JP6830969B2 - コレスチラミンペレット剤及びその調製のための方法 - Google Patents
コレスチラミンペレット剤及びその調製のための方法 Download PDFInfo
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- JP6830969B2 JP6830969B2 JP2018560427A JP2018560427A JP6830969B2 JP 6830969 B2 JP6830969 B2 JP 6830969B2 JP 2018560427 A JP2018560427 A JP 2018560427A JP 2018560427 A JP2018560427 A JP 2018560427A JP 6830969 B2 JP6830969 B2 JP 6830969B2
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- Prior art keywords
- cholestyramine
- pellet
- pellets
- microcrystalline cellulose
- acid
- Prior art date
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- 230000031200 bile acid secretion Effects 0.000 description 1
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- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- 239000011575 calcium Substances 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
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- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
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- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
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- 238000011068 loading method Methods 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 201000007183 prothrombin deficiency Diseases 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 229960004889 salicylic acid Drugs 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000021058 soft food Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000001162 steatorrhea Diseases 0.000 description 1
- 150000003429 steroid acids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- USFMMZYROHDWPJ-UHFFFAOYSA-N trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium Chemical compound CC(=C)C(=O)OCC[N+](C)(C)C USFMMZYROHDWPJ-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 208000016794 vitamin K deficiency hemorrhagic disease Diseases 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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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
- A61K9/16—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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- 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
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
i. 少なくとも7%w/wのビニルピロリドン系ポリマー、又は
ii. 少なくとも6%w/wのビニルピロリドン系ポリマーと少なくとも2%w/wのアクリレートコポリマーとの組合せ、又は
iii. 少なくとも5%w/wのビニルピロリドン系ポリマーと少なくとも3%w/wのアクリレートコポリマーとの組合せ、又は
iv. 少なくとも6%w/wのビニルピロリドン系ポリマー、少なくとも1%w/wのアクリレートコポリマー及び少なくとも10%w/wの微結晶セルロースの組合せ、又は
v. 少なくとも5%w/wのビニルピロリドン系ポリマー、少なくとも2%w/wのアクリレートコポリマー及び少なくとも20%w/wの微結晶セルロースの組合せ
を含むペレット剤に関する。
i. 少なくとも7%w/wのビニルピロリドン系ポリマー、又は
ii. 少なくとも6%w/wのビニルピロリドン系ポリマーと少なくとも2%w/wのアクリレートコポリマーとの組合せ
