KR102650566B1 - Ocular nanoemulsion composition for the treatment of macular degeneration - Google Patents
Ocular nanoemulsion composition for the treatment of macular degeneration Download PDFInfo
- Publication number
- KR102650566B1 KR102650566B1 KR1020210171437A KR20210171437A KR102650566B1 KR 102650566 B1 KR102650566 B1 KR 102650566B1 KR 1020210171437 A KR1020210171437 A KR 1020210171437A KR 20210171437 A KR20210171437 A KR 20210171437A KR 102650566 B1 KR102650566 B1 KR 102650566B1
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- methoxy
- trimethoxychroman
- phenyl
- tert
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 55
- 239000007908 nanoemulsion Substances 0.000 title claims abstract description 24
- 208000002780 macular degeneration Diseases 0.000 title claims description 10
- 229940079593 drug Drugs 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 40
- 239000003921 oil Substances 0.000 claims abstract description 38
- 239000004094 surface-active agent Substances 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 230000001419 dependent effect Effects 0.000 claims abstract description 17
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 239000004359 castor oil Substances 0.000 claims abstract description 14
- 235000019438 castor oil Nutrition 0.000 claims abstract description 14
- 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 abstract description 14
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 claims abstract description 8
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000008213 purified water Substances 0.000 claims abstract description 6
- 239000003889 eye drop Substances 0.000 claims description 32
- 239000012071 phase Substances 0.000 claims description 28
- -1 2-methoxy-5 -((5,6,7-trimethoxychroman-3-yl)methyl)phenol (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol) Chemical compound 0.000 claims description 26
- 229940012356 eye drops Drugs 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 15
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 239000008346 aqueous phase Substances 0.000 claims description 12
- 239000003755 preservative agent Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 230000002335 preservative effect Effects 0.000 claims description 7
- 230000001954 sterilising effect Effects 0.000 claims description 7
- 239000000872 buffer Substances 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 5
- 239000007951 isotonicity adjuster Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 235000013402 health food Nutrition 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- WNNRDODGEVJJGL-UHFFFAOYSA-N (1-benzylpiperidin-4-yl) carbamate Chemical compound C1CC(OC(=O)N)CCN1CC1=CC=CC=C1 WNNRDODGEVJJGL-UHFFFAOYSA-N 0.000 claims description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 201000005111 ocular hyperemia Diseases 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims 2
- 239000006172 buffering agent Substances 0.000 claims 1
- 239000006188 syrup Substances 0.000 claims 1
- 235000020357 syrup Nutrition 0.000 claims 1
- 238000009472 formulation Methods 0.000 abstract description 13
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000011156 evaluation Methods 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 14
- 239000008389 polyethoxylated castor oil Substances 0.000 description 13
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000002075 main ingredient Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005063 solubilization Methods 0.000 description 6
- 230000007928 solubilization Effects 0.000 description 6
- 238000013112 stability test Methods 0.000 description 6
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000003381 solubilizing effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 4
- 235000013373 food additive Nutrition 0.000 description 4
- 239000002778 food additive Substances 0.000 description 4
- 235000013376 functional food Nutrition 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000012395 formulation development Methods 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- RACFGZBMVCDIDQ-UHFFFAOYSA-N 2-methoxy-5-[(5,6,7-trimethoxy-3,4-dihydro-2H-chromen-3-yl)methyl]phenol Chemical compound C1(OC)=C(OC)C(OC)=C2CC(CC3=CC(O)=C(OC)C=C3)COC2=C1 RACFGZBMVCDIDQ-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000012062 aqueous buffer Substances 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 235000019219 chocolate Nutrition 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000015203 fruit juice Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- KQJAZWVNZZZJNM-UHFFFAOYSA-N 5-[[6-(cyclopropylmethoxy)-5,7-dimethoxy-3,4-dihydro-2H-chromen-3-yl]methyl]-2-methoxyphenol Chemical compound C1(CC1)COC=1C(=C2CC(COC2=CC1OC)CC=1C=CC(=C(C1)O)OC)OC KQJAZWVNZZZJNM-UHFFFAOYSA-N 0.000 description 1
- QPXDJAQCABFFAR-UHFFFAOYSA-N COc1ccc(CC2COc3cc(OC)c(OC)c(OC)c3C2=O)cc1O Chemical compound COc1ccc(CC2COc3cc(OC)c(OC)c(OC)c3C2=O)cc1O QPXDJAQCABFFAR-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- MLIWIXRXFRKLDS-UHFFFAOYSA-N butyl 2-[[2-methoxy-5-[(5,6,7-trimethoxy-3,4-dihydro-2H-chromen-3-yl)methyl]phenoxy]carbonylamino]acetate Chemical compound COC1=C(OC(=O)NCC(=O)OCCCC)C=C(C=C1)CC1COC2=CC(=C(C(=C2C1)OC)OC)OC MLIWIXRXFRKLDS-UHFFFAOYSA-N 0.000 description 1
- 235000014171 carbonated beverage Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000010415 colloidal nanoparticle Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940069445 licorice extract Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 235000019462 natural additive Nutrition 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- HWYNYLXTVJYPOW-UHFFFAOYSA-N piperidine-1,3-dicarboxylic acid Chemical compound OC(=O)C1CCCN(C(O)=O)C1 HWYNYLXTVJYPOW-UHFFFAOYSA-N 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물로서, 기존 수난용성 약물의 물에 대한 용해도가 낮아 제제개발이 어렵고 제형으로부터의 용출률이 낮아 흡수가 불량해지는 문제를 적정 pH로 조절하여, 제제를 제조하면서 이를 극복했다. poorly water-soluble drugs; Oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; A surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; and purified water. This is a pH-dependent nanoemulsion composition containing water, which makes it difficult to develop formulations due to the low solubility in water of existing poorly water-soluble drugs, and the problem of poor absorption due to low dissolution rate from the formulation is adjusted to an appropriate pH, and this is used while manufacturing the formulation. Overcame it.
Description
본 발명은 황반변성 치료를 위한 안과용 나노이멀젼 조성물 및 이의 제조방법을 제공한다.The present invention provides an ophthalmic nanoemulsion composition for treating macular degeneration and a method for producing the same.
약물이 약효를 나타내기 위해서는, 약물이 투여부위로부터 혈중으로 흡수되고, 혈류를 따라서 작용을 나타내는 장기나 조직으로 이행하여야 한다. 따라서 적용부위 혹은 투여부위에서 흡수의 장벽으로 작용하는 피부나 위장관막, 또는 기타 비강점막, 질점막 등의 다양한 생체점막을 투과하여 혈중으로 이행될 수 있어야 하며, 따라서 각종 생체막을 통한 투과가 약물의 작용발현을 위해 필수적이다.In order for a drug to exhibit efficacy, the drug must be absorbed into the blood from the administration site and travel through the bloodstream to the organs or tissues where it exerts its effect. Therefore, it must be able to penetrate into the blood through various biological mucosa, such as skin, gastrointestinal membrane, or other nasal mucosa and vaginal mucosa, which act as a barrier to absorption at the application or administration site. Therefore, the drug must be able to penetrate through various biological membranes. It is essential for the expression of action.
