CN114948881A - Octreotide acetate microsphere and preparation method thereof - Google Patents
Octreotide acetate microsphere and preparation method thereof Download PDFInfo
- Publication number
- CN114948881A CN114948881A CN202210752198.3A CN202210752198A CN114948881A CN 114948881 A CN114948881 A CN 114948881A CN 202210752198 A CN202210752198 A CN 202210752198A CN 114948881 A CN114948881 A CN 114948881A
- Authority
- CN
- China
- Prior art keywords
- octreotide acetate
- preparation
- plga
- release
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000004005 microsphere Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 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 41
- 108010016076 Octreotide Proteins 0.000 title claims abstract description 41
- 229960001494 octreotide acetate Drugs 0.000 title claims abstract description 35
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 4
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- 238000004945 emulsification Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 230000001804 emulsifying effect Effects 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 230000002572 peristaltic effect Effects 0.000 claims description 3
- 238000012216 screening Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 13
- 201000000052 gastrinoma Diseases 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 102000055135 Vasoactive Intestinal Peptide Human genes 0.000 abstract description 4
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 abstract description 4
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 abstract description 4
- 206010000599 Acromegaly Diseases 0.000 abstract description 3
- 208000003200 Adenoma Diseases 0.000 abstract description 3
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 abstract description 3
- 102100022831 Somatoliberin Human genes 0.000 abstract description 3
- 101710142969 Somatoliberin Proteins 0.000 abstract description 3
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 abstract description 3
- 208000002458 carcinoid tumor Diseases 0.000 abstract description 3
- 206010022498 insulinoma Diseases 0.000 abstract description 3
- 230000002459 sustained effect Effects 0.000 abstract description 2
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 abstract 1
- 201000011523 endocrine gland cancer Diseases 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 229940079593 drug Drugs 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 7
- 229960002700 octreotide Drugs 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 108010051696 Growth Hormone Proteins 0.000 description 3
- 102000018997 Growth Hormone Human genes 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000122 growth hormone Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 206010001233 Adenoma benign Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 208000017055 digestive system neuroendocrine neoplasm Diseases 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 208000021255 pancreatic insulinoma Diseases 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- HFDKKNHCYWNNNQ-YOGANYHLSA-N 75976-10-2 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)N)C(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 HFDKKNHCYWNNNQ-YOGANYHLSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 102100025841 Cholecystokinin Human genes 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000018886 Pancreatic Polypeptide Human genes 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 102100037505 Secretin Human genes 0.000 description 1
- 108010086019 Secretin Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 101000983124 Sus scrofa Pancreatic prohormone precursor Proteins 0.000 description 1
- 241001478428 Syngnathus Species 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 229940107137 cholecystokinin Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- PRYXPGFZVGZNBL-ADLFWFRXSA-N salviol Chemical compound CC(C)c1cc2CC[C@H]3C(C)(C)C[C@H](O)C[C@]3(C)c2cc1O PRYXPGFZVGZNBL-ADLFWFRXSA-N 0.000 description 1
- AJSGWTLZEUBGFV-UHFFFAOYSA-N salviol Natural products CC(C)c1cc2CCC3C(CC(O)CC3(C)C)c2cc1O AJSGWTLZEUBGFV-UHFFFAOYSA-N 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229960002101 secretin Drugs 0.000 description 1
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229960000874 thyrotropin Drugs 0.000 description 1
- 230000001748 thyrotropin Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides octreotide acetate microspheres and a preparation method thereof. The octreotide acetate microsphere preparation comprises octreotide acetate, PLGA and PLA, wherein the molar ratio of lactide to glycolide in the PLGA is 40-85: 60-15. Preferably the molar ratio of lactide to glycolide in the PLGA is 75: 25; also disclosed is the use of the medicament in acromegaly and in medicaments for gastro-pancreatic endocrine tumors such as carcinoids, growth hormone releasing factor adenomas, pancreatic hyperglycosemia, gastrinomas/Zollinger-Ellison syndrome, insulinomas, vasoactive intestinal peptide tumors. The microsphere preparation realizes the sustained and slow release of octreotide acetate for more than 3 months, and has no burst release and stable release in the release process.
Description
Technical Field
The invention relates to the technical field of microsphere medicinal preparations, in particular to octreotide acetate microspheres and a preparation method thereof.
