JP7394779B2 - ネブライザ及び容器 - Google Patents
ネブライザ及び容器 Download PDFInfo
- Publication number
- JP7394779B2 JP7394779B2 JP2020552863A JP2020552863A JP7394779B2 JP 7394779 B2 JP7394779 B2 JP 7394779B2 JP 2020552863 A JP2020552863 A JP 2020552863A JP 2020552863 A JP2020552863 A JP 2020552863A JP 7394779 B2 JP7394779 B2 JP 7394779B2
- Authority
- JP
- Japan
- Prior art keywords
- fluid
- container
- nebulizer
- pump
- pressure
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 37
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- B05B11/028—Pistons separating the content remaining in the container from the atmospheric air to compensate underpressure inside the container
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
- B05B11/01—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
- B05B11/10—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle
- B05B11/109—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle the dispensing stroke being affected by the stored energy of a spring
- B05B11/1091—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle the dispensing stroke being affected by the stored energy of a spring being first hold in a loaded state by locking means or the like, then released
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B15/00—Details of spraying plant or spraying apparatus not otherwise provided for; Accessories
- B05B15/40—Filters located upstream of the spraying outlets
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Description
ブデソニドの水性ナノ懸濁液(71.079mg/mL)は、0.0075%ツイーン80及び0.0075%SDS(これら両方がテンシドであり、すなわち、ツイーン80=ポリソルベート80はo/w乳化剤であり、SDS=ラウリル硫酸ナトリウムは=/W乳化剤である)を含む1%HPC-SL(分散助剤)中で調製した。HPC-SL(ヒドロキシプロピルセルロース)は、ナノ懸濁液を安定化するために使用され、すなわち、分散助剤であり、その添加は、結果として生じる流体の粘性の増加を誘発する。このナノ懸濁液の粘性に対して、106cPという値(せん断速度依存性に関する開始値)を測定した(実験室条件、すなわち室温で)。ブデソニド粒子のサイズ低減に粉砕処理を用いた。