を含むペレット剤に関する。
iii. 少なくとも7%w/wのコポビドン、又は
iv. 少なくとも6%w/wのコポビドンと少なくとも2%w/wのアンモニオメタクリレートコポリマーとの組合せ
を含むペレット剤に関する。
i) 乾燥成分を混合する工程、
ii) 水、及び場合によりアクリレートコポリマーを添加して、湿潤物質を得る工程、
iii) この湿潤物質を押出成形する工程、
iv) この押出物を球形化する工程、及び
v) 得られたペレット剤を乾燥する工程
を含む方法に関する。
i) 乾燥コレスチラミン及びコポビドン、並びに場合により微結晶セルロースを混合する工程、
ii) 水、及び場合によりアンモニオメタクリレートコポリマーを添加して、湿潤物質を得る工程、
iii) この湿潤物質を押出成形する工程、
iv) この押出物を球形化する工程、及び
v) 得られたペレット剤を乾燥する工程
を含む方法に関する。
押出成形試験
試験はすべて、100〜200gスケールで行った。乾燥成分(コレスチラミン、ビニルピロリドン系ポリマー及び/又は微結晶セルロース)を、以下に表示されている量で混合した。水を50〜100グラムに分けて、各添加の間に3分間混合して加えた。アクリレートコポリマーをこの試験に用いた場合、水中の2%w/wの分散体として加えた(20gのアクリレートコポリマー(水性分散体30%)を最大300gの水に加えた)。必要な場合、純水の最後の分量分を加えた。各試験において、添加した液体の総量は、固体物質の量の1.7〜2.3倍(w/w)の間であった。
ペレット剤の調製
表1の試験8による組成を有するペレット剤を、押出成形工程において200gのバッチサイズ、及び100gの球形化工程で製造した。170gのコレスチラミン、15gのコポビドン及び9gの微結晶セルロースをプラネタリーミキサーに投入した。このミキサーを中程度の速度で運転し、液体を各添加の間混合しながら、分けてゆっくりと加えた。20gのEudragit(登録商標)RL30D(30%の乾燥質量)を含む最初の水300gを、各添加の間3分間混合しながら、3回の等量分に分けて加えた。最後に、40gの純水を加え、混合を更に30秒間行った。次に、この湿潤物質を押出成形器に移した。1.5mmの篩を備えた押出成形器を25rpmで操作し、得られた押出物をステンレス鋼トレイ上に回収した。約100gの押出物を、1分間、730rpmの速度のスフェロナイザーで加工した。次に、球形化した材料を、ステンレス鋼トレイに移して、乾燥オーブンに入れ、50℃で16時間乾燥した。乾燥済みペレット剤を篩にかけ、1mm〜1.6mmの間の画分を回収した。
コレスチラミンペレット剤の安定性試験
実施例1のペレット(10g)を、プロペラスターラーを用いた300rpmでの撹拌下、リン酸緩衝液(50mM、pH6.8)400mLに加えた。表1の試験8のペレットは、1分25秒以内に完全に崩壊し、表2の試験1のペレットは、1分50秒以内に完全に崩壊した。
Claims (17)
- 少なくとも70%w/wのコレスチラミン、並びに
i. 少なくとも7%w/wのビニルピロリドン系ポリマー、又は
ii. 少なくとも6%w/wのビニルピロリドン系ポリマーと少なくとも2%w/wのアクリレートコポリマーとの組合せ、又は
iii. 少なくとも5%w/wのビニルピロリドン系ポリマーと少なくとも3%w/wのアクリレートコポリマーとの組合せ、又は
iv. 少なくとも6%w/wのビニルピロリドン系ポリマー、少なくとも1%w/wのアクリレートコポリマー及び少なくとも10%w/wの微結晶セルロースの組合せ、又は
v. 少なくとも5%w/wのビニルピロリドン系ポリマー、少なくとも2%w/wのアクリレートコポリマー及び少なくとも20%w/wの微結晶セルロースの組合せ
を含むペレット剤。 - 微結晶セルロースも含む、請求項1に記載のペレット剤。
- 微結晶セルロースを含まない、請求項1に記載のペレット剤。
- 少なくとも85%w/wのコレスチラミンを含む、請求項1から3のいずれか一項に記載のペレット剤。
- 少なくとも90%w/wのコレスチラミンを含む、請求項1から4のいずれか一項に記載のペレット剤。
- ビニルピロリドン系ポリマーがコポビドンである、請求項1から5のいずれか一項に記載のペレット剤。
- アクリレートコポリマーが、アンモニオメタクリレートコポリマーである、請求項1から6のいずれか一項に記載のペレット剤。
- 80〜92%w/wのコレスチラミン、6〜12%w/wのコポビドン、2〜5%w/wのアンモニオメタクリレートコポリマー、及び0〜5%w/wの微結晶セルロースを含む、請求項1から7のいずれか一項に記載のペレット剤。
- 80〜93%w/wのコレスチラミン、7〜12%w/wのコポビドン、及び0〜10%w/wの微結晶セルロースを含む、請求項1から6のいずれか一項に記載のペレット剤。
- ペレット剤の直径が1000μm〜1400μmである、請求項1から9のいずれか一項に記載のペレット剤。
- 結腸への標的送達のために製剤化されている、請求項1から10のいずれか一項に記載のペレット剤。
- i) 乾燥成分を混合する工程、
ii) 水、及び場合により前記アクリレートコポリマーを添加して、湿潤物質を得る工程、
iii) 前記湿潤物質を押出成形する工程、
iv) この押出物を球形化する工程、及び
v) 得られたペレット剤を乾燥する工程
を含む、請求項1から10のいずれか一項に記載のペレット剤の調製のための方法。 - 水が、コレスチラミンの量の少なくとも1.75倍の量(w/w)で乾燥成分の混合物に添加される、請求項12に記載の方法。
- 請求項1から10のいずれか一項に記載のコレスチラミンのペレット剤を複数含む多粒子薬物送達系。
- コレスチラミンのペレット剤が、結腸への標的送達のために製剤化されている、請求項14に記載の薬物送達系。
- 結腸への標的送達が酵素制御放出に基づく、請求項15に記載の薬物送達系。
- 結腸への標的送達がpH及び拡散制御放出に基づく、請求項15に記載の薬物送達系。
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