그러나 약물들 중 생체막 투과 자체는 큰 어려움이 없으나, 물에 대한 용해도가 낮아 제제개발이 어렵고 제형으로부터의 용출률이 낮아 흡수가 불량해지는 경우가 빈번하다. 이러한 난용성 약물의 경우에는 가용화 전략이 필요한데, 가용화 방안으로 난용성 약물을 염이나 무정형 고체로 하거나 혹은 보조용매나 계면활성제를 첨가하는 전략들이 사용되고 있는바, 수난용성 약물의 가용성을 높이기 위해 계속해서 연구가 진행 중에 있는 실정이다. However, although there is no major difficulty in permeating biological membranes among drugs, their solubility in water makes formulation development difficult, and the dissolution rate from the dosage form is low, resulting in poor absorption. In the case of these poorly soluble drugs, a solubilization strategy is necessary. Strategies for solubilizing the poorly soluble drug by converting it into a salt or amorphous solid or adding a co-solvent or surfactant are being used. In order to increase the solubility of poorly soluble drugs, continuous efforts are being made. Research is currently in progress.
본 발명의 목적은 수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물을 제공하는 데에 있다.The object of the present invention is to provide a drug that is poorly soluble in water; Oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; A surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; And to provide a pH-dependent nanoemulsion composition containing purified water.
본 발명의 또 다른 목적은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 치료용 약학 조성물 및 예방 또는 개선용 건강식품 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating macular degeneration and a health food composition for preventing or improving macular degeneration, including the pH-dependent nanoemulsion composition.
본 발명의 또 다른 목적은 (a) 오일류 및 계면활성제를 중량비 1 : 1 내지 3로 혼합한 후, 55 내지 65 ℃에서 수난용성 약물을 첨가하여 용해시켜 유상을 제조하는 단계; (b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계; (c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및 (d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법을 제공하는 데에 있다.Another object of the present invention is to prepare an oil phase by mixing oil and surfactant at a weight ratio of 1:1 to 3 and then adding and dissolving a poorly water-soluble drug at 55 to 65°C; (b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative, and water, and then adding a pH adjuster to adjust the pH to 4.5 to 6; (c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and (d) sterilizing the dispersed phase of step (c).
상기 목적을 달성하기 위하여, 본 발명은 수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물을 제공한다.In order to achieve the above object, the present invention provides a poorly water-soluble drug; Oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; A surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; and purified water.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 치료용 약학 조성물을 제공한다.Additionally, the present invention provides a pharmaceutical composition for preventing or treating macular degeneration comprising the pH-dependent nanoemulsion composition.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or improving macular degeneration comprising the pH-dependent nanoemulsion composition.
또한, 본 발명은 (a) 오일류 및 계면활성제를 중량비 1 : 1 내지 3로 혼합한 후, 55 내지 65 ℃에서 수난용성 약물을 첨가하여 용해시켜 유상을 제조하는 단계; (b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계; (c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및 (d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법을 제공한다.In addition, the present invention includes the steps of (a) mixing oil and surfactant at a weight ratio of 1:1 to 3, and then adding and dissolving a poorly water-soluble drug at 55 to 65° C. to prepare an oil phase; (b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative, and water, and then adding a pH adjuster to adjust the pH to 4.5 to 6; (c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and (d) sterilizing the dispersed phase of step (c).
본 발명은 수난용성 약물을 포함하는 pH 의존적 나노이멀젼 조성물에 관한 것으로, 수난용성 치료물질의 가용화, 안전하고 유효한 점안용 등의 첨가제로의 사용가능 및 물리화학적으로 안정화 효과가 있어, 무균여과로 대량생산이 가능한 제조방법으로 점안, 안구주사 및 경구제로 적용이 가능할 수 있다.The present invention relates to a pH-dependent nanoemulsion composition containing a poorly water-soluble drug, which solubilizes poorly water-soluble therapeutic substances, can be used as a safe and effective additive for eye drops, etc., and has a physicochemical stabilizing effect, so that it can be mass-produced through sterile filtration. It is a production method that can be used for eye drops, eye injections, and oral administration.
도 1은 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate; 이하, SH11037라고함)의 pH-stability 시험에서 얻어진 크로마토그램을 나타낸다.
도 2는 SH11037의 pH-stability에 따른 불순물 (Impurity) 생성 곡선과 대표적 조건의 크로마토그램을 나타낸다.
도 3은 나노 이멀젼 기제에 따른 60 ℃ (온수 중탕)에서의 용해도 (중량%) 평가를 나타낸다.
도 4는 MCT70과 계면활성제 및 피마자유와 계면활성제의 개별 중량비 혼합물의 물에 대한 분산시의 평균입자크기 평가를 나타낸다.
도 5는 나노이멀젼 기제 별 배합성 평가 결과를 나타낸다.
도 6은 SH11037의 최적화 점안제의 대표적 평가결과를 나타낸다.
도 7은 하기 실시예에 의해 제조된 1.5 중량% 점안제에 대한 가속조건 (40 ℃)에서의 간이 안정성 시험 결과를 나타낸다.
도 8은 다른 수난용성 물질인 1-(tert-부틸)3-(2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐)피페리딘-1,3-디카르복실레이트 (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate; 이하, SH-17040이라함), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페놀 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol; 이하, SH-17059라함), 5-((6-(사이클로프로필메톡시)-5,7-디메톡시크로만-3-일)메틸)-2-메톡시페놀 (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol; 이하, SH-19021이라함), 부틸((2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페녹시)카보닐)글리신 (butyl((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate; 이하, SHA-032라함), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(1-벤질피페리딘-4-일)카바메이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate; 이하, SHA-034라함) 및 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate; 이하, SH-17060이라함)에 대해, 하기 실시예에 의해 제조된 1.5 중량% 점안제와 동일한 첨가제 분량 및 제조방법에 따라서 제조하여 주요 품질항목에 대하여 평가한 결과를 나타낸다.Figure 1 shows 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate In the pH-stability test of (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate; hereinafter referred to as SH11037) The obtained chromatogram is shown.
Figure 2 shows the impurity generation curve and chromatogram of representative conditions according to pH-stability of SH11037.
Figure 3 shows the solubility (% by weight) evaluation at 60°C (hot water bath) according to the nano emulsion base.
Figure 4 shows the average particle size evaluation of the individual weight ratio mixtures of MCT70 and surfactant and castor oil and surfactant when dispersed in water.
