CN114288385B - Preparation method of octreotide acetate preparation - Google Patents
Preparation method of octreotide acetate preparation Download PDFInfo
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- CN114288385B CN114288385B CN202111620573.0A CN202111620573A CN114288385B CN 114288385 B CN114288385 B CN 114288385B CN 202111620573 A CN202111620573 A CN 202111620573A CN 114288385 B CN114288385 B CN 114288385B
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- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 title claims abstract description 59
- 108010016076 Octreotide Proteins 0.000 title claims abstract description 59
- 229960001494 octreotide acetate Drugs 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 76
- 239000000243 solution Substances 0.000 claims abstract description 73
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000003814 drug Substances 0.000 claims abstract description 49
- 239000008215 water for injection Substances 0.000 claims abstract description 49
- 239000004310 lactic acid Substances 0.000 claims abstract description 28
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 28
- 230000001105 regulatory effect Effects 0.000 claims abstract description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000001301 oxygen Substances 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000001681 protective effect Effects 0.000 claims abstract description 9
- 239000007789 gas Substances 0.000 claims abstract description 8
- 239000007951 isotonicity adjuster Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 7
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 60
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 48
- 238000002347 injection Methods 0.000 claims description 40
- 239000007924 injection Substances 0.000 claims description 40
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 31
- 229930195725 Mannitol Natural products 0.000 claims description 31
- 239000000594 mannitol Substances 0.000 claims description 31
- 235000010355 mannitol Nutrition 0.000 claims description 31
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 30
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 30
- 239000001569 carbon dioxide Substances 0.000 claims description 24
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 24
- -1 polytetrafluoroethylene Polymers 0.000 claims description 16
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- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 14
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- 229940079593 drug Drugs 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 13
- 239000004695 Polyether sulfone Substances 0.000 claims description 12
- 229920005557 bromobutyl Polymers 0.000 claims description 12
- 229920006393 polyether sulfone Polymers 0.000 claims description 12
- 230000003115 biocidal effect Effects 0.000 claims description 11
- 239000004033 plastic Substances 0.000 claims description 11
- 230000001954 sterilising effect Effects 0.000 claims description 11
- 238000011049 filling Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 6
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical group [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 239000002033 PVDF binder Substances 0.000 claims description 2
- 239000004743 Polypropylene Substances 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 45
- 239000007788 liquid Substances 0.000 description 28
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 13
- 229940001584 sodium metabisulfite Drugs 0.000 description 13
- 235000010262 sodium metabisulphite Nutrition 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 229930182555 Penicillin Natural products 0.000 description 9
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- CFOAUMXQOCBWNJ-UHFFFAOYSA-N [B].[Si] Chemical compound [B].[Si] CFOAUMXQOCBWNJ-UHFFFAOYSA-N 0.000 description 9
- 229940049954 penicillin Drugs 0.000 description 9
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 7
- 238000010979 pH adjustment Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000004659 sterilization and disinfection Methods 0.000 description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
- 235000018417 cysteine Nutrition 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 3
- 229940043349 potassium metabisulfite Drugs 0.000 description 3
- 235000010263 potassium metabisulphite Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
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- 230000004048 modification Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 206010057572 Gastric varices haemorrhage Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 238000011101 absolute filtration Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005262 decarbonization Methods 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
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- 239000011521 glass Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
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- 238000005457 optimization Methods 0.000 description 1
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- 230000008058 pain sensation Effects 0.000 description 1
- 230000009996 pancreatic endocrine effect Effects 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000004848 polyfunctional curative Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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Abstract
The invention relates to a preparation method of octreotide acetate preparation, which comprises the following steps: taking 50-80% of the total amount of water for injection, introducing protective gas until the residual oxygen content is less than 8%, adding an antioxidant, dissolving, and adding octreotide acetate as a raw material medicine to obtain a solution a; adding an isotonic agent into water for injection, dissolving, adding lactic acid, and regulating the pH value to obtain a solution b; and (3) uniformly mixing the solution a and the solution b, and regulating the pH value to 3.9-4.5 to obtain the octreotide acetate preparation. The preparation method disclosed by the invention is simple in process, and the obtained product is high in stability.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of octreotide acetate preparation.
