 deg.C for 2 h, performing wet heat sterilization at 121 deg.C for 25-35 min, and drying at 110 deg.C for 60-90 min to obtain the rubber plug.
7. The preparation method of the rubber plug of the powder injection according to claim 2, wherein the somatostatin and the derivative thereof comprise: octreotide, somatostatin acetate, somatostatin-14 and somatostatin-28.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010118166.9A CN111303473B (en) | 2020-02-26 | 2020-02-26 | Preparation method of powder injection rubber plug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010118166.9A CN111303473B (en) | 2020-02-26 | 2020-02-26 | Preparation method of powder injection rubber plug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111303473A true CN111303473A (en) | 2020-06-19 |
| CN111303473B CN111303473B (en) | 2022-03-18 |
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| CN111471206A (en) * | 2020-04-17 | 2020-07-31 | 北京市新里程医药科技有限公司 | Preparation method of rubber plug for powder injection of somatostatin and derivatives thereof |
| CN113702560A (en) * | 2021-08-31 | 2021-11-26 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting by-product generated in chemical synthesis of somatostatin |
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| CN111471206A (en) * | 2020-04-17 | 2020-07-31 | 北京市新里程医药科技有限公司 | Preparation method of rubber plug for powder injection of somatostatin and derivatives thereof |
| CN113702560A (en) * | 2021-08-31 | 2021-11-26 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting by-product generated in chemical synthesis of somatostatin |
| CN113702560B (en) * | 2021-08-31 | 2022-07-08 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting by-product generated in chemical synthesis of somatostatin |
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| CN111303473B (en) | 2022-03-18 |
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