JP5820805B2 - マイクロプロジェクションのアレイの製造のためのプロセス - Google Patents
マイクロプロジェクションのアレイの製造のためのプロセス Download PDFInfo
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Moulds For Moulding Plastics Or The Like (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Shaping Of Tube Ends By Bending Or Straightening (AREA)
- Micromachines (AREA)
Description
本願は、2009年4月24日に出願された米国仮特許出願第61/172,419号の利益を主張し、この仮特許出願の全内容は本明細書中に援用される。
本明細書に記載される主題は一般的に、活性薬剤の送達のためのマイクロプロジェクションのアレイの製造のためのプロセスに関する。
本発明はまた、以下の項目を提供する。
(項目1)
マイクロプロジェクションアレイを形成する方法であって、
ある量の調合物を基板上に分配するステップと、
上記アレイ中の個々のマイクロプロジェクションに対する複数の空洞を有する鋳型を、上記基板上に分配された上記調合物に接触させるステップであって、上記鋳型および上記調合物は、上記複数の空洞が上記調合物と流体連絡を行なうように接触されるステップと、 調合物を上記複数の空洞に移動させるステップと、
上記複数の空洞の各々に調合物を保持する様式で、上記調合物および上記基板から上記鋳型を分離するステップと
を含む、方法。
(項目2)
マイクロプロジェクションアレイを製作する方法であって、
マイクロプロジェクションのアレイ中のマイクロプロジェクションを形成するための複数の空洞を含む鋳型を固定具の中に位置決めするステップであって、上記固定具は第1の部材と、第2の部材と、少なくとも1つのポートとで構成され、上記鋳型は上記第1および第2の部材の間に位置決めされるステップと、
上記少なくとも1つのポートを通じて上記固定具の中に調合物を導入することによって、上記調合物が上記鋳型の上記複数の空洞の開口部に接触するようにするステップと、
上記固定具中に導入された上記調合物を上記複数の空洞に移動させるステップと、
上記複数の空洞に移動された調合物が上記複数の各空洞中に保持されるような速度で調合物を上記固定具から撤収するステップと
を含む、方法。
(項目3)
移動させるステップは、上記鋳型に接触する上記調合物に圧力を加えることによって、上記複数の空洞に調合物を移動させるステップを含む、項目1または2に記載の方法。
(項目4)
上記調合物および上記基板から上記鋳型を分離するステップは、各空洞に保持される調合物の量の標準偏差が、上記空洞に保持される調合物の平均量の約10%以下であることによって証明される場合、上記複数の空洞の各々における調合物の均一な保持を達成する、項目1に記載の方法。
(項目5)
上記調合物および上記基板から上記鋳型を分離するステップは、上記鋳型の端縁を持ち上げて、制御された速度で上記調合物および基板から上記鋳型を徐々に剥離することによって達成される、項目1または4に記載の方法。
(項目6)
上記制御された速度の分離は、上記鋳型に取り付け可能な回転可能な部材によって行なわれる、項目5に記載の方法。
(項目7)
上記移動させるステップおよび撤収するステップは、各空洞に保持される調合物の量の標準偏差が、上記空洞に保持される調合物の平均量の約10%以下であることによって証明される場合、上記複数の空洞の各々における調合物の均一な保持を達成する、項目2に記載の方法。
(項目8)
上記複数の空洞に保持されていない調合物を回収するステップをさらに含む、項目1または2に記載の方法。
(項目9)
上記複数の上記空洞に保持されていない上記調合物の少なくとも約90%が回収される、項目8に記載の方法。
(項目10)
