JP6768726B2 - 貯蔵安定性が改善された医薬組成物 - Google Patents
貯蔵安定性が改善された医薬組成物 Download PDFInfo
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- JP6768726B2 JP6768726B2 JP2018039622A JP2018039622A JP6768726B2 JP 6768726 B2 JP6768726 B2 JP 6768726B2 JP 2018039622 A JP2018039622 A JP 2018039622A JP 2018039622 A JP2018039622 A JP 2018039622A JP 6768726 B2 JP6768726 B2 JP 6768726B2
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- 239000001923 methylcellulose Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- RRIWSQXXBIFKQM-UHFFFAOYSA-N monomeric N-benzylcarbamic acid Natural products OC(=O)NCC1=CC=CC=C1 RRIWSQXXBIFKQM-UHFFFAOYSA-N 0.000 description 1
- 239000004050 mood stabilizer Substances 0.000 description 1
- 229940127237 mood stabilizer Drugs 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
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- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
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- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
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- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Chemical compound CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 229940127240 opiate Drugs 0.000 description 1
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- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229940054010 other antipsychotics in atc Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
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- 239000004031 partial agonist Substances 0.000 description 1
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- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000008103 phosphatidic acids Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 150000008106 phosphatidylserines Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 235000019275 potassium ascorbate Nutrition 0.000 description 1
- 229940017794 potassium ascorbate Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- CONVKSGEGAVTMB-RXSVEWSESA-M potassium-L-ascorbate Chemical compound [K+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] CONVKSGEGAVTMB-RXSVEWSESA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003196 psychodysleptic agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
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- 229940125723 sedative agent Drugs 0.000 description 1
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- 208000019116 sleep disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium erythorbate Chemical compound [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- ALPWRKFXEOAUDR-GKEJWYBXSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] hydrogen phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)([O-])=O)OC(=O)CCCCCCCCCCCCCCCCC ALPWRKFXEOAUDR-GKEJWYBXSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000019505 tobacco product Nutrition 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940039925 zyprexa Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
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- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本願は、2012年9月19日に出願された米国特許仮出願第61/702,881号および2013年3月13日に出願された米国特許仮出願第61/780,862号の優先権を主張する。これらの出願の全内容は、その全文の参照により本明細書に組み込まれる。
