WO2002005787A1 - Production method for freeze-dried products - Google Patents

Production method for freeze-dried products Download PDF

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Publication number
WO2002005787A1
WO2002005787A1 PCT/JP2001/006115 JP0106115W WO0205787A1 WO 2002005787 A1 WO2002005787 A1 WO 2002005787A1 JP 0106115 W JP0106115 W JP 0106115W WO 0205787 A1 WO0205787 A1 WO 0205787A1
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WO
WIPO (PCT)
Prior art keywords
freeze
layer
dried
frozen
ice layer
Prior art date
Application number
PCT/JP2001/006115
Other languages
French (fr)
Japanese (ja)
Inventor
Muneo Nonomura
Kei Mukai
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU2001269524A priority Critical patent/AU2001269524A1/en
Publication of WO2002005787A1 publication Critical patent/WO2002005787A1/en

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Classifications

    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

A production method for freeze-dried products for preventing the crumbling and scattering of freeze-dried cake and shortening time required for frozen water content to sublimate, the method comprising the steps of forming a frozen layer of an aqueous solution containing a material to be dried in a freeze-drying vessel covered on part or entire of the inner surface thereof with an ice layer, and freeze-drying the material to be dried, characterized in that the frozen layer is formed so that the ice layer is partially exposed to the surface of the frozen layer of the aqueous solution containing the material to be dried or a temperature control is effected so that the temperature of the freeze-drying vessel is kept at at least 0?C in the initial stage of sublimation of frozen water content and then is lowered to up to 0°C during the sublimation.

Claims

50 請 求 の 範 囲 50 Scope of Claim
1 . 内面の一部または全部が氷層で被覆された凍結乾燥用容器中で被乾燥物 含有水性液の凍結層を形成し、 被乾燥物を凍結乾燥する凍結乾燥物の製造法であ つて、 氷層が部分的に被乾燥物含有水性液の凍結層表面に露出するように凍結層 を形成させることを特徴とする凍結乾燥物の製造法。 1. A method for producing a freeze-dried product in which a frozen layer of an aqueous liquid containing a substance to be dried is formed in a freeze-drying container in which part or all of the inner surface is covered with an ice layer, and the substance to be dried is freeze-dried. A method for producing a freeze-dried product, comprising forming a frozen layer such that an ice layer is partially exposed on the surface of the frozen layer of the aqueous liquid containing the substance to be dried.
2 . 氷層上に、 凍結層を不連続に形成して氷層を露出させる請求項 1記載の製 造法。  2. The method according to claim 1, wherein a frozen layer is formed discontinuously on the ice layer to expose the ice layer.
3 . 凍結層に、 氷層と凍結層表面を繋ぐ開口が生ずるように凍結層を形成さ せ、 氷層を露出させる請求項 1記載の製造法。  3. The method according to claim 1, wherein the frozen layer is formed such that an opening is formed between the frozen layer and the surface of the frozen layer, and the ice layer is exposed.
4. 凍結乾燥用容器の内部底面に中空突起物を設け、 突起物周囲の氷層が露 出するように凍結層に開口を形成させる請求項 3記載の製造法。  4. The production method according to claim 3, wherein a hollow projection is provided on the inner bottom surface of the freeze-drying container, and an opening is formed in the frozen layer so that an ice layer around the projection is exposed.
5 . 氷層を部分的に凍結層表面に突出させ、 氷層を露出させる請求項 1記载 の製造法。  5. The method according to claim 1, wherein the ice layer is partially projected on the surface of the frozen layer to expose the ice layer.
6 . 凍結乾燥用容器の内部底面に突起物を設け、 氷層を部分的に凍結層表面 に突出するように形成させる請求項 5記載の製造法。  6. The method according to claim 5, wherein a protrusion is provided on the inner bottom surface of the freeze-drying container, and the ice layer is formed so as to partially protrude from the surface of the frozen layer.
7 . 内面の一部または全部が氷層で被覆された凍結乾燥用容器中で被乾燥物 含有水性液の凍結層を形成し、 被乾燥物を凍結乾燥する凍結乾燥物の製造法であ つて、 氷結水分の昇華初期に凍結乾燥用容器の温度を 0 °C以上にし、 昇華途中か ら 0 °C以下に下げる温度制御を行うことを特徴とする凍結乾燥物の製造法。  7. A method for producing a freeze-dried product in which a frozen layer of an aqueous liquid containing a substance to be dried is formed in a freeze-drying container in which part or all of the inner surface is covered with an ice layer, and the substance to be dried is freeze-dried. A method for producing a freeze-dried product, comprising controlling the temperature of a freeze-drying vessel to 0 ° C. or higher in the early stage of sublimation of frozen water and lowering the temperature to 0 ° C. or less during the sublimation.
8 . 昇華面が永層と被乾燥物含有水性液凍結層の界面付近に達したところで 0 °C以下に温度を下げる温度制御を行う請求項 7記載の製造法。  8. The production method according to claim 7, wherein when the sublimation surface reaches near the interface between the permanent layer and the aqueous liquid frozen layer containing the substance to be dried, the temperature is controlled to 0 ° C or lower.
9 . 氷結水分昇華初期温度を 5〜 4 0 °Cとし、 この温度を 5〜 1 0時間保持 した後、 0 °C以下に下げる温度制御を行う請求項 7記載の製造法。  9. The production method according to claim 7, wherein an initial temperature of sublimation of frozen water is 5 to 40 ° C, and after maintaining the temperature for 5 to 10 hours, temperature control is performed to lower the temperature to 0 ° C or less.
1 0. 撥水性基材で内面の一部または全部が被覆され、 かつその内面の一部 または全部が氷層で被覆された凍結乾燥用容器を使用する請求項 1または 7記載 の製造法。  10. The method according to claim 1 or 7, wherein a freeze-drying container is used in which a part or all of the inner surface is coated with a water-repellent substrate, and a part or the whole of the inner surface is coated with an ice layer.
1 1 . 内面が底面のみである請求項 1または 7記載の製造法。  11. The production method according to claim 1, wherein the inner surface is only the bottom surface.
1 2 . 凍結乾燥用容器がトレーである請求項 1または 7記載の製造法。 51 12. The method according to claim 1, wherein the freeze-drying container is a tray. 51
13. 氷層の厚さが約 0. 0 lmm〜約 3 Ommである請求項 1または 7記 載の製造法。 13. The method according to claim 1 or 7, wherein the thickness of the ice layer is about 0.01 mm to about 3 Omm.
14. 被乾燥物含有水性液が、 水溶液である請求項 1〜 13いずれか 1項記 載の製造法。  14. The method according to any one of claims 1 to 13, wherein the aqueous solution containing the substance to be dried is an aqueous solution.
15 · 水溶液が医薬活性成分含有水溶液である請求項 14記載の製造法。 15. The method according to claim 14, wherein the aqueous solution is a pharmaceutically active ingredient-containing aqueous solution.
16. 被乾燥物含有水性液が、 懸濁液である請求項 1〜 13いずれか 1項記 載の製造法。 16. The method according to any one of claims 1 to 13, wherein the aqueous liquid containing the substance to be dried is a suspension.
17 懸濁液が、 徐放性製剤懸濁液である請求項 16記載の製造法。  17. The method according to claim 16, wherein the suspension is a sustained-release preparation suspension.
18 徐放性製剤がマイクロスフエアである請求項 17記載の製造法。  18. The production method according to claim 17, wherein the sustained-release preparation is microsphere.
19 医薬活性成分の固形無菌濾過物を製造する請求項 1または 7記載の製 造法。 19. The process according to claim 1 or 7, wherein a solid sterile filtrate of the pharmaceutically active ingredient is produced.
20 徐放性製剤を製造する請求項 1または 7記載の製造法。  20. The production method according to claim 1 or 7, which produces a sustained-release preparation.
21 氷層の厚さが容器の深さの約 1Z1000〜約 4/5である請求項 1 または 7記載の製造法。  21. The method according to claim 1, wherein the thickness of the ice layer is about 1Z1000 to about 4/5 of the depth of the container.
22. 凍結層の厚さが容器の深さの lZl 000〜約 4/5である請求項 1 または 7記載の製造法。  22. The method of claim 1 or 7, wherein the thickness of the frozen layer is from lZl 000 to about 4/5 of the depth of the container.
23. 容器の大きさが横約 5 mm〜約 7， 000 mm、 縦約 5 mm〜約 7， 000mm、 深さ約 lmm〜： L 00mmであり、 氷層が約 0. 01 mm〜約 30 mmである請求項 1または 7記載の製造法。  23. The size of the container is about 5 mm to about 7,000 mm in width, about 5 mm to about 7,000 mm in height, about lmm to: L 00 mm, and the ice layer is about 0.01 mm to about 30 mm. The production method according to claim 1 or 7, which is mm.
24. 徐放性製剤が生理活性ぺプチドを含有する徐放性製剤である請求項 1 7記載の製造法。  24. The method according to claim 17, wherein the sustained-release preparation is a sustained-release preparation containing a bioactive peptide.
25. 徐放性製剤が生理活性ぺプチドおよび生体内分解性ポリマーを含有す る徐放性製剤である請求項 17記載の製造法。  25. The method according to claim 17, wherein the sustained release preparation is a sustained release preparation containing a bioactive peptide and a biodegradable polymer.
26. 生理活性ペプチドが LH— RHァゴニストまたは LH— RHアンタゴ ニストである請求項 24または 25記載の製造法。  26. The method according to claim 24 or 25, wherein the physiologically active peptide is an LH-RH agonist or an LH-RH antagonist.
27. 生理活性ペプチドが 5- OXO- Pro— His— Trp—Ser— Tyr— DLeu - Leu- Arg- Pro-NH-C2H5 (リュ一プロレリン) またはその塩である請求項 24または 25記載の製造法。 27. bioactive peptides 5- OXO- Pro- His- Trp-Ser- Tyr- DLeu - Leu- Arg- Pro-NH-C 2 H 5 ( Ryu one Purorerin) or claim 24 or 25 wherein a salt thereof Manufacturing method.
28. 生理活性ペプチドが 5- OXO- Pro— His— Trp— Ser— Tyr— DLeu 52 28. Bioactive peptide is 5-OXO-Pro—His—Trp—Ser—Tyr—DLeu 52
一 Leu— Arg— Pro— NH- C2H5 (リュープロレリン） の酢酸塩である請求項 24 または 25記載の製造法。 One Leu- Arg- Pro- NH- C 2 H 5 process according to claim 24 or 25 wherein the (leuprorelin) acetate.
29. 生体内分解性ポリマーが α—ヒドロキシカルボン酸重合体である請求 項 25記載の製造法。  29. The method according to claim 25, wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer.
30. α—ヒドロキシカルポン酸重合体が乳酸一グリコール酸重合体である 請求項 29記載の製造法。  30. The method according to claim 29, wherein the α-hydroxycarponic acid polymer is a lactic acid-glycolic acid polymer.
31. 乳酸とダリコール酸との組成比が約 100/0〜約 40/60 (モ ル％) である請求項 30記載の製造法。  31. The method according to claim 30, wherein the composition ratio of lactic acid and dalicholic acid is about 100/0 to about 40/60 (mol%).
32. 重合体の重量平均分子量が約 3， 000〜約 100， 000である請求 項 30記載の製造法。  32. The method according to claim 30, wherein the weight average molecular weight of the polymer is from about 3,000 to about 100,000.
33. 生体内分解性ポリマーがポリ乳酸である請求項 25記載の製造法。  33. The method according to claim 25, wherein the biodegradable polymer is polylactic acid.
34. ポリ乳酸の重量平均分子量が約 10, 000〜約 60 , 000である請 求項 33記載の製造法。 34. The method according to claim 33, wherein the polylactic acid has a weight average molecular weight of about 10,000 to about 60,000.
PCT/JP2001/006115 2000-07-17 2001-07-16 Production method for freeze-dried products WO2002005787A1 (en)