上記方法における上記ステップの1つまたはそれ以上が約23〜25℃の温度で行なわれる、項目1または2に記載の方法。
(項目11)
上記複数の空洞に保持された上記調合物から溶剤を除去するステップをさらに含む、項目1に記載の方法。
(項目12)
上記鋳型に第2の調合物を適用するステップをさらに含む、項目11に記載の方法。
(項目13)
上記複数の空洞は、ほぼ平面状の鋳型表面から上記鋳型内に突出する、項目1または2に記載の方法。
(項目14)
上記複数の空洞のうち少なくとも1つの空洞に対して、上記少なくとも1つの空洞と、上記平面状の鋳型表面に平行な面との交差部分の直径は、上記面の上記鋳型表面からの距離の関数として単調に減少する、項目13に記載の方法。
(項目15)
上記少なくとも1つの空洞と、上記平面状の鋳型表面に平行な面との上記交差部分の上記直径は、上記面が上記鋳型表面から遠いときよりも上記面が上記鋳型表面に近いときの方が急速に減少する、項目14に記載の方法。
(項目16)
上記少なくとも1つの空洞と、上記平面状の鋳型表面に平行な面との上記交差部分の上記直径は、上記鋳型表面に近い距離の範囲に対しては上記鋳型表面との距離の関数として直線的に減少し、次いで上記鋳型表面からより遠い距離の第2の範囲に対しては、直線的だがもっとゆっくり減少する、項目15に記載の方法。
(項目17)
位置決めするステップは、上記複数の空洞が長い方の寸法および短い方の寸法を有する伸長した空洞であるような鋳型を位置決めするステップを含み、上記鋳型は、上記複数の空洞の各空洞の上記長い方の寸法がほぼ水平であるような様式で上記固定具中に保持される、項目2または7に記載の方法。
(項目18)
上記調合物を導入および撤収するステップは、マイクロプロセッサの制御下で行なわれる、項目2、7または17のいずれか1項に記載の方法。
(項目19)
保持された調合物を有する上記鋳型を上記固定具から取り出すステップをさらに含む、項目2、7、17または18のいずれか1項に記載の方法。
(項目20)
上記複数の空洞の各々における上記保持された調合物から溶剤を除去するステップをさらに含む、先行する項目のいずれかに記載の方法。
本出願においては、簡便さのために、活性が投与される生体膜としてしばしば「皮膚」に言及する。ほとんどまたはすべての場合に、他の生体膜、たとえば口、胃腸管、血液脳関門、またはその他の体組織もしくは器官の内部を覆う生体膜など、または手術中もしくはたとえば腹腔鏡検査もしくは内視鏡検査などの手順の際に露出されるかもしくは接近可能となる生体膜を通じた投与にも、同じ発明原理が適用されることが当業者に理解されるだろう。
第1の局面においては、上述のものなどのマイクロプロジェクションアレイを形成する方法が提供される。この方法の実施形態の1つにおいて、図2A〜図2Dを参照して、マイクロプロジェクションアレイ鋳型20が提供され、この鋳型はアレイ中の個々の微小突起またはマイクロプロジェクションを定める複数の空洞を含む。マイクロプロジェクションはサイズが小さいため、図2A〜図2Dにおいては見えない。複数の空洞の各空洞は開口部と、所望のマイクロプロジェクション構成を与えるために選択されたたとえば直径および高さなどの寸法を有する内表面とを有する。たとえば、空洞の内部寸法は特定の高さ(または長さ)と直径とを有し、図1A〜図1Bに示される例示的マイクロプロジェクションから明らかであるとおり、その直径は高さに沿って変動し得る。鋳型のマイクロプロジェクション空洞の寸法は、製造プロセスのさまざまな因子に依存して、アレイ中の完成マイクロプロジェクションの寸法に正確に相関するか、またはほぼ相関する。同じかまたは異なるマイクロプロジェクションを有するマイクロプロジェクションアレイを得るために、鋳型中の空洞はすべて同じであってもよいし、異なっていてもよいことを熟練した技術者は認識するであろう。