Background
Octreotide acetate is a cyclic polypeptide compound composed of 8 amino acids (phenylalanine (Phe), cysteine (Cys), phenylalanine (Phe), tryptophan (Trp), lysine (Lys), threonine (Thr), cysteine (Cys), threonine (Thr-ol)). The octreotide acetate can reduce venous pressure at the joint of esophagus and stomach, is beneficial to blood circulation of the lateral branches of the portal body, reduces bleeding, is clinically used for emergency treatment of esophageal-gastric varices bleeding caused by liver cirrhosis, and is combined with special treatment (such as endoscope hardener treatment). Alleviating symptoms and signs associated with gastrointestinal pancreatic endocrine tumors. Such conditions are highly detrimental and require mutual administration, and therefore have high requirements for quality and stability of the drug.
At present, some documents have been studied for the problem, for example, chinese patent CN201710259895.4 discloses an octreotide acetate injection pharmaceutical composition which comprises the following components: octreotide acetate is prepared by adjusting pH to 3.7-4.7 with proper amount of sodium bicarbonate, and adding 1000ml with proper amount of injection water, wherein the weight of octreotide acetate is 0.1g, the weight of mannitol is 40-50 g, the weight of lactic acid is 3-4 g, the weight of sucrose is 1-3 g; the pharmaceutical composition is prepared by the following steps: taking mannitol with a prescription amount and lactic acid with a prescription amount of 2/3-3/4, adding 700ml of water for injection, stirring and dissolving, adding 0.1% active carbon, heating to 80 ℃ and stirring for 30 minutes, performing cyclic decarbonization through a titanium rod, cooling filtrate to 15-30 ℃, adding sodium bicarbonate and adjusting pH to 3.7-4.7 for later use; in addition, the octreotide acetate, sucrose and the rest lactic acid with the prescription amount are taken, 100ml of injection water with the temperature of 15-30 ℃ is added, 0.1% active carbon is added, the mixture is stirred for 30 minutes, the titanium rod is used for circulating decarburization, and sodium bicarbonate is added into filtrate to adjust the pH value to 3.7-4.7; mixing the two filtrates, adjusting pH to 3.7-4.7 with sodium bicarbonate if necessary, and adding water for injection to 1000ml; pumping into a sterile room by peristaltic pump, filtering with a microporous membrane of 0.22 μm, sterilizing, filling into glass bottles according to a filling amount of 1ml per bottle, and sealing to obtain octreotide acetate injection pharmaceutical composition; chinese patent CN202110685826.6 discloses a preparation method of octreotide acetate injection, comprising the following steps: mixing lactic acid, mannitol and water for injection, wherein the water for injection accounts for 85% -90% of the total volume of the octreotide acetate injection; regulating the pH value of the obtained mixture, and then adding octreotide acetate; filtering the mixture to obtain octreotide acetate injection; adding water for injection to the total amount; it comprises 3.4-3.8g of lactic acid, 40-45g of mannitol, 1.0g of octreotide acetate and water for injection based on 1L of octreotide acetate injection. However, octreotide acetate is a polypeptide drug, has poor stability and is susceptible to high temperature and oxidation, so that the stability, the effectiveness and the safety of clinical use of octreotide acetate are still required to be improved through the optimization of a prescription and a process.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of an octreotide acetate preparation, so that the quality stability of the octreotide acetate preparation and the effectiveness and safety of clinical use are improved.
The preparation method of the octreotide acetate preparation comprises the following steps:
(1) Taking 50-80% of the total amount of water for injection, introducing protective gas until the residual oxygen content is less than 8%, adding an antioxidant, dissolving, and adding octreotide acetate as a raw material medicine to obtain a solution a;
adding an isotonic agent into water for injection, dissolving, adding lactic acid, and regulating the pH value to obtain a solution b;
(2) And (3) uniformly mixing the solution a and the solution b, and regulating the pH value to 3.9-4.5 to obtain the octreotide acetate preparation.
