JP6655169B2 - ジェット粉砕法 - Google Patents
ジェット粉砕法 Download PDFInfo
- Publication number
- JP6655169B2 JP6655169B2 JP2018512559A JP2018512559A JP6655169B2 JP 6655169 B2 JP6655169 B2 JP 6655169B2 JP 2018512559 A JP2018512559 A JP 2018512559A JP 2018512559 A JP2018512559 A JP 2018512559A JP 6655169 B2 JP6655169 B2 JP 6655169B2
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- Prior art keywords
- liquid aerosol
- jet
- milling
- grinding chamber
- aerosol
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- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical group [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960005105 terbutaline sulfate Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229950000835 tralokinumab Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960004258 umeclidinium Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000010947 wet-dispersion method Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C19/00—Other disintegrating devices or methods
- B02C19/06—Jet mills
- B02C19/061—Jet mills of the cylindrical type
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C19/00—Other disintegrating devices or methods
- B02C19/06—Jet mills
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C23/00—Auxiliary methods or auxiliary devices or accessories specially adapted for crushing or disintegrating not provided for in preceding groups or not specially adapted to apparatus covered by a single preceding group
- B02C23/18—Adding fluid, other than for crushing or disintegrating by fluid energy
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Disintegrating Or Milling (AREA)
Description
使用される供給原料は、例えば呼吸器疾患の治療のための、吸入による投与に適した1つ以上の医薬活性物質、抗炎症薬、気管支拡張薬、抗ヒスタミン薬、うっ血除去薬および鎮咳薬物質を含み得る。好ましい医薬活性物質は、抗コリン薬、アデノシンA2A受容体アゴニスト、β2−アゴニスト、カルシウムブロッカー、IL−13阻害薬、ホスホジエステラーゼ−4−阻害薬、キナーゼ阻害薬、ステロイド、CXCR2、タンパク質、ペプチド、免疫グロブリン、例えば抗IG−E、核酸、特にDNAおよびRNA、小分子阻害薬およびロイコトリエンB4アンタゴニストを含む。
供給原料は、力制御剤などの添加剤材料を含むことができる。力制御剤は、粉末製剤内の微粒子間の凝集力を低下させる添加剤であり、それによって粉末を乾燥粉末吸入器から分配する際の解凝集(デアグロメレーション)を促進する。適切な力制御剤は、WO1996/023485に開示されており、物質が必ずしも肺に到達するとは限らないが、好ましくは生理学的に許容される材料からなる。
用語「共微細(co-micronise)」および「共ジェット粉砕(co-jet mill)」は、本明細書で使用される場合、同義語である。
さらなる実施形態において、供給原料は、医薬賦形剤を含む。呼吸器疾患の治療における吸入用の乾燥粉末製剤は、一般に微細化された活性医薬成分と粗い担体粒子とを混合して整った混合物を得ることによって製剤化される。担体粒子は、微細化された活性医薬成分の粘着性を低下させ、その流動性を改善する。これにより、製造プロセス中に粉末が取り扱いやすくなる。微細化された活性粒子は、乾燥粉末吸入器に貯蔵されたときに担体粒子の表面に付着する傾向があるが、呼吸器内に吸入されると担体粒子の表面から分散されて、細かいエアロゾルを提供する。大きな担体粒子は、その慣性により咽喉に衝突し、ほとんどが口腔咽頭腔に堆積する。
