JP5475443B2 - 硝酸ガリウム製剤 - Google Patents
硝酸ガリウム製剤 Download PDFInfo
- Publication number
- JP5475443B2 JP5475443B2 JP2009518557A JP2009518557A JP5475443B2 JP 5475443 B2 JP5475443 B2 JP 5475443B2 JP 2009518557 A JP2009518557 A JP 2009518557A JP 2009518557 A JP2009518557 A JP 2009518557A JP 5475443 B2 JP5475443 B2 JP 5475443B2
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- Prior art keywords
- gallium
- salt
- delivery agent
- substituted
- pat
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
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- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 title claims description 169
- 229940044658 gallium nitrate Drugs 0.000 title claims description 83
- 238000002360 preparation method Methods 0.000 title description 5
- 229940124447 delivery agent Drugs 0.000 claims description 114
- 150000002258 gallium Chemical class 0.000 claims description 104
- 239000008194 pharmaceutical composition Substances 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 63
- 239000008187 granular material Substances 0.000 claims description 48
- 229910052733 gallium Inorganic materials 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 36
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 35
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 30
- 230000000148 hypercalcaemia Effects 0.000 claims description 30
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 30
- 229910052791 calcium Inorganic materials 0.000 claims description 28
- 239000011575 calcium Substances 0.000 claims description 28
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 16
- 238000007906 compression Methods 0.000 claims description 16
- 230000006835 compression Effects 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 108010010803 Gelatin Proteins 0.000 claims description 11
- 229920000159 gelatin Polymers 0.000 claims description 11
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- 235000011852 gelatine desserts Nutrition 0.000 claims description 11
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- 230000008569 process Effects 0.000 claims description 8
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 6
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- 239000000203 mixture Substances 0.000 description 69
- 229910052739 hydrogen Inorganic materials 0.000 description 65