Further, the water temperature of the water for injection is 10-30 ℃. In the preparation process of the injection, the traditional method adopts water for injection below 8 ℃ to dissolve raw materials, and because the heating dissolution is extremely easy to cause fluctuation of related substances of a finished product and influence the quality stability of the preparation, the preparation can be carried out at the temperature of 30 ℃ under the coordination of lactic acid and sodium bicarbonate and the protective atmosphere, so that the stability of the prepared octreotide acetate injection in the normal temperature environment is obviously improved.
Further, the introduced shielding gas is carbon dioxide. The preparation method disclosed by the invention is carried out in a carbon dioxide environment in the whole process, and the raw material medicines are protected from oxidation, so that the product quality is improved. And the applicant researches show that the stability of the prepared preparation is obviously improved by adopting carbon dioxide to provide a protective atmosphere compared with other protective gases.
Further, in the octreotide acetate preparation, the concentration of the octreotide acetate bulk drug is 0.1-0.5mg/ml.
Further, the pH was adjusted with sodium bicarbonate.
Further, in octreotide acetate preparation, the concentration of lactic acid is 3.4-3.8mg/ml. In the invention, lactic acid/sodium bicarbonate is used to form buffer solution, and lactic acid and sodium bicarbonate react in water to generate carbon dioxide, so that the preparation is more stable.
Further, in octreotide acetate formulations, the concentration of the isotonic agent is 40-45mg/ml, and the isotonic agent includes, but is not limited to, mannitol, sorbitol, sodium chloride, and the like. If the isotonic agent is mannitol, it may be present in a concentration of 40-45mg/ml, such as 42mg/ml, mannitol not only acts as an isotonic agent, but also reduces the pain sensation at the site of injection during clinical use.
Further, the antioxidant is metabisulfite such as sodium metabisulfite, potassium metabisulfite and the like, and the concentration of the antioxidant is 0.005-0.02mg/ml, preferably 0.01mg/ml. It is well known to those skilled in the art that the antioxidant selected in the preparation of the injection may include various substances such as cysteine, methionine, etc., but that the addition of metabisulfite at a residual oxygen level of less than 8% is superior to other oxidants.
Further, the preparation method also comprises the step of absolute filtration sterilization after adjusting the pH to 3.9-4.5, wherein at least one sterilization operation is performed by adopting a filter membrane with the diameter of 0.45-0.22 mu m, and preferably, the sterilization operation is performed by adopting two filter membranes with the diameter of 0.22 mu m.
Further, the filter membrane is made of polytetrafluoroethylene, polyethersulfone, polyvinylidene fluoride or polypropylene. In the invention, the inventor screens the material of the octreotide acetate injection filter, and discovers that the polyethersulfone can not only sterilize and remove some insoluble impurities, but also reduce the adsorption of the octreotide acetate active ingredient.
Further, the preparation method further comprises the step of filling after filtering and sterilizing, and protective gas is filled during filling, wherein the protective gas can be selected from carbon dioxide, nitrogen, helium and the like, and is preferably carbon dioxide.
Further, a terminal sterilization step is included after filling, such as sterilization using a 12 minute sterilization process at 121 ℃.
Further, during final packaging, an injection bottle is manufactured by adopting a medium borosilicate glass tube, and the injection is partially covered with a polytetrafluoroethylene film brominated butyl rubber plug and an aluminum-plastic combined cover for an antibiotic bottle. Because the product belongs to an injection with acid property, the injection bottle is made of medium borosilicate glass, the water resistance of the inner surface of the medium borosilicate is HC1 level, the national standard of water resistance is 1.3mm, and the water resistance is much smaller than 2.6mm of low borosilicate, which indicates that the less harmful alkaline oxides such as potassium and sodium are on the inner wall of the medium borosilicate vial, the less the oxides are, the better the stability of the liquid medicine is, and the less the changes are in the process of the index stability of pH, clarity, related substances and the like. The water-resistant part of the inner surface of the low borosilicate glass is HCB grade, and the requirements are not met; the local polytetrafluoroethylene film-coated brominated butyl rubber plug for injection can block the contact between the rubber plug and the medicine, has small interaction with the medicine, and ensures the use safety of the film due to the stability of the film, thereby improving the stability of the medicine.
Further, the bacteriostat can be added by the person skilled in the art according to the requirement to further improve the stability of the injection.