本明細書で使用される「周囲条件」は、22℃±5℃および40〜50%RHとして定義される。ここで使用される「周囲温度」および「周囲湿度」という用語は、それぞれ22℃±5℃および40〜50%RHとして定義される。
以下、実施例を挙げて本発明の実施例を説明する。実施形態の以下の説明は、説明のためのものであり、添付の特許請求の範囲およびそれらの等価物によって定義される発明を限定する目的ではないことは当業者には明らかであろう。
微細化グリコピロレート製剤の粒径分布は、Malvern Mastersizer分析(Malvern Mastersizer 3000、4バール、30〜40%の供給速度でAero S乾式分散法を使用)によって決定した。使用された光学特性には、1.52の屈折率と1.0の吸収値が含まれる。
微細化グリコピロレート製剤の粒径分布は、以下のように、Hydro MV湿式分散ユニットを使用してMalvern Mastersizer 3000によって決定した:分散ユニットをイソオクタン(2,2,4−トリメチルペンタン)で充填した。ポンプ速度は、3000rpmに設定した。約10mgの微細化グリコピロレート製剤にイソオクタン中0.1%レシチン10ミリリットルを添加し、この予備分散液をSonopuls音波プローブを用いて50%強度で3分間超音波処理した。分散した粒子を分散ユニットに添加して、5〜15%の不明瞭さに到達させた。用いた光学特性は、グリコピロレートの屈折率1.52、吸収値1.0、ステアリン酸マグネシウムの屈折率1.45、吸収値1.0、イソオクタンの屈折率1.391であった。測定ごとに6回繰り返した。
微細化グリコピロレートの非晶質含量は、25℃の温度に設定されたSMS DVS Advantage装置を用いてDVSによって評価された。湿度は、10%RHのステップで0〜90%RHから増加し、0%RHに戻り、0.0001(%dm/dt)の質量変化によって引き起こされたステップ間で変化する。
製剤1a(乾燥ガス中でのみジェット粉砕されたグリコピロレート);製剤1b(液体エアロゾルを用い加湿ガス中でのみジェット粉砕されたグリコピロレート);製剤1c(液体エアロゾルを用い加湿ガス中で共ジェット粉砕されたグリコピロレートおよびステアリン酸マグネシウム)
3つの別個のグリコピロレート製剤を作製し、以下のように分析した:
AS−50スパイラルジェットミル(入口圧力=5bar、粉砕圧力=3バール、平均供給速度=2g/分)で微細化する前に、未微細化グリコピロレート(15g、D10=20.6μm、D50=148.7μm、D90=409.7μm)をガラスビーカー中で金属スパチュラを用いて30秒間予め撹拌した。湿度<20%RH(2.8〜3.5%RH)の乾燥粉砕ガスを用いて製剤1aを製造した。
液体エアロゾルを用いて粉砕ガスの湿度を上げた(22℃で31.6〜36.2%RH)以外は、製剤1bは、上記のように製造された。超音波ネブライザーの出口をチューブ配管によってAS−50ジェットミルの粉砕チャンバに接続し、水が粉砕チャンバに滴下しないように、噴霧された水エアロゾルと未微細化グリコピロレートを組み合わせた。収集容器の出口の出口ガス流にプローブを有するポータブル湿度計を置くことによって、ジェット粉砕前に湿度を測定した。
AS−50スパイラルジェットミル(入口圧力=5バール、粉砕圧力=3バール、平均供給速度=2g/分)で微細化する前に、未微細化グリコピロレート(14.25g、D10=20.6μm、D50=148.7μm、D90=409.7μm、Malvern Mastersizer 3000湿式分析法により測定)とステアリン酸マグネシウム(0.75g、D10=2.8μm、D50=8.8μm、D90=27.4μm、Malvern Mastersizer 3000湿式分析法により測定)をガラスビーカー中で金属スパチュラを用いて30秒間予め攪拌した。製剤1cは、液体エアロゾルを用いた高湿度(22℃で32.4〜37.1%RH)の粉砕ガスを使用して製造された。超音波ネブライザーの出口をチューブ配管によってAS−50ジェットミルの粉砕チャンバに接続し、水が粉砕チャンバに滴下しないように、噴霧された水エアロゾルと未微細化グリコピロレートを組み合わせた。収集容器の出口の出口ガス流にプローブを有するポータブル湿度計を置くことによって、ジェット粉砕前に湿度を測定した。
乾燥条件下で粉砕すると、ジェット粉砕されたばかりのグリコピロレートは、製剤1a(図3)のDVSデータによって確認されるように、実質量の非晶質物質を含有する。湿った状態でこの非晶質物質が存在すると、正しく制御されないと、予測不可能な形で大きな凝集塊が形成される。製剤1aの場合、ジェット粉砕粉末から3つの別々のサンプルが採取され、DVS、湿式PSDおよび乾式PSD分析のためにシールされたシンチレーションバイアルで短時間移送される。まず、DVS分析を開始し、続いて湿式および乾式PSD分析を開始した。製剤1aは、D90およびD50の値(表1)で示されるように、乾式PSD分析に先立って、シールされたシンチレーションバイアルにおいて相当量の大きな凝集塊を発達させた。乾式PSD分析はまた、製剤1aが他の製剤1b−1cと同等のD10値を有し、製剤1aがなお微細化成分を有することを実証している(表1)。湿式PSD分析は、製剤1aのPSD値が小さいことを示す(表1)。
2 粉砕チャンバ
3 中心軸
4 圧縮粉砕ガス
5 ガス吸入口
6 ガスマニホールド
7 ミル本体
8 噴射孔
9 渦
10 出口パイプ
11 混入粒子
12 液体エアロゾル
13 エアロゾル発生器
14 混入微細化粒子
15 渦調整器
16 供給漏斗
17 ポート
18 圧縮供給ガス
19 供給ガス入口
Claims (9)
- 粉砕チャンバと、液体エアロゾルを前記粉砕チャンバに供給するよう構成されたエアロゾル発生器と備え、
前記エアロゾル発生器が前記粉砕チャンバの外部にあり、かつ外部の前記エアロゾル発生器が、供給原料として粉砕材料および液体エアロゾルを同時に前記粉砕チャンバに供給するためのポートを有するように構成されているジェットミル。 - 前記ポートが、供給原料として、共存する粉砕材料および液体エアロゾルを前記粉砕チャンバに同時に供給するよう構成されている、請求項1に記載のジェットミル。
- 前記エアロゾル発生器が、前記粉砕チャンバに入る前にレーザ回折によって測定するとD90が100μm未満の液体エアロゾルを生成する、請求項1または請求項2に記載のジェットミル。
- 微細化材料を製造する方法であって、医薬活性物質、医薬添加剤および医薬賦形剤の少なくとも1つを含む粒子状の粉砕材料と、液体エアロゾルとを含む供給原料をジェット粉砕するステップを備える方法。
- 前記液体エアロゾルが、湿度計で測定して10%RHより高い粉砕湿度を粉砕チャンバに提供する、請求項4に記載の方法。
- 前記液体エアロゾルが医薬活性物質を含む、請求項4または請求項5に記載の方法。
- 前記液体エアロゾルが医薬添加剤を含む、請求項4から請求項6のいずれか一項に記載の方法。
- 前記液体エアロゾルが医薬賦形剤を含む、請求項4から請求項7のいずれか一項に記載の方法。
- 微細化された医薬活性物質の表面の非晶質物質の存在を低減する方法であって、供給原料として前記医薬活性物質および液体エアロゾルを粉砕チャンバで混合するステップと、前記供給原料をジェット粉砕するステップと、を備える方法。
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PCT/EP2016/071321 WO2017042341A1 (en) | 2015-09-09 | 2016-09-09 | Jet milling method |
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JO3510B1 (ar) | 2011-03-04 | 2020-07-05 | Heptares Therapeutics Ltd | استخدام جلايكوبيرولات لعلاج عدم انتظام دقات القلب |
DE102011102614A1 (de) | 2011-05-27 | 2012-11-29 | Roland Nied | Verfahren zum Betrieb einer Strahlmühle sowie Strahlmühle |
JP5872205B2 (ja) | 2011-08-22 | 2016-03-01 | 株式会社スギノマシン | 蒸気滅菌手段を備えた湿式微粒化装置 |
KR102391332B1 (ko) | 2013-03-15 | 2022-04-26 | 펄 테라퓨틱스 인코포레이티드 | 미립자 결정질 재료를 컨디셔닝하는 방법 및 시스템 |
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DK3346990T3 (da) | 2020-06-02 |
US20220105519A1 (en) | 2022-04-07 |
CN108135851B (zh) | 2022-03-15 |
US11229915B2 (en) | 2022-01-25 |
EP3346990B1 (en) | 2020-03-18 |
PL3346990T3 (pl) | 2020-08-24 |
ES2912506T3 (es) | 2022-05-26 |
WO2017042341A1 (en) | 2017-03-16 |
EP3689339B1 (en) | 2022-01-26 |
LT3346990T (lt) | 2020-10-12 |
ES2794775T3 (es) | 2020-11-19 |
EP3346990A1 (en) | 2018-07-18 |
JP2018529512A (ja) | 2018-10-11 |
HK1257259A1 (zh) | 2019-10-18 |
CN108135851A (zh) | 2018-06-08 |
US11759791B2 (en) | 2023-09-19 |
US20180257084A1 (en) | 2018-09-13 |
EP3689339A1 (en) | 2020-08-05 |
PT3346990T (pt) | 2020-05-18 |
CA2996072A1 (en) | 2017-03-16 |
SI3346990T1 (sl) | 2020-07-31 |
CA2996072C (en) | 2020-06-30 |
HUE050233T2 (hu) | 2020-11-30 |
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