Figure 5 shows the results of compatibility evaluation for each nanoemulsion base.
Figure 6 shows representative evaluation results of the optimized eye drop of SH11037.
Figure 7 shows the results of a simple stability test under accelerated conditions (40°C) for the 1.5% by weight eye drop prepared according to the following examples.
Figure 8 shows another poorly water-soluble substance, 1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl. ) Piperidine-1,3-dicarboxylate (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl) phenyl)piperidine-1,3-dicarboxylate; hereinafter referred to as SH-17040), 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (2- methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol; hereinafter referred to as SH-17059), 5-((6-(cyclopropylmethoxy)-5,7-dimethoxychrome mann-3-yl)methyl)-2-methoxyphenol (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol; hereinafter referred to as SH-19021) , butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl) methyl) phenoxy) carbonyl) glycine (butyl ((2-methoxy-5-(( 5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate; hereinafter referred to as SHA-032), 2-methoxy-5-((5,6,7-trimethoxychroman-3 -yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1-benzylpiperidin-4 -yl)carbamate; hereinafter referred to as SHA-034) and 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)- About L-phenylalaninate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate; hereinafter referred to as SH-17060) , prepared according to the same additive amount and manufacturing method as the 1.5% by weight eye drop prepared in the examples below, and the results of evaluation on major quality items are shown.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
기존 수난용성 약물의 물에 대한 용해도가 낮아 제제개발이 어렵고 제형으로부터의 용출률이 낮아 흡수가 불량해지는 경우가 빈번한 문제를 해결하기 위해, 오일 및 계면활성제의 적절한 선택으로 인한 최적의 pH에서 가용화되고, 물질 안정성이 있는 본 발명을 완성했다.In order to solve the problem that existing poorly water-soluble drugs often have poor absorption due to low water solubility, which makes formulation development difficult and low dissolution rate from the formulation, solubilization at optimal pH through appropriate selection of oil and surfactant, The present invention with material stability was completed.
본 발명은 수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물을 제공한다.The present invention relates to a drug that is poorly soluble in water; Oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; A surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; and purified water.
상기 조성물 총 100 중량%에 대하여 수난용성 약물을 바람직하게는 0.5 내지 2.0 중량%로 포함될 수 있으며, 더 바람직하게는 1.5 중량%일 수 있다.Preferably, the poorly water-soluble drug may be included in an amount of 0.5 to 2.0 wt%, and more preferably 1.5 wt%, based on a total of 100 wt% of the composition.
상기 조성물은 오일 및 계면활성제를 1:(1~3)의 중량비율로 포함될 수 있다.The composition may include oil and surfactant in a weight ratio of 1:(1-3).
상기 pH는 바람직하게는 4.5 내지 6.5일 수 있으며, 더 바람직하게는 5 내지 6 일 수 있다. The pH may preferably be 4.5 to 6.5, and more preferably 5 to 6.
상기 수난용성 약물은 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-부틸)3-(2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐)피페리딘-1,3-디카르복실레이트 (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페놀 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5-((6-(사이클로프로필메톡시)-5,7-디메톡시크로만-3-일)메틸)-2-메톡시페놀 (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol), 부틸((2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페녹시)카보닐)글리신 (butyl((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(1-벤질피페리딘-4-일)카바메이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate) 및 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate)로 이루어진 군에서 선택되는 하나일 수 있으나, 이에 한정 되는 것은 아니다.The poorly water-soluble drug is 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal. Laninate (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-butyl)3- (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate (1-( tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-methoxy-5 -((5,6,7-trimethoxychroman-3-yl)methyl)phenol (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5- ((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3 -yl)methyl)-2-methoxyphenol), butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycine (butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate) mann-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1- benzylpiperidin-4-yl)carbamate) and 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal It may be one selected from the group consisting of 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate), but is limited thereto. That is not the case.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 치료용 약학 조성물을 제공한다.Additionally, the present invention provides a pharmaceutical composition for preventing or treating macular degeneration comprising the pH-dependent nanoemulsion composition.
상기 약학 조성물은 통상적인 방법에 따라 안구주사제, 점안제, 과립제, 산제, 정제, 환제, 캡슐제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다. The pharmaceutical composition may be in any one dosage form selected from the group consisting of ocular injections, eye drops, granules, powders, tablets, pills, capsules, gels, suspensions, emulsions, drops or solutions according to conventional methods.
본 발명에 따른 유효성분의 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있고, 1일 투여량이 0.01 mg/kg 내지 200 mg/kg, 바람직하게는 0.1 mg/kg 내지 200 mg/kg, 보다 바람직하게는 0.1 mg/kg 내지 100 mg/kg 일 수 있다. 투여는 하루에 한번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다. The dosage of the active ingredient according to the present invention may vary depending on the subject's condition and weight, type and degree of disease, drug form, administration route and period, and may be appropriately selected by a person skilled in the art, and the daily dosage is 0.01 mg. /kg to 200 mg/kg, preferably 0.1 mg/kg to 200 mg/kg, more preferably 0.1 mg/kg to 100 mg/kg. Administration may be administered once a day or divided into several administrations, and the scope of the present invention is not limited thereby.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or improving macular degeneration comprising the pH-dependent nanoemulsion composition.
상기 건강기능식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다.The health functional food includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, It may contain organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
그밖에 천연 과일 주스, 합성 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 건강기능식품 조성물은 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알코올 및 비타민 복합제 중 어느 하나의 형태일 수 있다.In addition, it may contain pulp for the production of natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients can be used independently or in combination. In addition, the health functional food composition may be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverages, tea, functional water, drink, alcohol, and vitamin complex. It can be.
또한, 상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합 여부는 다른 규정이 없는 한 식품의약품안전청에 승인된 식품첨가물공전의 총칙 및 일반 시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In addition, the above-mentioned health functional food may additionally contain food additives, and its suitability as a “food additive” is determined according to the general provisions and general test methods of the Food Additives Code approved by the Food and Drug Administration, unless otherwise specified. Determination is made according to relevant standards and standards.
상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류 첨가 알칼리제, 보존료제제, 타르색소 제제 등의 혼합 제제류 등을 들 수 있다.Items listed in the "Food Additives Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as subchromic pigment, licorice extract, crystalline cellulose, cold pigment, and guar gum, L -Mixed preparations such as sodium glutamate preparations, noodle-added alkaline preparations, preservative preparations, and tar color preparations are included.
이때, 건강기능식품을 제조하는 과정에서 식품에 첨가되는 유효성분은 필요에 따라 그 함량을 적절히 가감할 수 있으며, 바람직하게는 식품 100 중량부에 1 중량부 내지 90 중량부 포함되도록 첨가될 수 있다.At this time, in the process of manufacturing health functional foods, the content of the active ingredients added to the food can be appropriately adjusted as needed, and is preferably added in an amount of 1 to 90 parts by weight per 100 parts by weight of the food. .