Background
Octreotide is an artificially synthesized octapeptide derivative of natural somatostatin, which is synthesized for the first time in 1979, retains the same pharmacological action as growth hormone, and can inhibit the secretion of many hormones including secretin, cholecystokinin, glucagon, Growth Hormone (GH), insulin, pancreatic polypeptide, thyrotropin, vasoactive intestinal peptide, etc. The traditional Chinese medicine composition is mainly used for clinically treating acromegaly and gastroenteropancreatic endocrine tumors (carcinoid, growth hormone releasing factor adenoma, pancreatic hyperglycosemia, gastrinoma/Zollinger-Ellison syndrome, insulinoma and vasoactive intestinal peptide tumor), and is widely applied clinically.
There are two octreotide acetate preparations approved by FDA to be marketed, one is injection subcutaneously, 3 times a day; the other is the microsphere for injection in a reservoir mode, and the microsphere is injected in an intramuscular mode and is taken once a month. The longest administration period is 1 month, the 1-month preparation solves the problem of partial compliance of a single-day injection, but the target indication is generally administered for a lifetime, the development of a longer-acting preparation can increase the compliance of a patient, reduce the relapse caused by poor compliance and drug withdrawal, reduce the medication price, save the medical cost and improve the diagnosis and treatment efficiency.
According to the invention, the octreotide acetate microspheres suitable for long-acting administration are screened and prepared by means of screening of sustained-release materials, preparation rotating speed, salt addition and the like, and the three-month release administration of the octreotide acetate microspheres is realized.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides octreotide acetate microspheres and a preparation method thereof. According to the invention, the octreotide acetate is prepared into microspheres, so that the continuous slow release of the octreotide acetate for more than 3 months is realized, no burst release occurs in the release process, and the release is stable.
The invention provides an octreotide acetate microsphere preparation which comprises octreotide acetate, PLGA and PLA, wherein the molar ratio of lactide to glycolide in the PLGA is 40-85: 60-15.
Further, the drug loading rate of octreotide acetate is 5-30%.
Further, the PLGA is PLGA75-1A, and the PLA is PLA-2A.
Furthermore, the grain diameter d50 of the octreotide acetate microsphere preparation is 30-100 um.
The octreotide acetate microsphere preparation provided by the invention also comprises other medicinal auxiliary materials.
The octreotide acetate microsphere preparation provided by the invention can be released for 3 months or more.
The invention provides a preparation method of a microsphere preparation.
The preparation method comprises the following steps: dissolving octreotide acetate in methanol, and dissolving PLGA and PLA in a dichloromethane solution; adding octreotide acetate methanol solution into dichloromethane solution containing PLGA and PLA, stirring and dissolving to obtain oil phase solution; adding ice into 1% PVA solution, cooling to 10 deg.C, starting homogenizing and stirring, adding oil phase solution into PVA solution by peristaltic pump, homogenizing and emulsifying; and after the emulsification is finished, starting a machine to stir and volatilize the solvent, and then screening, filtering, washing and freeze-drying the obtained solution to obtain the octreotide acetate microsphere preparation.
Furthermore, the optimal preparation rotating speed used in the preparation process of the octreotide acetate microsphere preparation provided by the invention is 2.6-3.2 kr/min.
Advantageous effects
The invention provides octreotide acetate microspheres and a preparation method thereof. The microsphere preparation realizes the sustained and slow release of octreotide acetate for more than 3 months, and has no burst release and stable release in the release process.
Meanwhile, the invention provides the application of the octreotide acetate microspheres in preparing medicines for treating acromegaly and gastroenteropancreatic endocrine tumors such as carcinoid, growth hormone releasing factor adenoma, pancreatic hyperglycemia tumor, gastrinoma/Zollinger-Ellison syndrome, insulinoma and vasoactive intestinal peptide tumor.
Drawings
FIG. 1 shows the in vitro release of PH10 from long-period microspheres in comparison with a Syngnathus (SL 882).
FIG. 2 shows the release of microspheres of different sizes in rats.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
Example 1
1. Effect of microsphere preparation and different prescription processes on drug loading of microspheres
PLA-2A, PLGA50-1A and PLGA75-1A are used as auxiliary materials, and the octreotide microspheres are prepared by a single emulsion process.