水中に0.1%シクロスポリンを含む市販で入手可能な乳濁液(水と、シクロスポリンと、グリセリンと、セタルコニウムクロリドと、中鎖トリグリセリド(MCT)と、水酸化ナトリウムと、ポロクサマー188と、チロキサポールとを含む重度角膜炎の治療に向けた点眼液であるIkervis(登録商標))を図1~図4に記載のソフトミスト吸入器(試験構成:バネ力60N、8μmの幅と5.6μmの高さとを有するノズルチャネル)を用いて成功裏に噴霧した。この場合、驚くべきことに、噴霧される懸濁液の微粒子分量は、類似のネブライザ(噴霧が二噴流衝突原理に従って発生する)を用いて噴霧された従来の水溶液に関する分量さえも上回る。すなわち、レーザ回折技法によるデータ測定は、75%の範囲内の微粒子分量(5ミクロン及びそれよりも小さい直径を有するエアロゾル粒子の分量)と1.6sのスプレー時間とを示した。(眼科投与では、小さい吸入可能分量しか取得しないようにバネ力及びノズル径を寸法変更しなければならず、この構成における測定は、水中油乳濁液を用いてスプレーを発生させるためのシステムの能力を証明するためだけのものであった。)
水性連続相中にゲル化剤を含有するゲル
水性連続相中にゲル化剤として0.5%アミロペクチン(コーンスターチ由来の)を含有するゲルを、100mlの冷水中に0.5gのスターチを分散させ、それを撹拌しながら60~70℃まで加熱することによって調製した。このゲルを図1~図4に記載のネブライザ1/ソフトミスト吸入器(試験構成:バネ力45N、8μmの幅と5.6μmの高さとを有するノズルチャネル)を用いて成功裏に噴霧した。この場合、レーザ回折技法によるデータ測定は、70%の範囲内の微粒子分量(5ミクロン及びそれよりも小さい直径を有するエアロゾル粒子の分量)と1.25sのスプレー時間とを示した。
眼科治療に向けて市販で入手可能なゲル「Artelac Nighttime Gel(登録商標)」、すなわち、ドライアイ(慢性涙液機能障害)を有する人々に向けて設計され、涙膜の3つ全ての層を補完し、2mgのカルボマーと、トリグリセリド脂質と、滅菌水とを含有し、それに加えてソルビトール、水酸化ナトリウム、及びセトリミドを防腐剤として含有するアイゲルを図1~図4に記載のネブライザ1/ソフトミスト吸入器(試験構成:バネ力45N、8μmの幅と5.6μmの高さとを有するノズルチャネル)を用いて同様に成功裏に噴霧した。この場合、レーザ回折技法によるデータ測定は、43%の範囲内の微粒子分量と1.8sのスプレー時間とを示した。粘性のせん断速度依存性測定は、300.000センチポアズの開始粘性(すなわち室温での「静止」粘性)は、1000s-1のせん断速度において200センチポアズまで線形に低減され、使用した試験機材(いわゆる「サール型」、すなわち、回転する内側シリンダを含む同心シリンダ粘度計)を用いてそれよりも高いせん断速度を印加することができなかったが、成功裏の噴霧の結果に起因して、ノズルチャネル12d内の高めのせん断速度に起因して粘性が更に一層低減されると仮定しなければならない。
大豆レシチンをエタノール中に溶かし、PEG400(ポリエチレングリコール)を添加して撹拌する(水中に分散させる)ことによって様々なリポソーム流体を調製した。その後、別個に撹拌したグリセリンと水(高純度)との混合物を添加し、更に別の撹拌を続けた。変形では、大豆レシチンの量(0.625%m/mから25%m/mまで、それぞれ75mg~3000mg)、グリセリンの量(0~16.7容積%、それぞれ0~2ml)、及びPEGの量(0~8.3容積%、それぞれ0~1ml)を一定量の水及びエタノール(6ml及び3ml)中で変化させた。流体の更に別の変形では、流体の安定性を求めて大豆レシチンの一部をコレステロールで置き換えた(0~35モル%のコレステロールを100~65モル%のレシチンと合せて、好ましくは、コレステロール含有量は25モル%であった、すなわち、例えば、いわゆる「1.25%m/mレシチン製剤」において、3mlのエタノール及び6mlの水の中で22.52mgのコレステロールを112mgの大豆レシチンと合せて、場合によってPEG400及びグリセリンを添加した)。
1 ネブライザ
1b ネブライザハウジング
2 流体
3 容器
4 可変/圧壊可能容積
5 圧力発生器/流体ポンプ
6 ホルダ
7 駆動バネ
8 阻止要素
8b ボタン