또한, 본 발명은 (a) 오일류 및 계면활성제를 중량비 1 : 1 내지 3로 혼합한 후, 55 내지 65 ℃에서 수난용성 약물을 첨가하여 용해시켜 유상을 제조하는 단계; (b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계; (c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및 (d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법을 제공한다.In addition, the present invention includes the steps of (a) mixing oil and surfactant at a weight ratio of 1:1 to 3, and then adding and dissolving a poorly water-soluble drug at 55 to 65° C. to prepare an oil phase; (b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative, and water, and then adding a pH adjuster to adjust the pH to 4.5 to 6; (c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and (d) sterilizing the dispersed phase of step (c).
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 다만 하기의 시험예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예 등에 한정되는 것은 아니다. 본 발명의 실시예 등은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, to aid understanding of the present invention, it will be described in detail through examples. However, the following test examples only illustrate the content of the present invention and the scope of the present invention is not limited to the following examples. Examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.
[실시예] 점안제 제조 방법[Example] Method for manufacturing eye drops
SH11037이 포함된 점안제제는 표 1의 원약분량표에 따라 하기와 같이, 제조했다.The eye drop preparation containing SH11037 was prepared as follows according to the raw drug quantity table in Table 1.
(i) 오일 및 계면활성제 조합을 10 mL 바이알에 첨가 및 혼합한 후, 60 ℃ (물중탕)에서 주성분인 SH11037 5, 10 및 15 mg을 넣고, 마그네틱 바로 교반 하여 용해시켰다.(유상)(i) After adding and mixing the oil and surfactant combination in a 10 mL vial, 5, 10, and 15 mg of SH11037, the main ingredient, were added at 60°C (water bath) and stirred with a magnetic bar to dissolve (oil phase).
(ii) 그 외에서 수산화나트륨 (NaOH)를 제외한 첨가제들은 표 1의 제제 분량에 맞게 각각 칭량하여 10 mL 바이알에 넣고, 증류수 10 mL를 넣어 충분히 교반 하여 용해시켰다. 그 후, 1N 수산화나트륨 (NaOH) 용액을 상기 (b) 단계의 용액에 적량 가하며 pH 6.0으로 조정했다.(수상)(ii) Other additives except sodium hydroxide (NaOH) were each weighed according to the preparation quantity in Table 1, placed in a 10 mL vial, and 10 mL of distilled water was added and thoroughly stirred to dissolve. After that, an appropriate amount of 1N sodium hydroxide (NaOH) solution was added to the solution in step (b) and the pH was adjusted to 6.0 (aqueous phase).
(iii) 약물의 손실를 줄이기 위해 상기 (i) 단계의 수상을 상기 (ii) 단계의 유상 바이알에 3 mL를 가하여 볼텍싱 1분하여 분산시키고, 이 분산상을 5 mL 용량플라스크에 옮겨 담았다.(iii) To reduce drug loss, 3 mL of the aqueous phase of step (i) was added to the oil phase vial of step (ii) and dispersed by vortexing for 1 minute, and the dispersed phase was transferred to a 5 mL volumetric flask.
(iv) 남은 상기 (i) 단계의 수상 1 mL로 상기 (ii) 단계의 유상 바이알의 잔류물을 세척하여 상기 (iii) 단계의 용량플라스크에 옮겨 담았고, 추가로 남은 수상 1 mL로 이 과정을 반복하여 유상 바이알에서 잔류하여 발생할 수 있는 손실을 최소화 했다.(iv) The residue from the oil phase vial of step (ii) was washed with the remaining 1 mL of aqueous phase of step (i) and transferred to the volumetric flask of step (iii), and this process was further performed with the remaining 1 mL of aqueous phase. This was repeated to minimize loss that may occur due to residue in the oil vial.
(v) 상기 (iv) 단계의 혼합액을 볼텍싱 1분을 하고, 남은 상기 (iii) 단계의 수상으로 5 mL 부피 플라스크를 표선했다.(v) The mixed solution from step (iv) was vortexed for 1 minute, and a 5 mL volumetric flask was filled with the remaining water phase from step (iii).
(vi) 제균 여과를 위하여 클린벤치 (Clean bench)에서 0.22 μm Syringe filter로 여과 한 후, 멸균된 튜브에 담아 농도별 (0.5 중량%, 1.0 중량% 및 1.5 중량%)로 최종 점안제제 (이하, F18이라함)를 제조했다.(vi) For sterilization filtration, filter through a 0.22 μm syringe filter on a clean bench, place in a sterilized tube, and prepare the final eye drop preparation (hereinafter, at 0.5% by weight, 1.0% by weight, and 1.5% by weight) by concentration. (referred to as F18) was manufactured.
[시험예 1] 제형 및 기제 선정[Test Example 1] Selection of formulation and base
1. SH11037의 pH-stability 평가1. pH-stability evaluation of SH11037
SH11037은 에스터 프로드러그 (ester prodrug)로 분류될 수 있으며, 도 1에 따를 때, 사전 안정성 연구에서 주요 분해생성물은 에스터 (ester) 결합 또는 아마이드 (amide) 결합이 절단되면서 생성되는 3-(3-하이드록시-4-메톡시벤질)-5,6,7-트리메톡시크로만-4-온 (3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one, SH11008; 이하, Impurity A라함) 및 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐 L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl L-phenylalaninate; 이하, Impurity B라함)임을 확인했다.SH11037 can be classified as an ester prodrug, and according to Figure 1, in preliminary stability studies, the main degradation product is 3-(3-) produced by cleavage of the ester bond or amide bond. Hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one, SH11008; hereinafter referred to as Impurity A) and 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl L-phenylalaninate (2- It was confirmed to be methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl L-phenylalaninate; hereinafter referred to as Impurity B).
점안제의 가장 중요한 특성 중에 하나인 pH에 따른 안정성을 평가하기 위하여 pH 2 내지 8까지의 수성완충액/에탄올 (부피비=6/4)를 사용하여 난용성 주성분을 40 ㎍/㎖의 농도로 녹이고, 40 ℃ 챔버에 보관하면서 일정시간 간격으로 샘플을 채취하여 HPLC 분석을 통해 분해생성물을 평가했다. 상기 수성완충액은 pH 2 내지 3 까지는 HCl/NaCl, pH 4 내지 5까지는 CH3COOH/CH3COONa, pH 6 내지 8 까지는 KH2PO4/Na2HPO4의 원료를 사용하였으며, 필요시 1N NaOH로 사용하여 정확히 원하는 pH로 조정하였다.In order to evaluate stability according to pH, which is one of the most important characteristics of eye drops, the poorly soluble main ingredient was dissolved at a concentration of 40 ㎍/㎖ using aqueous buffer/ethanol (volume ratio = 6/4) of pH 2 to 8, and 40 While stored in a ℃ chamber, samples were collected at regular time intervals and decomposition products were evaluated through HPLC analysis. The aqueous buffer solution used raw materials of HCl/NaCl for pH 2 to 3, CH 3 COOH/CH 3 COONa for pH 4 to 5, and KH 2 PO 4 /Na 2 HPO 4 for pH 6 to 8. If necessary, 1N NaOH was used. was used to accurately adjust the desired pH.
