JP2014501784A - 経口投与用の鉄の医薬組成物 - Google Patents
経口投与用の鉄の医薬組成物 Download PDFInfo
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- JP2014501784A JP2014501784A JP2013548578A JP2013548578A JP2014501784A JP 2014501784 A JP2014501784 A JP 2014501784A JP 2013548578 A JP2013548578 A JP 2013548578A JP 2013548578 A JP2013548578 A JP 2013548578A JP 2014501784 A JP2014501784 A JP 2014501784A
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- Prior art keywords
- iron
- dosage form
- pharmaceutical composition
- oral dosage
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 62
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims description 531
- 229910052742 iron Inorganic materials 0.000 title claims description 247
- 150000002506 iron compounds Chemical class 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 44
- 206010022971 Iron Deficiencies Diseases 0.000 claims abstract description 36
- -1 medium chain fatty acid salt Chemical class 0.000 claims abstract description 33
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 126
- 239000003826 tablet Substances 0.000 claims description 117
- 239000000203 mixture Substances 0.000 claims description 114
- 238000010521 absorption reaction Methods 0.000 claims description 79
- 239000006186 oral dosage form Substances 0.000 claims description 69
- 238000004090 dissolution Methods 0.000 claims description 61
- 239000002552 dosage form Substances 0.000 claims description 46
- 229920000642 polymer Polymers 0.000 claims description 45
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 38
- 239000003623 enhancer Substances 0.000 claims description 35
- 239000007787 solid Substances 0.000 claims description 34
- 210000004369 blood Anatomy 0.000 claims description 30
- 239000008280 blood Substances 0.000 claims description 30
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 claims description 29
- 239000000654 additive Substances 0.000 claims description 28
- 239000002775 capsule Substances 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 26
- 239000011706 ferric diphosphate Substances 0.000 claims description 26
- 235000007144 ferric diphosphate Nutrition 0.000 claims description 26
- 229940036404 ferric pyrophosphate Drugs 0.000 claims description 26
- 230000003111 delayed effect Effects 0.000 claims description 24