By means of the scheme, the invention has at least the following advantages:
according to the invention, the octreotide acetate bulk drug and the buffer solution are prepared separately and then mixed, which is different from the steps of adding other components of injection and adding octreotide acetate bulk drug in the prior art, the preparation process is simple, the industrial production is facilitated, the impurity content of the obtained octreotide acetate preparation is low, and the stability is obviously improved.
The foregoing description is only an overview of the present invention and is presented in terms of preferred embodiments of the present invention so that the present invention may be more clearly understood and implemented in accordance with the teachings of the present specification.
Detailed Description
The present invention will be further described with reference to specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the present invention and practice it.
Example 1
Table 1: prescription composition
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 15 ℃), charging carbon dioxide until the residual oxygen content is below 8%, adding 0.1g of sodium metabisulfite, stirring for dissolution, and then adding 1.0g of octreotide acetate bulk drug to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 15 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.4g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.2 by 5% sodium bicarbonate solution, the solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 4.2 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a filter element (the filter membrane material is polyethersulfone) with the thickness of 0.22 mu m. The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Example 2
Table 2: prescription composition
| Composition of the composition | Dosage of |
| Octreotide acetate | 2.0g |
| Mannitol (mannitol) | 40g |
| Lactic acid | 3.6g |
| Sodium metabisulfite | 0.08g |
| pH adjustment with 5% sodium bicarbonate solution | 4.0 |
| Water for injection | 1000ml |
The preparation process comprises the following steps:
600mL of water for injection is measured (the water temperature is controlled at 20 ℃), carbon dioxide is filled until the residual oxygen content is less than 8%, 0.08g of sodium metabisulfite is added, stirring is carried out for dissolution, and 2.0g of octreotide acetate raw material medicine is added to obtain a solution a;
200mL of water for injection (the water temperature is controlled at 20 ℃) is measured, 40g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.6g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.0 by 5% sodium bicarbonate solution, b solution is obtained, the b solution is added into the a solution, the pH value is regulated to 4.0 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a secondary 0.22 mu m filter element (the filter membrane material is polyethersulfone). The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Example 3
Table 3: prescription composition
| Composition of the composition | Dosage of |
| Octreotide acetate | 1.0g |
| Mannitol (mannitol) | 45g |
| Lactic acid | 3.8g |
| Potassium metabisulfite | 0.1g |
| pH adjustment with 5% sodium bicarbonate solution | 3.9 |
| Water for injection | 1000ml |
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 30 ℃), charging carbon dioxide until the residual oxygen content is below 8%, adding 0.1g of potassium metabisulfite, stirring for dissolution, and then adding 1.0g of octreotide acetate bulk drug to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 30 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.8g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 3.9 by 5% sodium bicarbonate solution, the solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 3.9 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a secondary 0.22 mu m filter element (the filter membrane material is polyethersulfone). The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Example 4
Table 4: prescription composition
| Composition of the composition | Dosage of |
| Octreotide acetate | 1.0g |
| Mannitol (mannitol) | 45g |
| Lactic acid | 3.4g |
| Sodium metabisulfite | 0.1g |
| pH adjustment with 5% sodium bicarbonate solution | 4.2 |
| Water for injection | 1000ml |
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 15 ℃), charging nitrogen until the residual oxygen content is below 8%, adding 0.1g of sodium metabisulfite, stirring for dissolution, and then adding 1.0g of octreotide acetate bulk drug to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 15 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.4g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.2 by 5% sodium bicarbonate solution, the solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 4.2 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a filter element (the filter membrane material is polyethersulfone) with the thickness of 0.22 mu m. The liquid medicine is filled in a 2mL medium boron-silicon penicillin bottle, nitrogen is filled, and the liquid medicine is rapidly plugged and rolled. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Example 5
Table 5: prescription composition
| Composition of the composition | Dosage of |
| Octreotide acetate | 1.0g |
| Mannitol (mannitol) | 45g |
| Lactic acid | 3.4g |
| Sodium metabisulfite | 0.1g |