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JP2000-215778 2000-07-17
JP2000-215782 2000-07-17
JP2000215778 2000-07-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7666856B2 (en) 2006-10-10 2010-02-23 Medivir Ab Antiviral nucleosides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6168412A (en) * 1984-09-10 1986-04-08 Fujisawa Pharmaceut Co Ltd Freeze-drying of medicine
JPH02104527A (en) * 1988-10-11 1990-04-17 Kayaku:Kk Production of freeze-dried pharmaceutical of 1-((4'-hydroxy-2'-butenoxy)methyl)-2-nitroimidazole
WO1999037288A1 (en) * 1998-01-21 1999-07-29 Takeda Chemical Industries, Ltd. Lyophilization method for sustained-release preparations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6168412A (en) * 1984-09-10 1986-04-08 Fujisawa Pharmaceut Co Ltd Freeze-drying of medicine
JPH02104527A (en) * 1988-10-11 1990-04-17 Kayaku:Kk Production of freeze-dried pharmaceutical of 1-((4'-hydroxy-2'-butenoxy)methyl)-2-nitroimidazole
WO1999037288A1 (en) * 1998-01-21 1999-07-29 Takeda Chemical Industries, Ltd. Lyophilization method for sustained-release preparations

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7666856B2 (en) 2006-10-10 2010-02-23 Medivir Ab Antiviral nucleosides
US7825239B2 (en) 2006-10-10 2010-11-02 Medivir Ab Antiviral nucleosides
US7935681B2 (en) 2006-10-10 2011-05-03 Medivir Ab Antiviral nucleosides
EP2361922A1 (en) 2006-10-10 2011-08-31 Medivir AB Intermediate to HCV-Nucleoside Inhibitors
US8158779B2 (en) 2006-10-10 2012-04-17 Medivir Ab Antiviral nucleosides

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