- 150000001875 compounds Chemical class 0.000 description 57
- 125000002947 alkylene group Chemical group 0.000 description 54
- 125000000217 alkyl group Chemical group 0.000 description 53
- 239000001257 hydrogen Substances 0.000 description 52
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- 150000002367 halogens Chemical class 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 37
- 238000009472 formulation Methods 0.000 description 37
- XUHVCHNJCBBXMP-UHFFFAOYSA-M sodium;10-[(2-hydroxybenzoyl)amino]decanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCCCC([O-])=O XUHVCHNJCBBXMP-UHFFFAOYSA-M 0.000 description 35
- -1 compressibility aids Substances 0.000 description 31
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- 210000000988 bone and bone Anatomy 0.000 description 23
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- VEYIMQVTPXPUHA-UHFFFAOYSA-N 3-hydroxypyran-4-one Chemical compound OC1=COC=CC1=O VEYIMQVTPXPUHA-UHFFFAOYSA-N 0.000 description 18
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 description 14
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- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 12
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- LIPRKYKMVQPYPG-UHFFFAOYSA-N 3-Hydroxy-2H-pyran-2-one Chemical compound OC1=CC=COC1=O LIPRKYKMVQPYPG-UHFFFAOYSA-N 0.000 description 11
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- 241000124008 Mammalia Species 0.000 description 10
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 239000002246 antineoplastic agent Substances 0.000 description 10
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- UQFYDAAKCZKDHS-UHFFFAOYSA-M sodium;4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate Chemical compound [Na+].OC1=CC(Cl)=CC=C1C(=O)NCCCC([O-])=O UQFYDAAKCZKDHS-UHFFFAOYSA-M 0.000 description 10
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 9
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- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 125000004450 alkenylene group Chemical group 0.000 description 8
- 229940014259 gelatin Drugs 0.000 description 8
- 238000005469 granulation Methods 0.000 description 8
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 125000001624 naphthyl group Chemical group 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