- 239000002245 particle Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 20
- 230000000996 additive effect Effects 0.000 claims description 19
- 239000011790 ferrous sulphate Substances 0.000 claims description 19
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 19
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 17
- 230000001965 increasing effect Effects 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 235000010323 ascorbic acid Nutrition 0.000 claims description 15
- 239000011668 ascorbic acid Substances 0.000 claims description 15
- 229960005070 ascorbic acid Drugs 0.000 claims description 14
- 150000004698 iron complex Chemical class 0.000 claims description 13
- SXAWSYZURCZSDX-UHFFFAOYSA-B hydron;[hydroxy(oxido)phosphoryl] hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylate;iron(3+);phosphonato phosphate Chemical compound [H+].[H+].[H+].[H+].[H+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].OP([O-])(=O)OP(O)([O-])=O.OP([O-])(=O)OP(O)([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O SXAWSYZURCZSDX-UHFFFAOYSA-B 0.000 claims description 12
- 238000013270 controlled release Methods 0.000 claims description 11
- 239000013543 active substance Substances 0.000 claims description 10
- 239000013522 chelant Substances 0.000 claims description 10
- 239000008188 pellet Substances 0.000 claims description 10
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 9
- 230000010437 erythropoiesis Effects 0.000 claims description 9
- 102000001554 Hemoglobins Human genes 0.000 claims description 8
- 108010054147 Hemoglobins Proteins 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000008185 minitablet Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 5
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 5
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 5
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 235000001465 calcium Nutrition 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- 150000002505 iron Chemical class 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 4
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 229930003268 Vitamin C Natural products 0.000 claims description 4
- 238000007385 chemical modification Methods 0.000 claims description 4
- 229960001231 choline Drugs 0.000 claims description 4
