KR20240149552A - High-content ceramide composition with excellent water dispersibility - Google Patents
High-content ceramide composition with excellent water dispersibility Download PDFInfo
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- KR20240149552A KR20240149552A KR1020230045220A KR20230045220A KR20240149552A KR 20240149552 A KR20240149552 A KR 20240149552A KR 1020230045220 A KR1020230045220 A KR 1020230045220A KR 20230045220 A KR20230045220 A KR 20230045220A KR 20240149552 A KR20240149552 A KR 20240149552A
- Authority
- KR
- South Korea
- Prior art keywords
- composition
- ceramide
- glycero
- paragraph
- lipid
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 100
- 229940106189 ceramide Drugs 0.000 title claims abstract description 86
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 title claims abstract description 72
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 title claims abstract description 72
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 title claims abstract description 72
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 title claims abstract description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 16
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 150000002632 lipids Chemical class 0.000 claims description 39
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 23
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 claims description 21
- -1 anionic lipid Chemical class 0.000 claims description 19
- 239000002105 nanoparticle Substances 0.000 claims description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 13
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 13
- 230000007935 neutral effect Effects 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 125000000129 anionic group Chemical group 0.000 claims description 10
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 5
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 claims description 5
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- PAZGBAOHGQRCBP-ZCXUNETKSA-N 1-Palmitoyl-2-oleoylglycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-ZCXUNETKSA-N 0.000 claims description 4
- ZLGYVWRJIZPQMM-HHHXNRCGSA-N 2-azaniumylethyl [(2r)-2,3-di(dodecanoyloxy)propyl] phosphate Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCC ZLGYVWRJIZPQMM-HHHXNRCGSA-N 0.000 claims description 4
- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- WLNARFZDISHUGS-MIXBDBMTSA-N cholesteryl hemisuccinate Chemical compound C1C=C2C[C@@H](OC(=O)CCC(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 WLNARFZDISHUGS-MIXBDBMTSA-N 0.000 claims description 4
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 claims description 4
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 claims description 4
- BPHQZTVXXXJVHI-AJQTZOPKSA-N ditetradecanoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-AJQTZOPKSA-N 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 150000003408 sphingolipids Chemical class 0.000 claims description 4
- FHQVHHIBKUMWTI-OTMQOFQLSA-N {1-hexadecanoyl-2-[(Z)-octadec-9-enoyl]-sn-glycero-3-phospho}ethanolamine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC FHQVHHIBKUMWTI-OTMQOFQLSA-N 0.000 claims description 4
- WKJDWDLHIOUPPL-JSOSNVBQSA-N (2s)-2-amino-3-({[(2r)-2,3-bis(tetradecanoyloxy)propoxy](hydroxy)phosphoryl}oxy)propanoic acid Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCC WKJDWDLHIOUPPL-JSOSNVBQSA-N 0.000 claims description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 3
- KLFKZIQAIPDJCW-HTIIIDOHSA-N Dipalmitoylphosphatidylserine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-HTIIIDOHSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229960003330 pentetic acid Drugs 0.000 claims description 3
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 2
- MWRBNPKJOOWZPW-NYVOMTAGSA-N 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-NYVOMTAGSA-N 0.000 claims description 2
- OZSITQMWYBNPMW-GDLZYMKVSA-N 1,2-ditetradecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCC OZSITQMWYBNPMW-GDLZYMKVSA-N 0.000 claims description 2
- HKJAWHYHRVVDHK-UHFFFAOYSA-N 15,16,17-trihydroxyhentriacontane-14,18-dione Chemical compound CCCCCCCCCCCCCC(=O)C(O)C(O)C(O)C(=O)CCCCCCCCCCCCC HKJAWHYHRVVDHK-UHFFFAOYSA-N 0.000 claims description 2
- ASISUQQISDMBAP-UHFFFAOYSA-N 2-(heptadecanoylcarbamoyl)heptadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(=O)NC(=O)C(C(O)=O)CCCCCCCCCCCCCCC ASISUQQISDMBAP-UHFFFAOYSA-N 0.000 claims description 2
- XLPHMKQBBCKEFO-DHYROEPTSA-N 2-azaniumylethyl [(2r)-2,3-bis(3,7,11,15-tetramethylhexadecanoyloxy)propyl] phosphate Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CC(C)CCCC(C)CCCC(C)CCCC(C)C XLPHMKQBBCKEFO-DHYROEPTSA-N 0.000 claims description 2
- 241000287828 Gallus gallus Species 0.000 claims description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 2
- RWKUXQNLWDTSLO-GWQJGLRPSA-N N-hexadecanoylsphingosine-1-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)N[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)[C@H](O)\C=C\CCCCCCCCCCCCC RWKUXQNLWDTSLO-GWQJGLRPSA-N 0.000 claims description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims description 2
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 claims description 2
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- 229960004502 levodopa Drugs 0.000 claims description 2
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- ZUVCYFMOHFTGDM-UHFFFAOYSA-N hexadecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(O)=O ZUVCYFMOHFTGDM-UHFFFAOYSA-N 0.000 claims 1
- 150000001783 ceramides Chemical class 0.000 abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 9
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- 230000000052 comparative effect Effects 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
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- VJSBNBBOSZJDKB-KPEYJIHVSA-N N-(15Z)-tetracosenoylsphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@H](CO)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC VJSBNBBOSZJDKB-KPEYJIHVSA-N 0.000 description 6
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
소수성 세라마이드는 수용액에서의 용해도가 극히 낮아서 사용이 제한적이었고, 이를 약물로 사용해도 세포 전달성이 낮았다. 본 발명은 수분산성이 우수한 고함량 세라마이드 조성물을 제공하기에, 본 발명을 통해 고용량의 소수성 세라마이드를 체내 타겟으로 용이하게 전달함으로써 목적하는 바에 따라 수분산성이 높은 약물 전달체, 약학 조성물로의 활용도를 높일 수도 있다. Hydrophobic ceramides have extremely low solubility in aqueous solutions, so their use has been limited, and even when used as drugs, their cell delivery properties have been low. The present invention provides a high-content ceramide composition with excellent water dispersibility, and thus, by easily delivering a high dose of hydrophobic ceramide to a target in the body through the present invention, the utility of the composition as a drug delivery vehicle or pharmaceutical composition with high water dispersibility can be increased depending on the intended purpose.
Description
본 발명은 알콜 등의 용매를 전혀 사용하지 않고 소수성 세라마이드를 수용액에 분산할 수 있는 수분산성이 우수한 세라마이드 조성물에 관한 것으로서, 상기 세라마이드 조성물은 수용액에 고형분으로 10중량%까지 분산되는 것을 특징으로 하는 수분산성이 우수한 세라마이드 조성물에 관한 것이다. The present invention relates to a ceramide composition having excellent water dispersibility, which can disperse hydrophobic ceramide in an aqueous solution without using any solvent such as alcohol, and is characterized in that the ceramide composition is dispersed in an aqueous solution in a solid content of up to 10 wt%.
세라마이드는 스핑고신과 다양한 사슬 길이의 지방산으로 구성된 스핑고리피드이다. 일반적으로 세라마이드의 내인성 형태는 동물 세포에서 다양한 탄소 길이의 장쇄 탄소 사슬 길이로 구성된다. 동물 세포에는 6가지 유형의 세라마이드 합성효소가 존재하는데, 이는 특정 길이의 지방 아실 CoA를 장쇄 염기에 부착하여 세라마이드, 스핑고미엘린 및 글리코스핑고리피드를 포함한 스핑고리피드의 아실 사슬 길이를 결정하는 역할을 한다. Ceramides are sphingolipids composed of sphingosine and fatty acids of various chain lengths. The endogenous form of ceramides is usually composed of long carbon chains of various carbon lengths in animal cells. Six types of ceramide synthases exist in animal cells, which are responsible for attaching fatty acyl CoA of specific lengths to long-chain bases to determine the acyl chain length of sphingolipids, including ceramides, sphingomyelins, and glycosphingolipids.