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- 239000000199 parathyroid hormone Substances 0.000 description 7
- 229960001319 parathyroid hormone Drugs 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 5
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- 125000000304 alkynyl group Chemical group 0.000 description 5
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- 239000001509 sodium citrate Substances 0.000 description 5
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
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- 241000282472 Canis lupus familiaris Species 0.000 description 4
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 4
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- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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Description
「約」または「ほぼ」という用語は、当業者によって求められた特定の値に対して、許容される誤差範囲内であることを意味し、誤差範囲は、一部は、その値がどのようにして測定または決定されたか、すなわち、測定系の限界に依存するであろう。例えば、「約」は、当技術分野における実践によって、1または1を超える標準偏差内であることを意味し得る。別に、製剤に関連して「約」は、10%、好ましくは5%までの範囲を意味し得る。
(a)発症を阻止すること、遅らせること(すなわち、疾患の臨床症状の前の期間)、および/または、疾患にかかる、もしくは悪化させる危険を減らすこと;
(b)例えば高カルシウム血症を含めて、哺乳動物における疾患の少なくとも1つの症状を和らげること、もしくは軽減すること;または
(c)これらに限らないが、所定の刺激(例えば、圧力、組織損傷または低温)に反応している哺乳動物を含めて、哺乳動物によって経験される疾患の発症の強度および/または持続を和らげること、もしくは軽減すること。「治療する」という用語はまた、病気(例えば、疾患)、病気の症状、または病気に向かう素質を、予防的に、防止し、治し、癒し、軽減し、和らげ、改め、矯正し、改良し、改善し、または変化をもたらすことを含む。
適切な送達剤には、次の構造を有するもの、および薬学的に許容されるこれらの塩が含まれる。
2-HO-Ar-C(O)-NR8-R7-COOH 式(1)
式中、
Arは、フェニルまたはナフチル(OH、ハロゲン、C1〜C4アルキル、C2〜C4アルケニル、C1〜C4アルコキシまたは、C1〜C4ハロアルコキシにより任意選択で置換されている)であり;
R7は、C4〜C20アルキル、C4〜C20アルケニル、フェニル、ナフチル、(C1〜C10アルキル)フェニル、(C1〜C10アルケニル)フェニル、(C1〜C10アルキル)ナフチル、(C1〜C10アルケニル)ナフチル、フェニル(C1〜C10アルキル)、フェニル(C1〜C10アルケニル)、ナフチル(C1〜C10アルキル)、またはナフチル(C1〜C10アルケニル)であり;
R8は、水素、C1からC4のアルキル、C2からC4のアルケニル、C1からC4のアルコキシ、C1〜C4またはハロアルコキシであり;
R7は、C1からC4のアルキル、C2からC4のアルケニル、C1からC4のアルコキシ、C1〜C4ハロアルコキシ、-OH、-SH、および-CO2R9、またはこれらの任意の組合せにより任意選択で置換されており;
R9は、水素、C1からC4のアルキル、またはC2からC4のアルケニルであり;また
R7は、酸素、窒素、硫黄、またはこれらの任意の組合せが任意選択で介在している;
但し、これらの化合物は、酸基またはその塩に対してアルファ位でアミノ基により置換されていないものとする。
2-OH-Ar-C(O)-NH-R1-R2 式(2)
式中、
Arは、フェニルまたはナフチルであり;
Arは、C1〜C4アルキル、C1〜C4アルコキシ、C2〜C4アルケニル、C2〜C4アルキニル、アリール、アリールオキシ、複素環式環、C5〜C7炭素環式環、ハロゲン、-OH、-SH、CO2R6、-NR7R8、または-N+R7R8R9Y-により任意選択で置換されており;
(a)R1は、C1〜C16アルキレン、C2〜C16アルケニレン、C2〜C16アルキニレン、C6〜C16アリーレン、(C1〜C16アルキル)アリーレン、またはアリール(C1〜C16アルキレン)であり;
R2は、-NR3R4または-N+R3R4R5Y-であり;