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002702 enteric coating Substances 0.000 claims description 4
- 238000009505 enteric coating Methods 0.000 claims description 4
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 235000019154 vitamin C Nutrition 0.000 claims description 4
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 3
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- 229920001577 copolymer Polymers 0.000 claims description 3
- 235000019152 folic acid Nutrition 0.000 claims description 3
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- 239000013563 matrix tablet Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 235000019166 vitamin D Nutrition 0.000 claims description 3
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- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 3
- 229940046009 vitamin E Drugs 0.000 claims description 3
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- 229940046008 vitamin d Drugs 0.000 claims description 3
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 2
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- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 2
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- 229910052804 chromium Inorganic materials 0.000 claims description 2
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- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 2
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Abstract
Description
本願は、米国特許法第119条(e)の下で、その開示が全体として参照により本明細書に組み込まれる2011年1月7日出願の米国特許仮出願第61/430,575号の利益を主張する。
(EDTA鉄ナトリウム錯体の薬物動態試験)
製剤化前実験から、提案されたカプリン酸ナトリウム製剤(55mg/mL)とEDTA鉄ナトリウムキレートとの全体的非相溶性は全く示されなかった(表1)。周囲温度での2週間の視覚的観察から、若干の沈殿が認められた試料5および6(鉄元素5.43および8.14mg)を除き、製剤全てで良好な溶液安定性が示された。データから、この鉄化合物が臨床使用に必要な鉄元素濃度の許容される用量の溶解度を有する促進鉄製剤になり易いことも示された。鉄含量をアッセイするための施設内分析法は実施せず、開発はラベル表示された鉄元素含量に基づいた。イヌへ投与された最終製剤は、契約検査室により実施され、鉄含量についてアッセイされた。
1.対照の非促進製剤:脱イオン水中の鉄錯体単独(0.783mg/mL鉄元素)の水性製剤。
2.促進鉄検査製剤A:55mg/mLカプリン酸ナトリウム水性溶液中の鉄錯体の水性製剤(0.783mg/mL鉄元素)。
本試験は、非促進対照に比較した、鉄元素の経口吸収に対する促進鉄製剤の相対的性能を示している。促進鉄製剤は、対照製剤に比較して、優れた吸収速度および吸収量を示した。動物は4時間後に鉄含有標準食を摂取したため、これらのデータのみを用いて、相対生物学的利用率を計算した。解析では、鉄の経口吸収速度および吸収量における有意な改善が実証される(即ち、5.5倍の相対生物学的利用率)。それゆえ、吸収率を高める技術は、(1)現在入手される非経口製剤、および(2)経口製剤にとってかわり、関連のGI副作用を排除する潜在的有用性を有する。
(促進剤システムを用いた鉄の形態の評価)
本試験により、経口促進製剤中で用いられる鉄の既存の塩およびキレートと、潜在的塩およびキレートとの評価の手順を開発した。鉄化合物を、カプリン酸ナトリウム(C10)との相溶性に関してスクリーニングした。最適化された溶解プロファイルを有する適当な製剤が、開発される。開発された手順に基づいて、溶液中の代表的鉄製剤を開発した。この手順を用いて、他の塩およびキレートをスクリーニングし、適切な促進鉄製剤を開発することができる。