Examples of the preparation of the microspheres are as follows:
table 1: sample preparation example recipe and solvent
The process comprises the following steps:
0.5g of octreotide acetate was dissolved in 2mL of methanol, and 0.5g of PLGA50-1A0.5g and PLA-2A2g were dissolved in 10g of a dichloromethane solution. And mixing the 2 parts of solution, and stirring to dissolve to obtain an oil phase solution.
Weighing PVA to prepare 1% PVA solution to obtain water phase solution; adding ice into the PVA solution, cooling to 10 ℃, starting homogenizing and stirring, adding the oil phase solution into the PVA solution through a peristaltic pump, and homogenizing and emulsifying for 2 min. And (3) reducing the homogenizing speed after emulsification is finished, starting a machine to stir and volatilize the solvent, and stopping after the temperature is maintained for 3 hours at room temperature. And filtering the obtained solution through a sieve with 100 meshes and 1200 meshes, collecting microspheres, and washing the microspheres on the sieve with 1200 meshes by purified water for 0.5 h. Transferring to a culture dish (penicillin bottle), and freeze-drying in a freeze dryer to obtain the microspheres;
by the same preparation method, the sustained-release material is replaced, other solvents and the amount are unchanged, and the microspheres shown in the table are prepared, and the drug loading rate and the particle size data of the microspheres are shown in the table.
Table 2: different microsphere formulations and their effect on drug loading of microspheres
The data in table 2 show that the encapsulation efficiency of the 4 examples reaches more than 7%, and the drug loading rate can reach about 9% after the API feeding is improved, which is 2 times of that of the reference drug-shanlong (1 month preparation). Considering that the octreotide bioavailability of emulsion microspheres is high, the octreotide contained in the microspheres can basically meet the release amount of 3 months under the condition of the same microsphere injection amount as Shanlong.
The data of the particle size of the microspheres at different rotating speeds can be obtained, and the rotating speed of 2.8-3k can be selected to obtain the microspheres with the optimal size.
2. In vitro release assay methods and results
2.1 in vitro Release method
1) Solution preparation
Releasing medium: the preparation method comprises the steps of weighing 5.4g of ammonium chloride and 12ml of triethylamine, adding water to dissolve and dilute the ammonium chloride and the triethylamine to 1000ml, adjusting the pH value to 10.0 by using the triethylamine, adding 21g of sodium dodecyl sulfate, and uniformly mixing.
Release control solution: the specific preparation method comprises the steps of weighing 14mg of octreotide reference substance into a 25ml volumetric flask, adding a diluent to dilute to a scale, sucking 5ml to 25ml of volumetric flask, adding the diluent and mixing uniformly.
2) Weighing sample
60mg were weighed precisely into 60ml ground bottles with caps.
3) Lofting
Precisely adding 30ml of release medium, placing in a constant temperature water bath oscillator at 50 + -1 rpm and 37 + -0.5 deg.C, shaking for 5min to suspend the microspheres after 1, 4, 8, and 12h, standing to settle the microspheres, precisely absorbing 1ml of supernatant, filtering with a filter membrane (Millex HV 0.45um), discarding 0.8ml of primary filtrate, and collecting 0.2ml of subsequent filtrate as sample solution.
4) Chromatographic conditions
A chromatographic column: inertsil ODS-2(15 cm. times.4.6 mm);
column temperature: 30 ℃; sample introduction amount: 10 mu l of the mixture;
mobile phase: acetonitrile-1 mol/L tetramethylammonium hydroxide solution-water (310:100:590) and adjusting the pH to 5.0 with phosphoric acid; flow rate: 2.0 ml/min; detection wavelength: 210nm, run time: 16min (control: 6 min).
2.2, in vitro release results:
table 3: in vitro pH4 burst release of differently formulated microspheres
| ph4 degree of release% | 1h | 4h | 24h |
| XSD330-0076-2 | 0.1 | 0.1 | 0.2 |
| XSD330-0076-4 | 0.5 | 3.7 | 18.7 |
| XSD330-0076-5 | 0.3 | 0.4 | 0.5 |
| XSD330-0077-1 | 0.8 | 1.3 | 4.3 |
From the release of ph4 from microspheres, the burst release is not large at 1h, only XSD330-0076-4 is large at 24h, and the release is not large at other times.
Table 4: in vitro pH10 complete Release of differently formulated microspheres
FIG. 1 records the above-prescribed pH10 release profile, and the microspheres were examined for complete release by in vitro pH 10. Under the condition of PH10, the January preparation, rhizoma Dioscoreae, is released to more than 80% within 24 h. The self-made preparation can release 90% only in three days or even in the fourth day, and the preparation has great potential of in vivo release in three months.