R3およびR4は独立に、水素;酸素;ヒドロキシ;置換または非置換C1〜C16アルキル;置換または非置換C2〜C16アルケニル;置換または非置換C2〜C16アルキニル;置換または非置換アリール;置換または非置換アルキルカルボニル;置換または非置換アリールカルボニル;置換または非置換アルカンスルフィニル;置換または非置換アリールスルフィニル;置換または非置換アルカンスルホニル;置換または非置換アリールスルホニル;置換または非置換アルコキシカルボニル;置換または非置換アリールオキシカルボニルであり;
R5は独立に、水素;置換または非置換C1〜C16アルキル;置換または非置換C2〜C16アルケニル;置換または非置換C2〜C16アルキニル;置換または非置換アリール;置換または非置換アルキルカルボニル;置換または非置換アリールカルボニル;置換または非置換アルカンスルフィニル;置換または非置換アリールスルフィニル;置換または非置換アルカンスルホニル;置換または非置換アリールスルホニル;置換または非置換アルコキシカルボニル;置換または非置換アリールオキシカルボニルである;
(b)R1、R2、およびR5は上で定義された通りであり;
R3およびR4は一緒になって5、6もしくは7員の複素環式環;または、C1〜C6アルキル、C1〜C6アルコキシ、アリール、アリールオキシ、オキソ基もしくは炭素環式環により置換された、5、6もしくは7員の複素環式環を形成している;あるいは
(c)R2およびR5は上で定義された通りであり;
R1およびR3は一緒になって5、6もしくは7員の複素環式環;または、C1〜C6アルキル、アルコキシ、アリール、アリールオキシ、またはオキソ基もしくは炭素環式環により置換された、5、6もしくは7員の複素環式環を形成しており;
R4は、水素;酸素;ヒドロキシ;置換または非置換C1〜C16アルキル;置換または非置換C2〜C16アルケニル;置換または非置換C2〜C16アルキニル;置換または非置換アリール;置換または非置換アルキルカルボニル;置換または非置換アリールカルボニル;置換または非置換アルカンスルフィニル;置換または非置換アリールスルフィニル;置換または非置換アルカンスルホニル;置換または非置換アリールスルホニル;置換または非置換アルコキシカルボニル;置換または非置換アリールオキシカルボニルであり;
R6は、水素;C1〜C4アルキル;ハロゲンまたは-OHにより置換されたC1〜C4アルキル;C2〜C4アルケニル;あるいはハロゲンまたは-OHにより置換されたC2〜C4アルケニルであり;
R7、R8、およびR9は独立に、水素;酸素; C1〜C4アルキル;ハロゲンまたは-OHにより置換されたC1〜C4アルキル; C2〜C4アルケニル;あるいはハロゲンまたは-OHにより置換されたC2〜C4アルケニルであり;また
Yは、ハロゲン、ヒドロキシド、サルフェート、ニトレート、ホスフェート、アルコキシ、パークロレート、テトラフルオロボレート、またはカルボキシレートである。適切なカルボキシレートの非限定的例はアセテートである。
R1、R2、R3、およびR4は独立に、水素、-OH、-NR6R7、ハロゲン、C1〜C4アルキル、またはC1〜C4アルコキシであり;
R5は、置換または非置換C2〜C16アルキレン、置換または非置換C2〜C16アルケニレン、置換または非置換C1〜C12アルキル(アリーレン)、あるいは置換または非置換アリール(C1〜C12アルキレン)であり;また
R6およびR7は独立に、水素、酸素、またはC1〜C4アルキルである。
(a)R1、R2、R3、およびR4は独立に、H、-OH、ハロゲン、C1〜C4アルキル、C1〜C4アルケニル、C1〜C4アルコキシ、-C(O)R8、-NO2、-NR9R10、または-N+R9R10R11(Y-)であり;
R8は、水素、-OH、C1〜C6アルキル、ハロゲンもしくは-OHにより置換されたC1〜C4アルキル、非置換またはハロゲンもしくは-OHにより置換されたC2〜C4アルケニル、あるいは-NR14R15であり;
R9、R10、およびR11は独立に、水素、酸素、非置換またはハロゲンもしくは-OHにより置換されたC1〜C4アルキル、非置換またはハロゲンもしくは-OHにより置換されたC2〜C4アルケニルであり;
Yは、ハライド、ヒドロキシド、サルフェート、ニトレート、ホスフェート、アルコキシ、パークロレート、テトラフルオロボレート、カルボキシレート、メシラート、フマレート、マロネート、サクシネート、タータレート、アセテート、グルコネート、マレエート(maleate)であり;
R5は、H、-OH、-NO2、ハロゲン、CF3、-NR14R15、-N+R14R15R16(Y-)、アミド、C1〜C12アルコキシ、C1〜C12アルキル、C2〜C12アルケニル、カルバメート、カルボネート、ウレア、または-C(O)R22であり;R5は、ハロゲン、-OH、-SH、または-COOHにより任意選択で置換されており;R5は、O、N、S、または-C(O)-が任意選択で介在しており;
R14、R15、およびR16は独立に、HまたはC1〜C10アルキルであり;
R22は、H、C1〜C6アルキル、-OH、-NR14R15であり;
R6は、置換または非置換のC1〜C16アルキレン、C2〜C16アルケニレン、C2〜C16アルキニレン、C5〜C16アリーレン、(C1〜C16アルキル)アリーレンまたはアリール(C1〜C16アルキレン)であり;R6は、C1〜C7アルキルまたはC1〜C7シクロアルキルにより任意選択で置換されており;
R7は、-NR18R19または-N+R18R19R20Y-であり;