沈殿に関する検査を実施した。溶液製剤を、最初、1000rpmで5分間遠心分離した。沈殿は認められなかった。それらをさらに、5000rpmで5分間遠心分離した。沈殿は認められなかった。こうしてこの鉄化合物は、C10と相溶性であると判断された。結果については表8を参照されたい。
可溶性ピロリン酸第二鉄およびピロリン酸第二鉄の水性溶解度試験を、精製水中の50mg/mLまでで実施した。増加量(50mg/mlまで)のこれらの鉄化合物を55mg/mLカプリン酸ナトリウムに溶解することにより、C10相溶性を検査した。
(糖またはクエン酸を用いた錠剤の調製)
可溶性ピロリン酸第二鉄を用いて、およそ33mgの鉄元素および異なる可溶化添加剤と共に錠剤を調製し、鉄元素およびC10の両方の溶解について検査した。成分は全て、秤量皿(weigh boat)内に量り取り、250mL Brawn PPボトルに移し替えた。混合を、ボトル内で3〜5分間、手作業で実施した。混合時間には、ステアリン酸との1分間の最終混合が含まれる。ブレンドを秤量皿に注意深く移し替え、打錠に使用した。目標重量に対してわずかに過剰(2〜5mg)のブレンドを圧縮用に計量することで、移し替えによる損失を回避した。Globe Pharma, MTCM1を用いて圧縮を実施したが、用いられた圧縮用工作機器は、18×8mm(上部および下部の両パンチならびにダイについてはS/N 426539931995−04)であり、1500〜2000psiで圧縮を実施した。
1.任意の糖添加剤を用いずに調製された錠剤は、非常に緩やかな溶解を示し、鉄およびC10の両方で3時間以内に76〜77%であり、完全な溶解および/またはプラトーが5.5時間以内に起こった。
2.糖(ソルビトール)を用いて調製された錠剤は、溶解プロファイルを改善して鉄78%およびC10 74%を2時間以内に放出し、その後、完全な放出が5時間以内に見出された。
3.クエン酸を可溶化補助剤として用いて調製された錠剤は、FeおよびC10の両方の溶解プロファイルを有意に改善し、完全な放出(>97%)が3時間以内に起こった。
(鉄元素65mgおよびクエン酸を含有する錠剤の調製)
鉄元素65mgを含有する可溶性FPP錠剤を、実施例3のものと同様に調製した。表14には、その錠剤の詳細が含まれる。これらの錠剤を、溶解プロファイルについて評価した(図3および4)。これまで認められた通り、クエン酸を用いない錠剤は、非常に緩やかな溶解プロファイルを示し、3時間後でも完全な放出に達せず、Feでは77%およびC10では82%のみが溶解された(表15)。その一方で、クエン酸(9%)を含有する錠剤は、良好な溶解プロファイルを示し、97%を超えるFe放出が、2時間以内に起こった。C10の放出は、完全ではなかったが、2時間目にプラトー(84%)に達した。
(クエン酸を用い、糖を用いた/用いない、鉄元素65mgを含有する錠剤)
鉄元素65mgを含む錠剤を、表16の処方に従い実施例3の手順を用いて、錠剤コア中のクエン酸と共に調製した。錠剤は、糖を用い、および用いずに調製した。以下の項目は、表16および17に示された結果を要約している。
1)高濃度のクエン酸(11.6%)(148mg/錠)。Feの完全な溶解が60分目に観察され、C10の溶解は完全ではなかったが、90分目にプラトーに達した(図5)。
2)クエン酸およびソルビトールの両方を含有する錠剤(それぞれ8.4%)。鉄の完全な溶解が90分目に認められ、C10の溶解は完全ではなかったが、90分目にプラトーに達した(図6)。
クエン酸(12%または148mg/錠)を含む錠剤が、好ましかった。これらの実験から、可溶性ピロリン酸第二鉄錠剤を製剤化して許容される溶解プロファイルを実現するのに、クエン酸(または類似の機能的薬剤)が必要であることが、明らかである。目標の溶解プロファイルは急速であり、鉄と促進剤との同時溶解をもたらす。
(様々な可溶化添加剤を用いた錠剤の調製)
以下の実験を実施して、クエン酸、クエン酸ナトリウムまたはアスコルビン酸を可溶化添加剤として検討した。
(クエン酸ナトリウムを用いた錠剤の調製)
鉄錠剤を、実施例3で用いられた手順に従って、クエン酸の代わりにクエン酸ナトリウムを用いて作製した。錠剤の詳細を、表20に示す。FeおよびC10の両方の溶解は緩やかであったが、Feの完全な放出および80%を超えるC10が、4時間以内に達した(図7)。
(アスコルビン酸を含有する鉄錠剤の調製)
アスコルビン酸は、鉄の経口吸収促進剤としても公知であるため、実施例2の手順に従い、クエン酸の代わりにアスコルビン酸を用いて錠剤を製造した。錠剤の詳細を、表21に示す。結果から、Feが60分以内に溶解し、C10の溶解が80%の放出でプラトーに達することが示される(図9)。C10単独で実施した対照実験(厳密な錠剤組成:550mg C10、3.5mg ステアリン酸、115mg ソルビトール)は、100%放出を示した。C10を標準化することによりデータを再度プロットし、97%のC10が90分後に溶解してプラトーに達したことが示された(図10)。クエン酸錠剤とアスコルビン酸錠剤との溶解プロファイルの比較を図11に示しており、結果から、クエン酸を用いた急速で完全な放出が示される。アスコルビン酸錠剤は、相対的に優れたFeおよびC10両方の同時放出を示したが、完全な放出には達しなかった。