本明細書で、(a)加水分解不安定性抗精神病薬;(b)非イオン性水不溶性および/または不混和性エステル系コサーファクタント;(c)水混和性および/または可溶性非イオン性界面活性剤;および(d)水性媒体を含む医薬組成物であって、医薬組成物が、特定の時間放置後、最小限量の加水分解された抗精神病薬分解生成物を含む医薬組成物が提供される。例えば、医薬組成物は、24ヶ月まで、または以上放置後、50ppm未満、例えば、30ppm未満、例えば、10ppm未満の加水分解された抗精神病薬分解生成物を含む。ある実施形態では、医薬組成物は、少なくとも1ヶ月、3ヶ月、6ヶ月、9ヶ月、12ヶ月、18ヶ月、または24ヶ月間放置後、50ppm未満、例えば、30ppm未満、例えば、10ppm未満の加水分解された抗精神病薬分解生成物を含む。
(a)15〜35重量%のアリピプラゾールプロドラッグ(例えば、式IまたはIIの化合物)またはオランザピンプロドラッグ(例えば、式III、IV、またはVの化合物);
(b)0.25〜0.45重量%のラウリン酸ソルビタン;
(c)0.2〜1重量%のポリソルベート20;および
(d)水性媒体
を含む。
(a)24〜30重量%のアリピプラゾールプロドラッグ(例えば、式IまたはIIの化合物)またはオランザピンプロドラッグ(例えば、式III、IV、またはVの化合物);
(b)0.3〜0.4重量%のラウリン酸ソルビタン;
(c)0.1〜0.3重量%のポリソルベート20;および
(d)水性媒体
を含む。
(a)約26.6重量%のアリピプラゾールプロドラッグ(例えば、式IまたはIIの化合物)またはオランザピンプロドラッグ(例えば、式III、IV、またはVの化合物);
(b)約0.37重量%のラウリン酸ソルビタン;
(c)約0.15重量%のポリソルベート20;および
(d)水性媒体
を含む。
(a)15〜35重量%の化合物I:
(b)0.25〜0.45重量%のラウリン酸ソルビタン;
(c)0.2〜1重量%のポリソルベート20;および
(d)水性媒体
を含む。
(a)24〜30重量%の化合物I:
(b)0.3〜0.4重量%のラウリン酸ソルビタン;
(c)0.1〜0.3重量%のポリソルベート20;および
(d)水性媒体
を含む。
(a)約26.6重量%の化合物I:
(b)約0.37重量%のラウリン酸ソルビタン;
(c)約0.15重量%のポリソルベート20;および
(d)水性媒体
を含む。
(1)表面張力低下、これは、「低表面張力」液体は、「高表面張力」より容易に、表面または粒子を濡らすので、濡れ性を促進し得る。液体の表面張力が低いほど、泡の発生率も低下させ得る。液体の表面張力は、界面活性剤を添加すると低下する。
(2)ミセル形成(すなわち、不溶解性成分を溶解可能にする溶液中の球状または非球状界面活性剤構造);および/または
(3)懸濁物理安定度の増加。
上記の通り、本明細書で提供される医薬組成物は、加水分解不安定性抗精神病薬を、対象に投与するために有用である。具体的には、医薬組成物は、医薬組成物が改善された有効期限を有するように、放置中にその中に含有される加水分解不安定性抗精神病薬の加水分解生成物の生成を最小にする。本明細書で、「抗精神病薬」という語は、精神病治療のために使用される全ての薬剤を表す。抗精神病薬が処方される共通の症状としては、抗精神病薬が、他の診断の広範囲に関連する精神病を治すためにも使用されるが、統合失調症、躁病、および妄想性障害が挙げられる。抗精神病薬は、双極性障害(精神病の症状が存在しないときでさえ)の治療のために適切にする気分安定剤としても作用する。本明細書で提供される医薬組成物は、注射可能組成物への水不溶性抗精神病薬の処方に、特に、有用である。
Raは、存在しなくて、Rbは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2または−C(O)R1であり;
または
Rbは、存在しなくて、Raは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2または−C(O)R1であり;
Rcは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2または−C(O)R1であり;
各R1は、独立して、水素、置換または非置換脂肪族、および置換または非置換アリールから成る群から選択され;および
各R2は、置換または非置換アリールおよび置換または非置換ヘテロアリールから成る群から選択され;
の化合物である。
Raは、−CH2OC(O)R1であり、R1は、置換または非置換脂肪族から選択される)の化合物である。
R1は、独立して、水素、置換または非置換脂肪族、および置換または非置換アリールから成る群から選択され;
各R4およびR5は、独立して、水素、C1〜C3アルキル、アリールまたは置換アリール;好ましくは、水素またはメチルから選択され;
G12は、NH、CH2、−S−または−O−から選択され;
mは、0または1であり;
R6は、C13〜C26アルキル、置換C13〜C26アルキル、C13〜C26アルケニル、置換C13〜C26アルケニル、C13〜C26アルキニル、置換C13〜C26アルキニル、C13〜C26シクロアルキル、および置換C13〜C26シクロアルキル、アリール−C13〜C26アルキル、置換アリール−C13〜C26アルキル、C1〜C10アリール、置換C1〜C10アリール、ヘテロアリール−C13〜C26アルキル、置換ヘテロアリール−C13〜C26アルキル;置換されていてもよいC13〜C26アルキルアリール、置換されていてもよいC13〜C26アルケニルアリールおよび置換されていてもよいC13〜C26アルキニルアリールから選択され;および
のオランザピンプロドラッグも含み得る。
本明細書で提供される医薬組成物は、それを必要とする対象の様々な障害の治療用途に使用され得る。例えば、開示された組成物は:心臓バイパス手術および移植後に続いて起こる脳欠損などの障害、脳卒中、脳虚血症、脊髄外傷、頭部外傷、周生期低酸素症、心停止、低血糖性神経障害、認知症(AIDS誘発性認知症を含む)、アルツハイマー病、ハンチントン舞踏病、筋萎縮性側索硬化症、眼損傷、網膜症、認知障害、原因不明および薬物性パーキンソン病、振戦を含む筋痙直関連性筋痙攣および障害、てんかん、痙攣、てんかん重積持続状態に続発する脳欠損、片頭痛(migraine)(片頭痛(migraine headache)を含む)、尿失禁、薬物耐性、薬物離脱(オピエート、ニコチン、タバコ製品、アルコール、ベンゾジアゼピン系薬、コカイン、鎮静剤、睡眠薬、他を含む)、精神障害、統合失調症、不安症(全般性不安障害、パニック障害、対人恐怖症、強迫性障害、および心的外傷後ストレス障害(PTSD)を含む)、注意欠陥障害(ADD)、注意欠陥多動障害(ADHD)、気分障害(うつ病、躁病、双極性障害を含む)、概日リズム障害(時差ぼけおよび交替勤務性を含む)、三叉神経痛、難聴、耳鳴症、嘔吐、眼の黄斑変性症、嘔吐、脳浮腫、疼痛(急性および慢性疼痛状態、激痛、難治性疼痛、神経因性疼痛、炎症痛、および外傷後疼痛を含む)、遅発性ジスキネジア、睡眠障害(ナルコレプシーを含む)、注意欠陥/多動障害、および行動障害から選択される症状を治療するために使用され得る。