3. Rat pharmacokinetic test and test results
3.1 method of in vivo drug delivery
1) Dosing regimens
Healthy male SD rats were randomly grouped into 3 per group. 3M formulation dosing: 15mg/kg (theoretical dose of 3M formulation 6 mg/kg); 1W dosage of formulation: 2.5 mg/kg. The administration volume: 2.0mL/kg, administration: and (4) carrying out intramuscular injection.
2) Blood sampling time points:
orbital venous bleeds were taken before (0h) and 0.5h, 2h, 6h, 1, 4, 7, 10, 14, 21, 28, 35, 42, 49, 52, 56, 59, 63, 70, 77, 84, 91d post-dose of the 3M formulation. 1W preparation before administration (0h) and 0.25h, 0.5h, 2h, 6h, 1, 2, 3, 5, 7, 9, 11, 14d after administration.
3) Plasma collection
After 0.5mL of blood was collected from the retro-orbital venous plexus of SD rats, the blood was added to a pre-set 5. mu.L of aprotinin at a concentration of 50TIU/mL and 5. mu.L of heparin in an anti-adsorption EP tube (on an ice box), and mixed well. Centrifuging at 3600rpm for 10min at 4 ℃, taking the supernatant to another anti-adsorption EP tube, and storing at-80 ℃ to be detected.
4) Biological sample determination: determining the concentration of octreotide in the plasma of rats by an LC-MS/MS method;
5) data processing: winnolin 8.0 carries out data statistical analysis, and kinetic parameters such as AUC0-56d, AUC0-56d, AUC56-91d, AUC0-t, AUCinf, Cmax, Tmax, Cmax,1, Tmax,1 (time to peak of initial release), Cmax,2, Tmax,2 (time to peak of sustained release) and MRTinf are calculated.
3.2 in vivo drug replacement results
The result of rat pharmacokinetics is shown in fig. 2, and because the test is divided into different batches, the batch numbers are different, and the corresponding relationship between the numbers in fig. 2 and fig. 1 is as follows: XSD330-0076-2 in FIG. 1 corresponds to XSD-76-2 in FIG. 2, XSD330-0076-4 in FIG. 1 corresponds to XSD-76-4 in FIG. 2, XSD330-0076-5 in FIG. 1 corresponds to XSD-76-5 in FIG. 2, XSD330-0077-1 in FIG. 1 corresponds to XSD-77-1 in FIG. 2, and SL882 in FIG. 1 corresponds to SL 35353573 in FIG. 2
The actual administration of the preparation for 3 months is 15mg/kg, the administration amount adopted by the preparation for comparison for 1 month is 10mg/kg, and in order to facilitate comparison of the same administration amount in the same time with the preparation for 3 months, the actually measured data is converted into half data of 5 mg/kg. The in vivo pharmacokinetics curve of rats shows that most of the long-period preparations prepared by the rats can be released for a longer time than the salviol, and more preferably, at least 2 self-made preparations can be released for more than 90 days continuously.
Wherein, XSD-76-2 and XSD-76-5 are taken as March preparations, the blood drug concentration is basically 0.6-1.5ng/ml in 90 days, the blood drug concentration is still higher in 91 days, and the possibility of releasing for a period of time is provided.
Claims (3)
1. The octreotide acetate microsphere preparation is characterized by comprising octreotide acetate, PLGA and PLA, wherein the molar ratio of lactide to glycolide in the PLGA is 40-85:60-15, the drug-loading rate of the octreotide acetate is 5% -30%, and the particle size d50 of the octreotide acetate microsphere preparation is 30-100 um.