R18およびR19は独立に、水素、酸素、ヒドロキシ、置換または非置換C1〜C16アルキル、置換または非置換C2〜C16アルケニル、置換または非置換C2〜C16アルキニル、置換または非置換アリール、置換または非置換アルキルカルボニル(例えば、置換または非置換(C1〜6アルキル)カルボニル)、置換または非置換アリールカルボニル、置換または非置換アルカンスルフィニル(例えば、置換または非置換(C1〜6アルカン)スルフィニル)、置換または非置換アリールスルフィニル、置換または非置換アルカンスルホニル(例えば、置換または非置換(C1〜6アルカン)スルホニル)、置換または非置換アリールスルホニル、置換または非置換アルコキシカルボニル(例えば、置換または非置換(C1〜6アルコキシ)カルボニル)、あるいは置換または非置換アリールオキシカルボニル、あるいは置換または非置換C5〜C7複素環式環(すなわち、5、6、または7-員の複素環式環)であり、これらの置換はハロゲンまたは-OHであることができ;また
R20は独立に、水素、置換または非置換C1〜C16アルキル、置換または非置換C2〜C16アルケニル、置換または非置換C2〜C16アルキニル、置換または非置換アリール、置換または非置換アルキルカルボニル(例えば、置換または非置換(C1〜6アルキル)カルボニル)、置換または非置換アリールカルボニル、置換または非置換アルカンスルフィニル(例えば、置換または非置換(C1〜6アルカン)スルフィニル)、置換または非置換アリールスルフィニル、置換または非置換アルカンスルホニル(例えば、置換または非置換(C1〜6アルカン)スルホニル)、置換または非置換アリールスルホニル、置換または非置換アルコキシカルボニル(例えば、置換または非置換(C1〜6アルコキシ)カルボニル)、あるいは置換または非置換アリールオキシカルボニルである;あるいは
(b)R1〜R16およびR20は上で定義された通りであり;また
R18およびR19は一緒になって5、6、または7-員の複素環式環(オキソ基が任意選択で介在しており、非置換であるか、またはC1〜C6アルキル、C1〜C6アルコキシ、アリール、アリールオキシ、もしくは炭素環式環により置換されている)を形成している。
R1、R2、R3、およびR4は独立に、H、-OH、ハロゲン、C1〜C4アルキル、C2〜C4アルケニル、C1〜C4アルコキシ、-C(O)R8、-NO2、-NR9R10、または-N+R9R10R11(R12)-であり;
R5は、H、-OH、-NO2、ハロゲン、-CF3、-NR14R15、-N+R14R15R16(R13)-、アミド、C1〜C12アルコキシ、C1〜C12アルキル、C2〜C12アルケニル、カルバメート、カルボネート、ウレア、または-C(O)R18であり;
R5は、ハロゲン、-OH、-SH、または-COOHにより任意選択で置換されており;
R5は、O、N、S、または-C(O)-が任意選択で介在しており;
R6は、C1〜C12アルキレン、C2〜C12アルケニレン、またはアレーレンであり;
R6は、C1〜C4アルキル、C2〜C4アルケニル、C1〜C4アルコキシ、-OH、-SH、ハロゲン、-NH2、または-CO2R8により任意選択で置換されており;
R6は、OまたはNが任意選択で介在しており;
R7は、結合またはアリーレンであり;
R7は、-OH、ハロゲン、-C(O)CH3、-NR10R11、または-N+R10R11R12(R13)-により任意選択で置換されており;
R8は、H、C1〜C4アルキル、C2〜C4アルケニル、または-NH2であり;
R9、R10、R11、およびR12は独立に、HまたはC1〜C10アルキルであり;
R13は、ハライド、ヒドロキシド、サルフェート、テトラフルオロボレート、またはホスフェートであり;
R14、R15およびR16は独立に、H、C1〜C10アルキル、-COOHにより置換されたC1〜C10アルキル、C2〜C12アルケニル、-COOHにより置換されたC2〜C12アルケニル、-C(O)R17であり;
R17は、-OH、C1〜C10アルキル、またはC2〜C12アルケニルであり;また
R18は、H、C1〜C6アルキル、-OH、-NR14R15、またはN+R14R15R16(R13)-である。
(1)R1、R2、R3、R4、およびR5がHであり、R7が結合である場合、R6は、C1〜C6、C9、またはC10アルキルでなく;
(2)R1、R2、R3、およびR4がHであり、R5が-OHであり、R7が結合である場合、R6は、C1〜C3アルキルでなく;
(3)R1、R2、R3、およびR4の少なくとも1つがHでなく、R5が-OHであり、R7が結合である場合、R6は、C1〜C4アルキルでなく;
(4)R1、R2、およびR3がHであり、R4が-OCH3であり、R5が-C(O)CH3であり、R6が結合である場合、R7は、C3アルキルでなく;
(5)R1、R2、R4、およびR5がHであり、R3が-OHであり、R7が結合である場合、R6はメチルではない。
R1、R2、R3、およびR4は独立に、H、-OH、ハロゲン、-OCH3、-NR10R11、または-N+R10R11R12(R13)-であり;
R5は、H、-OH、-NO2、-NR14R15、-N+R14R15R16(R13)-、アミド、C1〜C12アルコキシ、C1〜C12アルキル、C2〜C12アルケニル、カルバメート、カルボネート、ウレア、または-C(O)R18であり;