(様々な濃度のクエン酸を用いた鉄錠剤の調製)
促進錠剤の追加のバッチを、様々な濃度のクエン酸を用いて調製した。これらの濃度は、実施例3の手順に従い12%、15%、および21%であった。15%錠剤は、低濃度の鉄を有した。錠剤の詳細を、表22に示す。
(鉄錠剤のバッチの反復)
鉄錠の追加のバッチを実施例3の手順に従って調製し、製造および性能の再現性を評価した。錠剤バッチの詳細を、表23に示す。結果から、クエン酸による急速で完全な放出が示される。アスコルビン酸錠は、相対的に優れた、鉄およびC10両方の同時放出を示したが、完全な放出には達しなかった(表24および図13〜15)。
(様々なレベルのクエン酸およびクエン酸ナトリウムを用いて調製された鉄錠剤)
様々なレベルのクエン酸およびクエン酸ナトリウムを用いて製造したピロリン酸第二鉄を含有する鉄錠剤(Food Chemicals Codex (FCC))を、実施例3の手順に従って調製した。この錠剤の詳細を、表25および26に示す。
(ピロリン酸鉄の剤形の薬物動態試験)
鉄欠乏の十二指腸カニューレ挿入ビーグル犬モデルにおいて、鉄(可溶性ピロリン酸第二鉄)製剤対硫酸第一鉄の非促進対照製剤の相対的な絶食時経口生物学的利用率を評価するために、2期クロスオーバー前臨床試験を実施した。雌イヌ12匹を試験に含め、それぞれ6匹からなる群2つ(群A(n=6)および群B(n=6))に分けた。これらのイヌを、検査製剤の投与前に、瀉血により鉄欠乏にした。瀉血前の値に対して約25%の血漿鉄レベル降下および/または約20%のヘマトクリット(%パック細胞容積(PCV)として測定)降下を、鉄欠乏とみなした。
本試験の生存相部分は、18日間(鉄欠乏の誘導を含む)であり、生存相は臨床観察の3日前から開始し、期間2の24時間採血の後に生存相を終了した。
生物分析データを受け取り、個々の動物の血漿鉄濃度データをExcelスプレッドシート(Microsoft(登録商標) office Excel 2003)にロードした。AUC0−t、CmaxおよびTmaxをはじめとするPKパラメータは、UsanskyらによりMS Excelのために記載されたマクロを用いて計算した。
この概要は、1)薬物動態(PK)データの解析および2)鉄欠乏誘導の主な観察、を含む。
非促進TI1および鉄TI2についての個々の動物のベースライン補正済み血漿鉄濃度を、表28および29に表し、図19にプロットしている。
初回投与前に、動物をプロトコールに定義された鉄欠乏状態(血漿鉄レベルの約25%低下および/またはヘマトクリットの約20%降下)にした(表32、図20)。
検査品目投与後に認められた臨床観察の概要を、以下の表35に詳述する。予測通り、イヌは、貧血誘導期間の完了時に、様々な血漿鉄および%PCVレベルを有した。鉄欠乏の基準は、全ての動物で適っており、本試験の目的として十分とみなした。
本試験は、本試験用に設計された鉄欠乏のイヌモデルにおける硫酸第一鉄の非促進製剤に比較した促進鉄製剤の、鉄の経口吸収に関する相対的性能を要約している。相対的経口生物学的利用率を評価するために、絶食血漿鉄レベル(動物は投与6時間後に摂餌した)に基づき、測定レベルおよびベースラインレベル(投与直前に得られた)で補正されたレベルを用いて、PKパラメータを計算した。選択された血漿鉄およびヘマトクリット目標値は、各期間の用量投与前に達成されていたため、鉄欠乏状態は、試験の目的に適合しているとみなした。試験結果から、鉄TI2が、この2期クロスオーバー試験の異なる群および異なる投与期間において、硫酸第一鉄TI1に比較してより高い全身鉄吸収を示したことが実証される。6時間までの吸収量(AUC0−6)を用いて計算された鉄TI2の相対経口生物学的利用率(Frel)は、十二指腸内投与された硫酸第一鉄溶液に比較して相対経口生物学的利用率の3.45倍上昇(n=11)を示した(両方の溶液は、等量の鉄元素を含有した)。TI1(硫酸第一鉄製剤)および鉄TI2(促進製剤)を単一十二指腸内用量で2回投与された鉄欠乏雌ビーグル犬12匹は、死亡、罹患、または重度の有害臨床兆候を示さなかった。鉄TI2製剤の用量投与に関連する臨床兆候は軽度であり、嘔吐および下痢に限定された。
表36〜47は、追加の平均薬物動態値および個々の動物のデータを示す。
(鉄フィードバック機構に対する剤形の影響)
実施例12で回収されたデータを、試験期間それぞれの鉄吸収とベースライン鉄レベルとの関連性を決定するために評価した。ベースラインの鉄レベルが高い程、非促進製剤から吸収される鉄量が減少することが、この分析から見出された。図21は、この関連性を実証している。非促進製剤でのAUC対投与前鉄レベルから、投与前鉄レベルと吸収される鉄との明確な関連性が示される。投与前鉄レベルが高い動物程、非促進検査製剤からの鉄吸収が少なかった。これは、鉄が能動輸送により吸収され、フィードバック機構が存在する、という理論に合致する。
Claims (54)
- 鉄化合物と、炭素原子約4〜約20個の炭素鎖長を有する中鎖脂肪酸塩である吸収促進剤とを含む医薬組成物であって、前記医薬組成物が前記鉄化合物の化学修飾を含まない、医薬組成物。