| pH adjustment with 5% sodium hydroxide solution | 4.2 |
| Water for injection | 1000ml |
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 15 ℃), charging carbon dioxide until the residual oxygen content is below 8%, adding 0.1g of sodium metabisulfite, stirring for dissolution, and then adding 1.0g of octreotide acetate bulk drug to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 15 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.4g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.2 by 5% sodium hydroxide solution, a solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 4.2 by 5% sodium hydroxide again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a filter element (the filter membrane material is polyethersulfone) with the thickness of 0.22 mu m. The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Example 6
Table 6: prescription composition
| Composition of the composition | Dosage of |
| Octreotide acetate | 1.0g |
| Mannitol (mannitol) | 45g |
| Lactic acid | 3.4g |
| Cysteine (S) | 0.1g |
| pH adjustment with 5% sodium bicarbonate solution | 4.2 |
| Water for injection | 1000ml |
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 15 ℃), charging carbon dioxide until the residual oxygen content is less than 8%, adding 0.1g of cysteine, stirring for dissolution, and then adding 1.0g of octreotide acetate raw material to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 15 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.4g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.2 by 5% sodium bicarbonate solution, the solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 4.2 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a filter element (the filter membrane material is polyethersulfone) with the thickness of 0.22 mu m. The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Comparative example 1
Table 7: prescription composition
| Composition of the composition | Dosage of |
| Octreotide acetate | 1.0g |
| Mannitol (mannitol) | 45g |
| Lactic acid | 3.4g |
| Sodium metabisulfite | 0.1g |
| pH adjustment with 5% sodium bicarbonate solution | 4.2 |
| Water for injection | 1000ml |
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 40 ℃), charging carbon dioxide until the residual oxygen content is below 8%, adding 0.1g of sodium metabisulfite, stirring for dissolution, and then adding 1.0g of octreotide acetate bulk drug to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 40 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.4g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.2 by 5% sodium bicarbonate solution, the solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 4.2 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a filter element (the filter membrane material is polyethersulfone) with the thickness of 0.22 mu m. The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Comparative example 2
Table 8: prescription composition
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 5 ℃), charging carbon dioxide until the residual oxygen content is below 8%, adding 0.1g of sodium metabisulfite, stirring for dissolution, and then adding 1.0g of octreotide acetate bulk drug to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 5 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.4g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.2 by 5% sodium bicarbonate solution, the solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 4.2 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a filter element (the filter membrane material is polyethersulfone) with the thickness of 0.22 mu m. The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Comparative example 3
Table 9: prescription composition
| Composition of the composition | Dosage of |
| Octreotide acetate | 1.0g |
| Mannitol (mannitol) | 45g |
| Lactic acid | 3.4g |
| Sodium metabisulfite | 0.1g |
| pH adjustment with 5% sodium bicarbonate solution | 4.2 |
| Water for injection | 1000ml |
The preparation process comprises the following steps:
taking 800mL of water for injection (the water temperature is controlled at 15 ℃), charging carbon dioxide until the residual oxygen amount is 10%, adding 0.1g of sodium metabisulfite, stirring for dissolution, and then adding 1.0g of octreotide acetate raw material medicine to obtain a solution a;
100mL of water for injection (the water temperature is controlled at 15 ℃) is measured, 45g of mannitol is added, the mixture is stirred and dissolved uniformly, 3.4g of lactic acid is added, the mixture is stirred and dissolved uniformly, the pH value of the solution is regulated to 4.2 by 5% sodium bicarbonate solution, the solution b is obtained, the solution b is added into the solution a, the pH value is regulated to 4.2 by 5% sodium bicarbonate again, and the water for injection is added to 1L. The liquid medicine is sterilized and filtered by a filter element (the filter membrane material is polyethersulfone) with the thickness of 0.22 mu m. The liquid medicine is filled in a 2mL medium boron silicon penicillin bottle, carbon dioxide is filled, and the liquid medicine is rapidly tamponaded and capped. Wherein, the injection bottle is made of medium borosilicate glass tube, the injection is partially covered with polytetrafluoroethylene film brominated butyl rubber plug, and the antibiotic bottle is covered with aluminum-plastic combination.