図1は、特定のアリピプラゾールプロドラッグのN−メチル−ヒドロキシ加水分解生成物への生体外加水分解を示す。下記のように、これらの加水分解性生成物の生成は、本明細書に記載の医薬処方物中、生体外で(すなわち、放置中)、最小になる。
アリピプラゾールプロドラッグの合成
2−メチル−4−(4−メチルピペラジン−1−イル)−5H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−5−カルボン酸クロロメチル[A]の合成
2−メチル−4−(4−メチルピペラジン−1−イル)−10H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−10−カルボン酸クロロメチル[C]の合成
本明細書中に引用した全ての特許文献、公開特許出願、および他の文献の全内容は、その全文を参照することにより、明示的に、本明細書に組み込まれる。
Claims (5)
- 水性医薬組成物の製造方法であって、前記方法が、加水分解不安定性抗精神病薬および水性媒体を含む組成物に、(a)50ppm未満の前記加水分解不安定性抗精神病薬の加水分解生成物をもたらすのに十分な0.25〜0.45重量%のラウリン酸ソルビタンおよび(b)ポリソルベート20を添加することを含み、前記水性医薬組成物が、15〜35重量%の以下の化合物1
- 前記水性医薬組成物が、すぐ使用できる形態である、請求項1に記載の方法。
- 前記水性医薬組成物が、
(a)15〜35重量%の以下の化合物1
(b)0.25〜0.45重量%のラウリン酸ソルビタン;
(c)0.2〜1重量%のポリソルベート20;および
(d)水性媒体
を含む、請求項1に記載の方法。 - 前記水性医薬組成物が、少なくとも24ヶ月放置後に、30ppm未満の前記加水分解不安定性抗精神病薬の加水分解生成物を含む、請求項1に記載の方法。
- 前記加水分解不安定性抗精神病薬の加水分解生成物が、1つ以上の次式:
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Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2766088C (en) * | 2009-06-25 | 2017-06-13 | Alkermes, Inc. | Heterocyclic compounds for the treatment of neurological and psychological disorders |
ES2604558T3 (es) | 2011-03-18 | 2017-03-07 | Alkermes Pharma Ireland Limited | Composiciones farmacéuticas inyectables que comprenden un antipsicótico insoluble en agua, laurato de sorbitán y polisorbato 20 |
EP2827867B1 (en) | 2012-03-19 | 2019-11-06 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising glycerol esters |
NZ630428A (en) | 2012-03-19 | 2017-02-24 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising benzyl alcohol |
ES2765036T3 (es) | 2012-03-19 | 2020-06-05 | Alkermes Pharma Ireland Ltd | Composiciones farmacéuticas que comprenden esteres de ácidos grasos |
EP2897592B1 (en) | 2012-09-19 | 2020-02-19 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
MX2016012041A (es) * | 2014-03-20 | 2017-01-19 | Alkermes Pharma Ireland Ltd | Formulaciones de aripiprazol que tienen mayores velocidades de inyeccion. |
SI3508196T1 (sl) * | 2014-08-18 | 2021-12-31 | Alkermes Pharma Ireland Limited, | Sestavki aripiprazolnega predzdravila |
US10016415B2 (en) | 2014-08-18 | 2018-07-10 | Alkermes Pharma Ireland Limited | Aripiprazole prodrug compositions |
CN107106556B (zh) * | 2014-08-25 | 2020-06-05 | 奥克梅斯制药爱尔兰有限公司 | 用于治疗精神分裂症的缓释制剂中阿立哌唑衍生物的结晶方法 |
US10815216B2 (en) | 2016-12-14 | 2020-10-27 | Neuland Pharma Research Private Limited | Process for the preparation of aripiprazole lauroxil |
US20180265472A1 (en) * | 2017-03-17 | 2018-09-20 | Scinopharm Taiwan, Ltd. | Process for preparing aripiprazole lauroxil and intermediates thereof |
JP7246364B2 (ja) * | 2017-07-28 | 2023-03-27 | インテルキム、ソシエダッド アノニマ | アリピプラゾールラウロキシルの調製方法 |
US11273158B2 (en) | 2018-03-05 | 2022-03-15 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
CN110790703A (zh) * | 2018-08-01 | 2020-02-14 | 北京万全德众医药生物技术有限公司 | 月桂酰阿立哌唑的制备方法 |
Family Cites Families (133)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2418499A (en) | 1944-06-20 | 1947-04-08 | Du Pont | 2-alkoxymethylmercapto-thiazoles and thiazolines and a process for preparing the same |