本明細書に記載されるプロセスによって、多様な調合物が鋳型空洞に挿入されてもよい。調合物は「前駆物質調合物」とも呼ばれることによって、鋳型空洞に導入される調合物が、マイクロプロジェクションおよび/またはマイクロプロジェクションアレイを作製するための結果的に得られる固体材料の前駆物質であることを反映する。典型的には、前駆物質調合物の溶剤が除去されることによって、マイクロアレイを作製する最終材料が得られるが、前駆物質調合物に対する他の変化が起こるように設計されてもよいし(たとえば架橋結合または反応など)、偶然起こってもよい。
アレイ鋳造のための一般的なプロセス
マイクロニードル鋳型を、たとえば乾燥熱またはガンマ照射などによって滅菌する。25%のウシ血清アルブミン(bovine serum albumin:BSA)、20%のポリビニルアルコール、27%のトレハロース、および28%のマルチトールを含有し、水中に合計20%の固形分を有する調合物を調製する。ある量の調合物(本明細書においては前駆物質調合物と呼ばれる)、たとえば20μLが鋳型の上に分配される。刈り込まれた先端を有するホールピペットを用いて、調合物を鋳型の上に手動で広げる。次いで、市販の振動機器を用いて、調合物で覆われた鋳型を5秒間ボルテックスすることによって、鋳型に調合物を均一に分布させる。調合物被覆を有する鋳型を1atmの圧力容器に約10分間入れる。次いで圧力を取り除く。鋳型を32℃の温度のインキュベータに約30分間から1時間入れる。次いで両面接着テープを用いてアレイを離型し、任意には裏張りに取り付ける。
2層アレイを鋳造するための一般的なプロセス
実施例1の乾燥ステップの後、離型の前に、類似の手順を用いて鋳型上に付加的な層を鋳造する。付加的な層は、エタノールおよびイソプロピルアルコールの3:1混合物中の20wt%のメタクリル酸カチオンコポリマーEUDRAGIT(登録商標)EPO(ジメチルアミノエチルメタクリレート、ブチルメタクリレート、およびメチルメタクリレートに基づくカチオンコポリマー)の75μLからなる。付加的な層は、ガラススライドを用いて鋳型に均一に適用される。鋳型を圧力容器に入れて、1atmにて2分間加圧する。圧力を解除し、鋳型を乱すことなく圧力容器中で追加の5分間だけ乾燥させる。鋳型を再びインキュベータ中で32℃にて1時間乾燥し、次いで離型する。
剥離を用いて鋳型空洞にマイクロプロジェクション前駆物質を入れる
以下のとおりにマイクロプロジェクションアレイを製造した。平坦な金属基板の上にシリコーンシートを置いた。マイクロピペットを用いて、125μLのマイクロプロジェクション前駆物質調合物を液滴としてシリコーンシート上に分配した。シリコーンでできた柔軟なポリマーマイクロプロジェクションアレイ鋳型を調合物の上に置いて、個々のマイクロプロジェクションを定める複数の空洞の複数の開口部が調合物に面し、かつ鋳型の頂面が調合物と直接接触するようにした。複数の空洞の各空洞は先端領域および基底部(または「漏斗」領域)の両方を含み、約1nLの体積を有した。ピンセットで鋳型の後ろ側に手動で圧力を加えることによって、調合物を広げて鋳型の1”×1”(2.54cm×2.54cm)の範囲を覆うようにした。この集合体を圧力容器の中に入れて、50psi(344.7kPa)にて1分間加圧した。圧力を解除して集合体を圧力容器から取り出した。ピンセットで鋳型の1つの角をつかみ、鋳型をシリコーンシートから剥離した。
剥離を用いて鋳型空洞にマイクロプロジェクション前駆物質を入れる
pH5.5のヒスチジン緩衝液溶剤中の14%のデキストラン70、4.8%のソルビトール、2.8%のヒト副甲状腺ホルモン(1−34)(hPTH)によって構成された調合物を調製した。0.22ミクロンフィルタで調合物を滅菌濾過した。250μLの調合物を浅い貯蔵所に入れ、予め滅菌したシリコーン鋳型を浅い貯蔵所の上に置いて、鋳型中の各マイクロニードルの各空洞の開口部を下に向けることによって、調合物が空洞に入れるようにした。調合物で充填された貯蔵所を有する基板と鋳型とを圧力室内で50psi(344.7kPa)にて1分間加圧することによって、鋳型のマイクロプロジェクション空洞に前駆物質調合物を充填した。