Test case
The octreotide acetate preparations prepared in examples 1 to 6 and comparative examples 1 to 3 of the present invention were subjected to stability comparison investigation under conditions of 40 ℃,60 ℃, light irradiation (25 ℃, 5000+ -500 lux), acceleration (25 ℃ + -2 ℃,60% + -5% RH) and long term (2-8 ℃) respectively, and the results are shown in the following table;
it is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (6)
1. The preparation method of the octreotide acetate preparation is characterized by comprising the following steps of:
(1) Taking 50-80% of the total amount of water for injection, introducing protective gas until the residual oxygen content is less than 8%, adding an antioxidant, dissolving, and adding octreotide acetate as a raw material medicine to obtain a solution a;
adding an isotonic agent into water for injection, dissolving, adding lactic acid, and regulating the pH value to obtain a solution b;
(2) Uniformly mixing the solution a and the solution b, and regulating the pH value to 3.9-4.5 to obtain the octreotide acetate preparation;
the water temperature of the water for injection is 10-30 ℃; the protective gas is carbon dioxide; adjusting the pH value by sodium bicarbonate;
the antioxidant is metabisulfite; the isotonic agent is mannitol.
2. The method of manufacturing according to claim 1, characterized in that: in the octreotide acetate preparation, the concentration of the octreotide acetate bulk drug is 0.1-0.5mg/ml.
3. The method of manufacturing according to claim 1, characterized in that: the method further comprises the step of filtering and sterilizing after the pH value is regulated to 3.9-4.5, wherein in the filtering and sterilizing process, the filter membrane is made of polytetrafluoroethylene, polyethersulfone, polyvinylidene fluoride or polypropylene.
4. A method of preparation according to claim 3, characterized in that: the preparation method also comprises the steps of filtering, sterilizing, filling, and filling carbon dioxide during filling.
5. The method of manufacturing according to claim 4, wherein: the preparation method also comprises the step of packaging after filling, wherein the packaging adopts a medium borosilicate glass tube injection bottle, a local polytetrafluoroethylene film brominated butyl rubber plug is used for injection, and an aluminum plastic combined cover is used for an antibiotic bottle.
6. Octreotide acetate preparation prepared by the preparation method of any one of claims 1 to 5.
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Citations (5)
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| WO2009033660A3 (en) * | 2007-09-11 | 2009-05-28 | Mondobiotech Lab Ag | Use of octreotide as a therapeutic agent |
| CN104689297A (en) * | 2015-03-20 | 2015-06-10 | 陈卓杰 | Octreotide acetate sterile injection powder preparation and preparation method thereof |
| CN113318218A (en) * | 2021-07-20 | 2021-08-31 | 国药一心制药有限公司 | Octreotide acetate injection and preparation process thereof |
| CN113350276A (en) * | 2021-06-21 | 2021-09-07 | 上海上药第一生化药业有限公司 | Preparation method and packaging method of octreotide acetate injection |
| CN113509564A (en) * | 2021-08-06 | 2021-10-19 | 四川汇宇制药股份有限公司 | Sterilization and preparation method of octreotide acetate injection |
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| ES2167189B1 (en) * | 1999-12-17 | 2003-04-01 | Lipotec Sa | STABLE PHARMACEUTICAL FORMULATION FOR INTRAVENOUS OR INTRAMUSCULAR ADMINISTRATION, OF PEPTIDIC ACTIVE PRINCIPLES |
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| WO2009033660A3 (en) * | 2007-09-11 | 2009-05-28 | Mondobiotech Lab Ag | Use of octreotide as a therapeutic agent |
| CN104689297A (en) * | 2015-03-20 | 2015-06-10 | 陈卓杰 | Octreotide acetate sterile injection powder preparation and preparation method thereof |
| CN113350276A (en) * | 2021-06-21 | 2021-09-07 | 上海上药第一生化药业有限公司 | Preparation method and packaging method of octreotide acetate injection |
| CN113318218A (en) * | 2021-07-20 | 2021-08-31 | 国药一心制药有限公司 | Octreotide acetate injection and preparation process thereof |
| CN113509564A (en) * | 2021-08-06 | 2021-10-19 | 四川汇宇制药股份有限公司 | Sterilization and preparation method of octreotide acetate injection |
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