R5は、-OH、-SH、または-COOHにより任意選択で置換されており;
R5は、O、N、S、または-C(O)-が任意選択で介在し;
R6は、C1〜C12アルキレン、C2〜C12アルケニレン、またはアリーレンであり;
R6は、C1〜C4アルキル、C2〜C4アルケニル、C1〜C4アルコキシ、-OH、-SH、ハロゲン、-NH2、または-CO2R9により任意選択で置換されており;
R6は、OまたはNが任意選択で介在し;
R7は、結合またはアリーレンであり;
R7は、-OH、ハロゲン、-C(O)CH3、-NR10R11、または-N+R10R11R12(R13)-により任意選択で置換されており;
R8は、HまたはC1〜C4アルキルであり;
R9は、H、C1〜C4アルキル、またはC2〜C4アルケニルであり;
R10、R11、およびR12は独立に、HまたはC1〜C10アルキルであり;
R13は、ハライド、ヒドロキシド、サルフェート、テトラフルオロボレート、またはホスフェートであり;
R14、R15、およびR16は独立に、H、C1〜C10アルキル、C2〜C12アルケニル、O、または-C(O)R17であり;
R17は、-OH、C1〜C10アルキル、またはC2〜C12アルケニルであり;また
R18は、-OH、C1〜C6アルキル、-NR14R15、-N+R14R15R16(R13)-である。
R19は、-NO2、または-C(O)R23であり;
R20は、C1〜C12アルキレンまたはC1〜C12アルケニレンであり;
R21は、結合またはアリーレンであり;
R22は、HまたはC1〜C4アルキルであり;また
R23は、-OH、C1〜C6アルキル、または-NH2である。
使用され得るガリウム塩は、硝酸塩、マルトラート(maltrate)、クエン酸塩、ハロゲン化物(好ましくは、塩化物)、炭酸塩、酢酸塩、三酢酸塩、酒石酸塩、シュウ酸塩、酸化物塩、水酸化物および水和酸化物、さらには、米国特許第4529593号および米国特許第4704277号(これらは参照を通じて本明細書に組み込まれる)に記載のものを含めて、薬学的に許容されるものである。通常、これらのガリウム塩は非放射性である。好ましいガリウム塩には、これらに限らないが、塩化ガリウムおよび硝酸ガリウム、ならびにこれらの水和物、例えば、硝酸ガリウム一水和物が含まれる。
本発明の実施形態は、ガリウム塩、特に硝酸ガリウム、および送達剤化合物の経口製剤に伴う安定性の問題に対処する医薬製剤を提供する。ガリウム塩の経口製剤の開発で出会う主な問題は、硝酸ガリウムと送達剤化合物の存在下に起こる酸化反応である。水および痕跡量の硝酸(どちらも硝酸ガリウムに付随する)の存在が酸化反応に寄与すると考えられる。酸化反応は、投与形態が茶色に変色することによって明白に示され、送達剤および/またはガリウム塩の劣化生成物を生じ、これは望ましくない。例えば、硝酸ガリウムが溶解性に乏しい酸化ガリウムまたは水酸化ガリウム劣化生成物に変換されると、ガリウム分子の吸収を損ねる。
本発明の別の態様は、ガリウム塩および送達剤化合物を含む安定な医薬製剤を提供する。これらの製剤は、好ましくは、前記の方法によって調製される、あるいは、それらは、粉末ブレンドの調製、湿式造粒法、湿った顆粒の乾燥、直接圧縮のための粉末ブレンドの調製またはこれらの任意の組合せ(これらに限らないが)を含めて、当技術分野において知られている他の方法によって調製されてもよい。
本発明の医薬製剤は、ガリウム塩が治療および/または防止できることが知られている疾患を治療および/または防止するために投与され得る。通常、有効な量の医薬製剤が所望の疾患を治療および/または防止するために投与される。このような疾患には、これらに限らないが、高カルシウム血症(非小細胞肺癌、乳癌、前立腺癌、多発性骨髄腫、扁平上皮癌、腎臓癌、尿道および膀胱癌、および頭頸部癌を含めて、癌に関連する高カルシウム血症および悪性腫瘍に伴う高カルシウム血症が含まれる)、骨からの過度の(または、加速度的な)カルシウム喪失に伴う疾患、骨量減少、骨粗鬆症、悪性腫瘍からの転移に起因する骨の破壊、副甲状腺機能亢進症、ならびに歯周疾患が含まれる。
(1)哺乳動物(例えば、ヒト)の骨によるカルシウムの取り込みを増加させる、高カルシウム血症、骨脆弱、または異常に増加したカルシウムの再吸収(または放出)に伴う他の疾患を有する哺乳動物(例えば、ヒト)の骨からのカルシウムの再吸収(または放出)を抑制する、
(2)骨からの過度の(または、加速度的な)カルシウム喪失に起因する骨疼痛を治療する、および/または
(3)骨からの過度の(または、加速度的な)カルシウム喪失に起因する骨折を防止する、
(4)パジェット病を治療または防止する、
(5)破骨細胞活性を抑制する、および/または骨芽細胞活性を促進する、
(6)尿道(尿路)悪性腫瘍を治療または防止する、
(7)腫瘍を治療または防止する、
(8)尿道、小細胞肺、泌尿生殖器の悪性腫瘍(例えば、前立腺、睾丸および膀胱の癌)、リンパ腫、白血病、および多発性骨髄腫を含めて、癌を治療または防止する、
(9)骨転移(および、付随する疼痛)を処理する、
(10)同種移植での拒絶を含めて、免疫応答を弱める、
(11)鉄の代謝を中断させる、
(12)細胞遊走を促進させる、
(13)皮膚、結合組織および支持組織(例えば、皮膚、腱、筋膜、組織を包むコラーゲン含有組織、骨)の治療および増強、すなわち、創傷の治療を高める、