- 鉄化合物と吸収促進剤とを含む医薬組成物であって、前記医薬組成物が吸収促進剤を含有しない硫酸第一鉄を含む組成物によりもたらされる鉄の生物学的利用率より少なくとも1.5倍高い前記生物学的利用率をもたらす、医薬組成物。
- 吸収促進剤を含有しない硫酸第一鉄の錠剤によりもたらされる鉄の生物学的利用率より少なくとも4倍高い前記生物学的利用率をもたらす、請求項2に記載の医薬組成物。
- 前記鉄化合物が、鉄塩、鉄キレート、または鉄錯体である、請求項1〜3のいずれか一項に記載の医薬組成物。
- 前記鉄化合物が、第二鉄錯体である、請求項4に記載の医薬組成物。
- 前記鉄化合物が、EDTAおよびナトリウムを有する鉄の錯体である、請求項4に記載の医薬組成物。
- 前記鉄化合物が、第二鉄キレートである、請求項4に記載の医薬組成物。
- 前記鉄化合物が、ピロリン酸第二鉄である、請求項4に記載の医薬組成物。
- 前記鉄化合物が、可溶性ピロリン酸第二鉄である、請求項4に記載の医薬組成物。
- 前記中鎖脂肪酸塩が、室温で固体である、請求項1に記載の医薬組成物。
- 前記炭素鎖長が、炭素原子8〜14個である、請求項1に記載の医薬組成物。
- 前記吸収促進剤が、中鎖脂肪酸のナトリウム塩である、請求項1に記載の医薬組成物。
- 前記吸収促進剤が、カプリル酸ナトリウム、カプリン酸ナトリウム、およびラウリン酸ナトリウムからなる群より選択される、請求項1に記載の医薬組成物。
- 前記鉄化合物および前記吸収促進剤が、1:100,000〜10:1の比(鉄化合物:促進剤)で存在する、請求項1に記載の医薬組成物。
- 前記中鎖脂肪酸塩が、前記組成物中の唯一の吸収促進剤である、請求項1に記載の医薬組成物。
- 前記医薬組成物が2種以上の中鎖脂肪酸塩を含む、請求項1に記載の医薬組成物。
- 前記鉄化合物が、前記組成物中の唯一の活性剤である、請求項1に記載の医薬組成物。
- 前記医薬組成物が追加の活性剤をさらに含む、請求項1に記載の医薬組成物。
- 前記追加の活性剤が、葉酸、ビタミンA、ビタミンB(全種類)、ビタミンC、ビタミンD、ビタミンE、カルシウム、クロム、銅、マグネシウム、マンガン、カリウム、セレン、亜鉛、リン、ヨウ素、ビオチン、イノシトール、p−アミノ安息香酸、コリン、および任意のそれらの組合せからなる群より選択される、請求項18に記載の医薬組成物。
- 前記医薬組成物が補助添加剤をさらに含む、請求項1に記載の医薬組成物。
- 前記添加剤が、可溶化剤である、請求項20に記載の医薬組成物。
- 前記可溶化剤が、有機キレート化剤である、請求項21に記載の医薬組成物。
- 前記可溶化剤が、クエン酸、クエン酸の塩、アスコルビン酸、またはアスコルビン酸の塩である、請求項21に記載の医薬組成物。
- 前記可溶化剤が、前記鉄化合物および前記促進剤の溶解速度を約5%上昇させ、3時間以内に前記鉄化合物および前記促進剤の両方の少なくとも約80%の溶解を実現するのに十分な量で存在する、請求項21に記載の医薬組成物。
- 請求項1または2に記載の医薬組成物を含む経口剤形。
- 液体経口剤形である、請求項25に記載の経口剤形。
- 固形経口剤形である、請求項25に記載の経口剤形。
- 約1mg〜約200mgの鉄元素を含む、請求項25に記載の経口剤形。
- 前記剤形が、錠剤、カプセル剤、複数粒子剤、または散剤剤形である、請求項27に記載の固形経口剤形。
- 前記剤形が、制御放出性剤形である、請求項25に記載の固形経口剤形。
- 前記剤形が、遅延放出性剤形である、請求項25に記載の固形経口剤形。
- 前記剤形が、速度制御ポリマー材料をさらに含む、請求項25に記載の固形経口剤形。
- 前記剤形が、腸溶性コーティング剤形である、請求項27に記載の固形経口剤形。
- 前記速度制御ポリマーが、ヒドロキシプロピルメチルセルロースである、請求項32に記載の固形経口剤形。
- 前記速度制御ポリマーが、アクリル酸もしくはメタクリル酸もしくはそれらの各エステルのポリマー、またはアクリル酸もしくはメタクリル酸もしくはそれらの各エステルのコポリマーである、請求項32に記載の固形経口剤形。
- 前記鉄化合物、前記吸収促進剤、および少なくとも1種の補助添加剤が、速度制御ポリマーまたは遅延放出性ポリマーによってコーティングされる前に錠剤形態に圧縮されている、請求項27に記載の固形経口剤形。
- 前記鉄化合物、前記吸収促進剤、前記速度制御ポリマーおよび少なくとも1種の補助添加剤が、圧縮されて制御放出性マトリックス錠を形成し、場合により、速度制御ポリマーまたは遅延放出性ポリマーによってコーティングされている、請求項32に記載の固形経口剤形。
- 前記鉄化合物、前記吸収促進剤、および少なくとも1種の補助添加剤が、速度制御ポリマーまたは遅延放出性ポリマーによってコーティングされる前に複数層錠の形態に圧縮されている、請求項27に記載の固形経口剤形。
- 前記鉄化合物および前記吸収促進剤が、前記速度制御ポリマー材料中に分散され、複数層錠の形態に圧縮され、場合により、速度制御ポリマーまたは遅延放出性ポリマーによってコーティングされている、請求項27に記載の固形経口剤形。
- 前記鉄化合物、前記吸収促進剤、少なくとも1種の補助添加剤、および前記速度制御ポリマー材料が、組み合わされて複数粒子形態となっている、請求項27に記載の固形経口剤形。
- 前記複数粒子形態が、分離した粒子、ペレット、ミニ錠剤、またはそれらの組合せを含む、請求項40に記載の固形経口剤形。
- 異なるin vitroまたはin vivo放出特性を有する粒子、ペレットまたはミニ錠剤のうちの2つ以上のブレンドを含む、請求項40に記載の固形経口剤形。
- 前記複数粒子が、カプセル中にカプセル化され、場合により、速度制御ポリマーまたは遅延放出性ポリマーによってコーティングされている、請求項40に記載の固形経口剤形。
- 前記複数粒子がサシェ中に組み込まれている、請求項40に記載の固形経口剤形。
- 前記分離した粒子または前記ペレットが、錠剤形態に圧縮され、場合により、速度制御ポリマーまたは遅延放出性ポリマーによってコーティングされている、請求項41に記載の固形経口剤形。
- 前記分離した粒子または前記ペレットが、複数層錠に圧縮され、場合により、速度制御ポリマーまたは遅延放出性ポリマーによってコーティングされている、請求項41に記載の固形経口剤形。
- 対象に鉄を経口送達する方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
- それを必要とする対象の血中の鉄レベルを上昇させる方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
- それを必要とする対象の血中のヘモグロビンレベルを上昇させる方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
- それを必要とする対象における鉄欠乏を処置する方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
- それを必要とする対象における鉄欠乏を特徴とする疾患または障害を処置する方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
- それを必要とする対象における赤血球生成刺激剤の効能を高める方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
- 対象における治療効果に必要な赤血球生成刺激剤の用量を低減する方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
- 対象における赤血球生成刺激剤の必要性を遅らせる方法であって、前記対象に請求項25に記載の経口剤形を投与するステップを含む、方法。
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- 2012-01-06 KR KR1020137017418A patent/KR20140026354A/ko not_active Application Discontinuation
- 2012-01-06 AU AU2012204213A patent/AU2012204213A1/en not_active Abandoned
- 2012-01-06 JP JP2013548578A patent/JP2014501784A/ja active Pending
- 2012-01-06 US US13/345,185 patent/US8802114B2/en not_active Expired - Fee Related
- 2012-01-06 WO PCT/US2012/020487 patent/WO2012094598A2/en active Application Filing
- 2012-01-06 CN CN2012800046818A patent/CN103476419A/zh active Pending
- 2012-01-06 BR BR112013017169A patent/BR112013017169A2/pt not_active IP Right Cessation
- 2012-01-06 CA CA2819234A patent/CA2819234A1/en not_active Abandoned
- 2012-01-06 EP EP12732499.4A patent/EP2661273A4/en not_active Withdrawn
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Also Published As
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CN103476419A (zh) | 2013-12-25 |
CA2819234A1 (en) | 2012-07-12 |
EP2661273A4 (en) | 2014-06-04 |
WO2012094598A2 (en) | 2012-07-12 |
KR20140026354A (ko) | 2014-03-05 |
WO2012094598A3 (en) | 2012-10-26 |
EP2661273A2 (en) | 2013-11-13 |
US8802114B2 (en) | 2014-08-12 |
AU2012204213A1 (en) | 2013-06-13 |
US20120189692A1 (en) | 2012-07-26 |
BR112013017169A2 (pt) | 2016-10-04 |
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