9 搬送チューブ
10 逆止弁
11 圧力チャンバ
11b 前置フィルタ
12 ノズル
12a プレート
12b カバープレート
12c 流入領域
12d ノズルチャネル
12e ノズル開口部
12f 微細濾過フィルタ
12g 入口開口部(ノズルの)
13 マウスピース
14 エアロゾル
15 空気供給開口部
16 上側ハウジング部分
17 内側部分
17a 内側部分の上側部分
17b 内側部分の下側部分
18 ハウジング部分(下側部分)
18a 給気デバイス
18b 穿通要素
19 保持要素
20 (外側)ケーシング(容器の)
21 ヘッド(容器の)
22 ベース(容器の)
23 通気孔
24 シェル/内側ハウジング
25 閉鎖部
26 シール
27 通気開口部
28 流体ピストン
28a 凹部
29 シール(流体ピストンの)
30 空気ポンプ
31 ポンプピストン
32 シリンダ
33 インサート
33a 止め具
34 ポート
35 シール(ポートの)
36 伸縮バネ
37 担持部分
38 担持部分
39 ポンプチャンバ
40 弁
41 漏出通路
42 弁要素
42a 可撓性部分
43 入口/逆止弁
44 制御弁
45 開口部
46 チャネル
47 チャネル
48 出口開口部
49 改造端部
50 支持/スロットル要素
125 インジケータデバイス
126 ロックデバイス
C 曲線
X 軸
Y 軸
Claims (52)
- 流体(2)を噴霧するためのネブライザ(1)と、多様な用量の該流体(2)を収容する容器(3)とを含むシステムであって、
前記ネブライザ(1)は、前記流体(2)をエアロゾル(14)に変換する吸入器であり、エアロゾルのエアロゾル粒子は、3ミクロンから10ミクロンまでの空気動力学的直径を有し、一部の前記エアロゾル粒子が5ミクロンよりも小さく、
前記ネブライザ(1)は、前記容器(3)から前記流体(2)の用量を引き出し、かつそれぞれの用量を5MPaから250MPaまでの動作圧で噴霧に向けて加圧するための流体ポンプ(5)と、3ミクロンから20ミクロンまでの範囲内の水力直径を有するノズルチャネル(12d)を有するノズル(12)を形成するマイクロ構造化構成要素とを含み、
室温での前記流体(2)は、1.7×10-3パスカル秒(1.7センチポアズ)よりも高い静止時の粘性を有し、
前記流体(2)は、せん断減粘挙動を有する、
前記流体(2)は、リポソーム流体であり、
前記流体(2)は、少なくとも2つの成分から作製/生成され、前記容器(3)は、該少なくとも2つの成分のうちの1つを各々が閉じ込める少なくとも2つのチャンバ/内側容積を含み、該流体(2)は、該容器(3)内で該2つの成分を組み合わせる/混合することによって作製/生成される、
ことを特徴とするシステム。 - 前記流体ポンプ(5)は、前記流体(2)のそれぞれの用量を10MPaから50MPaまでの動作圧で噴霧に向けて加圧することを特徴とする請求項1に記載のシステム。
- 前記ノズル(12)は、4ミクロンから12ミクロンまでの範囲内の水力直径を有するノズルチャネル(12d)を有することを特徴とする請求項1に記載のシステム。
- 前記ノズル(12)は、5ミクロンから8ミクロンまでの範囲内の水力直径を有するノズルチャネル(12d)を有することを特徴とする請求項3に記載のシステム。
- 室温での前記流体(2)は、0.1パスカル秒(10センチポアズ)よりも高い静止時の粘性を有することを特徴とする請求項1に記載のシステム。
- 前記流体(2)は、室温で1.6×10-3パスカル秒(1.6センチポアズ)までの粘性を有する液体を含むことを特徴とする請求項1に記載のシステム。
- 前記流体(2)は、構造化流体であることを特徴とする請求項6に記載のシステム。
- 前記液体は、水又はエタノール、又は水及びエタノールの混合物であることを特徴とする請求項6に記載のシステム。
- 噴霧された前記エアロゾル粒子のうち60%の範囲内の前記エアロゾル粒子が、5ミクロンよりも小さいことを特徴とする請求項1から8のいずれか一項に記載のシステム。
- 前記流体(2)は、ナノ粒子の懸濁液であることを特徴とする請求項1から9のいずれか一項に記載のシステム。
- 前記ナノ粒子は、βアドレナリン作動薬又はグルココルチコステロイドのような活性成分を含むことを特徴とする請求項10に記載のシステム。
