JP7439171B2 - サイジング剤含有ナノアラム粒子 - Google Patents
サイジング剤含有ナノアラム粒子 Download PDFInfo
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- JP7439171B2 JP7439171B2 JP2022100579A JP2022100579A JP7439171B2 JP 7439171 B2 JP7439171 B2 JP 7439171B2 JP 2022100579 A JP2022100579 A JP 2022100579A JP 2022100579 A JP2022100579 A JP 2022100579A JP 7439171 B2 JP7439171 B2 JP 7439171B2
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- alum
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- nanoalum
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Description
開示は、0.5μm~20μmのサイズ、または0.5μm~10μmのサイズの前駆体アルミニウム塩粒子から、記載のナノアラム粒子を製造する方法を提供する。
本明細書に記載の本開示は、ナノアラム粒子、ナノアラム粒子を含んでなる組成物、ならびにナノアラム粒子の製造方法および使用方法を提供する。
I.定義
II.一般的方法
III.ナノアラム粒子
A.アルミニウム塩
B.サイジング剤
C.サイジング剤に結合した脂質
のいずれかを含んでなり、
式中、X-はアルカリ金属対イオンであり、Y+はハロゲン化物対イオンである。
D.ナノアラム粒子製造方法
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)プロセスが行われる温度は約4℃である;
e)アラムの濃度は約4mg/mlである
f)サイジング剤の濃度は約8mg/mlである;
g)アルミニウム塩対サイジング剤の比は約1:2である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)プロセスが行われる温度は約4℃である;
e)アラムの濃度は4mg/mlである;
f)サイジング剤の濃度は約10mg/mlである;
g)アルミニウム塩対サイジング剤の比は約1:2.5である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)プロセスが行われる温度は約4℃である;
e)アラムの濃度は4mg/mlである;
f)サイジング剤の濃度は約30mg/mlである;
g)アルミニウム塩対サイジング剤の比は約1:7.5である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)プロセスが行われる温度は約4℃である;
e)アラムの濃度は4mg/mlである;
f)サイジング剤の濃度は約20mg/mlである;
g)アルミニウム塩対サイジング剤の比は約1:5である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)プロセスが行われる温度は約4℃である;
e)アラムの濃度は1.6mg/mlである;
f)サイジング剤の濃度は約4.8mg/mlである;
g)アルミニウム塩対サイジング剤の比は約1:3である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)サイジング剤の濃度は約8mg/mlである;
e)アルミニウム塩対サイジング剤の比は約1:2である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)サイジング剤の濃度は約10mg/mlである;
e)アルミニウム塩対サイジング剤の比は約1:2.5である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)サイジング剤の濃度は、約1mg/ml~約8mg/ml、例えば4または8mg/mlである;
e)アルミニウム塩対サイジング剤の比は約1:1または1:2である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)サイジング剤の濃度は約10mg/mlである;
e)アルミニウム塩対サイジング剤の比は約1:2.5である。
a)高エネルギー源の種類はマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)高エネルギー源を通る混合物の通過回数は、1~10、例えば3、6、または10通過である;
d)サイジング剤の濃度は約10mg/mlである;
e)アルミニウム塩対サイジング剤の比は約1:25である。
a)高エネルギー源の種類は、高せん断ミキサー、次いでマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)マイクロフルイダイザーを通る混合物の通過回数は、1~30、好ましくは10~30である;
d)高せん断ミキサーは約5,000rpmで混合する
e)アラムの濃度は約2mgアルミニウム/mlである
f)サイジング剤の濃度は約2mg/mlである;
g)アルミニウム塩対サイジング剤の質量比は約1:1である
h)サイジング剤は低分子量キトサンである。
a)高エネルギー源の種類は、高せん断ミキサー、次いでマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)マイクロフルイダイザーを通る混合物の通過回数は、1~30、好ましくは10~30である;
d)高せん断ミキサーは約5,000rpmで混合する
e)アラムの濃度は約2mgアルミニウム/mlである
f)サイジング剤の濃度は約0.5mg/ml(例えば、0.44mg/ml)である;
g)アルミニウム塩対サイジング剤の質量比は約4.5:1である
h)サイジング剤は低分子量硫酸デキストランナトリウム塩である。
a)高エネルギー源の種類は、高せん断ミキサー、次いでマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)マイクロフルイダイザーを通る混合物の通過回数は、1~30、好ましくは10~30である;
d)高せん断ミキサーは約5,000rpmで混合する
e)アラムの濃度は約2mgアルミニウム/mlである
f)サイジング剤の濃度は約1mg/mlである;
g)アルミニウム塩対サイジング剤の質量比は約2:1である
h)サイジング剤は低分子量キトサンである。
i)アルミニウム塩とサイジング剤を混合する前に、アルミニウム塩をリガンド交換(例えば、リン酸リガンド交換)に付す。
a)高エネルギー源の種類は、高せん断ミキサー、次いでマイクロフルイダイザーである;
b)高エネルギー源によって加えられる圧力は約30k psiである;
c)マイクロフルイダイザーを通る混合物の通過回数は、1~30、好ましくは10~30である;
d)高せん断ミキサーは約5,000rpmで混合する
e)アラムの濃度は約2mgアルミニウム/mlである
f)サイジング剤の濃度は約0.5mg/mlである;
g)アルミニウム塩対サイジング剤の質量比は約4:1である
h)サイジング剤は約15kDaである
i)アルミニウム塩とサイジング剤を混合する前に、アルミニウム塩をリガンド交換(例えば、リン酸リガンド交換)に付す。
E.ナノアラム粒子のサイズ
F.安定性
IV.ナノアラム粒子組成物
A.生物活性剤
i.巨大分子
a.ポリヌクレオチド
1.組み換え発現コンストラクト
2.交互ヌクレオシド間結合および核酸類似体
3.レプリコン
b.ポリペプチド
c.抗原
II.アジュバント
D.TLRアゴニスト
b.TLR7/8アゴニスト
TLR4アゴニスト
または薬剤的に許容できるその塩であり、式中、
L1、L2、L3、L4、L5、およびL6は、同じかまたは異なり、独立して、-O-、-NH-、または-(CH2)-であり、
L7、L8、L9、およびL10は、同じかまたは異なり、独立して、存在しないか、または-C(=O)-であり、
Y1は酸官能基であり、
Y2およびY3は、同じかまたは異なり、独立して、-OH、-SH、または酸官能基であり、
Y4は、-OHまたは-SHであり、
R1、R3、R5、およびR6は、同じかまたは異なり、独立して、C8~13アルキルであり、
R2およびR4は、同じかまたは異なり、独立して、C6~11アルキルである。
d.CpGヌクレオチド
CpG7909:Cooper et al., “CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults.”AIDS, 2005 Sep 23;19(14):1473-9.
CpG10101:Bayes et al., “Gateways to clinical trials.”Methods Find.Exp.Clin.Pharmacol.2005 Apr;27(3):193-219.
Vollmer J., “Progress in drug development of immunostimulatory CpG oligodeoxynucleotide ligands for TLR9.”Expert Opinion on Biological Therapy.2005 May; 5(5): 673-682
iii.生物およびウイルス
B.ナノアラム粒子との会合
i.リガンド交換
II.静電相互作用
C.用量節約
D.医薬組成物
V.ナノアラム粒子および組成物の使用
A.治療薬
B.ワクチン
C.診断薬
VI.キット
ナノアラム製剤の製造。水酸化アルミニウム2%またはAl(OH)3、水酸化アルミニウム、オキシ水酸化アルミニウム2%(Alhydrogel(登録商標)85)を湿性ゲル懸濁液としてEM Sargeantから購入した。以下の脂質をCorden Pharma(スイスのリースタル)から購入した:ジステアロイルグリセロホスホエタノールアミン(DSPE)、N-カルボニル-メトキシポリエチレングリコール-750)-1.2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン(mPEG750-DSPE)、N-(カルボニル-メトキシポリエチレングリコール-2000)-1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン(mPEG2000-DSPE)、N-(カルボニル-メトキシポリエチレングリコール-5000)-1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン(mPEG5000-DSPE)、1,2-ジパルミトイル-sn-グリセロ-3-ホスホエタノールアミン-N-[メトキシ(ポリエチレングリコール)-2000](mPEG2000-DPPE)、1,2-ジパルミトイル-sn-グリセロ-3-ホスホエタノールアミン-N-[メトキシ(ポリエチレングリコール)-5000](mPEG5000-DPPE)、N-(カルボニル-メトキシポリエチレングリコール-2000)-1.2-ジミリストイル-sn-グリセロ-3-ホスホエタノールアミン(mPEG2000-DMPE)、およびN-(カルボニル-メトキシポリエチレングリコール-5000)-1,2-ジミリストイル-sn-グリセロ-3-ホスホエタノールアミン(mPEG5000-DMPE)。Alhydrogel(登録商標)「85」は、EM Sergeant Pulp and Chemical Company(ニュージャージー州クリフトン)から購入し、Brenntag(ドイツのミュールハイム・アン・デア・ルール)によって製造された。ポリ(アクリル酸)(PAA)はSigma Aldrichから購入した。
ナノアラム製剤のCryoEM分析
ナノアラム製剤の生成-サイジング剤の開発
PEGナノアラム-PEG化リン脂質サイジング剤
濃HCL、HNO 3 、およびプロピオン酸によるpHの低下
PAAナノアラム-サイジング剤としてのポリアクリル酸(PAA)
ナノアラム製剤の安定性およびキャラクタリゼーション
実施例2:免疫応答を刺激するためのタンパク質またはペプチド(例えば、ID97)の送達のためのPEG5000およびPAAナノアラム製剤の使用
実施例3.核酸薬剤を送達するためのPAAナノアラム製剤の使用。
実施例4.免疫応答を刺激するためのタンパク質またはペプチド(ID93)送達用PEGナノアラム製剤(様々な長さのPEG)の使用
抗体応答
実施例4:キトサン-、デキストラン-、およびポリ(アリルアミン)-ナノアラム製剤の製造
表6.出発物質としてAdjuphos(登録商標)、安定剤として低分子量キトサン(約120,000Da、最低85%DD)を用いて製造されたナノアラムの組成。
表7.出発アラム物質としてAlhydrogel、安定化剤として硫酸デキストラン(40kDa)を使用して製造したナノアラムの組成
表8.PE-Alhydrogel(登録商標)とキトサンとの混合条件の例。
表9.キトサン(15kDa、最低85%DD)で安定化されたAlhydrogel(登録商標)由来のナノアラムの組成。
表10.ポリ(アリルアミン)で安定化されたAlhydrogel(登録商標)由来のナノアラムを調製するために使用される混合比の例。
表11.ポリ(アリルアミン)で安定化されたAlhydrogel(登録商標)由来のナノアラム製剤の例
参考文献
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2.Weichert R, editor.Determination of Extinction Efficiency and Particle Size Distribution by Photosedimentation using Light of Different Wavelengths.Particle Size Analysis 1981 Proc 4 th Conf held at Loughborough Univ of Technology, 21-24 Sept, 1981 Edited by N G Stanley-Wood and T Allen Chichester, Wiley, 1982; 1981.
4.Xiang SD, Scholzen A, Minigo G, David C, Aspostolopoulos v, Mottram PL, Plebanski M. Pathogen Recognition and Development of Particulate Vaccines: Does Size Matter? Methods.2006: 1-9.
5.Kalkanidis M, Pietersiz GA, Ziang SD, Mottram PL, Crimeen-Irwin B, Ardipradja K, Plebanski M. Methods for Nano-Particle Based Vaccine Formulation and Evaluation of their Immunogenicity.Methods.2006: 20-29
6.Fung HWM, Mikasa TJT, Vergara J, Sivananthan SJ, Guderian JA, Duthie MS, Vedvick TS, Fox CB.Optimizing Manufacturing and Composition of a TLR4 Nanosuspension: Physicochemical Stability and Vaccine Adjuvant Activity.Journal of Nanobiotechnology.2013: 11-43.
7.Weichert R, editor.Determination of Extinction Efficiency and Particle Size Distribution by Photosedimentation using Light of Different Wavelengths.Particle Size Analysis 1981 Proc 4 th Conf held at Loughborough Univ of Technology, 21-24 Sept, 1981 Edited by N G Stanley-Wood and T Allen Chichester, Wiley, 1982; 1981.
8.Schwendener RA.Liposomes as vaccine delivery systems: a review of the recent advances Ther Adv Vaccines.2014 Nov; 2(6): 159-182.
9.A.L.Nail, J.L.White, S.L.Hem, Structure of aluminum hydroxide I: initial precipitate.J Pharm Sci, 65 (1976), pp. 1188-1191.
10.E.B.Lindblad.Aluminium adjuvants D.E.S.Stewart-Tull (Ed.), The theory and practical application of adjuvants, John Wiley & Sons, Ltd, New York (1995), pp. 21-35.
11.S.J.Seeber, J.L.White, S.L.Hem.Predicting the adsorption of proteins by aluminum-containing adjuvantsVaccine, 9 (1991), pp. 201-203.
12.S. Iyer, R.S.Robin Robinett, H. HogenEsch, S.L.Hem.Mechanism of adsorption of hepatitis B surface antigen by aluminum hydroxide adjuvant Vaccine, 22 (2004), pp. 1475-1479.
13.J.V.Rinella Jr., R.F.Workman, M.A. Hermondson, J.L.White, S.L.Hem.Elutability of proteins from aluminum-containing vaccine adjuvants by treatment with surfactants
J Colloid Interface Sci, 197 (1998), pp. 48-56.
14.Baldwin, et.al., 2009, Bertholet, et.al., A Defined Tuberculosis Vaccine Candidate Boosts BCG and Protects Against Multidrug-Resistant Mycobacterium tuberculosis 2010Sci Transl Med 2, 53ra74 (2010)); Baldwin, et.al.The Importance of Adjuvant Formulation in the Development of a Tuberculosis Vaccine.The Journal of Immunology, 2012, 188: 000-000.
Claims (22)
- (a)アルミニウム塩、および
(b)サイジング剤
を含んでなるナノアラム粒子であって、
前記サイジング剤が脂質に結合したPEGであり、
前記粒子のサイズが約1nm~450nmの範囲である、前記ナノアラム粒子。 - 前記アルミニウム塩が、水酸化アルミニウム、水酸化アルミニウムゲル、AlPO4、AlO(OH)、Al(OH)(PO4)、およびKAl(SO4)2からなる群から選択される、請求項1に記載のナノアラム粒子。
- 前記脂質に結合したPEGがリン脂質に結合したPEGである、請求項1に記載のナノアラム粒子。
- 前記サイジング剤が脂質に結合したPEGであり、前記PEGの平均分子量が約750ダルトン~約5000ダルトンの範囲であり、前記脂質が、DSPE、DPPE、DMPE、およびDLPEからなる群から任意に選択される、請求項1に記載のナノアラム粒子。
- 前記ナノアラム粒子が、濾過滅菌された液体製剤中にあり、任意に前記ナノアラム粒子が、約0℃~約8℃で、少なくとも約1ヶ月、少なくとも約6ヶ月、または少なくとも約1年、液体製剤中で安定である、または前記ナノアラム粒子が、約37℃で、少なくとも約1ヶ月、液体製剤中で安定である、請求項1~4のいずれか一項に記載のナノアラム粒子。
- ナノアラム粒子の製造方法であって、サイジング剤の存在下でアルミニウム塩を高エネルギー源に付し、それによりナノアラム粒子を製造することを含んでなり、前記サイジング剤が脂質に結合したPEGであり、前記ナノアラム粒子のサイズが約1nm~約450nmの範囲である、前記方法。
- 前記高エネルギー源が、マイクロフルイダイザー、押出機、超音波処理機、高せん断ミキサー(例えば、シルバーソンミキサー)、またはホモジナイザーのうちの1、2又はそれ以上から得られる、請求項6に記載の方法。
- 前記高エネルギー源が、マイクロフルイダイザーおよび高せん断混合物から得られ、前記アルミニウム塩およびサイジング剤を含んでなる前記混合物を、前記マイクロフルイダイザーに1回~約30回通過させるか、又は、前記高エネルギー源が、マイクロフルイダイザーから得られ、前記アルミニウム塩およびサイジング剤を含んでなる前記混合物を、前記マイクロフルイダイザーに1回~約15回通過させる、請求項6に記載の方法。
- 前記アルミニウム塩が、サイズが0.5~10μmまたは0.5~20μmの粒子からなり、前記アルミニウム塩が、水酸化アルミニウム、水酸化アルミニウムゲル、AlPO4、AlO(OH)、Al(OH)x(PO4)y、およびKAl(SO4)2からなる群から選択されてもよい、請求項6~8のいずれか一項に記載の方法。
- 前記サイジング剤が脂質に結合したPEGであり、前記PEGの平均分子量が約750ダルトン~約5000ダルトンの範囲である、請求項6~9のいずれか一項に記載の方法。
- 請求項1~5のいずれか一項に記載のナノアラム粒子を含んでなる組成物。
- 生物活性剤をさらに含んでなり、ゲル電気泳動によって測定される、約75%を超える前記生物活性剤が、組成物中のナノアラム粒子と会合していてもよい、請求項11に記載の組成物。
- 前記生物活性剤が、ポリペプチド、ポリヌクレオチド、抗原、アジュバント、診断薬、治療薬、または生物であり、前記ポリペプチドが融合タンパク質、全長タンパク質、ペプチド、またはペプチド模倣物であってもよく、前記ポリヌクレオチドが任意にポリペプチドをコードするDNAまたはRNAであってもよく、前記抗原がRig-IアゴニストまたはID97であってもよい、請求項12に記載の組成物。
- 前記組成物がアジュバントをさらに含んでなり、前記アジュバントが、AS-2、モノホスホリルリピドA、3-デ-O-アシル化モノホスホリルリピドA、IFA、QS21、CWS、TOM、AGP、CpG含有オリゴヌクレオチド、トール様受容体(TLR)アゴニスト、Leif、サポニン、サポニン模倣物、生物由来および合成のリピドA、イミキモド、ガーディキモド、レシキモド、ポリI:C、フラジェリン、GLA、SLA、STING、ならびにそれらの組み合わせからなる群から選択されてもよい、請求項11~13のいずれか一項に記載の組成物。
- (a) 前記組成物が液体製剤であり、任意に0.45ミクロンサイズのフィルターまたは0.20ミクロンサイズのフィルターを通して濾過することができる、及び/又は
(b) 前記組成物はバイアルに入れる前に最終的に滅菌することができる、及び/又は
(c) 前記組成物は約0℃~約8℃で、少なくとも約1ヶ月、少なくとも約6ヶ月、または少なくとも約1年間、安定である、及び/又は
(d) 前記組成物は約37℃で、少なくとも約1ヶ月、安定である、
請求項11~14のいずれか一項に記載の組成物。 - 請求項11~15のいずれか一項に記載の組成物を含んでなるワクチン製剤。
- ヒト以外の哺乳類において免疫応答を刺激する方法であって、請求項11~15のいずれか一項に記載の組成物を前記ヒト以外の哺乳類に投与し、それによって前記ヒト以外の哺乳類において免疫応答を刺激することを含んでなる、方法。
- 前記免疫応答が非特異的免疫応答であるか、または抗原特異的免疫応答である、請求項17に記載の方法。
- 前記免疫応答が主にTH1免疫応答であるか、または前記免疫応答が主にTH2免疫応答であるか、または前記免疫応答がTH1およびTH2免疫応答の両方である、請求項18に記載の方法。
- 前記免疫応答が、B細胞の活性化、T細胞の活性化、抗体の産生、またはサイトカインの放出を伴う、請求項18に記載の方法。
- 前記組成物が、アレルギー、嗜癖、癌、または自己免疫の治療に使用される、請求項17~20のいずれか一項に記載の方法。
- 前記ヒト以外の哺乳類が、イヌ、ネコ、ウシ、またはウマである、請求項17~21のいずれか一項に記載の方法。
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AU2022263559A1 (en) | 2022-12-15 |
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CA3023271A1 (en) | 2017-12-07 |
WO2017210364A1 (en) | 2017-12-07 |
AU2017273650B2 (en) | 2022-08-18 |
JP2019521960A (ja) | 2019-08-08 |
CN109195587A (zh) | 2019-01-11 |
EP3463300A1 (en) | 2019-04-10 |
RU2018137841A (ru) | 2020-07-09 |
BR112018074352B1 (pt) | 2021-11-30 |
RU2753874C2 (ru) | 2021-08-24 |
IL262877A (en) | 2018-12-31 |
KR102472026B1 (ko) | 2022-11-30 |
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RU2018137841A3 (ja) | 2020-07-24 |
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IL262877B1 (en) | 2023-01-01 |
JP2022130524A (ja) | 2022-09-06 |
US20200085757A1 (en) | 2020-03-19 |
ZA201807107B (en) | 2019-06-26 |
KR20190015255A (ko) | 2019-02-13 |
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