그 결과, 도 2에 의할 때, pH-stability 시험에서 SH11037은 pH 5 내지 6의 범위에서 가장 안정함을 확인했다. 이는 점안제로서 비교적 낮은 pH 범위에 속하지만 안자극성을 감안하여도 설정 가능한 pH 범위였다. pH 4.0 이하이거나 pH 7.0 이상일 때 해당 수용액에서의 약물 분해가 급격히 증가하는 pH 의존적인 경향성을 분명히 나타내는 것을 확인했다. 도 1에서 Impurity A의 경우, 비교적 pH 7 이상의 조건에서 SH11037의 에스터 결합이 가수분해되면서 형성되고, 또한 이외의 경로로 Impurity B가 생성되더라도 이 역시 추가적인 에스터 결합 가수분해에 의해서 Impurity A로 전환되었다. Impurity B의 경우, 낮은 pH 조건에서의 주요생성물이며 SH11037의 아마이드 결합이 깨지면서 형성되었다. 기타 특별한 분해생성물은 관찰되지 않았고, 따라서 pH를 규명된 안정한 범위에서 설정하는 것이 점안제의 안정화에 크게 기여할 수 있을 것으로 판단했다.As a result, according to Figure 2, it was confirmed that SH11037 was most stable in the pH range of 5 to 6 in the pH-stability test. Although this falls within a relatively low pH range for an eye drop, it was within a pH range that could be set even considering eye irritation. It was confirmed that the pH-dependent tendency of drug decomposition in the aqueous solution to rapidly increases when pH is below 4.0 or above pH 7.0 is clearly observed. In the case of Impurity A in Figure 1, it was formed by hydrolysis of the ester bond of SH11037 under conditions of relatively pH 7 or higher, and even if Impurity B was generated through another route, it was also converted to Impurity A through additional ester bond hydrolysis. In the case of Impurity B, it is the main product under low pH conditions and is formed when the amide bond of SH11037 is broken. No other special decomposition products were observed, and therefore, it was judged that setting the pH in an identified stable range would greatly contribute to the stabilization of the eye drop.
2. 용해도 평가2. Solubility evaluation
SH11037은 그 구조에서 벤젠고리 구조가 다수 포함되어 있어서 물에 대한 용해도가 불량하고, Log P가 4.82로서 지용성의 특성을 크게 나타낼 것으로 판단되었다. 수난용성이며 지용성을 나타내는 물질을 가용화하여 안전하고 유효한 제형으로는 나노이멀젼 제제가 있으며, 이미 점안제로 상용화된 사례가 있는데, 이러한 나노이멀젼 개발을 위해서는 우선적으로 점안으로 사용가능한 기제를 선정해야 했다. 따라서, 표 2과 같이, 국내에서 점안제로 사용가능한 나노이멀젼 기제를 식약처 및 FDA 데이터 베이스를 검색하여 선정하여 제제개발의 출발로 삼았다.SH11037 has poor solubility in water because it contains many benzene ring structures in its structure, and Log P was 4.82, which was judged to show significant fat-soluble characteristics. Nanoimulsion preparations are safe and effective formulations made by solubilizing substances that are poorly soluble in water and oil-soluble, and have already been commercialized as eye drops. In order to develop such nanoimulsions, a base that can be used as eye drops had to be selected first. Therefore, as shown in Table 2, nanoimulsion bases that can be used as eye drops in Korea were selected by searching the Ministry of Food and Drug Safety and FDA databases and used as a starting point for formulation development.
나노이멀젼 기제 중에는 실온에서 고체 또는 반고형의 상태를 나타내는 것들이 있어서 이들을 녹이고, 최대치의 가용성을 평가하기 위하여 60 ℃ 온수 중탕에서 용해도 평가를 실시했다. 적은 양의 SH11037 양을 고려한 용해도 평가 방법을 사용했는데, 각각의 기제 50 mg을 가온하고, SH11037을 3 mg씩 가하여 녹을 때까지 교반했다. 이 과정을 반복하여 충분히 교반하여도 녹지 않는 시점에 가해진 SH11037의 양을 산출하여 용해도를 계산했다. Among the nanoemulsion bases, some were in a solid or semi-solid state at room temperature, so they were dissolved and solubility was evaluated in a hot water bath at 60°C to evaluate the maximum solubility. A solubility evaluation method considering a small amount of SH11037 was used: 50 mg of each base was heated, 3 mg of SH11037 was added at a time, and stirred until dissolved. This process was repeated and the solubility was calculated by calculating the amount of SH11037 added at the point where it did not dissolve even after sufficient stirring.
그 결과, 도 3에 따를 때, 용해도 평가 결과에서 오일류에서는 O1, O2, O7에서 4 내지 9 중량%의 우수한 용해도를 나타내었으며, 계면활성제에서는 S2가 9 중량%를 나타냄으로 가장 높았고, 다른 계면활성제류도 의미 있는 용해도 값을 나타내는 것을 확인했다.As a result, according to Figure 3, the solubility evaluation results showed excellent solubility of 4 to 9% by weight in O1, O2, and O7 in oils, and in surfactants, S2 showed the highest at 9% by weight, and other surfactants It was confirmed that Ryu also showed meaningful solubility values.
3. 나노이멀젼 구성 및 분산성 평가 (1)3. Nanoimulsion composition and dispersibility evaluation (1)
나노이멀젼을 구성하는 오일 및 계면활성제 조합을 선정하기 위하여 오일 및 계면활성제 24가지 조합을 배합하여 물에 대한 분산성 평가를 실시했다. 이 중, 상분리 없이 안정한 분산성을 나타내며, 200 nm 미만의 평균입자경을 나타내는 나노이멀젼을 나타내는 배합을 선정했다.In order to select the combination of oil and surfactant that constitutes the nanoemulsion, 24 combinations of oil and surfactant were mixed and their dispersibility in water was evaluated. Among these, a formulation showing stable dispersibility without phase separation and nanoimulsion with an average particle diameter of less than 200 nm was selected.