탄소 사슬 길이에 따라 나뉘는 세라마이드는 다양한 세포 과정을 조절하는 활성 신호 분자로 작용할 수 있다. 그 중에서도 특히, 소수성을 갖는 장쇄 세라마이드는 세라마이드 합성효소 2에 의해 합성된다. 세라마이드는 주로 피부조직 지질층의 약 50%를 차지하는 주요성분으로 지질장벽 구조유지 역할을 하며, 성분에 따라 세포의 성장/증식을 촉진시키거나 암세포를 사멸하여 항암제로 이용하는 것으로도 알려져 있다. 그러나 이러한 세라마이드는 수용액 상에서 용해도가 극도로 낮기 때문에 에탄올 등의 유기용매에 용해시켜 적용할 수밖에 없기 때문에 세라마이드가 갖는 강력한 세포 증식/사멸 효능에도 불구하고 수분상 형태의 다양한 제품으로의 적용이 극히 제한적이다. Ceramides, which are divided by carbon chain length, can act as active signaling molecules that regulate various cellular processes. In particular, long-chain ceramides with hydrophobicity are synthesized by ceramide synthase 2. Ceramides are major components that account for about 50% of the lipid layer of skin tissue and play a role in maintaining the lipid barrier structure. Depending on the component, they are also known to promote cell growth/proliferation or kill cancer cells and be used as anticancer agents. However, since these ceramides have extremely low solubility in aqueous solutions, they can only be dissolved in organic solvents such as ethanol and applied. Therefore, despite the strong cell proliferation/death efficacy of ceramides, their application in various products in aqueous form is extremely limited.
이러한 점에서 수용해성이 극히 떨어지는 장쇄 사슬을 갖는 세라마이드를 수분산시키며, 장기간 안정적으로 분산된 상태로 유지하여 이를 활용할 수 있는 방안이 절실히 필요한 실정이다. In this regard, there is an urgent need for a method to disperse ceramides with long chains that have extremely low water solubility and to maintain them in a stable dispersed state for a long period of time so that they can be utilized.
본 발명의 목적은 알콜 등의 용매를 전혀 사용하지 않고 소수성 세라마이드를 수용액에 분산할 수 있는 수분산성이 우수한 세라마이드 조성물을 제공하는 데에 있으며, 상기 세라마이드 조성물은 수용액에 고형분으로 10중량%까지 분산되는 것을 특징으로 한다. The purpose of the present invention is to provide a ceramide composition having excellent water dispersibility capable of dispersing hydrophobic ceramide in an aqueous solution without using any solvent such as alcohol, and the ceramide composition is characterized in that it is dispersed in an aqueous solution in a solid content of up to 10 wt%.
본 발명은 수용액에 분산된 소수성 세라마이드를 포함하는 수분산성 제형을 갖는 조성물에 관한 것으로서, 상기 조성물은 음이온성 지질, 중성 지질 및 콜레스테롤을 포함하는 것을 특징으로 한다. The present invention relates to a composition having a water-dispersible formulation comprising a hydrophobic ceramide dispersed in an aqueous solution, wherein the composition is characterized in that it comprises anionic lipids, neutral lipids and cholesterol.
상기 소수성 세라마이드는 전체 조성물에 40 mol% 이상 포함될 수 있고, 60 mol% 이하로 포함되는 것이 바람직하다. The above hydrophobic ceramide may be included in an amount of 40 mol% or more in the entire composition, and is preferably included in an amount of 60 mol% or less.
상기 음이온성 지질은 전체 조성물에 3 내지 7 mol%를 포함될 수 있다. The anionic lipid may be included in an amount of 3 to 7 mol% in the total composition.
상기 중성 지질은 전체 조성물에 7 내지 10 mol%, 콜레스테롤은 전체 조성물에 30 내지 50 mol%를 포함하는 것이 특징이다. The neutral lipid is characterized in that it comprises 7 to 10 mol% of the total composition, and cholesterol comprises 30 to 50 mol% of the total composition.
상기 조성물은 수용액에 고형분으로 10중량% 이하가 포함될 수 있다. The above composition may contain 10 wt% or less of solid content in an aqueous solution.
상기 소수성 세라마이드는 하기 화학식 1의 구조를 갖는 것이 특징이다. The above hydrophobic ceramide is characterized by having a structure represented by the following chemical formula 1.
[화학식 1][Chemical Formula 1]
(상기 화학식 1에서 R1은 탄소수가 17 내지 30개의 포화 또는 불포화 지방족 사슬이고, R2는 수산기가 있거나 없는 탄소수가 10 내지 20개의 포화 또는 불포화 지방족 사슬이다.) (In the above chemical formula 1, R 1 is a saturated or unsaturated aliphatic chain having 17 to 30 carbon atoms, and R 2 is a saturated or unsaturated aliphatic chain having 10 to 20 carbon atoms with or without a hydroxyl group.)
상기 중성 지질은 HSPC(hydrogenated soy phosphatidylcholine), DOPC(1,2-dioleoyl-sn-glycero-3-phosphocholine), POPE(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), DSPC(1,2-distearoyl-sn-glycero-3-phosphocholine), DSPE(1,2-distearoyl-sn-glycero-3-phosphoethanolamine), DPPC(1,2-dipalmitoyl-sn-glycero-3-phosphocholine), POPC(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), DOPE(1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), SM(N-palmitoyl-D-erythro-sphingosylphosphorylcholine), DLPE(1,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPE(1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine), 포스파티딜 콜린(phosphatidyl choline), 디미리스톨글리세롤(dimyristoylglycerol), 석시노일 디아글리세롤(succinoyl-diacylglycerol), 포스파티딜 에탄올아민(phosphatidyl ethanolamine), 테트라에테르 리피드(tetraether lipid), 스핑고리피드(sphingolipid), 디아크릴 글리세롤(diacryl glycerol) 및 글리세리드(glyceride)로 이루어진 군으로부터 선택된 어느 하나 이상을 포함할 수 있다. The neutral lipids include HSPC (hydrogenated soy phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), and DSPC (1 ,2-distearoyl-sn-glycero-3-phosphocholine), DSPE(1,2-distearoyl-sn-glycero-3-phosphoethanolamine), DPPC(1,2-dipalmitoyl-sn-glycero-3-phosphocholine), POPC( 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), SM (N-palmitoyl-D-erythro-sphingosylphosphorylcholine), DLPE(1,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPE(1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine), phosphatidyl choline, dimyristoylglycerol, A compound selected from the group consisting of succinoyl-diacylglycerol, phosphatidyl ethanolamine, tetraether lipid, sphingolipid, diacryl glycerol and glyceride. It may include one or more of the following:
상기 음이온성 지질은 DSPG(1,2-distearoyl-sn-glycero-3-phosphatidylglycerol), SOPG(1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol), Soy PG(L-α-phosphatidylglycerol (Soy)), Egg PG(L-α-phosphatidylglycerol (Egg, Chicken)), DLPG(1,2-dilauroyl-sn-glycero-3-phosphatidylglycerol), Cardiolipin(1',3'-bis[1,2-dioleoyl-sn-glycero-3-phospho]-glycerol), DMPG(dimyristoylphosphatidylglycerol), DPPG(dipalmitoylphosphatidylglycerol), DOPG(dioleoylphosphatidylglycerol), POPG(palmitoyloleoylphosphatidylglycerol), DOPS(dioleoylphosphatidylserine), DTPA(diethylenetriamine pentaacetic acid), DPTGA(1,4-dipalmitoyl-tartarate-2,3-diglutaric acid), DSTSA(1,4-disteroyl-tartarate-2,3-disuccinic acid), CHHDA(2-carboxyheptadecanoyl heptadecylamide), DMPS(dimyristoylphosphatidylserine), DPPS(dipalmitoylphosphatidylserine), POPS(palmitoyloleoylphosphatidylserine), DMPA(dimyristoylphosphatidic acid), DPPA(dipalmitoylphosphatidic acid), DOPA(dioleoylphosphatidic acid), POPA(palmitoyl-oleoylphosphatidic acid), CetylP(Cetyl phosphate) 및 CHEMS(cholesterol hemisuccinate)로 이루어진 군으로부터 선택된 어느 하나 이상을 포함하는 지질인 것을 특징으로 한다. The anionic lipids include DSPG (1,2-distearoyl-sn-glycero-3-phosphatidylglycerol), SOPG (1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol), Soy PG (L-α-phosphatidylglycerol ( Soy)), Egg PG (L-α-phosphatidylglycerol (Egg, Chicken)), DLPG (1,2-dilauroyl-sn-glycero-3-phosphatidylglycerol), Cardiolipin (1',3'-bis[1,2- dioleoyl-sn-glycero-3-phospho]-glycerol), DMPG (dimyristoylphosphatidylglycerol), DPPG (dipalmitoylphosphatidylglycerol), DOPG (dioleoylphosphatidylglycerol), POPG (palmitoyloleoylphosphatidylglycerol), DOPS(dioleoylphosphatidylserine), DTPA(diethylenetriamine pentaacetic acid), DPTGA(1,4-dipalmitoyl-tartarate-2,3-diglutaric acid), DSTSA(1,4-disteroyl-tartarate-2,3-disuccinic acid), CHHDA( 2-carboxyheptadecanoyl heptadecylamide, DMPS(dimyristoylphosphatidylserine), DPPS(dipalmitoylphosphatidylserine), POPS(palmitoyloleoylphosphatidylserine), DMPA(dimyristoylphosphatidic acid), DPPA(dipalmitoylphosphatidic acid), DOPA(dioleoylphosphatidic acid), POPA(palmitoyl-oleoylphosphatidic acid), CetylP(Cetyl It is characterized by being a lipid comprising at least one selected from the group consisting of phosphate (CHEP) and CHEMS (cholesterol hemisuccinate).
상기 세라마이드 조성물은 지질 나노입자, 나노리포좀 또는 에멀전일 수 있다. The above ceramide composition may be a lipid nanoparticle, a nanoliposome or an emulsion.
상기 화학식 1의 구조를 갖는 소수성 세라마이드는, The hydrophobic ceramide having the structure of the above chemical formula 1 is
N-스테아로일-에리트로-스핑고신 (N-stearoyl-erythro-sphingosine) 계열의 화합물 또는 이의 유도체; A compound of the N-stearoyl-erythro-sphingosine series or a derivative thereof;
N-올레오일-에리트로-스핑고신 (N-Oleoyl-erythro-sphingosine) 계열의 화합물; Compounds of the N-oleoyl-erythro-sphingosine series;
N-스테아로일-에리트로-스핑가닌 (N-stearoyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체; A compound of the N-stearoyl-erythro-sphinganine series or a derivative thereof;
N-올레오일-에리트로-스핑가닌 (N-oleoyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체; A compound of the N-oleoyl-erythro-sphinganine series or a derivative thereof;
N-네르보노일-에리트로-스핑고신 (N-Nervonoyl-erythro-sphingosine) 계열의 화합물 또는 이의 유도체; A compound of the N-Nervonoyl-erythro-sphingosine series or a derivative thereof;
N-리그노세로일-에리트로-스핑고신 (N-Lignoceroyl-erythro-sphingosine) 계열의 화합물 또는 이의 유도체; A compound of the N-lignoceroyl-erythro-sphingosine series or a derivative thereof;
N-네르보노일-에리트로-스핑가닌 (N-nervonoyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체; 및, Compounds of the N-nervonoyl-erythro-sphinganine series or derivatives thereof; and
N-리그노세로일-에리트로-스핑가닌 (N-lignoceroyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체;A compound of the N-lignoceroyl-erythro-sphinganine series or a derivative thereof;
중에서 선택되는 화합물일 수 있다. It may be a compound selected from among:
상기 N-스테아로일-에리트로-스핑고신 (N-stearoyl-erythro-sphingosine) 계열의 화합물 또는 이의 유도체는, The above N-stearoyl-erythro-sphingosine series compound or derivative thereof,
(E)-N-(1,3-디히드록시옥타데크-4-엔-2-일)스테아르아미드 ((E)-N-(1,3-dihydroxyoctadec-4-en-2-yl)stearamide) 또는 이의 유도체이거나, (E)-N-(1,3-dihydroxyoctadec-4-en-2-yl)stearamide or a derivative thereof,
(E)-N-(1,3-디히드록시헵타데크-4-엔-2-일)스테아르아미드 ((E)-N-(1,3-dihydroxyheptadec-4-en-2-yl)stearamide) 또는 이의 유도체일 수 있다. It may be (E)-N-(1,3-dihydroxyheptadec-4-en-2-yl)stearamide or a derivative thereof.
상기 N-올레오일-에리트로-스핑고신 (N-Oleoyl-erythro-sphingosine) 계열의 화합물 또는 이의 유도체는, The above N-oleoyl-erythro-sphingosine series compound or derivative thereof,
N-((E)-1,3-디히드록시옥타데크-4-엔-2-일)올레아미드 (N-((E)-1,3-dihydroxyoctadec-4-en-2-yl)oleamide) 또는 이의 유도체이거나, N-((E)-1,3-dihydroxyoctadec-4-en-2-yl)oleamide or a derivative thereof,
N-((E)-1,3-디히드록시헵타데크-4-엔-2-일)올레아미드 (N-((E)-1,3-dihydroxyheptadec-4-en-2-yl)oleamide) 또는 이의 유도체일 수 있다. It may be N-((E)-1,3-dihydroxyheptadec-4-en-2-yl)oleamide or a derivative thereof.
상기 N-스테아로일-에리트로-스핑가닌 (N-stearoyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체는,The above N-stearoyl-erythro-sphinganine series compound or derivative thereof,
N-(1,3-디히드록시옥타데칸-2-일)스테아르아미드 (N-(1,3-dihydroxyoctadecan-2-yl)stearamide) 또는 이의 유도체일 수 있다. It may be N-(1,3-dihydroxyoctadecan-2-yl)stearamide or a derivative thereof.
상기 N-올레오일-에리트로-스핑가닌 (N-oleoyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체는, The above N-oleoyl-erythro-sphinganine series compound or derivative thereof,
N-(1,3-히드로옥시옥타데칸-2-일)올레아미드 (N-(1,3-dihydroxyoctadecan-2-yl)oleamide) 또는 이의 유도체일 수 있다. It may be N-(1,3-dihydroxyoctadecan-2-yl)oleamide or a derivative thereof.
상기 N-네르보노일-에리트로-스핑고신 (N-Nervonoyl-erythro-sphingosine) 계열의 화합물 또는 이의 유도체는, The above N-Nervonoyl-erythro-sphingosine series compound or derivative thereof,
(Z)-N-((4E,8Z)-1,3-디히드록시옥타데카-4,8-디엔-2-일)테트라코스-15-엔아미드(Z)-N-((4E,8Z)-1,3-dihydroxyoctadeca-4,8-dien-2-yl)tetracos-15-enamide
((Z)-N-((4E,8Z)-1,3-dihydroxyoctadeca-4,8-dien-2-yl)tetracos-15-enamide) 또는 이의 유도체, ((Z)-N-((4E,8Z)-1,3-dihydroxyoctadeca-4,8-dien-2-yl)tetracos-15-enamide) or a derivative thereof,
(Z)-N-((E)-1,3-디히드록시헵타데크-4-엔-2-일)테트라코스-15-엔아미드 ((Z)-N-((E)-1,3-dihydroxyheptadec-4-en-2-yl)tetracos-15-enamide) 또는 이의 유도체,(Z)-N-((E)-1,3-dihydroxyheptadec-4-en-2-yl)tetracos-15-enamide or a derivative thereof,
(Z)-N-((E)-1,3-디히드록시옥타데크-4-엔-2-일)테트라코스-15-엔아미드(Z)-N-((E)-1,3-dihydroxyoctadec-4-en-2-yl)tetracos-15-enamide
((Z)-N-((E)-1,3-dihydroxyoctadec-4-en-2-yl)tetracos-15-enamide) 또는 이의 유도체일 수 있다. ((Z)-N-((E)-1,3-dihydroxyoctadec-4-en-2-yl)tetracos-15-enamide) or a derivative thereof.
상기 N-리그노세로일-에리트로-스핑고신 (N-Lignoceroyl-erythro-sphingosine) 계열의 화합물 또는 이의 유도체는, The above N-Lignoceroyl-erythro-sphingosine series compound or derivative thereof,
N-((4E,8Z)-1,3-디히드록시옥타데카-4,8-디엔-2-일)테트라코산아미드 (N-((4E,8Z)-1,3-dihydroxyoctadeca-4,8-dien-2-yl)tetracosanamide) 또는 이의 유도체,N-((4E,8Z)-1,3-dihydroxyoctadeca-4,8-dien-2-yl)tetracosanamide or a derivative thereof,
(E)-N-(1,3-디히드록시헵타데크-4-엔-2-일)테트라코산아미드 ((E)-N-(1,3-dihydroxyoctadec-4-en-2-yl)tetracosanamide) 또는 이의 유도체일 수 있다. (E)-N-(1,3-dihydroxyheptadec-4-en-2-yl)tetracosanamide or a derivative thereof.
상기 N-네르보노일-에리트로-스핑가닌 (N-nervonoyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체는, The above N-nervonoyl-erythro-sphinganine series compound or derivative thereof,
(Z)-N-(1,3-디히드록시옥타데칸-2-일)테트라코스-15-엔아미드 ((Z)-N-(1,3-dihydroxyoctadecan-2-yl)tetracos-15-enamide) 또는 이의 유도체일 수 있다. It may be (Z)-N-(1,3-dihydroxyoctadecan-2-yl)tetracos-15-enamide or a derivative thereof.
상기 N-리그노세로일-에리트로-스핑가닌 (N-lignoceroyl-erythro-sphinganine) 계열의 화합물 또는 이의 유도체는, The above N-lignoceroyl-erythro-sphinganine series compound or derivative thereof,
N-(1,3-디하이드로옥시옥타데칸-2-일)테트라코산아미드 (N-(1,3-dihydroxyoctadecan-2-yl)tetracosanamide) 또는 이의 유도체일 수 있다. It may be N-(1,3-dihydroxyoctadecan-2-yl)tetracosanamide or a derivative thereof.
상기 콜레스테롤은 상기 지질 나노입자 내에서 지질 충전에 형태적 측면에서 견고성을 부여하며, 나노입자의 코어 및 표면에 분산되어 나노입자의 안정성을 향상시키는 역할을 한다. The above cholesterol provides morphological rigidity to the lipid filling within the lipid nanoparticle, and is dispersed in the core and surface of the nanoparticle, thereby enhancing the stability of the nanoparticle.
상기 중성 지질은, 비이온성 계면활성제로서, pH 4.0 내지 8.0의 범위 내에서 전하되지 않거나(uncharged) 중성 양성 이온성(zwitterion) 형태를 갖는 지질을 의미한다. 또한, 상기 중성 지질은 당업계의 통상의 기술자에게 공지된 어떠한 중성 지질을 모두 포함할 수 있다. The neutral lipid above means a lipid that is uncharged or has a neutral zwitterion form within the range of pH 4.0 to 8.0 as a nonionic surfactant. In addition, the neutral lipid may include any neutral lipid known to those skilled in the art.
상기 음이온성 지질은, 음이온성 계면활성제로서, pH 4.0 내지 pH 8.0의 범위 내에서 최소 하나의 음전하를 갖는 어떠한 양친매성 지질을 의미한다. 또한 상기 음이온성 지질은 당업계의 통상의 기술자에게 공지된 어떠한 음이온성 지질을 모두 포함할 수 있다. The above anionic lipid means any amphipathic lipid having at least one negative charge within the range of pH 4.0 to pH 8.0 as an anionic surfactant. In addition, the above anionic lipid may include any anionic lipid known to those skilled in the art.
상기 세라마이드 조성물이 지질 나노입자일 때, 10 ~ 2,000 nm의 입자크기를 가질 수 있다. 지질 나노입자의 크기가 10 nm 미만일 경우나 2,000 nm를 초과할 경우에는 입자 안정성이 낮아질 수 있어 바람직하지 않다.When the above ceramide composition is a lipid nanoparticle, it may have a particle size of 10 to 2,000 nm. When the size of the lipid nanoparticle is less than 10 nm or greater than 2,000 nm, particle stability may be reduced, which is not preferable.
상기 세라마이드 조성물에서, 화학식 1의 구조를 갖는 소수성 세라마이드는 전체 조성물 기준으로 40~60 mol%인 것이 좋다. 소수성 세라마이드의 농도가 40 mol%보다 낮아도 되나, 약물 전달체가 나타날 수 있는 약리학적 생리학적 효능을 높이기 위해 고함량의 세라마이드를 포함시키는 것이 특징이다. 또한 전체 조성물 기준으로, 음이온성 지질은 3 mol% 미만이거나 7 mol%를 초과하는 경우, 중성 지질이 7 mol% 미만이거나 10 mol%를 초과하는 경우, 콜레스테롤이 30 mol% 미만이거나 50 mol%를 초과할 경우, 수분산성이 유지되지 않거나, 단기간 동안은 안정한 것처럼 보일 수 있으나 제조 후 장기간 상태 유지가 안정적이지 않을 수 있어 바람직하지 않다. 특히, 음이온성 지질이 이들의 안정성을 위해 적어도 3 mol% 이상이어야 한다. In the above ceramide composition, it is preferable that the hydrophobic ceramide having the structure of chemical formula 1 is 40 to 60 mol% based on the entire composition. Although the concentration of the hydrophobic ceramide may be lower than 40 mol%, it is characterized by including a high content of ceramide in order to increase the pharmacological and physiological efficacy that a drug delivery system can exhibit. In addition, based on the entire composition, if the anionic lipid is less than 3 mol% or more than 7 mol%, if the neutral lipid is less than 7 mol% or more than 10 mol%, or if the cholesterol is less than 30 mol% or more than 50 mol%, water dispersibility may not be maintained, or although it may appear to be stable for a short period of time, it may not be stable in maintaining the state for a long period of time after manufacturing, which is not preferable. In particular, the anionic lipid should be at least 3 mol% or more for their stability.
본 발명은 또한 상기 세라마이드 조성물의 제조 방법에 관한 것이다. The present invention also relates to a method for producing the ceramide composition.
바람직하게는 (제1단계) 중성지질; 콜레스테롤; 및, 음이온성 지질;에서 선택되는 1종 이상의 지질 및 화학식 1의 소수성 세라마이드를 유기용매 상에서 혼합하여 혼합 조성물을 제조하는 단계; 및,Preferably, (step 1) a step of preparing a mixed composition by mixing at least one lipid selected from neutral lipid; cholesterol; and anionic lipid; and a hydrophobic ceramide of chemical formula 1 in an organic solvent phase; and,
(제2단계) 상기 혼합 조성물을 분산액 상태로 제조하는 단계; (Step 2) A step of preparing the above mixed composition in a dispersion state;
를 포함할 수 있다.may include.
이 때, 상기 제1단계에서, 각 원료의 총 합을 100 중량부라 할 때, 유기용매가 100~5000 중량부가 혼합될 수 있다. At this time, in the first step, when the total of each raw material is 100 parts by weight, 100 to 5,000 parts by weight of the organic solvent can be mixed.
상기 2단계 이후, 필요에 따라, 상기 분산액을 고압 균질화할 수 있다. After the above step 2, if necessary, the dispersion can be homogenized under high pressure.
또한 상기 분산액을 컬럼 정제하여 정제물을 얻은 후 멸균 여과할 수 있다. 상기 멸균 여과에 사용하는 필터는 0.1 내지 0.4 μm의 공극 크기를 갖는 것을 특징으로 한다. In addition, the above dispersion can be purified through a column to obtain a purified product and then sterilized by filtration. The filter used for the above sterilized filtration is characterized by having a pore size of 0.1 to 0.4 μm.
상기 고압 균질화는 50~60℃에서 20000~30000 psi에서 수행할 수 있고 1~3회 반복 가능하다. 상기 균질화 전 분산액을 50~60℃로 가온하여 사용할 수 있다. The above high pressure homogenization can be performed at 20,000 to 30,000 psi at 50 to 60°C and can be repeated 1 to 3 times. The dispersion before the above homogenization can be used by heating it to 50 to 60°C.
상기 유기용매는 메탄올, 에탄올, 벤젠, 부탄올, 부틸 아세테이트, 카본 테트라클로라이드, 클로로포름, 사이클로헥세인, 디클로로에테인, 디클로로메테인, 디에틸 에테르, 디이소프로필 에테르, 에틸 아세테이트, 헵테인, 헥세인, 이소옥테인, 메틸 에틸 케톤(MEK), 메틸 t-부틸 에테르(MTBE), 펜테인, 톨루엔, 트리클로로에틸렌, 자일렌 및 이들의 혼합 용매에서 선택될 수 있다. The above organic solvent may be selected from methanol, ethanol, benzene, butanol, butyl acetate, carbon tetrachloride, chloroform, cyclohexane, dichloroethane, dichloromethane, diethyl ether, diisopropyl ether, ethyl acetate, heptane, hexane, isooctane, methyl ethyl ketone (MEK), methyl t-butyl ether (MTBE), pentane, toluene, trichloroethylene, xylene, and mixed solvents thereof.
이 때, 상기 제2단계에서 초음파 처리하거나 동결-해동하여 분산액을 제조할 수 있다. 혼합 조성물을 동결하거나 해동하는 과정이 수행될 경우, 바람직하게는, 1 ~ 12회 반복할 수 있다. 혼합 조성물을 동결하고 해동하는 단계를 반복함으로써 보다 균일한 크기의 지질 나노입자가 형성될 수 있고, 지질 나노입자의 형성 효율을 높일 수 있다. 12회를 초과하면 고른 크기의 지질 나노입자 형성이 오히려 줄어들 수 있기 때문에 12회 이내가 바람직하다.At this time, in the second step, a dispersion may be prepared by sonication or freeze-thawing. When the process of freezing or thawing the mixed composition is performed, it may be preferably repeated 1 to 12 times. By repeating the steps of freezing and thawing the mixed composition, lipid nanoparticles of a more uniform size may be formed, and the formation efficiency of lipid nanoparticles may be increased. If it exceeds 12 times, the formation of lipid nanoparticles of a uniform size may actually decrease, so it is preferably 12 times or less.
이 때, 상기 제2단계에서 분산액은 별도의 반응기에서 제조될 수 있다. 상기 반응기 내에서 혼합 조성물이 동결하거나 해동하는 과정을 반복하여 지질 나노입자가 형성될 수 있다. At this time, the dispersion in the second step can be prepared in a separate reactor. By repeating the process of freezing and thawing the mixed composition within the reactor, lipid nanoparticles can be formed.
또 다른 방법으로서, 상기 제2단계에서 액적-기반 미세유체 시스템으로 분산액을 제조할 수 있다. As another method, the dispersion can be prepared using a droplet-based microfluidic system in the second step.
본 발명의 조성물은 약학 조성물 또는 화장료 조성물로 제공될 수 있다. The composition of the present invention can be provided as a pharmaceutical composition or a cosmetic composition.
상기 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. The above pharmaceutical composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. Carriers, excipients, and diluents that can be included in the above pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, it is prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants that are commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, and capsules, and these solid preparations are prepared by mixing the composition of the present invention with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspending agents can be used, such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases can be used, such as witepsol, macrogol, Tween 61, cocoa butter, laurin butter, and glycerogelatin.
본 발명의 약학 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중과, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1㎎/㎏/일 내지 500㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the judgment of the prescriber. The determination of the dosage based on these factors is within the level of those skilled in the art, and the dosage is generally in the range of 0.01 mg/kg/day to about 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. The administration may be administered once a day or divided into several times. The above dosage does not limit the scope of the present invention in any way.
본 발명의 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention can be administered to mammals such as mice, livestock, and humans by various routes. All modes of administration can be envisaged, for example, oral, rectal, or intravenous, intramuscular, subcutaneous, intrauterine, epidural, or intracerebrovascular injection.
본 발명의 화장료 조성물의 제형으로는 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 에센스, 로션, 에멀젼, 팩, 핸드크림, 풋크림, 립밤, 립스틱, 아이섀도우, 아이라이너, 아이브로우 펜슬, 블러셔, 하이라이터, 일반화장수, 스킨, 크림, 세럼, 미용비누, 유연화장수, 약용화장수, 전신세정제, 클렌징폼, 클렌징로션, 겔, 클렌징 오일, 클렌징 크림, 샴푸, 린스, 헤어트리트먼트, 헤어로션, 클렌징 티슈 및 클렌징 워터에서 선택되는 것을 제공할 수 있다. The formulation of the cosmetic composition of the present invention is It can be manufactured in any formulation commonly manufactured in the art, and can provide one selected from essence, lotion, emulsion, pack, hand cream, foot cream, lip balm, lipstick, eye shadow, eyeliner, eyebrow pencil, blusher, highlighter, general toner, skin, cream, serum, cosmetic soap, emollient toner, medicated toner, body cleanser, cleansing foam, cleansing lotion, gel, cleansing oil, cleansing cream, shampoo, rinse, hair treatment, hair lotion, cleansing tissue, and cleansing water.
상기 화장료 조성물에는 통상의 부형제 조성물이라면 어느 것이든지 포함될 수 있다. 바람직하게는 유지 성분, 에몰리엔트제, 계면 활성제, 유기 및 무기 안료, 유기 분체, 자외선 흡수제, 방부제, 살균제, 산화 방지제, pH 조정제, 알콜, 색소, 향료, 혈행 촉진제, 냉감제, 제한제, 정제수 등이 포함될 수 있다. The above cosmetic composition may contain any conventional excipient composition. Preferably, it may contain a maintenance component, an emollient, a surfactant, an organic and inorganic pigment, an organic powder, an ultraviolet absorber, a preservative, a bactericide, an antioxidant, a pH adjuster, alcohol, a pigment, a fragrance, a blood circulation promoter, a cooling agent, an antiperspirant, purified water, etc.
또한 상기 화장료 조성물에는 또 다른 유효성분이 포함될 수 있고, 바람직하게는 주름개선제, 피부노화억제제, 피부미백제, 항산화제, 피부 항염제, 보습제 또는 발모제가 포함될 수 있다. In addition, the cosmetic composition may contain another active ingredient, and preferably, it may contain an anti-wrinkle agent, an anti-aging agent, a skin whitening agent, an antioxidant, an anti-inflammatory agent, a moisturizer, or a hair growth agent.
상기 주름개선제로서는 세포외 기질(Extracellular matrix, ECM) 단백질 분해 효소인 MMP-1을 저해하는 물질로서, 규산(Silicic acid), N-메틸-L-세린(N-Methyl-Lserine), 이소플라보노이드(Isoflavonoids), 디히드로에피엔드로스테론(Dehydroepiendrosteron), 파오니플로린 (Paoniflorin) 등이 선택될 수 있으며, ECM의 붕괴를 촉진하는 활성산소를 제거하여 피부의 노화 방지하는 물질로서 벤자스타틴(Benzastatins), 코엔자임 큐10(Coenzyme Q10) 등이 사용될 수 있고, 이 외에도 각종 주름개선효과가 알려진 아데노신(adenosine), 아스코르빌글루코사이드(ascorbyl glucoside), 키네틴(kinetin), 옥신(auxin), 펩타이드(peptide), 레티놀(retinol), 레티닐팔미테이트(retinyl palmitate), 폴리에톡실레이티드레틴아마이드(Polyethoxylated Retinamide), 알파-하이드록시산(alpha hydroxyl acid) 등이 이용가능하다.As the above-mentioned wrinkle-improving agent, substances that inhibit MMP-1, an extracellular matrix (ECM) protein-decomposing enzyme, can be selected, such as silicic acid, N-methyl-L-serine, isoflavonoids, dehydroepiendrosterone, and paoniflorin. As substances that remove active oxygen that promotes the collapse of ECM and prevent skin aging, such as benzastatins and coenzyme Q10 can be used. In addition, adenosine, ascorbyl glucoside, kinetin, auxin, peptide, retinol, retinyl palmitate, etc., which are known to have various wrinkle-improving effects, can be used. Polyethoxylated retinamide, alpha hydroxyl acid, etc. are available.
상기 미백제는 알부틴(arbutin), 나이아신아마이드(niacinamide), 아스코르빈산(ascorbic acid), 마그네슘 아스코빌 포스페이트(magnesium ascorbyl phosphate), 아스코빌 애시드-2-글루코사이드(ascorbyl acid-2-glucoside), 닥나무 추출물, 에틸아스코빌에티르(Ethyl ascorbyl ether, 유용성 감초 추출물 등이 사용 가능하다.The above whitening agents that can be used include arbutin, niacinamide, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl acid-2-glucoside, mulberry extract, ethyl ascorbyl ether, and soluble licorice extract.
상기 보습제로는 하이드록시 프롤린, 글리세린, 글리세롤, 우레아, 아미노산, 락테이트 및 피로글루탐산으로 이루어진 군 중에서 선택되는 1종 이상을 사용할 수 있다. As the above-mentioned moisturizing agent, at least one selected from the group consisting of hydroxyproline, glycerin, glycerol, urea, amino acid, lactate, and pyroglutamic acid can be used.
상기 세라마이드 조성물은 약학적 조성물 또는 화장료 조성물로 적용될 경우, mL당 1 x 102 내지 1 x 1012 개의 입자가 포함된 상태로 사용할 수 있다. When the above ceramide composition is applied as a pharmaceutical composition or cosmetic composition, it can be used in a state containing 1 x 10 2 to 1 x 10 12 particles per mL.
소수성 세라마이드는 수용액에서의 용해도가 극히 낮아서 사용이 제한적이었고, 이를 약물로 사용해도 세포 전달성이 낮았다. 기존에 세라마이드를 지질 나노입자화하여 하는 기술들도 확인되었지만, 총 지질 중, 세라마이드가 50%를 초과할 경우, 분산 안정성이 떨어지고 뭉침 현상이 일어나 생물 의학적 응용에 어려움이 있었다. Hydrophobic ceramides have extremely low solubility in aqueous solutions, so their use has been limited, and even when used as drugs, their cell delivery has been low. Although existing technologies for converting ceramides into lipid nanoparticles have been identified, when ceramides exceed 50% of the total lipids, dispersion stability has decreased and agglomeration has occurred, making biomedical applications difficult.
이에 반해 본 발명은 소수성 세라마이드를 고함량으로 포함하는 수분산 상태의 조성물로서 제공하기에, 본 발명을 통해 체내 타겟으로 용이하게 전달함으로써 목적하는 바에 따라 수용해성과 수분산성이 높은 약물 전달체, 약학 조성물로의 활용도를 높일 수도 있다. In contrast, since the present invention provides a composition in a water-dispersed state containing a high content of hydrophobic ceramide, the present invention can easily deliver the composition to a target in the body, thereby increasing its usability as a drug delivery vehicle with high water solubility and water dispersibility and as a pharmaceutical composition, depending on the intended purpose.
도 1은 본 발명의 실시예 1에서 제조한 세라마이드 조성물 내 나노입자의 구조 모식도를 나타낸다.
도 2는 음이온성 지질을 포함하지 않은 원료를 이용하여 제조된 세라마이드 조성물로서, 제조 직후의 상태에 대한 사진이다.
도 3은 세라마이드 조성물의 제조 후, 원료 중, 음이온성 지질의 농도에 따른 나노입자의 상태를 각각 확인한 사진이다. Figure 1 shows a structural schematic diagram of nanoparticles in a ceramide composition manufactured in Example 1 of the present invention.
Figure 2 is a photograph of a ceramide composition manufactured using a raw material that does not contain anionic lipids, taken immediately after manufacture.
Figure 3 is a photograph showing the state of nanoparticles according to the concentration of anionic lipids among raw materials after manufacturing a ceramide composition.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나, 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지도록, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다. Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the contents introduced herein are provided to sufficiently convey the idea of the present invention to those skilled in the art so that they are thorough and complete.
<실시예 1 내지 12 및 비교예 1 내지 10> <Examples 1 to 12 and Comparative Examples 1 to 10>
Microfluics 방법을 이용하여 고함량 세라마이드 조성물을 제조하였다. A high-content ceramide composition was prepared using a microfluids method.
먼저, 에탄올 1mL에 하기 표 1의 조건으로 각 지질을 첨가하였다. First, each lipid was added to 1 mL of ethanol under the conditions shown in Table 1 below.
나노입자Geology
Nanoparticles
스테롤Cole
Sterol
(mM)density
(mM)
(mM)density
(mM)
(mM)density
(mM)
(mM)density
(mM)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860525P)N-nervonoyl-D-erythro-sphingosine
(Merck #860525P)
(Merck #860525P)N-nervonoyl-D-erythro-sphingosine
(Merck #860525P)
(Merck #860525P)N-nervonoyl-D-erythro-sphingosine
(Merck #860525P)
(Merck #860525P)N-nervonoyl-D-erythro-sphingosine
(Merck #860525P)
(Merck #860525P)N-nervonoyl-D-erythro-sphingosine
(Merck #860525P)
(Merck #860519P)N-Oleoyl-D-erythro-sphingosine
(Merck #860519P)
(Merck #860627P)N-stearoyl-D-erythro-sphinganine
(Merck #860627P)
(Merck #860624P)N-oleoyl-D-erythro-sphinganine
(Merck #860624P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860524P)N-lignoceroyl-D-erythro-sphingosine
(Merck #860524P)
(Merck #860525P)N-nervonoyl-D-erythro-sphingosine
(Merck #860525P)
이 후 각 원료가 용해되면, 세라마이드 조성물을 분산액 상태로 제조하기 위해 액적-기반 미세유체 시스템인 마이크로플루이딕스(microfluics) 장비를 이용하여 유기 용매 라인을 통해 흘려 보내고, 물은 물 용매 라인으로 흘려 보냈다. 이 때, 용매의 혼합비는 에탄올:물을 1:3의 부피비로 하였다. 나노입자가 형성된 분산액 상태의 액상을 얻은 후, 용매 치환기를 이용하여 에탄올을 제거하였다. 에탄올이 제거된 분산액 상태의 세라마이드 조성물을 필요에 따라 High pressure homogenizer를 이용하여 60℃, 27,000 psi에서 2회 균질화하여 분산액 상태의 세라마이드 조성물을 얻었다. After each raw material is dissolved, a microfluidic device, which is a droplet-based microfluidic system, is used to manufacture the ceramide composition in a dispersion state, by flowing the organic solvent line and water into the water solvent line. At this time, the mixing ratio of the solvents was ethanol:water in a volume ratio of 1:3. After obtaining a liquid phase in a dispersion state in which nanoparticles were formed, ethanol was removed using a solvent displacer. The ceramide composition in a dispersion state from which ethanol was removed was homogenized twice at 60°C and 27,000 psi using a high pressure homogenizer as needed to obtain a ceramide composition in a dispersion state.
<실시예 13> <Example 13>
박막 수화 방법을 이용한 고함량 세라마이드 조성물을 다음과 같이 제조하였다. A high-content ceramide composition was prepared using a thin film hydration method as follows.
클로로포름 1 mL에 4종의 각 지질을 첨가하였다. 각 지질과 세라마이드의 종류 및 총 함량비는 실시예 1과 같다. Each of the four lipids was added to 1 mL of chloroform. The type and total content ratio of each lipid and ceramide were as in Example 1.
이 후 각 원료가 용해되면, 클로로포름 용매를 증발시켜 지질 필름을 형성하였다. 다음으로, 상기 지질 필름을 1 mL 포스페이트 완충 식염수 (PBS) (pH 7.2)로 수화하였다. 수화된 액상을 초음파 처리한 후, 액체질소를 이용하여 수화된 지질필름을 동결하고 해동하는 절차를 5차례 반복하는 동결-해동 절차를 수행하고, 다시 초음파 처리하여 분산액 상태의 액상을 얻었다. 상기 분산액 상태의 세라마이드 조성물을 필요에 따라 High pressure homogenizer를 이용하여 60℃, 27,000 psi에서 2회 균질화하였다. After each raw material was dissolved, the chloroform solvent was evaporated to form a lipid film. Next, the lipid film was hydrated with 1 mL of phosphate buffered saline (PBS) (pH 7.2). After sonicating the hydrated liquid phase, the freeze-thaw procedure of freezing and thawing the hydrated lipid film using liquid nitrogen was repeated five times, and sonicated again to obtain a liquid phase in a dispersion state. The ceramide composition in the dispersion state was homogenized twice at 60° C. and 27,000 psi using a high pressure homogenizer, if necessary.
<실험예 1> 고함량 세라마이드 조성물의 특성 확인<Experimental Example 1> Confirmation of the characteristics of a high-content ceramide composition
본 발명에서 제조한 고함량 세라마이드에 대해, 최종 입자 크기를 측정하고, DLS(dynamic light scattering) 분석을 측정하여 이를 다음과 같이 나타내었다. 또한 제조된 각 세라마이드 조성물에 대해 조성물 내에 제조된 나노입자 수를 수분산 상태에서 확인한 바, 대략 1.0 x 1012 내지 6 x 1012 particles/ml로 제조되었다. For the high-content ceramides manufactured in the present invention, the final particle size was measured and DLS (dynamic light scattering) analysis was performed, which was expressed as follows. In addition, for each manufactured ceramide composition, the number of nanoparticles manufactured in the composition was confirmed in an aqueous dispersion state, and was manufactured to be approximately 1.0 x 10 12 to 6 x 10 12 particles/ml.
2일 후manufacturing
2 days later
7일 후manufacturing
7 days later
4주 후manufacturing
4 weeks later
× : 뭉침 등의 이상 현상 발생
- : 뭉침 현상 등의 이상 현상 발생 후 더 이상 상태를 확인하지 않은 것○: No abnormality (stable condition)
×: Occurrence of abnormal phenomena such as lumps
- : After an abnormal phenomenon such as a lumping phenomenon occurs, the condition is no longer checked.
확인 결과, 입자의 물리적 특성은 크게 다르지 않았고, 실시예 1과 비교예 1 및 2에 대해 대표적으로 나타내어 표 2 내지 4에 기재하여 나타내었다. As a result of the verification, the physical properties of the particles did not differ significantly, and were representatively shown for Example 1 and Comparative Examples 1 and 2, and are presented in Tables 2 to 4.
수분산성에 대한 확인 결과는 상기 표 5에 본 발명에서 제조한 모든 세라마이드 조성물의 상태를 기재하였고, 이에 대한 사진은 대표적으로 도 2와 도 3에 나타내었다. The results of the verification of water dispersibility are described in Table 5 above for the status of all ceramide compositions manufactured in the present invention, and photographs thereof are representatively shown in FIGS. 2 and 3.
도 2는 음이온성 지질이 포함되지 않은 채로 제조된 비교예 3 조성물의 사진으로, 0.2 μm 주사기 필터 후의 상태를 찍은 사진이다. 각 실험은 3회 반복하여 실시하였으나 같은 상태였는데, 도 2와 같이 고함량 세라마이드 조성물의 제조 시, 음이온성 지질이 포함되지 않으면, 물에서의 조성물의 분산 안정성이 떨어져 뭉침이 일어나 가라앉게 된다. 이 조성물은 고압 분산을 추가적으로 실시해도 재분산되지 않는다. Figure 2 is a photograph of a composition of Comparative Example 3 manufactured without anionic lipids, and is a photograph taken after passing through a 0.2 μm syringe filter. Each experiment was repeated three times, but the condition was the same. As shown in Figure 2, when manufacturing a high-content ceramide composition, if anionic lipids are not included, the dispersion stability of the composition in water decreases, causing clumping and sinking. This composition is not redispersed even if additional high-pressure dispersion is performed.
한편, 본 발명의 실시예의 조건으로 제조된 세라마이드 조성물은 도 3과 같이 4주 이상 모두 수분상 상태를 유지하였다. 도 3은 고압 분산 과정을 최종적으로 수행 후, 이를 4주간 보관한 각 조성물의 사진을 나타내는데, 음이온성 지질이 소량 포함된 비교예 1과 비교예 2의 조성물은 제조직후에는 수분산 상태가 좋아보였으나 2일째에 응집이 일어났고, 실시예 1의 조성물은 4주까지 안정적이었다. Meanwhile, the ceramide compositions manufactured under the conditions of the examples of the present invention all maintained a moisture state for more than 4 weeks, as shown in FIG. 3. FIG. 3 shows photographs of each composition stored for 4 weeks after the final high-pressure dispersion process. The compositions of Comparative Examples 1 and 2 containing a small amount of anionic lipids appeared to have a good moisture dispersion state immediately after manufacture, but coagulation occurred on the second day, and the composition of Example 1 was stable for up to 4 weeks.
표 5와 도 2 및 도 3의 결과들을 종합적으로 확인한 바, 제조 직후에 각 입자의 물성은 유사해보였으나, 4주 이상 안정적인 상태로 제조되는 것은 본 발명의 실시예의 조건으로 제조된 세라마이드 조성물인 것으로 확인된다. As a result of comprehensively confirming the results of Table 5 and Figures 2 and 3, the properties of each particle appeared similar immediately after manufacturing, but it was confirmed that the ceramide composition manufactured under the conditions of the example of the present invention was manufactured in a stable state for more than 4 weeks.
<실험예 2> 세라마이드 조성물 처리로 인한 세포 생존율 확인<Experimental Example 2> Confirmation of cell survival rate due to treatment with ceramide composition
DP(Dermal papilla) 세포, MDA-MB-231 및 MDA-MB-468 세포를 10% 소 태아 혈청 (fetal bovine serum; FBS) 및 1 % 페니실린/스트렙토마이신이 보충된 ATCC modified RPMI medium (Gibco), 5 % CO2 하에서 37 ℃에서 배양하였다.DP (Dermal papilla) cells, MDA-MB-231, and MDA-MB-468 cells were cultured in ATCC modified RPMI medium (Gibco) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin at 37 °C in 5% CO 2 .
실험을 위해, 96-웰 플레이트 (1.5 x 103 세포/웰)에 접종된 MDA-MB-231 및 MDA-MB-468 세포에 본 발명에서 제조한 세라마이드 조성물을 각각 처리 (입자 수 : 4.5 x 108 ± 2.05 x 108) 하였다. 24 시간 배양 후 WST-8 시약 (Dojindo)을 37 ℃에서 1 시간 동안 배지에 첨가하였다. 마이크로 플레이트 리더 (BioTek)를 사용하여 450nm에서 흡광도를 측정하였다. 이후 24시간 마다 흡광도를 측정하여 세포 생존율을 확인하였다. For the experiment, MDA-MB-231 and MDA-MB-468 cells seeded in 96-well plates (1.5 x 10 3 cells/well) were each treated with the ceramide composition prepared in the present invention (particle number: 4.5 x 10 8 ± 2.05 x 10 8 ). After 24 hours of incubation, WST-8 reagent (Dojindo) was added to the medium at 37 °C for 1 hour. The absorbance was measured at 450 nm using a microplate reader (BioTek). Thereafter, the cell viability was confirmed by measuring the absorbance every 24 hours.
실험 결과, MDA-MB-231 세포에는 N-Oleoyl-D-sphingosine(Merck)이 포함된 세라마이드 조성물을 처리하여 이 세라마이드 조성물이 처리된 경우 세포 생존률이 평균 50~70 %로 감소하였다. 또한, MDA-MB-468 세포에는 N-Oleoyl-D-sphingosine(Merck)이 포함된 세라마이드 조성물을 처리하여 40~55 %까지 세포생존률이 감소하였다. As a result of the experiment, when MDA-MB-231 cells were treated with a ceramide composition containing N-Oleoyl-D-sphingosine (Merck), the cell viability decreased by an average of 50 to 70%. In addition, when MDA-MB-468 cells were treated with a ceramide composition containing N-Oleoyl-D-sphingosine (Merck), the cell viability decreased by 40 to 55%.
또한, Dermal papilla 세포에 N-lignoceroyl-D-erythro-sphingosine(Merck)가 포함된 세라마이드 조성물이 처리된 경우 세포 생존률이 평균 300~400%로 증가하였고, MDA-MB-468 암세포에 상기 N-lignoceroyl-D-erythro-sphingosine(Merck)의 세라마이드 조성물이 농도별로 처리되어도 세포 생존률에 차이는 없었으나 사멸하는 효과(독성)도 나타나지 않았다. In addition, when dermal papilla cells were treated with a ceramide composition containing N-lignoceroyl-D-erythro-sphingosine (Merck), the cell viability increased to an average of 300 to 400%, and when MDA-MB-468 cancer cells were treated with the ceramide composition of N-lignoceroyl-D-erythro-sphingosine (Merck) at various concentrations, there was no difference in cell viability, but no death effect (toxicity) was observed.
추가적으로 세라마이드가 포함된 세라마이드 조성물과 대비하여 세라마이드 단독으로 세라마이드 자체를 세라마이드 조성물 제조 시의 농도로 수용액상에 분산시키고 컬럼정제하여 위의 조건과 같은 세포 생존율 발현 실험을 진행하였으나, 세포 사멸이나 증식 등의 아무런 변화가 없음을 확인하였다. 이는 세라마이드가 자체가 수용액상에서 불용성이기 때문에, 실험용 시료인 수용액상에 유효성분으로 세라마이드가 없어 상기 세라마이드 자체가 갖는 효과가 나타나지 않는다는 것을 알 수 있다.Additionally, in comparison with a ceramide composition containing ceramide, ceramide alone was dispersed in an aqueous solution at the concentration used when preparing the ceramide composition and purified by column to conduct a cell viability expression experiment under the same conditions as above, but it was confirmed that there was no change in cell death or proliferation. This shows that since ceramide itself is insoluble in an aqueous solution, there is no ceramide as an active ingredient in the aqueous solution, which is the experimental sample, and thus the effect of the ceramide itself does not appear.
이와 같은 결과는 본원발명의 조성물이 난용성인 세라마이드를 수분산화하여 약물 전달성이 높은 조성물이 되었음을 입증한다. These results demonstrate that the composition of the present invention has a high drug delivery property by hydrating poorly soluble ceramide.
Claims (9)
상기 조성물은 음이온성 지질, 중성 지질 및 콜레스테롤을 포함하되,
상기 소수성 세라마이드는 전체 조성물에 40 mol% 이상을 포함하는 것을 특징으로 하는 수분산성이 우수한 세라마이드 조성물. A composition having a water-dispersible formulation comprising hydrophobic ceramide dispersed in an aqueous solution,
The composition comprises anionic lipids, neutral lipids and cholesterol,
A ceramide composition having excellent water dispersibility, characterized in that the hydrophobic ceramide comprises 40 mol% or more of the total composition.
상기 음이온성 지질은 전체 조성물에 3 내지 7 mol%를 포함하는 것을 특징으로 하는 수분산성이 우수한 세라마이드 조성물. In the first paragraph,
A ceramide composition having excellent water dispersibility, characterized in that the anionic lipid comprises 3 to 7 mol% of the total composition.
상기 조성물은 수용액에 고형분으로 10중량% 이하 포함되는 것을 특징으로 하는 수분산성이 우수한 세라마이드 조성물.In the first paragraph,
The above composition is a ceramide composition having excellent water dispersibility, characterized in that the solid content in the aqueous solution is 10 wt% or less.
상기 소수성 세라마이드는 아래의 화학식 1의 구조를 갖는 것을 특징으로 수분산성이 우수한 세라마이드 조성물.
[화학식 1]
(상기 화학식 1에서 R1은 탄소수가 17 내지 30개의 포화 또는 불포화 지방족 사슬이고, R2는 수산기가 있거나 없는 탄소수가 10 내지 20개의 포화 또는 불포화 지방족 사슬이다.) In the first paragraph,
A ceramide composition having excellent water dispersibility, characterized in that the hydrophobic ceramide has a structure represented by the chemical formula 1 below.
[Chemical Formula 1]
(In the above chemical formula 1, R 1 is a saturated or unsaturated aliphatic chain having 17 to 30 carbon atoms, and R 2 is a saturated or unsaturated aliphatic chain having 10 to 20 carbon atoms with or without a hydroxyl group.)
상기 중성 지질은 HSPC(hydrogenated soy phosphatidylcholine), DOPC(1,2-dioleoyl-sn-glycero-3-phosphocholine), POPE(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), DSPC(1,2-distearoyl-sn-glycero-3-phosphocholine), DSPE(1,2-distearoyl-sn-glycero-3-phosphoethanolamine), DPPC(1,2-dipalmitoyl-sn-glycero-3-phosphocholine), POPC(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), DOPE(1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), SM(N-palmitoyl-D-erythro-sphingosylphosphorylcholine), DLPE(1,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPE(1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine), 포스파티딜 콜린(phosphatidyl choline), 디미리스톨글리세롤(dimyristoylglycerol), 석시노일 디아글리세롤(succinoyl-diacylglycerol), 포스파티딜 에탄올아민(phosphatidyl ethanolamine), 테트라에테르 리피드(tetraether lipid), 스핑고리피드(sphingolipid), 디아크릴 글리세롤(diacryl glycerol) 및 글리세리드(glyceride)로 이루어진 군으로부터 선택된 어느 하나 이상을 포함하는 지질인 것을 특징으로 하는 세라마이드 조성물.In the first paragraph,
The neutral lipids include HSPC (hydrogenated soy phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DSPE (1,2-distearoyl-sn-glycero-3-phosphocholine), -phosphoethanolamine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), SM (N-palmitoyl-D-erythro-sphingosylphosphorylcholine), A ceramide composition characterized in that the lipid comprises at least one selected from the group consisting of DLPE (1,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPE (1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine), phosphatidyl choline, dimyristoylglycerol, succinoyl-diacylglycerol, phosphatidyl ethanolamine, tetraether lipid, sphingolipid, diacryl glycerol, and glyceride.
상기 음이온성 지질은 DSPG(1,2-distearoyl-sn-glycero-3-phosphatidylglycerol), SOPG(1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol), Soy PG(L-α-phosphatidylglycerol (Soy)), Egg PG(L-α-phosphatidylglycerol (Egg, Chicken)), DLPG(1,2-dilauroyl-sn-glycero-3-phosphatidylglycerol), Cardiolipin(1',3'-bis[1,2-dioleoyl-sn-glycero-3-phospho]-glycerol), DMPG(dimyristoylphosphatidylglycerol), DPPG(dipalmitoylphosphatidylglycerol), DOPG(dioleoylphosphatidylglycerol), POPG(palmitoyloleoylphosphatidylglycerol), DOPS(dioleoylphosphatidylserine), DTPA(diethylenetriamine pentaacetic acid), DPTGA(1,4-dipalmitoyl-tartarate-2,3-diglutaric acid), DSTSA(1,4-disteroyl-tartarate-2,3-disuccinic acid), CHHDA(2-carboxyheptadecanoyl heptadecylamide), DMPS(dimyristoylphosphatidylserine), DPPS(dipalmitoylphosphatidylserine), POPS(palmitoyloleoylphosphatidylserine), DMPA(dimyristoylphosphatidic acid), DPPA(dipalmitoylphosphatidic acid), DOPA(dioleoylphosphatidic acid), POPA(palmitoyl-oleoylphosphatidic acid), CetylP(Cetyl phosphate) 및 CHEMS(cholesterol hemisuccinate)로 이루어진 군으로부터 선택된 어느 하나 이상을 포함하는 지질인 것을 특징으로 하는 세라마이드 조성물.In the first paragraph,
The anionic lipids include DSPG (1,2-distearoyl-sn-glycero-3-phosphatidylglycerol), SOPG (1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol), Soy PG (L-α-phosphatidylglycerol (Soy)), Egg PG (L-α-phosphatidylglycerol (Egg, Chicken)), DL PG (1,2-dilauroyl-sn-glycero-3-phosphatidylglycerol), Cardiolipin (1',3'-bis[1,2-dioleoyl-sn-glycero-3-phospho]-glycerol), DMPG (dimyristoylphosphatidylglycerol), DPPG (dipalmitoylphosphatidylglycerol), DOPG (dioleoylphosphatidylglycerol) , POPG (palmitoyloleoylphosphatidylglycerol), Ceramide characterized by being a lipid comprising at least one selected from the group consisting of DOPS (dioleoylphosphatidylserine), DTPA (diethylenetriamine pentaacetic acid), DPTGA (1,4-dipalmitoyl-tartarate-2,3-diglutaric acid), DSTSA (1,4-disteroyl-tartarate-2,3-disuccinic acid), CHHDA (2-carboxyheptadecanoyl heptadecylamide), DMPS (dimyristoylphosphatidylserine), DPPS (dipalmitoylphosphatidylserine), POPS (palmitoyloleoylphosphatidylserine), DMPA (dimyristoylphosphatidic acid), DPPA (dipalmitoylphosphatidic acid), DOPA (dioleoylphosphatidic acid), POPA (palmitoyl-oleoylphosphatidic acid), CetylP (Cetyl phosphate), and CHEMS (cholesterol hemisuccinate). Composition.
상기 조성물은 지질 나노입자인 것을 특징으로 하는 세라마이드 조성물.In the first paragraph,
A ceramide composition characterized in that the composition is a lipid nanoparticle.
상기 조성물은 나노리포좀인 것을 특징으로 하는 세라마이드 조성물.In the first paragraph,
A ceramide composition characterized in that the composition is a nanoliposome.
상기 조성물은 에멀전인 것을 특징으로 하는 세라마이드 조성물.In the first paragraph,
A ceramide composition characterized in that the composition is an emulsion.
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| PCT/KR2024/095092 WO2024210692A1 (en) | 2023-04-06 | 2024-02-07 | Highly water-dispersible composition having high ceramide content |
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