- 前記ナノ粒子は、前記流体(2)中で10%までの濃度を有することを特徴とする請求項10に記載のシステム。
- 前記ナノ粒子は、前記流体(2)中で7%までの濃度を有することを特徴とする請求項12に記載のシステム。
- 前記ナノ粒子は、前記流体(2)中で1%よりも高い濃度を有することを特徴とする請求項12又は13に記載のシステム。
- 前記流体(2)は、乳濁液であることを特徴とする請求項1から8のいずれか一項に記載のシステム。
- 前記流体(2)は、水中油乳濁液であることを特徴とする請求項15に記載のシステム。
- 前記流体(2)は、リポソーム、又は脂質小滴、又は脂質粒子を含み、該リポソーム、又は脂質小滴、又は脂質粒子は、溶解した又は埋め込まれた活性成分を含むことを特徴とする請求項1乃至16のいずれか1項に記載のシステム。
- 前記リポソーム流体は、生理的脂質を含むことを特徴とする請求項1乃至17のいずれか1項に記載のシステム。
- 前記リポソーム流体は、リン脂質を含むことを特徴とする請求項18に記載のシステム。
- 前記リポソーム流体は、レシチン又はレシチン及びコレステロールの混合物を含むことを特徴とする請求項18に記載のシステム。
- 前記流体(2)は、17%よりも少ないグリセリンを含むことを特徴とする請求項1から20のいずれか一項に記載のシステム。
- 前記流体(2)は、10%よりも少ないグリセリンを含むことを特徴とする請求項21に記載のシステム。
- 前記流体(2)は、1%よりも少ないグリセリンを含むことを特徴とする請求項22に記載のシステム。
- 前記流体(2)は、グリセリンを含まないことを特徴とする請求項1から20のいずれか一項に記載のシステム。
- 容器(3)が、前記流体(2)を閉じ込める可変、又は圧壊可能、又は圧縮性の容積(4)を含むことを特徴とする請求項1から24のいずれか一項に記載のシステム。
- 前記容器(3)は、前記流体(2)を閉じ込める圧壊可能容積(4)としての圧壊可能バッグを含むことを特徴とする請求項25に記載のシステム。
- 前記容器(3)は、前記流体(2)を直接に受け入れるための空間又は該流体(2)を閉じ込める前記可変又は圧縮性の容積(4)を形成する剛性ケーシング(20)とそこで移動可能な流体ピストン(28)とを含むことを特徴とする請求項25に記載のシステム。
- システムが、前記容器(3)内の前記流体(2)を加圧する手段、又は該流体(2)を閉じ込める前記可変、又は圧壊可能、又は圧縮性の容積(4)に圧力を印加する手段を含むことを特徴とする請求項25から27のいずれか一項に記載のシステム。
- 前記手段は、前記容器(3)からの流体(2)の引き出し中に該流体(2)を(周囲圧に加えて)5000から3×105パスカルまで(0.05から3barまで)の圧力で加圧し、又は5000から3×105パスカルまで(0.05から3barまで)の圧力を印加することができることを特徴とする請求項28に記載のシステム。
- 前記手段は、前記容器(3)からの流体(2)の引き出し中に該流体(2)を(周囲圧に加えて)20000から105パスカルまで、又は105から2×105パスカルまで(0.2~1bar又は1~2bar)の圧力を印加することができることを特徴とする請求項29に記載のシステム。
- 前記可変又は圧壊可能又は圧縮性の容積(4)に圧力を印加する前記手段は、前記流体(2)の引き出し中に前記容器(3)の流体出口の方向に及び/又は流体入口の方向に前記ネブライザ(1)の中に該圧力を印加するように構成されることを特徴とする請求項29または30に記載のシステム。
- 前記手段は、前記容器(3)内の前記流体(2)を加圧して該容器(3)から該流体(2)を用量単位で引き出すのを支援するために該容器(3)に関連付けられた空気ポンプ(30)によって形成される又はそれを含むことを特徴とする請求項29または30に記載のシステム。
- 前記ネブライザ(1)の使用中に、前記空気ポンプ(30)及び前記流体ポンプ(5)は、交互に加圧することを特徴とする請求項32に記載のシステム。
- 前記ネブライザ(1)の使用中に、前記空気ポンプ(30)は、該ネブライザ(1)を引張又は装填する時に空気を加圧し、前記流体ポンプ(5)は、流体(2)の前記用量を分配又は噴霧する時に流体(2)の用量を加圧することを特徴とする請求項33に記載のシステム。
- 前記空気ポンプ(30)は、前記ネブライザ(1)のハウジング(1b)内の前記容器(3)の相対移動によって作動されることを特徴とする請求項32から34のいずれか一項に記載のシステム。
- 前記容器(3)は、流体(2)の用量を引き出す時及び/又は該流体(2)の用量を加圧又は分配する時に前記ネブライザ(1)内で移動可能であることを特徴とする請求項35記載のシステム。
- 前記容器(3)は、前記ネブライザ(1)内でストローク状に移動可能であることを特徴とする請求項36に記載のシステム。
- 前記空気ポンプ(30)は、前記容器(3)から前記流体(2)を用量単位で引き出すのを支援するために空気をポンピングするためのピストン/シリンダ配置を含む又は形成することを特徴とする請求項32から37のいずれか一項に記載のシステム。
- 前記容器(3)は、前記空気ポンプ(30)のポンプピストン(31)を駆動する又は形成することを特徴とする請求項32から38のいずれか一項に記載のシステム。
- 前記空気ポンプ(30)のポンプピストン(31)は、ハウジング部分(18)、又は関連のシリンダ(32)、又はインサート(33)と協働する又はその中で移動可能であることを特徴とする請求項39に記載のシステム。
- 前記ハウジング部分(18)は、切り離し可能であることを特徴とする請求項40に記載のシステム。
- 前記ネブライザ(1)又は空気ポンプ(30)は、該空気ポンプ(30)又はそのポンプチャンバ(39)内のいずれの圧力不足も防止する入口弁(44)を含むことを特徴とする請求項32から41のいずれか一項に記載のシステム。
- 前記ネブライザ(1)は、手持ち式デバイス及び/又は可搬デバイスである、ことを特徴とする請求項1から42のいずれか一項に記載のシステム。
- 前記流体(2)は、リポソーム流体であり、該リポソーム流体は、少なくとも第1の成分及び第2の成分から生成され、前記第1の成分は、レシチン又はジパルミトイルホスファチジルコリン(DPPC)を含み、前記第2の成分は、液体を含むことを特徴とする請求項1から43のいずれか一項に記載のシステム。
- 前記第2の成分は、水溶液を含むことを特徴とする請求項44に記載のシステム。
- 前記少なくとも2つの成分は、容器(3)内の前記少なくとも2つのチャンバ/内側容積内に貯蔵され、各チャンバ/内側容積が、該少なくとも2つの成分のうちの1つを閉じ込め、前記少なくとも2つのチャンバ/内側容積は(最初に)流体分離され、
前記チャンバ/内側容積は、前記成分のうちの少なくとも1つが他方の中に/他のチャンバのうちの1つの中に少なくとも部分的に移送され、それによって該少なくとも2つの成分が前記流体(2)を作製する/生成する/発生させるために混合される/組み合わされるように流体接続可能である、
ことを特徴とする請求項1から43のいずれか一項に記載のシステム。 - 前記流体は、該流体(2)を噴霧するために前記容器(3)が前記ネブライザ(1)に流体接続される前に作製可能/発生可能/生成可能であることを特徴とする請求項46に記載のシステム。
- 前記チャンバは、前記ネブライザ(1)を用いて前記容器(3)から流体(2)を噴霧するわずか前に流体接続可能であることを特徴とする請求項46又は47に記載のシステム。
- 前記リポソーム流体は、少なくとも第1の成分及び第2の成分から生成され、前記第1の成分は、レシチン又はジパルミトイルホスファチジルコリン(DPPC)を含み、前記第2の成分は、液体を含むことを特徴とする請求項48に記載のシステム。
- 前記第2の成分は、水溶液を含むことを特徴とする請求項49に記載のシステム。
- 前記リポソーム流体は、少なくとも第1の成分及び第2の成分から生成され、前記第1の成分は、貯蔵中に固体であり、前記第2の成分は、液体であることを特徴とする請求項48に記載のシステム。
- 前記第1の成分は、貯蔵中に、粉末の形態にある、及び/又は、フリーズドライ又は凍結乾燥された粒子の形態にある、固体であることを特徴とする請求項51に記載のシステム。
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