각각의 오일 및 계면활성제의 중량비를 1:3, 2:2 및 3:1의 비율로 변화시켜서 혼합하고, 이 혼합물 100 mg을 취하여 3 mL의 물에 분산시켜 성상을 관찰하고 입자크기를 측정하여 평가했다.The weight ratio of each oil and surfactant was changed and mixed at a ratio of 1:3, 2:2, and 3:1, and 100 mg of this mixture was taken and dispersed in 3 mL of water to observe the properties and measure the particle size. evaluated.
그 결과, 도 4에 따를 때, 총 24종의 평가 결과에서 MCT70 및 Cremophor EL 조합 내지는 Castor Oil 및 Cremophor EL 조합에서 100 nm 보다 작은 균질한 입자크기를 나타내며 안정한 나노이멀젼을 형성하는 것을 확인했다. 하지만, 기존 허가받은 점안제에 대한 사용 가능량에서 Castor Oil 및 Cremophor 조합이 MCT 및 Cremophor EL 조합보다 크기 때문에 가용화 능력 또한 클 것으로 예상되어, 나노이멀젼 제조를 위한 오일 및 계면활성제 조합으로 선정할 수 있었다.As a result, according to Figure 4, it was confirmed that the combination of MCT70 and Cremophor EL or the combination of Castor Oil and Cremophor EL showed a homogeneous particle size smaller than 100 nm and formed a stable nanoemulsion in a total of 24 evaluation results. However, since the combination of Castor Oil and Cremophor is larger than the combination of MCT and Cremophor EL in the amount available for existing approved eye drops, the solubilization ability is also expected to be greater, so it was selected as a combination of oil and surfactant for nanoemulsion production.
4. 나노이멀젼 구성 및 분산성 평가 (2)4. Nanoimulsion composition and dispersibility evaluation (2)
SH11037을 제외한 분산성 및 입자도 평가에서 선정된 오일 및 계면활성제의 조합에 대하여, SH11037을 가하여 60 ℃ (온수중탕)에서 가용화시켜 물을 사용해 분산시켜 침전유무를 평가하여 가용화 수준을 평가했다.For the combination of oil and surfactant selected in the dispersibility and particle size evaluation, excluding SH11037, SH11037 was added and solubilized at 60°C (in a hot water bath), dispersed using water, and the presence or absence of precipitation was evaluated to evaluate the level of solubilization.
그 결과, 표 2에 따를 때, Cremophor EL에서 분산상 기준으로 SH11037을 1.5 중량%까지 가용화 가능하였으며, 분산상의 입자크기도 계면활성제가 70 중량% 이상에서 200 nm보다 작은 평균입자경을 나타내어서, 바람직한 나노이멀젼 구성의 오일 및 계면활성제 조합임을 확인했다.As a result, according to Table 2, it was possible to solubilize up to 1.5% by weight of SH11037 based on the dispersed phase in Cremophor EL, and the particle size of the dispersed phase also showed an average particle diameter smaller than 200 nm at 70% by weight or more of the surfactant, making it a desirable nanomaterial. It was confirmed that it was a combination of oil and surfactant forming a mulsion.
5. 나노이멀젼 구성 기제의 배합성 평가5. Evaluation of compatibility of nanoimulsion composition mechanism
12주 동안 40 ℃ 챔버에서 샘플을 보관하며 HPLC 분석을 통해 기제 및 약물간의 배합적합성 연구를 진행했다.Samples were stored in a chamber at 40°C for 12 weeks, and compatibility between the base and drug was studied through HPLC analysis.
그 결과, 도 5에 따를 때, Cremophor 계열에서 약물의 분해율이 가장 크게 나타났고, TPGS에서 약물이 가장 안정한 것을 확인했다. 또한, 기제별로 약물의 분해율이 다른 요인을 분석하기 위해 샘플 각각의 pH를 측정한 결과, Cremophor 계열을 포함한 샘플의 pH가 7 이상이며, 약물의 분해율이 50 % 이상을 나타낸 것을 확인했다. 반면, 나머지 기제들은 pH 4 내지 6 사이의 범위에 들었고, 약물의 분해율이 4 내지 20 %의 범위를 나타내었다. 이를 통해, 각 기제의 pH 및 약물의 안정성간의 상관성이 매우 크다는 것을 재확인했다. As a result, according to Figure 5, the decomposition rate of the drug was highest in the Cremophor series, and it was confirmed that the drug was most stable in TPGS. In addition, as a result of measuring the pH of each sample to analyze the factors that cause different drug decomposition rates by mechanism, it was confirmed that the pH of the samples including the Cremophor series was over 7 and the drug decomposition rate was over 50%. On the other hand, the remaining substances ranged from pH 4 to 6, and the drug decomposition rate ranged from 4 to 20%. Through this, it was reconfirmed that the correlation between the pH of each base and the stability of the drug is very high.
6. 나노이멀젼 최적 제제 개발 및 점안제 평가결과6. Development of optimal nanoimulsion formulation and eye drop evaluation results
SH11037을 최대로 가용화하고, 분산상이 안정하면서 입자크기가 최소화된 점안제제를 개발하기 위하여 앞서 선정된 나노이멀젼 기제 및 추가로 pH 조절제, 삼투압제, 보존제를 사용하여 30여 가지의 처방을 제조 및 평가하여 상기 표 1의 원약분량표에 따른 SH11037 농도별 (0.5 중량%, 1.0 중량% 및 1.5 중량%) 점안제제 (F18) 후보를 도출했고, 상기 원약분량표 및 상기 실시예의 제조 방법에 따라서 제조된 점안제제에 대해서 중요한 품질특성에 대해서 평가했다. In order to develop an eye drop formulation that maximizes SH11037 solubilization, has a stable dispersion phase, and minimizes particle size, we manufactured and evaluated about 30 formulations using the previously selected nanoemulsion base and additional pH adjusters, osmotic agents, and preservatives. Thus, a candidate eye drop preparation (F18) was derived for each SH11037 concentration (0.5 wt%, 1.0 wt%, and 1.5 wt%) according to the raw drug quantity table in Table 1, and the product was prepared according to the raw drug quantity table and the manufacturing method of the above example. Eye drops were evaluated for important quality characteristics.
그 결과, 도 6에 따를 때, 성상에서 균질하고 안정한 반투명의 콜로이드 나노입자 분산상을 나타내었으며, 주성분 농도가 감소함에 따라서 평균입자크기가 100 nm 부근에서 감소하는 경향을 나타내었다. 점안감과 직결되는 pH는 안정성 시험 결과를 바탕으로 pH 6으로 설정하였는데, 삼투성도 저장성으로 하여 제조하여 230 내지 250 mOsm의 범위를 나타냈다. pH 및 삼투성은 점안제제로서 사용가능한 수준이였다. 보존제 사용으로 인한 배합성 이슈도 없었으며, 무균화를 위한 멸균 여과도 가능하여 무균성의 달성과 유지가 가능했다.As a result, according to Figure 6, a homogeneous and stable translucent colloidal nanoparticle dispersed phase was exhibited, and as the concentration of the main component decreased, the average particle size tended to decrease around 100 nm. The pH, which is directly related to the eye drop, was set to pH 6 based on the stability test results, and the osmosis was also manufactured to be storage, so it was in the range of 230 to 250 mOsm. The pH and osmotic properties were at a level that could be used as an eye drop preparation. There were no mixability issues due to the use of preservatives, and sterilization filtration for sterilization was possible, making it possible to achieve and maintain sterility.
점안제는 최대 1.5 중량%의 농도로 주성분을 가용화할 수 있었으며, 그 이하의 농도에서도 역시 안정하고 균질한 분산상의 점안제제의 제제화가 가능하였다. 주성분 농도에 따라서 평균입자크기가 감소하였고, 삼투압에서는 유의적인 차이를 나타내지 않았고 230 내지 250 mOsm 범위를 나타냈다.The eye drops were able to solubilize the main ingredient at a concentration of up to 1.5% by weight, and even at concentrations lower than that, it was possible to formulate a stable and homogeneously dispersed eye drop preparation. The average particle size decreased depending on the concentration of the main ingredient, and there was no significant difference in osmotic pressure, ranging from 230 to 250 mOsm.
7. 나노이멀젼 점안제 안정성 시험7. Nanoimulsion eye drop stability test
상기 실시예에 의해 제조된 점안제제에서 최대 주성분 농도인 1.5 중량% 점안제제에 대하여 가속조건 (40 ℃)에서 6개월 (24주)동안 보관하며, 주요 항목에 대한 간이 안정성 시험을 실시했다.The eye drop preparation prepared in the above example with a maximum active ingredient concentration of 1.5% by weight was stored under accelerated conditions (40°C) for 6 months (24 weeks), and a simple stability test was conducted on major items.
그 결과, 도 7에 의할 때, 시험기간 동안 입자크기가 증가하고, 액성이 낮은 수준으로 산성화되는 경향성을 나타내었지만 안정성에 크게 영향을 미치는 수준은 아니며 설정 범위에 따라서 충분히 기준에 적합하다고 판단했다.As a result, according to Figure 7, the particle size increased during the test period and the liquid tended to acidify to a low level, but it was not at a level that significantly affected stability and was judged to sufficiently meet the standards according to the setting range. .
분해생성물 평가에서 주성분 피크 (%)가 6개월 동안 7 % 순감소 하였으나, 대부분 기지의 상기 표 1의 Impurity A 및 Impurity B로 분해되는 것이며, 이 정도 피크면적 감소는 유효기간 확보에 긍정적이며, Impurity A 및 Impurity B는 기지의 물질로서 독성 측면에서 뒷받침되면 그 기준한도를 상향할 수 있을 것으로 판단했다. 6개월간 특이적 침전이나 성상변화는 관찰되지 않았고, 미생물의 오염과 증식도 관찰되지 않았다. 아직 후보물질 평가단계 이지만 상용화를 위한 기본 중요 품질 특성을 갖춘 것으로 볼 수 있었다.In the evaluation of decomposition products, the main component peak (%) decreased by a net of 7% over 6 months, but most of them are decomposed into Impurity A and Impurity B in Table 1 above, and this level of reduction in peak area is positive for securing the shelf life, and Impurity As A and Impurity B are known substances, it was judged that the standard limit could be raised if supported in terms of toxicity. No specific precipitation or change in properties was observed for 6 months, and no contamination or growth of microorganisms was observed. Although it is still in the candidate evaluation stage, it can be seen as having basic important quality characteristics for commercialization.
[시험예 2] 다른 수난용성 약물에 대한 적용[Test Example 2] Application to other poorly water-soluble drugs
SH11037을 적용한 상기 실시예에 따른 점안제제를 다른 후보물질인 SH-17040, SH-17059, SH-19021, SHA-032, SHA-034 및 SH-17060에 적용하여 가용화및 제제화 특성에 대해서 평가했다. The eye drop preparation according to the above example using SH11037 was applied to other candidate substances SH-17040, SH-17059, SH-19021, SHA-032, SHA-034, and SH-17060 and evaluated for solubilization and formulation characteristics.
그 결과, 표 4에 의할 때, 제시된 후보물질들은 1.5 중량%의 농도까지 가용화 할 수 있음을 확인했다. 제조상에서 특이 사항이 없이 SH11037 제제를 확대 적용할 수 있었다.As a result, according to Table 4, it was confirmed that the presented candidate substances could be solubilized up to a concentration of 1.5% by weight. The SH11037 formulation could be expanded and applied without any unusual manufacturing issues.
ELCremophor
EL
ChlorideBenzalkonium
Chloride
(in 수상)D.W.
(in award)
또한, 상기 실시예와 동일한 첨가제 분량과 제조방법에 따라서 제조하여 주요 품질항목에 대하여 평가한 결과, 도 8에 의할 때, 분산 시에 침전 없이 안정하고 균일한 분산상을 얻을 수 있었고, 삼투성도 조절되었고, 평균입자크기도 모두 100 nm 이내의 값을 나타냈다. In addition, as a result of evaluating the main quality items by manufacturing according to the same additive amount and manufacturing method as in the above example, as shown in Figure 8, a stable and uniform dispersion phase was obtained without precipitation during dispersion, and osmosis was also controlled. and the average particle size was all within 100 nm.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The above description of the present invention is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.
Claims (11)
상기 pH는 4.5 내지 6.5인 것을 특징으로 하고,
상기 수난용성 약물은 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-부틸)3-(2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐)피페리딘-1,3-디카르복실레이트 (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페놀 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5-((6-(사이클로프로필메톡시)-5,7-디메톡시크로만-3-일)메틸)-2-메톡시페놀 (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol), 부틸((2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페녹시)카보닐)글리신 (butyl((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(1-벤질피페리딘-4-일)카바메이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate) 및 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate)로 이루어진 군에서 선택되는 하나이고,
상기 조성물은 오일 및 계면활성제를 1:(1~3)의 중량비율로 포함하며,
상기 조성물의 평균입자경은 20 내지 300 nm인 것을 특징으로 하는 pH 의존적 나노이멀젼 조성물.poorly water-soluble drugs; Oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; TPGS (d-α-tocopheryl-polyethylene Glycol 1000 Succinate) surfactant; A surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; and purified water as a pH-dependent nanoemulsion composition,
The pH is characterized in that it is 4.5 to 6.5,
The poorly water-soluble drug is 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal. Laninate (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-butyl)3- (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate (1-( tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-methoxy-5 -((5,6,7-trimethoxychroman-3-yl)methyl)phenol (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5- ((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3 -yl)methyl)-2-methoxyphenol), butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycine (butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate) mann-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1- benzylpiperidin-4-yl)carbamate) and 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal It is one selected from the group consisting of 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate),
The composition includes oil and surfactant in a weight ratio of 1:(1-3),
A pH-dependent nanoemulsion composition, characterized in that the average particle diameter of the composition is 20 to 300 nm.
(b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계;
(c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및
(d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법으로,
상기 오일류는 MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)이고,
상기 계면활성제는 TPGS (d-α-tocopheryl-polyethylene Glycol 1000 Succinate) 계면활성제 및 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)이고,
상기 수난용성 약물은 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-부틸)3-(2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐)피페리딘-1,3-디카르복실레이트 (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페놀 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5-((6-(사이클로프로필메톡시)-5,7-디메톡시크로만-3-일)메틸)-2-메톡시페놀 (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol), 부틸((2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페녹시)카보닐)글리신 (butyl((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(1-벤질피페리딘-4-일)카바메이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate) 및 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate)로 이루어진 군에서 선택되는 하나인 것을 특징으로 하는 pH 의존적 나노이멀젼 조성물 제조방법.(a) mixing oil and surfactant at a weight ratio of 1:1 to 3, then adding and dissolving a poorly water-soluble drug at 55 to 65°C to prepare an oil phase;
(b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative, and water, and then adding a pH adjuster to adjust the pH to 4.5 to 6;
(c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and
(d) sterilizing the dispersed phase of step (c); a method for producing a pH-dependent nanoemulsion composition, comprising:
The oils are MCT (Medium Chain Triglyceride) or Castor Oil,
The surfactant is TPGS (d-α-tocopheryl-polyethylene Glycol 1000 Succinate) surfactant and Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil,
The poorly water-soluble drug is 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal. Laninate (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-butyl)3- (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate (1-( tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-methoxy-5 -((5,6,7-trimethoxychroman-3-yl)methyl)phenol (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5- ((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3 -yl)methyl)-2-methoxyphenol), butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycine (butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate) mann-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1- benzylpiperidin-4-yl)carbamate) and 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal pH dependent, characterized in that it is selected from the group consisting of 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate) Method for producing nanoimulsion composition.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210171437A KR102650566B1 (en) | 2021-12-03 | 2021-12-03 | Ocular nanoemulsion composition for the treatment of macular degeneration |
| PCT/KR2022/017681 WO2023101252A1 (en) | 2021-12-03 | 2022-11-11 | Ophthalmic nanoemulsion composition for treating macular degeneration and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210171437A KR102650566B1 (en) | 2021-12-03 | 2021-12-03 | Ocular nanoemulsion composition for the treatment of macular degeneration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20230083444A KR20230083444A (en) | 2023-06-12 |
| KR102650566B1 true KR102650566B1 (en) | 2024-03-26 |
Family
ID=86612741
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020210171437A KR102650566B1 (en) | 2021-12-03 | 2021-12-03 | Ocular nanoemulsion composition for the treatment of macular degeneration |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR102650566B1 (en) |
| WO (1) | WO2023101252A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7443592B2 (en) * | 2002-08-29 | 2008-10-28 | Genie Lens Technologies, Llc | Visual effect apparatus for displaying interlaced images using block out grids |
| KR101492447B1 (en) * | 2013-05-20 | 2015-02-23 | 주식회사태준제약 | Eye composition containing a cyclosporine and a method of preparing the same |
| KR20170120161A (en) * | 2015-03-05 | 2017-10-30 | 알러간, 인코포레이티드 | Self-emulsifying drug delivery system (SEDDS) for ophthalmic drug delivery |
| KR101806681B1 (en) | 2015-04-15 | 2017-12-07 | 아주대학교산학협력단 | Biomarker composition for diagnosing still's diseases, diagnosing kit, and diagnosing method |
| EP4349327A2 (en) * | 2018-08-28 | 2024-04-10 | Cloudbreak Therapeutics, LLC | Emulsion formulations of multikinase inhibitors |
| KR102435238B1 (en) * | 2019-04-24 | 2022-08-23 | 가천대학교 산학협력단 | chromane derivatives, and pharmaceutical composition for preventing or treating neovascular eye disease or cancer containing the same as an active ingredient |
-
2021
- 2021-12-03 KR KR1020210171437A patent/KR102650566B1/en active IP Right Grant
-
2022
- 2022-11-11 WO PCT/KR2022/017681 patent/WO2023101252A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023101252A1 (en) | 2023-06-08 |
| KR20230083444A (en) | 2023-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11819491B2 (en) | Dilutable formulations of cannabinoids and processes for their preparation | |
| US8357380B2 (en) | Coenzyme Q10-containing composition | |
| JPH11514221A (en) | New process | |
| WO2006035900A1 (en) | Coenzyme q10-containing emulsified composition | |
| CN107970208B (en) | Butylphthalide injection and preparation method thereof | |
| WO2006030850A1 (en) | Method of preparing solution of lipid-soluble ingredient | |
| JP6459206B2 (en) | Superabsorbent ubiquinol formulation | |
| KR20100135316A (en) | Liquid formulation for deferiprone with palatable taste | |
| WO2014188861A1 (en) | Gel-like composition having high ubiquinol content | |
| KR20200089785A (en) | Antimicrobial emulsion compositon comprising yuja seed oil and yuja juice as an active ingredient, use thereof and method preparing the same | |
| JP3870740B2 (en) | Ceramide dispersion, production method and application | |
| KR102650566B1 (en) | Ocular nanoemulsion composition for the treatment of macular degeneration | |
| US11957709B2 (en) | Oxygen gas sustained released nano-emulsion composition and method for producing the same | |
| CN114522142A (en) | Nano stabilizer and preparation method and application thereof | |
| JP4117119B2 (en) | Fat-soluble substance solubilizing solution | |
| WO2007080787A1 (en) | Coenzyme q10-containing water-soluble compositions | |
| AU2012236355A1 (en) | Menthol liquids composition | |
| EP2452577B1 (en) | Aqueous solution of phytin and use of said solution for preparing a liquid food supplement or a cosmetic composition | |
| JPH0698729A (en) | Ginseng extract-containing beverage and its production | |
| US20230000734A1 (en) | Nano-emulsion composition for tooth whitening and method for producing the same | |
| KR102300737B1 (en) | A Composition for Solubilizing Alpinumisoflavone and Uses Thereof | |
| JPH01221312A (en) | Oral liquid containing fat-soluble substance | |
| JP2002176936A (en) | Royal jelly-formulated liquid and drink | |
| KR20230000401A (en) | Nano-emulsion composition for tooth whitening and method for producing the same | |
| KR20220096718A (en) | Donepezil jelly preparation comprising donepezil or pharmaceutically acceptable salts thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |