JP5696150B2 - 高い強度を有するシームレスなアルギン酸塩カプセル - Google Patents
高い強度を有するシームレスなアルギン酸塩カプセル Download PDFInfo
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- JP5696150B2 JP5696150B2 JP2012528841A JP2012528841A JP5696150B2 JP 5696150 B2 JP5696150 B2 JP 5696150B2 JP 2012528841 A JP2012528841 A JP 2012528841A JP 2012528841 A JP2012528841 A JP 2012528841A JP 5696150 B2 JP5696150 B2 JP 5696150B2
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- capsule
- alginate
- film
- glycerol
- oil
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- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical group OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
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- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
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- 229960003387 progesterone Drugs 0.000 description 1
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- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004071 soot Substances 0.000 description 1
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- 238000013112 stability test Methods 0.000 description 1
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- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 235000010965 sucrose esters of fatty acids Nutrition 0.000 description 1
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- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K40/00—Shaping or working-up of animal feeding-stuffs
- A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
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- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
- B01J13/046—Making microcapsules or microballoons by physical processes, e.g. drying, spraying combined with gelification or coagulation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/20—After-treatment of capsule walls, e.g. hardening
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/20—After-treatment of capsule walls, e.g. hardening
- B01J13/206—Hardening; drying
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
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- Diabetes (AREA)
- Medicinal Preparation (AREA)
- General Preparation And Processing Of Foods (AREA)
- Formation And Processing Of Food Products (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
可塑剤浴組成
カプセルは、以下の通り、可塑化溶液中の異なる可塑剤組成を用いて調製された。
予測、充填マテリアルの酸化
充填マテリアルの酸化は、フィルム組成物とは異なり得る。一般に、カプセルを調製するためのプロセス工程のいくつかは、得られるカプセルの低酸素レベルを達成するために、無酸素環境下で調製される必要がある。乾燥プロセスの制御は、乾燥工程の間、活性薬学的成分の酸化を回避するために重要である。
カプセルシェルの吸湿
アルギン酸塩カプセルのフィルムにおける吸湿の経時的変化を、25℃及び60%相対湿度(RH)で開放容器において保存することで評価した。