次いで鋳型をシリンダに取り付け、シリンダを2〜4mm/分の速度で回転させることによって、浅い貯蔵所から鋳型を剥離した。鋳型の空洞に所望の量の前駆物質調合物が保持され、32℃にて30分間乾燥された。次いで、実施例3に記載されるとおりに乾燥前駆物質の上に基底部層をコートして、微細構造アレイ(直径1cm2に打ち抜かれる)を形成した。各マイクロプロジェクションアレイのhPTH含有量を分析するためにアレイを光学的に検査し、顕微鏡写真が図4に示される。マイクロプロジェクションの先端に集められた薬物が観察される。次いでマイクロアレイを緩衝液に溶解し、hPTH含有量をHPLCによって測定した。テストされた30アレイのサンプルサイズに対して、アレイ当りの平均hPTH含有量は32.9μgであり、変動係数は10%であった。
固定具を用いてマイクロプロジェクション前駆物質を鋳型に入れる
マイクロプロジェクションアレイのための1インチ×1インチ(2.54cm×2.54cm)の鋳型が提供された。鋳型の複数の空洞の各空洞は、先端領域と基底部(または「漏斗」領域)との両方を含み、約1nLの体積を有した。pH5.5のヒスチジン緩衝液溶剤中の2.1%のhPTH(1−34)、14%のテトラデンプン、4.8%のソルビトールによって構成されたマイクロプロジェクション前駆物質調合物を調製した。
剥離を用いて鋳型空洞にマイクロプロジェクション前駆物質を入れる
マイクロプロジェクションアレイのための18mm掛ける30mmの鋳型を得た。pH5.5のヒスチジン緩衝液溶剤中の14%のデキストラン70、4.8%のソルビトール、2.1%のヒト副甲状腺ホルモン(1−34)(hPTH)によって構成された前駆物質を調製した。0.22μmフィルタで前駆物質調合物を滅菌濾過した。
Claims (18)
- マイクロプロジェクションアレイを形成する方法であって、
ある量の調合物を基板上に分配するステップと、
前記アレイ中の個々のマイクロプロジェクションに対する複数の空洞を有する鋳型を、前記基板上に分配された前記調合物に接触させるステップであって、前記鋳型および前記調合物は、前記複数の空洞が前記調合物と流体連絡を行なうように接触されるステップと、
調合物を前記複数の空洞に移動させるステップと、
前記複数の空洞の各々に調合物を保持する様式で、前記調合物および前記基板から前記鋳型を分離するステップと
を含み、前記調合物および前記基板から前記鋳型を分離するステップは、前記複数の空洞の各々における調合物の均一な保持を達成し、標準偏差が、前記空洞に保持される調合物の平均量の10%以下である、方法。 - マイクロプロジェクションアレイを製作する方法であって、
マイクロプロジェクションのアレイ中のマイクロプロジェクションを形成するための複数の空洞を含む鋳型を固定具の中に位置決めするステップであって、前記固定具は第1の部材と、第2の部材と、少なくとも1つのポートとで構成され、前記鋳型は前記第1および第2の部材の間に位置決めされるステップと、
前記少なくとも1つのポートを通じて前記固定具の中に調合物を導入することによって、前記調合物が前記鋳型の前記複数の空洞の開口部に接触するようにするステップと、
前記固定具中に導入された前記調合物を前記複数の空洞に移動させるステップと、
前記複数の空洞に移動された調合物が前記複数の各空洞中に保持されるような速度で調合物を前記固定具から撤収するステップと
を含み、前記移動させるステップおよび撤収するステップは、前記複数の空洞の各々における調合物の均一な保持を達成し、標準偏差が、前記空洞に保持される調合物の平均量の10%以下である、方法。 - 移動させるステップは、前記鋳型に接触する前記調合物に圧力を加えることによって、前記複数の空洞に調合物を移動させるステップを含む、請求項1または2に記載の方法。
- 前記調合物および前記基板から前記鋳型を分離するステップは、前記鋳型の端縁を持ち上げて、制御された速度で前記調合物および基板から前記鋳型を徐々に剥離することによって達成される、請求項1に記載の方法。
