WO2024049279A2 - Microsphères à libération prolongée contenant du leuprolide, préparation injectable les comprenant, et leur procédé de préparation - Google Patents
Microsphères à libération prolongée contenant du leuprolide, préparation injectable les comprenant, et leur procédé de préparation Download PDFInfo
- Publication number
- WO2024049279A2 WO2024049279A2 PCT/KR2023/013112 KR2023013112W WO2024049279A2 WO 2024049279 A2 WO2024049279 A2 WO 2024049279A2 KR 2023013112 W KR2023013112 W KR 2023013112W WO 2024049279 A2 WO2024049279 A2 WO 2024049279A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- microspheres
- leuprolide
- injectable preparation
- sustained
- release
- Prior art date
Links
- 239000004005 microsphere Substances 0.000 title claims abstract description 213
- 108010000817 Leuprolide Proteins 0.000 title claims abstract description 103
- 229960004338 leuprorelin Drugs 0.000 title claims abstract description 103
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 77
- 238000013268 sustained release Methods 0.000 title claims abstract description 51
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 51
- 229940079593 drug Drugs 0.000 claims abstract description 65
- 239000003814 drug Substances 0.000 claims abstract description 65
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 143
- 229920000249 biocompatible polymer Polymers 0.000 claims description 56
- 239000000243 solution Substances 0.000 claims description 49
- 239000007864 aqueous solution Substances 0.000 claims description 45
- 235000019441 ethanol Nutrition 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 44
- 239000003960 organic solvent Substances 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 41
- 238000004519 manufacturing process Methods 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 38
- 239000004094 surface-active agent Substances 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000000725 suspension Substances 0.000 claims description 30
- 230000001186 cumulative effect Effects 0.000 claims description 28
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 27
- 239000006185 dispersion Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000004480 active ingredient Substances 0.000 claims description 24
- 238000002347 injection Methods 0.000 claims description 23
- 239000007924 injection Substances 0.000 claims description 23
- 239000003921 oil Substances 0.000 claims description 22
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 21
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 21
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- 239000013557 residual solvent Substances 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 18
- 229920000642 polymer Polymers 0.000 claims description 18
- -1 polyethylene Polymers 0.000 claims description 17
- 238000000638 solvent extraction Methods 0.000 claims description 16
- 239000007762 w/o emulsion Substances 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000000839 emulsion Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 239000004698 Polyethylene Substances 0.000 claims description 12
- 229920001400 block copolymer Polymers 0.000 claims description 12
- 229920000573 polyethylene Polymers 0.000 claims description 12
- 238000005538 encapsulation Methods 0.000 claims description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 229920001610 polycaprolactone Polymers 0.000 claims description 8
- 239000004632 polycaprolactone Substances 0.000 claims description 8
- 239000003125 aqueous solvent Substances 0.000 claims description 7
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 6
- 239000007972 injectable composition Substances 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 5
- 201000010260 leiomyoma Diseases 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 229920000954 Polyglycolide Polymers 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 201000009273 Endometriosis Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010046798 Uterine leiomyoma Diseases 0.000 claims description 3
- 239000000178 monomer Substances 0.000 claims description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 3
- 208000006155 precocious puberty Diseases 0.000 claims description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- 206010000084 Abdominal pain lower Diseases 0.000 claims description 2
- 206010057654 Breast cancer female Diseases 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 208000015474 Central precocious puberty Diseases 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 208000008930 Low Back Pain Diseases 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- 208000007502 anemia Diseases 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 208000022168 hypermenorrhea Diseases 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 208000007106 menorrhagia Diseases 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 abstract description 11
- 230000004054 inflammatory process Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 5
- 239000012071 phase Substances 0.000 description 55
- 230000000052 comparative effect Effects 0.000 description 44
- 238000009472 formulation Methods 0.000 description 23
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 17
- 102100022258 Disks large homolog 5 Human genes 0.000 description 12
- 101100063489 Homo sapiens DLG5 gene Proteins 0.000 description 12
- 239000002245 particle Substances 0.000 description 11
- 239000011859 microparticle Substances 0.000 description 10
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 8
- 108700012941 GNRH1 Proteins 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 238000000935 solvent evaporation Methods 0.000 description 7
- 239000000556 agonist Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000004945 emulsification Methods 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 230000008595 infiltration Effects 0.000 description 5
- 238000001764 infiltration Methods 0.000 description 5
- 210000004969 inflammatory cell Anatomy 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 229910021642 ultra pure water Inorganic materials 0.000 description 4
- 239000012498 ultrapure water Substances 0.000 description 4
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000000877 morphologic effect Effects 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000007711 solidification Methods 0.000 description 3
- 230000008023 solidification Effects 0.000 description 3
- 208000017667 Chronic Disease Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001493 electron microscopy Methods 0.000 description 2
- 238000002481 ethanol extraction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011806 microball Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010036049 Polycystic ovaries Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000001456 gonadotroph Effects 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
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000007712 rapid solidification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to sustained-release microspheres containing leuprolide, an injectable preparation containing the same, a method for producing the same, and a pharmaceutical composition containing the sustained-release microspheres.
- sustained-release microspheres that contain a high content of leuprolide in the microspheres and exhibit effective drug release characteristics initially while providing stable drug release characteristics for a long period of time, and a method of producing the same, the leuprolide It relates to an injectable preparation containing sustained-release microspheres containing Lyde.
- Luteinizing hormone-releasing hormone also known as gonadotropin-releasing hormone (GnRH)
- GnRH gonadotropin-releasing hormone
- pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg- a hypothalamic decapeptide that regulates the reproductive system in vertebrates. Pro-Gly-NH 2 ).
- LHRH agonists and antagonists are used for the treatment of endometriosis, fibroids, polycystic ovary, breast, ovarian and endometrial cancer in women, gonadotropic pituitary desensitization during medically assisted birth protocols, benign prostate and polymorphism and prostate cancer in men. It is reported to be effective in the treatment of and treatment of precocious puberty in men or women.
- LHRH agonists are peptide compounds that generally must be administered via injection due to low oral bioavailability.