GB849541A (en) | 1956-02-23 | 1960-09-28 | Rohm & Haas | Preparation of unsaturated cyclic urea derivatives |
DE1273533B (de) | 1962-09-08 | 1968-07-25 | Hoechst Ag | Verfahren zur Herstellung von N-(ª‡-Alkoxy-alkyl)-carbonsaeureamiden |
NL128370C (ja) | 1964-08-28 | |||
US3523121A (en) | 1967-03-09 | 1970-08-04 | Rohm & Haas | Certain 2-carbamoyl-3-isothiazolenes |
US3573308A (en) | 1969-04-03 | 1971-03-30 | Hoffmann La Roche | 3-lower alkoxy methyl-3,4-dihydro-4-hydroxy-4-aryl quinazolin-2(1h) ones and related compounds |
US3957808A (en) | 1969-09-03 | 1976-05-18 | Rohm And Haas Company | 3-alkoxyisothiazoles |
US4727151A (en) | 1974-06-24 | 1988-02-23 | Interx Research Corporation | Labile quaternary ammonium salts as prodrugs |
US3998815A (en) | 1974-06-24 | 1976-12-21 | Interx Research Corporation | 1-hydrocarbonoyloxymethyl-3-carbamoyl or 3-carboethoxy-pyridinium salts |
US4204065A (en) | 1975-09-22 | 1980-05-20 | Interx Research Corporation | Soft quaternary surface active agents and method of using same |
JPS5331676A (en) | 1976-09-06 | 1978-03-25 | Mitsui Toatsu Chem Inc | Uracil derivatives and their preparation |
US4260769A (en) | 1977-04-22 | 1981-04-07 | Interx Research Corporation | 5,5-Diphenylhydantoins |
JPS54125896A (en) | 1978-03-23 | 1979-09-29 | Kuraray Co | Absorbing body that have excellent water absorbing capacity |
JPS54130587A (en) | 1978-03-30 | 1979-10-09 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
JPS568318A (en) | 1979-06-28 | 1981-01-28 | Janssen Pharmaceutica Nv | Non oral long acting composition of haloperidol and bromperidol derivative |
DE3149010A1 (de) | 1981-12-10 | 1983-07-07 | A. Nattermann & Cie GmbH, 5000 Köln | (+)-2-(1-(2,6-dichlorphenoxy)-ethyl)-1,3- diazacyclopent-2-en, dessen herstellung und seine verwendung in pharamazeutischen praeparaten |
US4428935A (en) | 1982-05-24 | 1984-01-31 | Pfizer Inc. | Penicillanic acid dioxide prodrug |
IT1212743B (it) | 1983-05-17 | 1989-11-30 | Dompe Farmaceutici Spa | Sali quaternari di derivati di benzo[ 1,4 ]diazepinonici,pirido [1,4]benzodiazepinonici,prido [1,5]benzodiazepinonici e loro atti vita' farmacologica |
JPS602331A (ja) | 1983-06-20 | 1985-01-08 | Yoshino Kogyosho Co Ltd | 飽和ポリエステル樹脂製壜の成形方法 |
US4760057A (en) | 1983-06-23 | 1988-07-26 | Merck & Co., Inc. | (Acyloxyalkoxy)carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs |
DK302883D0 (da) | 1983-06-30 | 1983-06-30 | Hans Bundgaard | Allopurinol prodrugs |
DE3544134A1 (de) | 1984-12-15 | 1986-06-19 | Mitsubishi Chemical Industries Ltd., Tokio/Tokyo | Verfahren zur herstellung von n-((alpha)-alkoxyethyl) pyrrolidon |
GB8513754D0 (en) | 1985-05-31 | 1985-07-03 | Jones T R | Anti-cancer quinazoline derivatives |
DK588486A (da) | 1985-12-09 | 1987-06-10 | Otsuka Pharma Co Ltd | Anvendelse af en forbindelse til behandling af hypoxi |
GB8607683D0 (en) | 1986-03-27 | 1986-04-30 | Ici Plc | Anti-tumor agents |
US4925860A (en) | 1987-08-05 | 1990-05-15 | E. I. Du Pont De Nemours And Company | Stable pharmaceutical composition of 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester |
US5006528A (en) | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
WO1991000863A1 (en) | 1989-07-07 | 1991-01-24 | Pfizer Inc. | Heteroaryl piperazine antipsychotic agents |
US5350747A (en) | 1989-07-07 | 1994-09-27 | Pfizer Inc | Heteroaryl piperazine antipsychotic agents |
US5229382A (en) | 1990-04-25 | 1993-07-20 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
JP2800953B2 (ja) | 1990-07-06 | 1998-09-21 | 住友製薬株式会社 | 新規なイミド誘導体 |
US5206386A (en) | 1991-03-20 | 1993-04-27 | Isp Investments Inc. | Controlled release N-substituted pyrrolidone esters and process for the use thereof |
IL101722A (en) | 1991-05-02 | 1996-05-14 | Wyeth John & Brother Ltd | History of piperazine, their preparation and pharmaceutical preparations containing them |
TW226016B (ja) | 1991-12-30 | 1994-07-01 | Sterling Winthrop Inc | |
US5462934A (en) | 1992-03-09 | 1995-10-31 | Takeda Chemical Industries | Condensed heterocyclic ketone derivatives and their use |
AU4534593A (en) | 1992-06-12 | 1994-01-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
EP0688325A1 (en) | 1993-03-08 | 1995-12-27 | Eisai Co., Ltd. | Phosphonic acid derivatives |
TW376319B (en) | 1993-04-28 | 1999-12-11 | Janssen Pharmaceutica Nv | Pharmaceutical composition containing risperidone pamoate and having a long acting activity for treating psychoses induced by the release of dopamine |
DE4439493A1 (de) | 1994-10-25 | 1996-05-02 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
JP3571795B2 (ja) | 1995-04-18 | 2004-09-29 | 株式会社日本触媒 | N−(1−アルキルオキシアルキル)カルバメート類の気相分子内脱アルコール反応用触媒およびn−ビニルカルバメート類の製造方法 |
US7833543B2 (en) | 1995-06-07 | 2010-11-16 | Durect Corporation | High viscosity liquid controlled delivery system and medical or surgical device |
AU725556B2 (en) | 1996-03-25 | 2000-10-12 | Eli Lilly And Company | Method for treating pain |
DE19619819A1 (de) | 1996-05-16 | 1997-11-20 | Boehringer Mannheim Gmbh | Neue Thiazolidindione, Verfahren zu ihrer Herstellung und diese enthaltenden Arzneimittel |
CZ299790B6 (cs) | 1996-08-22 | 2008-11-26 | Skyepharma Canada Inc. | Kompozice mikrocástic ve vode nerozpustné látky, farmaceutická kompozice, zpusob prípravy stabilních cástic, mikrocástice ve vode nerozpustné nebo slabe rozpustné slouceniny, kompozice obsahující tyto mikrocástice a zpusob prípravy mikrocástic |
EP0986403B1 (en) | 1997-06-13 | 2003-11-12 | Cydex Inc. | Composition with extended shelf-life storage comprising cyclodextrin and drugs or prodrugs that decompose to water-insoluble components |
PL339864A1 (en) | 1997-09-30 | 2001-01-15 | Lilly Co Eli | Preparation containing 2-methylthiene benzodiazepin |
UA72189C2 (uk) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Фармацевтична композиція, що містить водну суспензію субмікронних ефірів 9-гідроксирисперидон жирних кислот |
US6180095B1 (en) | 1997-12-17 | 2001-01-30 | Enzon, Inc. | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
EP1051181B1 (en) | 1997-12-31 | 2004-03-17 | The University Of Kansas | Water soluble prodrugs of tertiary amine containing drugs and methods of making thereof |
EP1114028B1 (en) | 1998-08-26 | 2006-11-29 | Aventis Pharma Limited | Aza-bicycles which modulate the inhibition of cell adhesion |
FR2783519B1 (fr) | 1998-09-23 | 2003-01-24 | Sod Conseils Rech Applic | Nouveaux derives d'amidines, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant |
US7374779B2 (en) | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
US20060034937A1 (en) | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
CA2311734C (en) | 2000-04-12 | 2011-03-08 | Bristol-Myers Squibb Company | Flash-melt oral dosage formulation |
MY128449A (en) | 2000-05-24 | 2007-02-28 | Sugen Inc | Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
US6656505B2 (en) | 2000-07-21 | 2003-12-02 | Alpharma Uspd Inc. | Method for forming an aqueous flocculated suspension |
US20030049320A1 (en) | 2000-12-18 | 2003-03-13 | Wockhardt Limited | Novel in-situ forming controlled release microcarrier delivery system |
US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
WO2002064578A1 (en) | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Llc | Benzo thiadiazine matrix metalloproteinase inhibitors |
US20060293217A1 (en) | 2001-03-19 | 2006-12-28 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained release |
AU2002258563A1 (en) | 2001-03-19 | 2002-10-03 | Praecis Pharmaceuticals Incorporated | Pharmaceutical formulations for sustained release |
US6686377B2 (en) | 2001-04-03 | 2004-02-03 | Aryx Therapeutics | Ultrashort-acting opioids for transdermal application |
MY129350A (en) | 2001-04-25 | 2007-03-30 | Bristol Myers Squibb Co | Aripiprazole oral solution |
AR033485A1 (es) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma |
JP2005526723A (ja) | 2002-02-15 | 2005-09-08 | グラクソ グループ リミテッド | バニロイド受容体モジュレーター |
AU2003257145B2 (en) | 2002-08-02 | 2008-11-13 | Merck Sharp & Dohme Corp. | Substituted furo (2,3-b) pyridine derivatives |
SI1542668T1 (sl) | 2002-08-20 | 2009-08-31 | Bristol Myers Squibb Co | Aripiprazol sestavljena formulacija in postopek |
AP2005003250A0 (en) | 2002-09-17 | 2005-03-31 | Warner Lambert Co | Heterocyclic substituted piperazines for the treatment of schizophrenia. |
US7148211B2 (en) | 2002-09-18 | 2006-12-12 | Genzyme Corporation | Formulation for lipophilic agents |
CN102205127A (zh) | 2002-12-18 | 2011-10-05 | 阿尔乔医疗公司 | 类辣椒素的给药 |
US20040156931A1 (en) | 2002-12-18 | 2004-08-12 | Algorx | Administration of capsaicinoids |
DE10303669A1 (de) | 2003-01-28 | 2004-07-29 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Tetraalkylammoniumsalze vom Kohlensäureestertyp, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
SG160211A1 (en) | 2003-04-03 | 2010-04-29 | Semafore Pharmaceuticals Inc | Pi-3 kinase inhibitor prodrugs |
WO2004105682A2 (en) | 2003-05-23 | 2004-12-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives and mood stabilizers for treating mood disorders |
AU2004259034C1 (en) | 2003-07-24 | 2010-12-16 | Boehringer Ingelheim Animal Health USA Inc. | Vaccine formulations comprising an oil-in-water emulsion |
US20050032811A1 (en) | 2003-08-06 | 2005-02-10 | Josiah Brown | Methods for administering aripiprazole |
US6987111B2 (en) | 2003-08-06 | 2006-01-17 | Alkermes Controlled Therapeutics, Ii | Aripiprazole, olanzapine and haloperidol pamoate salts |
US7160888B2 (en) | 2003-08-22 | 2007-01-09 | Warner Lambert Company Llc | [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia |
TW200510721A (en) | 2003-08-29 | 2005-03-16 | Toshiba Kk | Color reagent, concentration measuring kit, concentration measuring method and sensor chip for use therein |
SI1675573T2 (sl) | 2003-10-23 | 2012-08-31 | Otsuka Pharma Co Ltd | Sterilna injektibilna aripiprazolna formulacija z nadzorovanim sproščanjem in postopek |
CA2551346A1 (en) | 2003-12-31 | 2005-07-21 | Warner-Lambert Company Llc | N-substituted piperidine and piperazine derivatives |
EP1718311A1 (en) | 2004-02-13 | 2006-11-08 | Pfizer Products Incorporated | Therapeutic combinations of atypical antipsychotics with corticotropin releasing factor antagonists |
US7169803B2 (en) | 2004-03-15 | 2007-01-30 | Bristol-Myers Squibb Company | N-substituted prodrugs of fluorooxindoles |
US7119214B2 (en) | 2004-04-13 | 2006-10-10 | Cephalon France | Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives |
GB2413795A (en) | 2004-05-05 | 2005-11-09 | Cipla Ltd | Process for the preparation of rosiglitazone |
WO2006037090A2 (en) | 2004-09-28 | 2006-04-06 | Purdue Research Foundation | Drug-phosphate conjugates as prodrugs |
CA2587710C (en) | 2004-11-16 | 2014-10-21 | Elan Pharma International Ltd. | Injectable nanoparticulate olanzapine formulations |
EP1848541A4 (en) | 2005-02-07 | 2013-01-16 | Pharmalight Inc | METHOD AND DEVICE FOR OPHTHALMIC DELIVERY OF PHARMACEUTICALLY ACTIVE INGREDIENTS |
WO2006090273A2 (en) | 2005-02-22 | 2006-08-31 | Warner-Lambert Company Llc | [1,8]naphthyridin-2-ones and related compounds with keto or hydroxyl linkers for the treatment of schizophrenia |
CN101198331B (zh) | 2005-06-13 | 2012-05-02 | 大日本住友制药株式会社 | 增溶化制剂 |
JP2009508859A (ja) | 2005-09-15 | 2009-03-05 | エラン ファーマ インターナショナル リミテッド | ナノ粒子アリピプラゾール製剤 |
EP1777222A1 (en) | 2005-09-22 | 2007-04-25 | Galantos Pharma GmbH | Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment |
RU2008109958A (ru) | 2005-10-31 | 2009-12-10 | Пфайзер Продактс Инк. (Us) | Кристаллические соли 7-[4-(4-нафталин-1-илпиперазин-1-ил)бутокси]-3, 4-дигидро-1н-[1, 8]нафтиридин-2-она |
US20070185069A1 (en) | 2005-11-14 | 2007-08-09 | Plum Stacy M | Anti-angiogenic activity of 2-methoxyestradiol in combination with anti-cancer agents |
JP2010501625A (ja) | 2006-08-31 | 2010-01-21 | ソルベイ・フアーマシユーチカルズ・ベー・ブイ | 統合失調症を処置するためのビフェプルノックスの滴定スケジュールおよびそれにおける使用のためのキット |
US20090068290A1 (en) | 2006-08-31 | 2009-03-12 | Michel Bourin | Bifeprunox doses for treating schizophrenia |
TW200829244A (en) | 2006-09-15 | 2008-07-16 | Astrazeneca Ab | Therapeutic combinations 482 |
US20090291134A1 (en) | 2006-11-21 | 2009-11-26 | Jina Pharmaceuticals, Inc. | Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases |
BRPI0719937A2 (pt) | 2006-12-05 | 2014-03-11 | Neurogesx Inc | Pró-fármacos e métodos de fazer e de usar os mesmos |
US20080312199A1 (en) | 2006-12-15 | 2008-12-18 | Glinsky Gennadi V | Treatments of therapy resistant diseases and drug combinations for treating the same |
EP1961412A1 (en) | 2006-12-27 | 2008-08-27 | LEK Pharmaceuticals D.D. | Self-microemulsifying drug delivery systems |
US20080186971A1 (en) | 2007-02-02 | 2008-08-07 | Tarari, Inc. | Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic |
PL2134330T3 (pl) | 2007-03-19 | 2013-10-31 | Acadia Pharm Inc | Kombinacje odwrotnych agonistów i antagonistów 5-HT2A z antypsychotykami |
AU2008236705B2 (en) | 2007-04-04 | 2014-01-23 | Merck Sharp & Dohme Corp. | Therapeutic agents |
WO2009012096A2 (en) | 2007-07-18 | 2009-01-22 | Research Development Foundation | Improved therapeutic methods and compositions comprising chroman ring compounds |
SA08290475B1 (ar) | 2007-08-02 | 2013-06-22 | Targacept Inc | (2s، 3r)-n-(2-((3-بيردينيل)ميثيل)-1-آزا بيسيكلو[2، 2، 2]أوكت-3-يل)بنزو فيوران-2-كربوكساميد، وصور أملاحه الجديدة وطرق استخدامه |
WO2009052467A1 (en) | 2007-10-19 | 2009-04-23 | Board Of Regents Of The University Of Texas System | Methods of identifying pi-3-kinase inhibitor resistance |
WO2009060473A2 (en) | 2007-11-06 | 2009-05-14 | Panacea Biotec Limited | Injectable compositions, processes and uses thereof |
DK2234617T3 (da) | 2007-12-19 | 2021-05-25 | Janssen Pharmaceutica Nv | Doseringsskema forbundet med langtidsvirkende injicerbare paliperidonestere |
US8642660B2 (en) | 2007-12-21 | 2014-02-04 | The University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
US9161943B2 (en) | 2007-12-31 | 2015-10-20 | Industrial Technology Research Institute | Sustained release composition and manufacturing method thereof |
US8138169B2 (en) | 2008-04-11 | 2012-03-20 | Comgenrx, Inc. | Combination therapy for bipolar disorder |
RU2011112802A (ru) | 2008-09-03 | 2012-10-10 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | Сокристаллы и содержащие их фармацевтические композиции |
US8017515B2 (en) | 2008-12-10 | 2011-09-13 | Stats Chippac, Ltd. | Semiconductor device and method of forming compliant polymer layer between UBM and conformal dielectric layer/RDL for stress relief |
NZ594071A (en) | 2009-01-26 | 2013-01-25 | Egalet Ltd | Controlled release formulations comprising morphine sulphate for continuous treatment of pain |
WO2010129843A1 (en) | 2009-05-08 | 2010-11-11 | Cytopathfinder, Inc. | Dihydronaphthyridinyl and related compounds for use in treating ophthalmological disorders |
CA2766088C (en) | 2009-06-25 | 2017-06-13 | Alkermes, Inc. | Heterocyclic compounds for the treatment of neurological and psychological disorders |
NZ597108A (en) | 2009-06-25 | 2014-04-30 | Alkermes Pharma Ireland Ltd | Prodrugs of nh-acidic compounds |
NZ599558A (en) | 2009-10-30 | 2014-09-26 | Janssen Pharmaceutica Nv | Dosing regimen associated with long-acting injectable paliperidone esters |
US20110166156A1 (en) | 2010-01-07 | 2011-07-07 | Alkermes, Inc. | Prodrugs for the Treatment of Schizophrenia and Bipolar Disease |
WO2011084849A1 (en) | 2010-01-07 | 2011-07-14 | Alkermes, Inc. | Diaryldiazepine prodrugs for the treatment of neurological and psychological disorders |
CA2798172C (en) | 2010-01-07 | 2017-11-21 | Alkermes Pharma Ireland Limited | Quaternary ammonium salt prodrugs |
US20110166194A1 (en) | 2010-01-07 | 2011-07-07 | Alkermes, