JP2014502615A - 陽イオン性脂質を含む陰イオン性薬物伝達体およびその製造方法 - Google Patents
陽イオン性脂質を含む陰イオン性薬物伝達体およびその製造方法 Download PDFInfo
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- JP2014502615A JP2014502615A JP2013547365A JP2013547365A JP2014502615A JP 2014502615 A JP2014502615 A JP 2014502615A JP 2013547365 A JP2013547365 A JP 2013547365A JP 2013547365 A JP2013547365 A JP 2013547365A JP 2014502615 A JP2014502615 A JP 2014502615A
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- cationic lipid
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- LIRDJALZRPAZOR-UHFFFAOYSA-N indolin-3-one Chemical group C1=CC=C2C(=O)CNC2=C1 LIRDJALZRPAZOR-UHFFFAOYSA-N 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940041290 mannose Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- YNPFMWCWRVTGKJ-UHFFFAOYSA-N mianserin hydrochloride Chemical compound [H+].[Cl-].C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 YNPFMWCWRVTGKJ-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- XPVOJYDIBHYVFL-UHFFFAOYSA-N n'-[2-(2-aminoethylamino)ethyl]ethane-1,2-diamine;hydrochloride Chemical compound Cl.NCCNCCNCCN XPVOJYDIBHYVFL-UHFFFAOYSA-N 0.000 description 1
- IMENJLNZKOMSMC-UHFFFAOYSA-N n'-[2-[2-[2-[2-[2-(2-aminoethylamino)ethylamino]ethylamino]ethylamino]ethylamino]ethyl]ethane-1,2-diamine Chemical compound NCCNCCNCCNCCNCCNCCNCCN IMENJLNZKOMSMC-UHFFFAOYSA-N 0.000 description 1
- RUSNFULRUJHOPI-UHFFFAOYSA-N n'-[2-[2-[2-[2-[2-[2-(2-aminoethylamino)ethylamino]ethylamino]ethylamino]ethylamino]ethylamino]ethyl]ethane-1,2-diamine Chemical compound NCCNCCNCCNCCNCCNCCNCCNCCN RUSNFULRUJHOPI-UHFFFAOYSA-N 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- DVEKCXOJTLDBFE-UHFFFAOYSA-N n-dodecyl-n,n-dimethylglycinate Chemical compound CCCCCCCCCCCC[N+](C)(C)CC([O-])=O DVEKCXOJTLDBFE-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001293 nucleolytic effect Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 108700004121 sarkosyl Proteins 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
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Abstract
【選択図】図1
Description
nとmは、独立して0〜12であり、ただし、2≦n+m≦12であり、aとbは、独立して1〜6であり、およびR1とR2は、独立して炭素数11〜25個の飽和または不飽和炭化水素である。
nとmは、独立して0〜12であり、ただし、2≦n+m≦12であり、
aとbは、独立して1〜6であり、
R1とR2は、独立して炭素数11〜25個の飽和または不飽和炭化水素であり、および
Xはハロゲンである。
(a)陰イオン性薬物と化学式1の陽イオン性脂質を水混和性有機溶媒または水溶液と有機溶媒の混合溶媒で溶解して相分離させる段階;
(b)前記(a)段階の有機溶媒層を分離する段階;
(c)前記(b)段階の有機溶媒層に両親媒性ブロック共重合体を混合し、有機溶媒を除去する段階;および
(d)前記有機溶媒が除去された混合物に水溶液を添加してミセル化する段階を含む。
(a’)陰イオン性薬物、化学式1の陽イオン性脂質および両親媒性ブロック共重合体を水混和性有機溶媒または水溶液と有機溶媒の混合溶媒で溶解する段階;
(b’)前記(a’)段階の有機溶媒層を除去する段階;
(c’)前記(b’)段階の有機溶媒が除去された混合物に水溶液を添加してミセル化する段階を含む。
トリエチレンテトラミン(triethylenetetramine)とオレオイル クロライド(oleoyl chloride)間の親核性添加反応(nucleophilic addition)により次のとおり合成した。
トリエチレンテトラミンとオレオイルクロライドの代わりに、6.2mmolのリノレオイルクロライド(linoleoyl chloride)を4.1mmolのテトラエチレンペンタミン(tetraethylenepentamine)に添加した以外は、実施例1と同様な方法を経て1,8−ジリノレオイルテトラエチレンペンタミドの合成および精製を行った。最終的に得られた生成物の構造およびリノレオイル基の導入程度を水素核磁気共鳴分光器を用いて確認し、その結果は図2に示した。収率は78.9%であり、1.9当量のリノレオイル基がテトラエチレンペンタミンに導入された。
トリエチレンテトラミンとオレオイルクロライドの代わりに、8.1mmolのミリストレオイルクロライド(myristoleolinoleoyl chloride)を13.5mmolのジエチレントリアミン(diethylenetriamine)に添加した以外は、実施例1と同様な方法を経て1,4−ジミリストレオイルジエチレントリアミドの合成および精製を行った。最終的に得られた生成物の構造およびミリストレオイル基の導入程度を水素核磁気共鳴分光器を用いて確認し、その結果は図3に示した。収率は80.4%であり、2.1当量のミリストレオイル基がジエチレントリアミンに導入された。
トリエチレンテトラミンとオレオイルクロライドの代わりに、4.2mmolのステアロイルクロライド(stearoyl chloride)を6.9mmolのペンタエチレンヘキサミン(pentaethylenehexamine)に添加した以外は、実施例1と同様な方法を経て1,10−ジステアロイルペンタエチレンヘキサミドの合成および精製を行った。最終的に得られた生成物の構造およびステアロイル基の導入程度を水素核磁気共鳴分光器を用いて確認し、その結果は図4に示した。収率は87.1%であり、2.0当量のステアロイル基がペンタエチレンヘキサミンに導入された。
トリエチレンテトラミンの代わりに、10.0mmolのペンタエチレンヘキサミンを使用した以外は、実施例1と同様な方法を経て1,10−ジオレオイルペンタエチレンヘキサミドの合成および精製を行った。最終的に得られた生成物の構造およびオレオイル基の導入程度を水素核磁気共鳴分光器を用いて確認し、その結果は図5に示した。収率は88.2%であり、2.1当量のオレオイル基がペンタエチレンヘキサミンに導入された。
10gのモノメトキシポリエチレングリコール(monomethoxy poly(ethylene glycol)、分子量5,000ダルトン)を100mLの二口丸低フラスコに入れ、減圧(1mmHg)下で5時間かけて120℃で真空乾燥した。反応フラスコに乾燥窒素を満たし、50%濃度にトルエンに溶解されているオクチル酸スズ(Sn(Oct)2)反応触媒を注射器でDL−ラクチド(DL−lactide)の0.3wt%(30mg)注入した。反応混合物を30分間かけて攪拌し、120℃で1時間かけて1mmHgに減圧してトルエンを除去した。8.46gの精製されたラクチドを添加し、混合物を6時間かけて130℃で加熱した。前記過程を通じて得られたmPEG−PLAの数平均分子量は5,000−4,000ダルトンであり、図6の1H−NMRによりA−Bタイプと確認された。
製造例1で合成したmPEG−PLAの5gを100mlの二口丸底フラスコに入れ、減圧下で3時間かけて120℃で真空乾燥した。ここに3mLのトルエンに溶解されている35.5mg(645μmol)のトコフェロールサクシニルクロライド(tocopherol succinyl chloride)を投入して100℃で8時間かけて減圧条件で反応させた。得られた高分子をジクロロメタン(dichloromethane)に溶かし、ヘプタンに沈殿させて精製を行った。精製された高分子は真空乾燥して、白色の粉粒子形態を得た。収率は94.2%であり、図7の1H−NMR分析で純度は97.0%以上であり、トコフェロール導入率は99.9%であった。
本発明の陽イオン性脂質と細胞伝達効能を比較するために、公知となったAC−コレステロール陽イオン性脂質を次のとおり合成した。
実施例1で合成した陽イオン性脂質である1,6−ジオレオイルトリエチレンテトラミド1.3mgと細胞融合性リン脂質であるDOPE(Avanti polar lipids)1.7mgをそれぞれ1mLのクロロホルムに溶かした後、一口丸底フラスコで混合した後、回転蒸留濃縮装置(rotary evaporator)でクロロホルムを低速で除去して薄い脂質フィルムを製造した。得られた脂質フィルムにリン酸緩衝溶液(phosphate buffered saline)1mLを添加し、37℃で3分間かけて攪拌して前記脂質からなるリポソームを製造した。得られたリポソーム溶液を空隙の大きさ0.2umのポリカーボネート膜が装着された押出機(extruder)に数回反復通過させて粒子の大きさが均一なリポソームを製造した。このように製造された陽イオン性リポソームは使用する前まで4℃で保管した。
Opti−MEM血清培養液(Invitrogen)17.5μLに実施例6−1で製造された陽イオン性リポソーム溶液0.5μLを加えて混合した。前記リポソーム溶液にST Pharm株式会社(韓国)で購入した下記の配列番号1および2のGFP siRNAの2μL(34ng/μL)を加えて攪拌機で混合した。前記リポソーム剤型は20分間室温で保管後、細胞株培養液に加えた。
GFP siRNA(ST Pharm株式会社、韓国):
センス鎖:5’−GCAAGCUGACCCUGAAGUUdTdT−3’(配列番号1−dTdT)
アンチセンス鎖:5’−AACUUCAGGGUCAGCUUGCdTdT−3’(配列番号2−dTdT)
siRNAの陰イオン電荷に対する陽イオン性脂質の陽イオン電荷比率(N/P比率)を6にして次のとおりsiRNA−陽イオン性脂質複合体を含有するミセルを製造した。
実施例7と同様な方法を用い、ただし、mPEG−PLAの代わりに、製造例2のmPEG−PLA−トコフェロールを使用してsiRNA/1,6−ジオレオイルトリエチレンテトラミド/mPEG−PLA−トコフェロールミセル伝達体を製造した。この時、mPEG−PLA−トコフェロールに対するsiRNA/1,6−ジオレオイルトリエチレンテトラミド複合体の比率が0.42wt%になるように混合した。この混合物を回転蒸留濃縮装置で減圧蒸留して溶媒を除去した。フラスコに蒸溜水300μLを加えて、柔らかく振って溶かすことによって高分子ミセル伝達体を製造した。
本発明の陽イオン性脂質剤型と細胞伝達効能を比較するために、実施例6−2の5μgのsiRNAに対してN/P比率が6になるように製造例3で合成されたAC−コレステロール46μgを使用して実施例7と同様な方法でmPEG−PLA−トコフェロールミセルを製造した。この時、mPEG−PLA−トコフェロールに対するsiRNA/AC−コレステロール複合体の比率が0.57wt%になるように混合した。
実施例1で製造した陽イオン性脂質である1,6−ジオレオイルトリエチレンテトラミド5.5mgに0.1倍モル比率のTween−80の1.0mgを混合した。ここにリン酸緩衝溶液10mLを添加し、均質器(homogenizer)を利用して常温で約2分間かけて均質化させて油相が水相内に分散した水中油型(O/W型)陽イオン性エマルジョンを製造した。Opti−MEM血清培養液(Invitrogen)15.5μLに前記陽イオン性エマルジョン溶液2.5μLを加えて混合した。ここに実施例6−2のGFP siRNAの2μL(34ng/μL)を加えて攪拌機で混合してエマルジョンを得た。前記エマルジョン剤型は、20分間室温で保管後、細胞株培養液に加えた。
実施例6〜9および比較例1で製造された剤型に対して次のとおり緑色蛍光蛋白質(GFP、Green fluorescence protein)を安定的に発現するA549 GFP細胞株に処理し、GFP蛋白質の発現程度を確認した。
本発明の実施例6〜9および比較例1の剤型に対して、細胞株に対するsiRNA伝達効能をmRNA水準でそれぞれ確認した。各伝達体を実験例1と同様な条件で処理し、siRNA投与濃度を5nMおよび15nMに異にしてqRT−PCR(quantitative Reverse Transcription−Polymerase Chain Reaction)を用いて次のような方法でGFP mRNA発現量を測定した。
Claims (15)
- 下記化学式1の陽イオン性脂質を含む、陰イオン性薬物を伝達するための薬物伝達体:
nとmは、独立して0〜12であり、ただし、2≦n+m≦12であり、
aとbは、独立して1〜6であり、および
R1とR2は、独立して炭素数11〜25個の飽和または不飽和炭化水素である。 - nとmは、独立して1〜9であり、2≦n+m≦10である、請求項1に記載の薬物伝達体。
- aとbは、独立して2〜4である、請求項1に記載の薬物伝達体。
- R1とR2は、独立して炭素数13〜21個の不飽和炭化水素である、請求項1に記載の薬物伝達体。
- R1とR2は、独立してラウリル、ミリスチル、パルミチル、ステアリル、アラキジル、ベヘニル、リグノセリル、ミリストレイル、パルミトレイル、サピエニル、オレイル、リノレイル、アラキドニル、エイコサペンタエニル、エルシル、ドコサヘキサエニルおよびセロチルからなる群より選択される、請求項1に記載の薬物伝達体。
- 記陰イオン性薬物は、アンチセンスオリゴヌクレオチド、アプタマー、または短鎖干渉リボ核酸(siRNA)である、請求項1に記載の薬物伝達体。
- 下記化学式2のオリゴアルキレンアミンを下記化学式3の脂肪酸のアシルハロゲン化合物および下記化学式4の脂肪酸のアシルハロゲン化合物と反応させて化学式1の陽イオン性脂質を製造する段階を含む、請求項1〜6のいずれか一項に記載の薬物伝達体を製造する方法:
nとmは、独立して0〜12であり、ただし、2≦n+m≦12であり、
aとbは、独立して1〜6であり、
R1とR2は、独立して炭素数11〜25個の飽和または不飽和炭化水素であり、および
Xは、ハロゲンである。 - 陰イオン性薬物および化学式1で表される陽イオン性脂質を含み、前記陰イオン性薬物と前記陽イオン性脂質が複合体を形成する薬剤学的組成物:
nとmは、独立して0〜12であり、ただし、2≦n+m≦12であり、
aとbは、独立して1〜6であり、および
R1とR2は、独立して炭素数11〜25個の飽和または不飽和炭化水素である。 - 前記組成物は、リポソーム、ミセル、エマルジョンおよびナノ粒子からなる群より選択される剤型を有する、請求項8に記載の薬剤学的組成物。
- 前記陰イオン性薬物と陽イオン性脂質の電荷量の比率は、0.1〜128であることを特徴とする、請求項8に記載の薬剤学的組成物。
- 前記陽イオン性脂質は、全体組成物の0.001〜10重量%であることを特徴とする、請求項8に記載の薬剤学的組成物。
- 陰イオン性薬物;化学式1の陽イオン性脂質;および両親媒性ブロック共重合体を含み、
前記陰イオン性薬物は、前記陽イオン性脂質と複合体を形成し、および前記複合体は、両親媒性ブロック共重合体のミセル構造内部に封入されていることを特徴とするミセル剤型を有する、請求項8に記載の薬剤学的組成物。 - 陰イオン性薬物;化学式1の陽イオン性脂質;および細胞融合性リン脂質を含み、
前記陰イオン性薬物は、陽イオン性脂質と複合体を形成し、および前記複合体は、細胞融合性リン脂質から構成されたリポソームに結合されていることを特徴とするリポソーム剤型を有する、請求項8に記載の薬剤学的組成物。 - 陰イオン性薬物;化学式1の陽イオン性脂質;および界面活性剤を含み、
前記陰イオン性薬物は、前記陽イオン性脂質と複合体を形成し、および前記複合体は、界面活性剤のミセル構造内部に封入されていることを特徴とするミセル剤型を有する、請求項8に記載の薬剤学的組成物。 - 陰イオン性薬物;化学式1の陽イオン性脂質;および界面活性剤を含み、
前記陰イオン性薬物は、前記陽イオン性脂質と複合体を形成し、および前記複合体は、エマルジョン内部に封入されていることを特徴とするエマルジョン剤型を有する、請求項8に記載の薬剤学的組成物。
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JP2018527413A (ja) * | 2015-09-15 | 2018-09-20 | サムヤン バイオファーマシューティカルズ コーポレイションSamyang Biopharmaceuticals Corporation | アニオン性薬物含有医薬組成物及びその製造方法 |
JP2019501900A (ja) * | 2015-12-18 | 2019-01-24 | サムヤン バイオファーマシューティカルズ コーポレイションSamyang Biopharmaceuticals Corporation | 陰イオン性薬物を含有する高分子ミセルの製造方法 |
CN108473417A (zh) * | 2015-12-30 | 2018-08-31 | 株式会社三养生物制药 | 选择性合成阳离子脂质的方法 |
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EP2658577A4 (en) | 2016-08-24 |
CN103476431A (zh) | 2013-12-25 |
WO2012091523A3 (en) | 2012-12-06 |
US9220779B2 (en) | 2015-12-29 |
JP5836394B2 (ja) | 2015-12-24 |
WO2012091523A8 (en) | 2013-10-10 |
KR101308591B1 (ko) | 2013-09-13 |
US20130266641A1 (en) | 2013-10-10 |
CN103476431B (zh) | 2015-08-26 |
CA2823182C (en) | 2016-02-23 |
AU2011353233B2 (en) | 2016-02-11 |
AU2011353233A1 (en) | 2013-07-11 |
EP3695850A1 (en) | 2020-08-19 |
NZ611439A (en) | 2015-05-29 |
KR20120078661A (ko) | 2012-07-10 |
EP2658577A2 (en) | 2013-11-06 |
CA2823182A1 (en) | 2012-07-05 |
WO2012091523A2 (en) | 2012-07-05 |
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