- LHRH agonists are drugs for chronic diseases that require long-term administration, and that early and rapid exposure to a sufficient amount of the drug is required for drug efficacy to manifest. It is known that for the drug efficacy of leuprolide acetate, one of the LHRH agonists, to be expressed, a sufficient amount of drug exposure to the target area is required at the beginning of administration, and it is known that it is desirable to have a high initial drug release rate.
- the present invention was designed to solve the above-described conventional problems. It can contain a high content of leuprolide in the microspheres, and not only exhibits effective drug release characteristics initially, but also provides stable drug release characteristics for a long period of time.
- the purpose is to provide sustained-release microspheres containing a high content of leuprolide that minimize pain or inflammatory reactions at the site of administration after administration due to administering a relatively small number of microspheres, and a method for producing the same.
- an injectable preparation comprising sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof as an active ingredient and a biocompatible polymer
- the content of the active ingredient in the injection preparation includes 1 to 50 mg/mL as leuprolide,
- the injectable preparation may have a number of microspheres of 1,000,000 to 6,000,000/ml.
- leuprolide or a pharmaceutically acceptable salt thereof in the microspheres may be 9.5 to 40% by weight, 10 to 30% by weight, or 12 to 25% by weight based on the total weight of the microspheres.
- the biocompatible polymer includes polyethylene glycol-poly(lactide-co-glycolide) block-copolymer, polyethylene glycol-polylactide block-copolymer, and polyethylene glycol-polycaprolactone block-copolymer. It is one or more selected from the group consisting of polymer, polylactide, polyglycolide, poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polycaprolactone, and mixtures thereof. You can.
- the biocompatible polymer in the microspheres may be 70 to 90% by weight, 75 to 90% by weight, or 80 to 90% by weight based on the total weight of the microspheres.
- the weight ratio of the active ingredient to the biocompatible polymer in the microspheres may be 1:4 to 1:9, 1:3.5 to 1:9, or 1:3 to 1:9.
- the biocompatible polymer may be a combination of polymers of the same type having different intrinsic viscosity and/or monomer ratios.
- the pharmaceutically acceptable salt of leuprolide may be leuprolide acetate.
- the weight average molecular weight of the biocompatible polymer may be 4,000 to 240,000.
- the in vitro release rate of the injectable formulation may be 8 to 40%, more specifically 10 to 30%, 24 hours after release of the active ingredient.
- the injectable formulation may be for a 1-month to 3-month formulation.
- the cumulative drug area under the curve up to 24 hours after administration is the cumulative drug area under the curve up to the target administration period (AUC 0-24hrs, Area under the curve)
- AUC total that is, for a 1-month formulation, AUC total is the area under the cumulative drug curve from 0 to 28 days after administration, and for a 3-month formulation, AUC total refers to the area under the cumulative drug curve from 0 to 84 days after administration. It may be 0.5 to 55%, 15 to 50%, or 20 to 50% of the total.
- the ratio of the area under the cumulative drug curve at 0 to 24 hours after administration to the area under the cumulative drug curve at 48 hours to 168 hours after administration is 2:1 to 10:1, preferably 2:1 to 8:1, more preferably It may be 2:1 to 6:1.
- the residual solvent in the sustained-release microspheres of the injectable formulation may be less than 1,000 ppm.
- the C max of the drug after administration of the injection preparation may be 5,000 to 2,000,000 pg/mL.
- the particle size (D50) of the sustained-release microspheres in the injection preparation may be 10 to 40 um.
- the injectable preparation reduces fibroid nuclei and improves symptoms in uterine fibroids accompanied by endometriosis, hypermenorrhea, lower abdominal pain, back pain, and anemia, prostate cancer, premenopausal breast cancer, or central precocious puberty. It may be for prevention or treatment.
- a method for producing sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof comprising the following steps:
- a) (i) prepare a dispersed solution by dissolving the biocompatible polymer and leuprolide or a pharmaceutically acceptable salt thereof in one or more organic solvents, or (ii) prepare an oil phase by dissolving the biocompatible polymer in one or more organic solvents.
- Prepare a solution for the oil phase prepare an aqueous solution by dissolving leuprolide or a pharmaceutically acceptable salt thereof in an aqueous solvent, and add the aqueous solution to the oil phase solution to form a water-in-oil (W/O) solution.
- step b) The dispersion solution or water-in-oil emulsion prepared in step a) is added to an aqueous solution containing a surfactant as a continuous phase to form microspheres, and the dispersion solution or water-in-oil emulsion is injected and stirred to solidify the microspheres.
- step b) extracting the organic solvent by adding an aqueous solution containing ethanol and a surfactant to the suspension containing the solidified microspheres of step b);
- step d) exchanging the continuous phase in the suspension containing the microspheres of step c) with an aqueous solution containing fresh ethanol and a surfactant and stirring;
- a method for producing sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof comprising the following steps:
- a' (i) dissolving the biocompatible polymer and leuprolide or a pharmaceutically acceptable salt thereof in one or more organic solvents to prepare a dispersion solution, or (ii) dissolving the biocompatible polymer in one or more organic solvents to prepare a dispersion solution.
- a solution for the oil phase was prepared, and leuprolide or a pharmaceutically acceptable salt thereof was dissolved in an aqueous solvent to prepare an aqueous solution, and the aqueous solution was added to the oil phase solution to form a water-in-oil type (W/ O) preparing an emulsion;
- step b' The dispersion solution or water-in-oil emulsion prepared in step a') is added to an aqueous solution containing ethanol and a surfactant as a continuous phase to form microspheres, and the microspheres are solidified after injection of the dispersion solution or water-in-oil emulsion. and preparing a suspension containing microspheres by stirring for organic solvent extraction;
- step b' exchanging the continuous phase in the suspension containing the microspheres of step b') with an aqueous solution containing fresh ethanol and a surfactant and stirring;
- sustained-release microspheres containing leuprolide unlike the conventional production method, it is possible to produce sustained-release microspheres containing leuprolide at a high encapsulation rate, allowing the drug to be contained for a long time. It is possible to manufacture microspheres that maximize the therapeutic effect by maintaining the concentration in the therapeutic range.
- Figure 1 is a graph showing the in vivo pharmacokinetics of microspheres for a 1-month formulation according to the present invention (Example 1) and Leuprin 3.75 mg (Comparative Example 1), a reference drug.
- Figure 2 is a graph showing the in vivo pharmacokinetics of microspheres for a 3-month formulation (Examples 5 and 6) according to the present invention.
- Figures 3a and 3b are scanning electron microscope photographs confirming the shape of microspheres of an example according to the present invention.
- Figures 4A to 4C are diagrams showing the histopathology slide samples of Example 4 and Comparative Example 2 showing the infiltration of inflammatory cells at the injection site by extracting tissues on the 3rd, 10th, and 28th days after administration of microspheres.
- the present invention is an injectable preparation comprising sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof as an active ingredient and a biocompatible polymer,
- the content of the active ingredient in the injection preparation includes 1 to 50 mg/mL as leuprolide,
- the present invention relates to an injectable preparation in which the number of microspheres in the injectable preparation is 1,000,000 to 6,000,000/mL.
- the content of the active ingredient in the injection preparation is leuprolide, 2 to 50 mg/mL, 2 to 47 mg/mL, 2 to 45 mg/mL, 2 to 30 mg/mL, 2 to 27.5 mg/mL, 2 to 5 mg/mL. It may be 25 mg/mL, 3 to 25 mg/mL, or 3 to 22.5 mg/mL.
- the injectable preparation is a 1-month preparation, it may be 1 to 15 mg/mL, 1 to 12.5 mg/mL, or 2 to 12.5 mg/mL, and if the injectable preparation is a 3-month preparation, it may be 7 to 30 mg/mL, 9 It may be from 27.5 mg/mL or 10 to 25 mg/mL, and for a 6-month preparation, it may be 20 to 50 mg/mL, 20 to 47.5 mg/mL, 25 to 45 mg/mL, 30 to 50 mg/mL, 30 to 47.5 mg/mL. mL, or 30 to 45 mg/mL.
- the number of microspheres in the injection preparation is 1,000,000 to 5,000,000/ml, 1,200,000 to 4,500,000/ml, 1,000,000 to 4,000,000/ml, 1,200,000 to 3,500,000/ml or 1,500,000. It may be 0 to 3,000,000/mL. More specifically, if the injectable preparation is a 1-month preparation, it may be 1,000,000 to 2,500,000 units/mL or 1,500,000 to 2,000,000 units/mL, and if the injectable preparation is a 3-month preparation, it may be 2,000,000 to 3,500,000 units/mL or 2,500,000 to 3,000, 000 units/mL , if the injectable preparation is a 6-month preparation, it may be 3,000,000 to 6,000,000 units/mL, 3,500,000 to 5,500,000 units/mL, or 4,000,000 to 5,000,000 units/mL.
- the present invention unlike conventional leuprolide-containing microspheres and preparations containing the same, contains a high content of the active ingredient leuprolide or a pharmaceutically acceptable salt thereof in the microspheres, thereby providing an effective level of effective pharmacological effect. It is characterized by containing a sufficient number of ingredients, while allowing a significantly small number of microspheres per unit volume of the injectable preparation to be included in the injectable preparation. Due to these characteristics, the injectable formulation according to the present invention not only exhibits effective drug release characteristics initially and provides stable drug release characteristics for a long period of time, but also provides stable drug release characteristics for a long period of time, and by administering a relatively small number of microspheres, It can minimize pain or inflammatory reactions.
- 'leuprolide' is 5-oxo-L-prolyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L -Arginyl-L-prolyl ethylamide is an LHGH agonist.
- the leuprolide may be expressed as leuprorelin. Additionally, in the present invention, all pharmaceutically acceptable salts of leuprolide can be used.
- 'pharmaceutically acceptable means that it is physiologically acceptable and does not usually cause allergic reactions or similar reactions when administered to humans.
- 'pharmaceutically acceptable salt' refers to an acid addition salt formed from a pharmaceutically acceptable free acid.
- Organic acids and inorganic acids can be used as the free acids.
- the organic acids are not limited thereto, but include citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Includes glutamic acid and aspartic acid.
- the inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.
- the pharmaceutically acceptable salt of leuprolide of the present invention may be leuprolide acetate.
- the leuprolide or a pharmaceutically acceptable salt thereof may be used in an amount of 9.5 to 40% by weight, 10 to 30% by weight, or 12 to 25% by weight based on the total weight of the microspheres.
- the biocompatible polymer is polyethylene glycol-poly(lactide-co-glycolide) block-copolymer, polyethylene glycol-polylactide block-copolymer, polyethylene glycol-polycaprolactone block-copolymer, At least one selected from the group consisting of polylactide, polyglycolide, poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polycaprolactone, and mixtures thereof. It may be from 3 types, 1 to 2 types, or 2 to 3 types.
- “Two or more types of biocompatible polymers” means a combination or blend of different types of biocompatible polymer materials (for example, a blend of poly(lactide-co-glycolide) and polylactide).
- a combination of polymers of the same type with different intrinsic viscosity, molecular weight, and/or monomer ratio e.g., poly(lactide-co-) with a molar ratio of lactide to glycolide of 40:60
- it may be the same type of polymer with different end groups (for example, an ester end group or an acid end group).
- Examples of commercially available biocompatible polymers that can be used in the present invention include RG 502H, RG 503H, RG 504H, RG 502, RG 503, RG 504, and RG 653H from the Resomer series of Evonik Rohm GmbH.
- the biocompatible polymer may preferably be polylactide.
- biocompatible polymer being a combination (blend) of two or more types of polymers
- polylactide is contained at least 50%.
- the molar ratio of lactide to glycolide in the polymer is 40:60 to 90:10, 45:55 to 85:15, or 50:50 to 75:25, For example, it could be 45:55, 50:50, 75:25, or 85:15.
- the intrinsic viscosity of the poly(lactide-co-glycolide) or polylactide is 0.16 dL/g to 1.7 dL/g, 0.16 dL/g to 1.5 dL/g, and 0.16 dL/g to 1.2 dL/g. , 0.16 dL/g to 0.9 dL/g, 0.16 dL/g to 0.6 dL/g, 0.16 dL/g to 0.4 dL/g, 0.2 dL/g to 1.3 dL/g, 0.2 dL/g to 1.0 dL/g.
- 0.2 dL/g to 0.7 dL/g 0.2 dL/g to 0.5 dL/g, 0.24 dL/g to 1.2 dL/g, 0.24 dL/g to 0.7 dL/g, or 0.24 dL/g to 0.5 dL/. It may be g.
- the intrinsic viscosity of poly(lactide-co-glycolide) or polylactide used in the present invention is measured at a concentration of 0.1% (w/v) in chloroform at 25°C using an Ubbelohde viscometer. . If the intrinsic viscosity of poly(lactide-co-glycolide) or polylactide is less than 0.16 dL/g, the molecular weight of the polymer is insufficient, making it difficult to exhibit the sustained-release effect of leuprolide or a pharmaceutically acceptable salt thereof. , if the intrinsic viscosity exceeds 1.7 dL/g, the release of leuprolide or a pharmaceutically acceptable salt thereof may be delayed too much. In addition, when manufacturing microspheres using a polymer with high intrinsic viscosity, there is a problem of having to use an excessive amount of production solvent due to the high viscosity of the polymer, and it is difficult to manufacture reproducible microspheres.
- the weight average molecular weight of the biocompatible polymer is not particularly limited, but may have a weight average molecular weight of 4,000 to 240,000.
- the weight average molecular weight of the biocompatible polymer is 4,000 to 100,000, 7,000 to 50,000, 5,000 to 20,000, 10,000 to 18,000, and 18,000 to 28,000. Includes all lower numerical ranges within the above range, such as average molecular weight.
- the biocompatible polymer in the microspheres may be 70 to 90% by weight, 75 to 90% by weight, or 80 to 90% by weight based on the total weight of the microspheres.
- the weight ratio of the active ingredient to the biocompatible polymer in the microspheres may be 1:4 to 1:9, 1:35 to 1:9, or 1:3 to 1:9.
- the sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof of the present invention may have a particle diameter (D50) of 10 to 40 ⁇ m.
- the sustained-release microspheres prepared according to the production method according to the present invention may have a significant amount of residual solvent removed compared to the prior art.
- the residual solvent in the microspheres may be less than 1000 ppm, less than 900 ppm, or 800 ppm. It may be less than, less than 700 ppm, less than 600 ppm, 1000 to 0.01 ppm, 900 to 0.01 ppm, 800 to 0.01 ppm, 700 to 0.01 ppm, or 600 to 0.01 ppm.
- the sustained-release microspheres may be suitable for a 1-month to 3-month formulation.
- the sustained-release microspheres may have an in vitro release rate of 8 to 40% or 10 to 30% 24 hours after release of the active ingredient.
- the sustained-release microspheres may have a C max of 20,000 to 2,000,000 pg/mL after being administered to rats as an active ingredient at a dose of 1.5 mg/head for 1 month (4 weeks).
- the C max of the drug may be 20,000 to 900,000 pg/mL
- the C max of the drug may be 50,000 to 2,000,000 pg/mL.
- the cumulative drug area under the curve up to 24 hours after administration is the cumulative drug area under the curve up to the target administration period (AUC) total , for a 1-month formulation, the area under the cumulative drug curve up to 28 days after drug administration; for a 3-month formulation, the cumulative area under the drug curve up to 84 days after drug administration; and for a 6-month formulation, the area under the cumulative drug curve up to 168 days after drug administration. It may be 0.5 to 55%, 0.6 to 50%, or 0.7 to 50% of the cumulative drug curve area.
- the cumulative area under the drug curve up to 24 hours after administration (AUC 0-24hrs , Area under the curve ) is 12. It may be from 45% to 45%, 20 to 42% or 30 to 40%.
- the cumulative area under the drug curve up to 24 hours after administration (AUC 0-24hrs , Area under the curve) is 30 to 55% or 35% of the cumulative area under the curve until the target administration period (AUC total ). It may be from 40 to 53%, or from 40 to 50%.
- the cumulative area under the drug curve up to 24 hours after administration (AUC 0-24hrs , Area under the curve ) is 0.5 to 55%, 0.6%. It may be from 0.7 to 50% or from 0.7 to 50%.
- the ratio of the area under the cumulative drug curve at 0 to 24 hours after administration to the area under the cumulative drug curve at 48 hours to 168 hours after administration is 2:1 to 10:1, preferably 2:1 to 8:1, more preferably 2. :1 to 6:1.
- sustained-release microspheres according to the present invention when administered in vivo as described above, exhibit the ratio of the area under the cumulative drug curve at 0 to 24 hours after administration: the area under the cumulative drug curve at 48 hours to 168 hours after administration, Not only does it ensure sufficient initial release of leuprolide or a pharmaceutically acceptable salt thereof, but also maintains the efficacy of the active ingredient for a desired period of time, for example, 1 month or more, 3 months or more, 1 month to 3 months, etc. Enable continuous and sufficient performance.
- a) (i) prepare a dispersed solution by dissolving the biocompatible polymer and leuprolide or a pharmaceutically acceptable salt thereof in one or more organic solvents, or (ii) prepare an oil phase by dissolving the biocompatible polymer in one or more organic solvents.
- Prepare a solution for the oil phase prepare an aqueous solution by dissolving leuprolide or a pharmaceutically acceptable salt thereof in an aqueous solvent, and add the aqueous solution to the oil phase solution to form a water-in-oil (W/O) solution.
- step b) The dispersion solution or water-in-oil emulsion prepared in step a) is added to an aqueous solution containing a surfactant as a continuous phase to form microspheres, and the dispersion solution or water-in-oil emulsion is injected and stirred to solidify the microspheres.
- step b) extracting the organic solvent by adding an aqueous solution containing ethanol and a surfactant to the suspension containing the solidified microspheres of step b);
- step d) exchanging the continuous phase in the suspension containing the microspheres of step c) with an aqueous solution containing fresh ethanol and a surfactant and stirring;
- e relates to a manufacturing method comprising the step of recovering microspheres.
- the present invention provides another method for producing sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof,
- a' (i) dissolving the biocompatible polymer and leuprolide or a pharmaceutically acceptable salt thereof in one or more organic solvents to prepare a dispersion solution, or (ii) dissolving the biocompatible polymer in one or more organic solvents to prepare a dispersion solution.
- a solution for the oil phase was prepared, and leuprolide or a pharmaceutically acceptable salt thereof was dissolved in an aqueous solvent to prepare an aqueous solution, and the aqueous solution was added to the oil phase solution to form a water-in-oil type (W/ O) preparing an emulsion;
- step b' The dispersion solution or water-in-oil emulsion prepared in step a') is added to an aqueous solution containing ethanol and a surfactant as a continuous phase to form microspheres, and the microspheres are solidified after injection of the dispersion solution or water-in-oil emulsion. and preparing a suspension containing microspheres by stirring for organic solvent extraction;
- step b' exchanging the continuous phase in the suspension containing the microspheres of step b') with an aqueous solution containing fresh ethanol and a surfactant and stirring;
- d' relates to a manufacturing method comprising the step of recovering microspheres.
- microsphere preparations using biocompatible polymers to develop sustained-release preparations have developed into a field of active research interest and clinical application.
- the drug to be contained in the microspheres must be encapsulated in a high amount considering the administration period and dosage.
- the present invention is a method for producing sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof, and is characterized in that ethanol is used without heating to remove the residual solvent of the microspheres.
- the step a) or a') is a step of preparing (i) a dispersion solution or (ii) a water-in-oil emulsion for producing microspheres.
- the emulsion prepared in step b) or b') below is an O/W emulsion
- the water-in-oil emulsion of (ii), step b) or The emulsion prepared in b') may be a W/O/W type emulsion.
- the biocompatible polymer and leuprolide or a pharmaceutically acceptable salt thereof are dissolved in one or more organic solvents to prepare a dispersed phase solution.
- the one or more organic solvents may be two or more organic solvents, and one of the two or more organic solvents may be used as a co-solvent.
- the biocompatible polymer is dissolved in one organic solvent, and leuprolide or a pharmaceutically acceptable salt thereof is dissolved in another organic solvent to prepare each solution, and then mixed to form a dispersed phase. (i) can be performed by obtaining a solution.
- Step a) or step a') may be performed at 15 to 25°C, or at room temperature.
- the organic solvent used in steps (i) and (ii) of step a) or a') is dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide, It may be at least one solvent selected from the group consisting of enmethylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol, or a mixed solvent of two or more of the above solvents.
- the amount of leuprolide or a pharmaceutically acceptable salt thereof is 9 to 40% compared to the total weight (i.e., total solid weight) of the biocompatible polymer and leuprolide or a pharmaceutically acceptable salt thereof to be prepared. It may be used in weight percent, 10 to 35 weight percent, or 12 to 25 weight percent.
- biocompatible polymer may be applied to the injectable preparation containing the sustained-release microspheres, unless otherwise defined.
- the method for producing leuprolide sustained-release microspheres according to the present invention is b) or b') adding the dispersed phase solution or water-in-oil emulsion prepared in step a) or a') to an aqueous solution containing a surfactant as a continuous phase.
- This includes forming microspheres, and after completing the injection of the dispersion acid solution or water-in-oil emulsion, stirring to solidify the microspheres to prepare a suspension containing the microspheres.
- the content of the surfactant in the continuous phase containing the surfactant is 0.01% by weight to 20% by weight, preferably 0.1% by weight to 5% by weight, based on the total volume of the continuous phase. You can. If the surfactant content is less than 0.01% by weight, a dispersed phase or emulsion in the form of droplets may not be formed in the continuous phase, and if the surfactant content exceeds 20% by weight, excessive surfactant may cause the formation of a dispersed phase or emulsion in the continuous phase. After the particulates are formed, it may be difficult to remove the surfactant.
- the surfactant in step b) or b') is methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil derivatives, and their It may be one or more types selected from the group consisting of mixtures.
- the aqueous solvent for preparing the aqueous solution containing the surfactant in step b) or b') is water, or a solvent selected from the group consisting of water and methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate, or a mixed solvent thereof. It may be.
- the method of homogeneously mixing the biocompatible polymer solution in which leuprolide or a pharmaceutically acceptable salt thereof is dispersed and the continuous phase containing the surfactant is not particularly limited, but includes a high-speed stirrer, It can be performed using an in-line mixer, ultrasonic disperser, static mixer, membrane emulsion method, microfluidics emulsion method, etc.
- a high-speed stirrer it can be performed using an in-line mixer, ultrasonic disperser, static mixer, membrane emulsion method, microfluidics emulsion method, etc.
- the stirring process in step b) or b') may be performed for 1 to 5 hours, 2 to 4 hours, or 3 hours for solidification.
- step b) or b') may be performed at 4 to 24°C, 10 to 17°C, or 15°C.
- an aqueous solution further containing ethanol in addition to a surfactant may be used as a continuous phase to extract the organic solvent during the formation and solidification of the microspheres.
- the content of ethanol in the aqueous solution containing ethanol and surfactant is 5 to 40 (v/v)%, 5 to 30 (v/v)%, 5 to 5%, based on the total volume of the aqueous solution. It may be 20(v/v)%, 7 to 40(v/v)%, 7 to 30(v/v)%, 7 to 20(v/v)% or 10 to 20(v/v)%. . If the ethanol content is less than 5(v/v)%, the residual amount of organic solvent may increase, and if it exceeds 30(v/v)%, the encapsulation rate may be reduced or initial release control may be difficult. .
- step c) an aqueous solution containing ethanol and a surfactant is added to the suspension containing the solidified microspheres prepared in step b) to extract the organic solvent in a continuous phase.
- the temperature is lower than that of the prior art, at 4 to 24°C, 10 to 17°C, or 15°C for a certain period of time, for example, 1 hour to 48 hours, 5 to 36 hours, or 7 to 15°C.
- the organic solvent can be effectively extracted from the microspheres by maintaining or stirring for 24 hours, 10 to 20 hours, or 15 hours. Some of the extracted organic solvent may evaporate from the surface of the microspheres.
- step c) The type of surfactant used in step c) may be the same as that used in step b).
- the solvent in the aqueous solution of step c) may be water or a mixed solvent of water and one or more solvents selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate.
- the content of ethanol in the aqueous solution containing ethanol and surfactant is 5 to 40 (v/v)%, 5 to 30 (v/v)%, 5%, based on the total volume of the aqueous solution. to 20 (v/v)%, 7 to 40 (v/v)%, 7 to 30 (v/v)%, 7 to 20 (v/v)% or 10 to 20 (v/v)%. there is. If the ethanol content is less than 5(v/v)%, the residual amount of organic solvent may increase, and if it exceeds 30(v/v)%, the encapsulation rate may be reduced or initial release control may be difficult. .
- step d) or c' after extracting the organic solvent in step c) or b'), it is exchanged with an aqueous solution containing fresh ethanol and a surfactant and incubated for a certain period of time, specifically 1 hour to 48 hours, 1 hour to 48 hours. Stir for 24 hours, 1 hour to 12 hours, and 1 hour to 5 hours.
- the holding time may be 3 hours, but is not limited thereto.
- step e) or d' the microspheres are finally recovered.
- step e) or d' the method of recovering microspheres according to the present invention may be performed using various known techniques, for example, methods such as filtration or centrifugation may be used.
- step e) or d' the microsphere suspension upon recovery is further washed with a washing liquid (e.g. water, specifically ultrapure water), preferably repeatedly, to remove residual surfactant.
- a washing liquid e.g. water, specifically ultrapure water
- the obtained microspheres are dried using a conventional drying method, for example, freeze-drying, to obtain final dried microspheres.
- the sustained-release microspheres containing leuprolide or a pharmaceutically acceptable salt thereof prepared by the production method of the present invention may have a particle diameter (D50) of 10 to 40 ⁇ m.
- the sustained-release microspheres prepared according to the production method according to the present invention may have a significant amount of residual solvent removed compared to the prior art.
- the residual solvent in the microspheres may be less than 1000 ppm.
- the encapsulation rate of the prepared sustained-release microspheres is 60% or more, 60 to 100%, 70% or more, 70 to 100%, 75% or more, 75 to 100%, 75 to 98%, or 75%. It may be from 95% to 95%. Preferably, it may be 80% or more, 80 to 100%, 80 to 98%, 90 to 100%, 95 to 100%, or 80 to 95%.
- microspheres of leuprolide or a pharmaceutically acceptable salt thereof were prepared.
- the dispersed phase is a mixture of biocompatible polymers PLGA or PLA and leuprolide acetate (manufacturer: Polypeptide Laboratories Pvt, Ltd., India) with dichloromethane (manufacturer: J.T Baker, USA) and methyl alcohol (manufacturer: Tedia Company, USA). Alternatively, it was mixed with ethyl acetate (manufacturer: Junsei chemical Co. Ltd., Japan) and methyl alcohol (manufacturer: Tedia Company, USA) and dissolved until it became transparent to the naked eye.
- a 1.0% (w/v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa ⁇ s) aqueous solution was used as the continuous phase, and the continuous phase was connected to an emulsifier equipped with a porous membrane and the prepared dispersed phase was injected to prepare microspheres. did.
- the temperature of the membrane emulsification device, preparation vessel, and microsphere suspension was maintained at 15°C, and after dispersion phase injection was completed, it was stirred at 200 rpm for 3 hours. Ethanol was added and stirred for 18 hours to extract the organic solvent, and then stirred in the same continuous phase for 3 hours.
- the microsphere suspension was washed several times with ultrapure water to remove residual polyvinyl alcohol, and the microspheres were recovered by lyophilization.
- Example 4 R202H 20 DCM MeOH PVA Solvent Extraction (10% EtOH) 15
- Example 5 R202H 20 DCM MeOH PVA Solvent Extraction (20% EtOH) 15
- Leuprolide microspheres that did not use the ethanol process for organic solvent extraction were prepared by the following method.
- the dispersed phase is a mixture of biocompatible polymers PLGA or PLA and leuprolide acetate (manufacturer: Polypeptide Laboratories Pvt, Ltd., India) with dichloromethane (manufacturer: J.T Baker, USA) and methyl alcohol (manufacturer: Tedia Company, USA). It was dissolved until it became transparent to the naked eye. A 0.5% (w/v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa ⁇ s) aqueous solution was used as the continuous phase, and the continuous phase was connected to an emulsifier equipped with a porous membrane and the prepared dispersed phase was injected to prepare microspheres. did.
- the temperature of the membrane emulsification device, preparation vessel, and microparticle suspension was maintained at 25°C, and after the injection of the dispersed phase was completed, the organic solvent was removed while maintaining the temperature of the microparticle suspension at 36°C for 3 hours. After removal of the organic solvent, the temperature of the microparticle suspension was lowered to 25°C. The microsphere suspension was washed several times with ultrapure water to remove residual polyvinyl alcohol, and the microspheres were freeze-dried.
- Leuprolide microspheres that did not use the ethanol process for organic solvent extraction were prepared by the following method.
- the dispersed phase was prepared by dissolving the biocompatible polymers PLGA or PLA and leuprolide acetate (manufacturer: Polypeptide Laboratories Pvt, Ltd., India) in dichloromethane (manufacturer: J.T Baker, USA) and distilled water, respectively, to prepare an oil phase and an aqueous phase.
- a W/O emulsion was formed by emulsifying at 12,000 rpm using an IKA homogenizer.
- a 0.5% (w/v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa ⁇ s) aqueous solution was used as the continuous phase, and microspheres were prepared by connecting the continuous phase to an emulsifier equipped with a porous membrane and simultaneously injecting the prepared dispersed phase. .