アルギン酸塩カプセルのフィルムの厚さは、較正された光学顕微鏡により測定された。安定性試験の間、フィルムの厚さの進行が測定された。フィルムの厚さは概して、ソルビトール含量の増加に伴い増加した。フィルムの厚さは、ほとんどのカプセルにおいて、0日目から1日目へと増加し、概して1日後からは不変であった。
カプセルの破断強度及び弾性の経時変化は、開始時、乾燥コンディション(0日目)及び25℃及び60%相対湿度(RH)での開放容器中の段階的期間での保存において、評価された。
脆性は、落下試験により評価された。表2は、開始時のコンディション(およそ30%RH及び23℃)での落下試験の結果(10カプセルのうち、1.5メートルの高さからスチールバケットへ落下させた後に破損せずに残ったカプセルの数)を示す。これらのコンディションは、相対的に乾燥状態であるとみなされ、“乾燥コンディション”を示す。
本実施例において、発明者らは、可塑剤組成が、エマルションの単層の油層への変化に影響を与えるかについて検討した。エマルションは、安定的なエマルションから、乾燥状態の液体油相に変化するらしい。いくつかのパラメータが、変化のプロセスに影響を与え、可塑剤組成は、これらのひとつである。コアの変化を評価するために、カプセルを切り開き、視覚的に評価した。
充填マテリアルの酸化は、フィルム組成物によって異なり得る。概して、プロセス工程のいくつかは、完成されたカプセルにおいて低い酸素レベルを達成するために、無酸素条件下で操作される必要がある。乾燥プロセスの制御は、乾燥工程の間、活性薬学的成分の酸化を回避するのに不可欠である。さらに、唯一の可塑剤としてグリセロールを有するアルギン酸塩カプセルの閉鎖容器における安定性は、酸化に関連して比較的低く、唯一の可塑剤としての非結晶性ソルビトールの使用は、低い弾性を有するアルギン酸塩カプセルをもたらすことが示された。
Claims (21)
- 充填マテリアルを封入するフィルムを含むシームレスなアルギン酸塩カプセルであって、
フィルムは、アルギン酸塩、グリセロール及び非結晶性ソルビトールを含有し、
非結晶性ソルビトールとグリセロールとの重量比は、1:1と8:1との間である、
ことを特徴とするカプセル。 - 重量比は、2:1と6:1との間である、
ことを特徴とする請求項1に記載のカプセル。 - 重量比は、3:1である、
ことを特徴とする請求項1に記載のカプセル。 - グリセロールは、フィルムの6%(wt/wt)と22%(wt/wt)との間で含まれ、
非結晶性可塑剤は、フィルムの6%(wt/wt)と54%(wt/wt)との間で含まれる、
ことを特徴とする請求項1に記載のカプセル。 - グリセロールは、フィルムの18重量%未満で含まれる、
ことを特徴とする請求項1に記載のカプセル。 - グリセロールは、フィルムの16重量%未満で含まれる、
ことを特徴とする請求項1に記載のカプセル。 - グリセロールは、フィルムの14重量%で含まれる、
ことを特徴とする請求項1に記載のカプセル。 - 非結晶性ソルビトールは、フィルムの36重量%で含まれる、
ことを特徴とする請求項1に記載のカプセル。 - フィルムは、80重量%よりも多い乾燥含量を有する、
ことを特徴とする請求項1に記載のカプセル。 - アルギン酸塩は、Mアルギン酸塩及びGアルギン酸塩を含有し、
Mアルギン酸塩は、Mアルギン酸塩及びGアルギン酸塩の重量に基づき、50%と62%との間である、
ことを特徴とする請求項1に記載のカプセル。 - 充填マテリアルは、少なくとも1つの不飽和油を含有する、
ことを特徴とする請求項1に記載のカプセル。 - カプセル中の充填マテリアルは、25℃/60%RHで、開放容器で保存される2週間ごとに、8TOTOX単位未満の酸化率の増加を示す、
ことを特徴とする請求項11に記載のカプセル。 - 充填マテリアルは、少なくとも50%(wt/wt)油である、
ことを特徴とする請求項11に記載のカプセル。 - 充填マテリアルは、さらに、薬学的、栄養補助的、又は獣医学的な活性剤又はそのキャリアを含有する、
ことを特徴とする請求項11に記載のカプセル。 - 油は、ω−3脂肪酸、トリグリセリド、又はその塩若しくはエステルを含む、
ことを特徴とする請求項11に記載のカプセル。 - 充填マテリアルを封入するアルギン酸塩フィルムを含むシームレスなアルギン酸塩カプセルを製造する方法であって、
a)エマルションの少なくとも50重量%の量で存在する油、水、任意に乳化剤、並びに水溶性多価金属塩及び酸のうち少なくとも1つを含むエマルションを得ること又は調製することと、
b)エマルションを複数の部分(portions)に分けることと、
c)少なくとも1つの湿潤カプセルを形成するように、アルギン酸塩を含む水性ゲル化溶液にエマルションの少なくとも1つの部分(one portion)を加えることと、
d)少なくとも1つの洗浄された湿潤カプセルを形成するように、前記少なくとも1つの湿潤カプセルを洗浄溶液で洗浄することと、
e)少なくとも1つの可塑化された湿潤カプセルを形成するように、(i)2%(wt/wt)と18%(wt/wt)との間の非結晶性ソルビトール、及び(ii)6%(wt/wt)と3%(wt/wt)との間のグリセロールを含む可塑化溶液に、前記少なくとも1つの洗浄された湿潤カプセルを接触させることと、
f)前記少なくとも1つの可塑化された湿潤カプセルを乾燥させることと、
を含む方法。 - 可塑化溶液は、7%(wt/wt)と15%(wt/wt)との間の非結晶性ソルビトール又は5%(wt/wt)と3%(wt/wt)との間のグリセロールを含む、
ことを特徴とする請求項16に記載の方法。 - 可塑化溶液は、13%(wt/wt)の非結晶性ソルビトール及び4%(wt/wt)のグリセロールを含む、
ことを特徴とする請求項16に記載の方法。 - アルギン酸塩は、50%(wt/wt)と62%(wt/wt)との間の平均M含量を有する、
ことを特徴とする請求項16に記載の方法。 - 請求項16に記載の方法により調製されたシームレスなアルギン酸塩カプセル。
- 充填マテリアルは、薬学的、栄養補助的、又は獣医学的な活性剤又はそのキャリアを含有する、
ことを特徴とする請求項20に記載のカプセル。
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