2. The microsphere formulation according to claim 1, wherein PLGA is PLGA75-1A and PLA is PLA-2A.
3. The method for preparing octreotide acetate microsphere preparation according to claim 1, which is characterized by comprising the following steps:
dissolving octreotide acetate in methanol, and dissolving PLGA and PLA in a dichloromethane solution;
adding octreotide acetate methanol solution into dichloromethane solution containing PLGA and PLA, stirring and dissolving to obtain oil phase solution;
adding ice into the 1% PVA solution, cooling to 10 ℃, starting homogenizing and stirring, adding the oil phase solution into the PVA solution through a peristaltic pump, and homogenizing and emulsifying;
and after the emulsification is finished, starting a machine to stir and volatilize the solvent, and then screening, filtering, washing and freeze-drying the obtained solution to obtain the octreotide acetate microsphere preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210752198.3A CN114948881A (en) | 2022-06-28 | 2022-06-28 | Octreotide acetate microsphere and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210752198.3A CN114948881A (en) | 2022-06-28 | 2022-06-28 | Octreotide acetate microsphere and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114948881A true CN114948881A (en) | 2022-08-30 |
Family
ID=82966947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210752198.3A Pending CN114948881A (en) | 2022-06-28 | 2022-06-28 | Octreotide acetate microsphere and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114948881A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116139256A (en) * | 2023-03-14 | 2023-05-23 | 复旦大学附属肿瘤医院 | Somatostatin/somatostatin analogue slow-release film and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011087496A1 (en) * | 2010-01-13 | 2011-07-21 | Oakwood Laboratories LLC | Microspheres for the sustained release of octreotide without an initial time lag |
| US20220088150A1 (en) * | 2018-09-20 | 2022-03-24 | Biovena Science, Llc | Octreotide Microsphere-Based Arterial Embolization for Treating Obesity |
-
2022
- 2022-06-28 CN CN202210752198.3A patent/CN114948881A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011087496A1 (en) * | 2010-01-13 | 2011-07-21 | Oakwood Laboratories LLC | Microspheres for the sustained release of octreotide without an initial time lag |
| US20220088150A1 (en) * | 2018-09-20 | 2022-03-24 | Biovena Science, Llc | Octreotide Microsphere-Based Arterial Embolization for Treating Obesity |
Non-Patent Citations (1)
| Title |
|---|
| 于力 等: "不同PLGA 型号对奥曲肽微球的包封率和体外释放行为的影响" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116139256A (en) * | 2023-03-14 | 2023-05-23 | 复旦大学附属肿瘤医院 | Somatostatin/somatostatin analogue slow-release film and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lam et al. | Sustained release of recombinant human insulin-like growth factor-I for treatment of diabetes | |
| CN101657190B (en) | A biodegradable microsphere composition suitable for the controlled release of glucose controlling peptide and formulation thereof | |
| CN1102854C (en) | Composition for sustained release of human growth hormone | |
| Johnson et al. | A month–long effect from a single injection of microencapsulated human growth hormone | |
| KR100446924B1 (en) | Sustained release of peptides from pharmaceutical composition | |
| JP5933025B2 (en) | Microspheres for controlled or sustained release of medication | |
| EP1480618B1 (en) | Sustained release drug formulations containing a carrier peptide | |
| JP6006225B2 (en) | Rotigotine, a derivative thereof, or a composition of a pharmaceutically acceptable salt of rotigotine or a derivative thereof | |
| CN101056643A (en) | Long acting injectable crystal formulations of estradiol metabolites and methods of using same | |
| CA2275422A1 (en) | Method of producing a sustained-release preparation | |
| SE512992C2 (en) | Delayed-release preparations of water-soluble peptides | |
| CN102085355A (en) | Liraglutide long-acting microsphere injection and preparation method thereof | |
| JP2010507612A (en) | Sustained release formulation of VLMW polymer | |
| EP2793865B1 (en) | Pharmaceutical compositions of triptorelin microspheres | |
| CN114948881A (en) | Octreotide acetate microsphere and preparation method thereof | |
| CN107335048B (en) | Sustained-release microsphere carrying gonadotropin releasing hormone compound and preparation method thereof | |
| KR20160065968A (en) | Microparticles comprising gnrh made by pgss | |
| CN108403643B (en) | Long-acting microsphere of protein polypeptide drug and preparation method thereof | |
| CN103222963A (en) | Somatostatin freeze-dried powder injection | |
| CN107405307A (en) | A kind of Exenatide microball preparation and preparation method thereof | |
| CN104667258A (en) | Octreotide acetate tablet and preparation method thereof | |
| CN1093597A (en) | The implantable somatotropin composition of sustained release | |
| CN106727362A (en) | A kind of Triptorelin microballoon and preparation method and application | |
| CN110859811B (en) | Medicine slow-release composition and preparation method thereof | |
| CN104107434B (en) | Goserelin slow release microsphere medicine composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220830 |