- the temperature of the membrane emulsification device, preparation vessel, and microparticle suspension was maintained at 25°C, and after the injection of the dispersed phase was completed, the microparticle suspension was heated and maintained for 3 hours to remove the organic solvent. After removal of the organic solvent, the temperature of the microparticle suspension was lowered to 25°C.
- the microsphere suspension was washed several times with ultrapure water to remove residual polyvinyl alcohol, and the microspheres were freeze-dried.
- microspheres prepared in the above example 10 mg were completely dissolved in 2.5 mL of acetonitrile, and then extracted by adding 7.5 mL of 0.1% (w/w) trifluoroacetic acid aqueous solution. The solution filtered using a 0.45 um filter was used as the test solution. 20uL of the test solution was injected into the HPLC and measured at a detection wavelength of 280nm. The column used in this measurement was Inertsil ODS-3, 5 um, 4.6x150 mm, and the mobile phase was acetonitrile containing 0.1% (w/w) trifluoroacetic acid and 0.1% (w/w) trifluoroacetic acid. Acetic acid aqueous solution was mixed and used at a ratio of 25:75 (v/v). The measured encapsulation amounts are shown in Table 3.
- a test was conducted using laser diffraction to quantitatively measure the average particle size, distribution, and uniformity of microspheres.
- Example 2 32.45 E.E 91.2% DC 13.67%
- Example 3 27.64 E.E 79.6% DC 15.92% 3 months
- the following experiment was performed to confirm the initial drug release of the microspheres prepared in the above Examples and Comparative Examples. Place 10 mg of microspheres in an HDPE wide-mouth bottle, fill with 50 mL of release test solution, and store in an incubator at 37°C. After 24 hours, 1 mL of this sample solution was taken and centrifuged, and the obtained supernatant was analyzed for leuprolide content and release rate using HPLC under the same analysis conditions as in Experimental Example 1.
- the release test solution for this measurement was a pH 7.4 aqueous solution containing phosphate and sodium azide.
- Pharmacokinetic evaluation was performed on the microspheres of Examples and Preparation Examples using 9-week-old SD (Sprague-Dawly) rats.
- the microsphere injection preparations of Examples and Preparation Examples in rats were measured at a dose of 1.5 mg/head as an active ingredient for 1 month (4 weeks) in rats, suspended in 0.3 mL dispersion solvent, and then subcutaneously injected into SD rats. . 0.25 to 0.5 mL of blood was collected at pre-planned times, and blood leuprolide concentration was measured using LC-MS/MS. The measurement results are shown in Table 5 and Figures 1 (1-month formulation) and Figure 2 (3-month formulation).
- the morphological characteristics of the microspheres according to the present invention were analyzed through electron microscopy.
- the experimental procedure is as follows. 5 mg of microspheres prepared in Examples and Preparation Examples were placed on an aluminum stub with carbon tape attached and coated with platinum using ION-COATER (COXEM, Korea). An aluminum stub was mounted on a scanning electron microscope (COXEM EM-30, Korea), and the morphological characteristics of the microspheres were observed at an acceleration voltage of 10 ⁇ kV. The results are shown in Figures 3a (1-month formulation) and 3b (3-month formulation).
- microspheres according to the present invention have excellent storage stability and safety to the human body due to the low residual solvent amount of less than 1000 ppm.
- the particle number of microspheres according to the present invention was measured as follows. The number of microspheres was confirmed by directly checking the number of particles using an optical microscope. 10 mg of microspheres prepared in Examples and Comparative Examples were weighed and dispersed in 0.5 (w/w)% PVA. At this time, the comparative example containing 15 (w/w)% mannitol was performed by correcting the weight (weight correction was performed by weighing 11.8 mg so that the weight of the microspheres was 10 mg when mannitol was excluded). The microspheres dispersed in 0.5 (w/w)% PVA were diluted with 0.5 (w/w)% PVA so that the concentration was 0.1 mg/mL. 10 ⁇ m of the diluted 0.1 mg/mL concentration microsphere solution was taken and the number of particles was confirmed under a microscope.
- the administration dose was adjusted so that the content of the active ingredient (API) in the examples and comparative examples was the same, and is shown in Tables 7 and 8.
- Table 7 shows the 1-month formulation
- Table 8 shows the 3-month formulation.
- Example 2 Based on one administration Example 2 Comparative Example 1 (Leuplin 3.75mg) API concentration (mg/mL) 3.75 3.75 Microparticle concentration (mg/mL) 27.4 44.1 Number of microspheres (piece/mg) 67,000 149,300 Number of administered microspheres (number/mL) 1,836,623 6,586,765
- Example 4 Based on one administration Example 4 Comparative Example 2 (Leuplin 11.25mg) API concentration (mg/mL) 11.25 11.25 Microparticle concentration (mg/mL) 58.9 130.1 Number of microspheres (piece/mg) 49,700 262,300 Number of administered microspheres (number/mL) 2,927,356 34,114,162
- the conventional injection preparation containing leuprolide has a microparticle concentration that is 1.6 to 2.2 times higher than the injection preparation according to the present invention. With this, it was confirmed that the number of microspheres was also 3.6 to 11.7 times greater. This has the advantage that the injection preparation according to the present invention has a significantly lower number and concentration of microspheres compared to the same active ingredient content, and can reduce various problems that may occur due to a large number of microspheres and a high concentration of microspheres upon administration, such as the level of inflammation. You can have it.
- Example 4 The degree of inflammation at the administration site when the microspheres prepared in Example 4 and Comparative Example 2 were administered was confirmed.
- 0.5 mL of suspension (Diluent) 0.5(w/w)% NaCMC, 5(w/w)% Mannitol, 0.1(w/w)% Tween 80
- the microspheres were added. Mix well until completely dispersed.
- the microspheres were administered subcutaneously to the back of SD rats at a dose of 4.5mg/head. Tissues were removed on the 3rd, 10th, and 28th days after administration and analysis of inflammation at the administration site was performed, which is shown in Table 9.
- Example 4 (SD rat, male 8 weeks old) At each confirmation time, histopathology slide samples of Example 4 and Comparative Example 2 were prepared, stained with H&E (Hematoxylin and Eosin), and inflammatory cell infiltration was confirmed. Photographs of samples stained in this way are shown in Figures 4a (3 days), 4b (10 days), and 4c (28 days). Yellow circles represent infiltrated cells, red arrows represent angiogenesis, and blue arrows represent fibrous tissue formation.
- H&E Hematoxylin and Eosin
- Table 10 is a table that quantifies the degree of inflammatory cell infiltration on the 3rd, 10th, and 28th days after administration of microspheres to SD rats.
- Inflammatory cell infiltration is graded from 0 to 3 by randomly selecting three parts at 400x field of view (HPF), counting the number of cells.
- HPF 400x field of view
- Example 4 On the 3rd day after microball administration, the inflammatory response was strong in both Example 4 and Comparative Example 2, so no significant difference could be confirmed, but on the 10th and 28th day after microball administration, the inflammatory response was strong. While the inflammatory response continued in Example 2, it was confirmed that the inflammatory response was relatively reduced in Example 4.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pain & Pain Management (AREA)
Abstract
La présente invention concerne des microsphères à libération prolongée contenant une quantité élevée de leuprolide, une préparation injectable la comprenant, et un procédé de préparation associé. Pendant l'administration, le leuprolide est libéré à un niveau suffisant à une étape précoce de telle sorte que les effets du leuprolide sont présentés, ce qui permet une exposition à une quantité suffisante d'un médicament tandis que des réactions inflammatoires et similaires, qui peuvent être problématiques pendant l'administration, sont réduites à un minimum, et ainsi les effets du leuprolide peuvent être présentés en toute sécurité au moins 1 mois.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20220110883 | 2022-09-01 | ||
KR10-2022-0110883 | 2022-09-01 | ||
KR20220147421 | 2022-11-07 | ||
KR10-2022-0147421 | 2022-11-07 | ||
KR1020230059471A KR20240031868A (ko) | 2022-09-01 | 2023-05-08 | 류프롤라이드를 포함하는 서방형 미립구, 이를 포함하는 주사제제 및 이의 제조방법 |
KR10-2023-0059471 | 2023-05-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024049279A2 true WO2024049279A2 (fr) | 2024-03-07 |
Family
ID=90098380
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2023/013112 WO2024049279A2 (fr) | 2022-09-01 | 2023-09-01 | Microsphères à libération prolongée contenant du leuprolide, préparation injectable les comprenant, et leur procédé de préparation |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024049279A2 (fr) |
-
2023
- 2023-09-01 WO PCT/KR2023/013112 patent/WO2024049279A2/fr unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2011081406A2 (fr) | Macromolécule pour administration de médicaments protéiques, polypeptidiques pou peptidiques et son procédé de fabrication, et composition à libération lente pour protéine, peptide ou médicaments protéiques, polypeptidiques ou peptidiques, et son procédé de fabrication | |
WO2019078583A1 (fr) | Microparticules à libération prolongée comprenant un médicament, et procédé de préparation associé | |
WO2020197190A1 (fr) | Procédé de préparation de microsphères chargées d'apixaban à base de polymère biocompatible | |
US10478470B2 (en) | Pharmaceutical composition containing leuprolide and having both immediate and sustained release properties | |
WO2020040438A1 (fr) | Préparation pharmaceutique ayant d'excellentes propriétés de dissolution, contenant de l'ésoméprazole et du bicarbonate de sodium | |
WO2021010719A1 (fr) | Formulation à longue durée d'action contenant de la rivastigmine et son procédé de préparation | |
WO2021162532A2 (fr) | Composition pharmaceutique comprenant des microsphères à libération prolongée comportant un analogue de glp -1 ou un sel pharmaceutiquement acceptable de celui-ci | |
WO2021091246A1 (fr) | Microsphères à libération prolongée en mesure de réguler la libération initiale et procédé de préparation associé | |
WO2018147660A1 (fr) | Préparation d'administration de médicament pour le traitement de maladies mentales ou de troubles du système nerveux central | |
EP3946273A1 (fr) | Compositions de phase dispersée pour la préparation de microsphères chargées d'apixaban et microsphères chargées d'apixaban à base de polymère biocompatible préparées à partir de celles-ci | |
WO2016114521A1 (fr) | Composition de dutastéride sous forme de comprimé présentant une stabilité améliorée | |
WO2022010317A1 (fr) | Procédé de préparation de microsphères de plga à libération prolongée contenant du donépézil | |
WO2022050783A1 (fr) | Microparticules à libération prolongée pour la libération prolongée de médicament | |
WO2024049279A2 (fr) | Microsphères à libération prolongée contenant du leuprolide, préparation injectable les comprenant, et leur procédé de préparation | |
WO2020130585A1 (fr) | Injection à libération prolongée comprenant de la desloréline, et son procédé de préparation | |
WO2016036093A1 (fr) | Film dispersible oral de tadalafil et son procédé de préparation | |
WO2023101348A1 (fr) | Microparticules contenant du leuprolide, et leur procédé de préparation | |
WO2012087051A2 (fr) | Microparticules contenant un peptide physiologiquement actif, procédé pour les préparer et composition pharmaceutique les contenant | |
WO2020242234A1 (fr) | Composition injectable contenant un promédicament d'inhibiteurs de caspase, et son procédé de préparation | |
WO2023038202A1 (fr) | Microsphère à libération prolongée utilisant un polymère biodégradable et procédé pour sa préparation | |
WO2019208982A1 (fr) | Procédé de préparation de microshères biodégradables à l'aide d'une solution de mélange à phase unique stabilisée | |
WO2021167364A1 (fr) | Composition pharmaceutique comprenant de l'ésoméprazole et du bicarbonate de sodium présentant d'excellentes propriétés de libération | |
WO2023249464A1 (fr) | Microparticules à libération prolongée contenant un médicament et de l'acide pamoïque | |
WO2024101859A1 (fr) | Préparation injectable à libération prolongée comprenant de l'acétate de dexaméthasone et procédé de préparation s'y rapportant | |
WO2022005169A1 (fr) | Composition injectable comprenant des dérivés de gnrh |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23860954 Country of ref document: EP Kind code of ref document: A2 |