(14)マイコバクテリウム種(これらに限らないが、結核菌、およびマイコバクテリウム・アビウム・コンプレックス(Mycobacterium avium complex))の感染過程を弱める、治療する、または防止する、
(15)皮膚の疾患および欠点(blemish)を治療する、例えば、皮膚の裂傷、破損、皺、または欠陥の治癒を容易にする、
(16)AIDSに伴う非ホジキンリンパ腫(米国特許第6562870号を参照)を治療する、
(17)ウイルス感染症を治療する、例えば、HIVを治療する(米国特許第5525598号を参照)、
(18)骨の成長を増大させる、ヒドロキシアパタイトの溶解性を低下させる、骨におけるヒドロキシアパタイト結晶の大きさおよび/または完全さを増大させる、および/または、骨の引張り強さを増大させる、
(19)骨組織におけるカルシウム付加を増大させる、および/または骨再吸収を減少させる、また
(20)尿路上皮癌または非扁平上皮細胞癌を治療または防止する(Bernsteinら、Metal-Based Drugs 7(1):33〜47頁(2000年)を参照)。
Claims (14)
- (a)薬学的に許容されるガリウム塩と(b)N-(8-[2-ヒドロキシベンゾイル]-アミノ)カプリル酸、N-(10-[2-ヒドロキシベンゾイル]-アミノ)デカン酸、及び薬学的に許容されるそれらの塩から選択される少なくとも1種の送達剤とを含む医薬製剤の調製方法であって、次の工程:
(a) (i)ガリウム塩と、デンプン、コロイダルシリカ、ゼラチン、及びこれらの組み合わせから選択される親水剤と、少なくとも1種の送達剤とから本質的になる湿った顆粒を調製し、(ii) 30〜50℃の範囲の温度で湿った顆粒を乾燥する工程;
(b) 800psi未満の低圧縮圧力を用いて、少なくとも1種の送達剤と、コロイダルシリカと、ガリウム塩とを含む錠剤を調製する工程
の少なくとも1つを含む方法。 - 乾燥が2〜12時間行なわれる、請求項1に記載の方法。
- 送達剤がN-(10-[2-ヒドロキシベンゾイル]-アミノ)デカン酸または薬学的に許容されるそれらの塩である、請求項1に記載の方法。
- 送達剤がN-(10-[2-ヒドロキシベンゾイル]-アミノ)デカン酸の二ナトリウム塩である、請求項3に記載の方法。
- 送達剤がN-(8-[2-ヒドロキシベンゾイル]-アミノ)カプリル酸または薬学的に許容されるそれらの塩である、請求項1に記載の方法。
- 医薬製剤が、ヒトへの経口摂取で、
(a)0.1から5μg/ml、または0.9から2.0μg/mlの血漿ガリウム濃度、
(b)1000から2500ng/mlのガリウムの平均定常状態血漿レベル、または
(c)高カルシウム血症(例えば、癌に関連する高カルシウム血症)のヒトにおける、少なくとも2.0mg/dlの血清カルシウム(アルブミンについて補正して)の低下
の1つまたは複数をもたらす、請求項1に記載の方法。 - ガリウム塩が硝酸ガリウムまたはその水和物である、請求項1に記載の方法。
- ガリウム塩が硝酸ガリウム九水和物である、請求項7に記載の方法。
- 工程(a)を含む、請求項1に記載の方法。
- 工程(b)を含む、請求項1に記載の方法。
- 親水剤がデンプンである、請求項1に記載の方法。
- 親水剤がコロイダルシリカである、請求項1に記載の方法。
- 親水剤がゼラチンである、請求項1に記載の方法。
- 顆粒を40℃で乾燥する、請求項1に記載の方法。
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2007
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- 2007-06-28 US US12/305,907 patent/US9364502B2/en not_active Expired - Fee Related
- 2007-06-28 EP EP07812429.4A patent/EP2040718B1/en not_active Not-in-force
- 2007-06-28 WO PCT/US2007/072373 patent/WO2008003050A2/en active Application Filing
- 2007-06-28 JP JP2009518557A patent/JP5475443B2/ja not_active Expired - Fee Related
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WO2008003050A3 (en) | 2009-05-28 |
JP2009542711A (ja) | 2009-12-03 |
EP2040718A4 (en) | 2012-10-03 |
US9364502B2 (en) | 2016-06-14 |
EP2040718A2 (en) | 2009-04-01 |
EP2040718B1 (en) | 2017-12-27 |
WO2008003050A2 (en) | 2008-01-03 |
CA2656019A1 (en) | 2008-01-03 |
CA2656019C (en) | 2016-09-13 |
US20100239658A1 (en) | 2010-09-23 |
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