- 前記制御された速度の分離は、前記鋳型に取り付け可能な回転可能な部材によって行なわれる、請求項4に記載の方法。
- 前記複数の空洞に保持されていない調合物を回収するステップをさらに含む、請求項1または2に記載の方法。
- 前記複数の前記空洞に保持されていない前記調合物の少なくとも90%が回収される、請求項6に記載の方法。
- 前記方法における前記ステップの1つまたはそれ以上が23〜25℃の温度で行なわれる、請求項1または2に記載の方法。
- 前記複数の空洞に保持された前記調合物から溶剤を除去するステップをさらに含む、請求項1に記載の方法。
- 前記鋳型に第2の調合物を適用するステップをさらに含む、請求項9に記載の方法。
- 前記複数の空洞は、ほぼ平面状の鋳型表面から前記鋳型内に突出する、請求項1または2に記載の方法。
- 前記複数の空洞のうち少なくとも1つの空洞に対して、前記少なくとも1つの空洞と、前記平面状の鋳型表面に平行な面との交差部分の直径は、前記面の前記鋳型表面からの距離の関数として単調に減少する、請求項11に記載の方法。
- 前記少なくとも1つの空洞と、前記平面状の鋳型表面に平行な面との前記交差部分の前記直径は、前記面が前記鋳型表面から遠いときよりも前記面が前記鋳型表面に近いときの方が急速に減少する、請求項12に記載の方法。
- 前記少なくとも1つの空洞と、前記平面状の鋳型表面に平行な面との前記交差部分の前記直径は、前記鋳型表面に近い距離の範囲に対しては前記鋳型表面との距離の関数として直線的に減少し、次いで前記鋳型表面からより遠い距離の第2の範囲に対しては、直線的だがもっとゆっくり減少する、請求項13に記載の方法。
- 位置決めするステップは、前記複数の空洞が長い方の寸法および短い方の寸法を有する伸長した空洞であるような鋳型を位置決めするステップを含み、前記鋳型は、前記複数の空洞の各空洞の前記長い方の寸法がほぼ水平であるような様式で前記固定具中に保持される、請求項2に記載の方法。
- 前記調合物を導入および撤収するステップは、マイクロプロセッサの制御下で行なわれる、請求項2または15のいずれか1項に記載の方法。
- 保持された調合物を有する前記鋳型を前記固定具から取り出すステップをさらに含む、請求項2、15または16のいずれか1項に記載の方法。
- 前記複数の空洞の各々における前記保持された調合物から溶剤を除去するステップをさらに含む、請求項1〜17のいずれか1項に記載の方法。
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CA2759850C (en) | 2019-10-22 |
US20110006458A1 (en) | 2011-01-13 |
EP2429627A2 (en) | 2012-03-21 |
JP2017060807A (ja) | 2017-03-30 |
CA2759850A1 (en) | 2010-10-28 |
JP2012524637A (ja) | 2012-10-18 |
US20130131598A1 (en) | 2013-05-23 |
EP2429627A4 (en) | 2012-12-19 |
JP2016025949A (ja) | 2016-02-12 |
AU2010238605B2 (en) | 2015-10-29 |
US20130292886A1 (en) | 2013-11-07 |
AU2010238605A1 (en) | 2011-11-24 |
WO2010124255A2 (en) | 2010-10-28 |
ES2634667T3 (es) | 2017-09-28 |
JP6159770B2 (ja) | 2017-07-05 |
WO2010124255A3 (en) | 2011-02-03 |
EP2429627B1 (en) | 2017-06-14 |
US20240066277A1 (en) | 2024-02-29 |
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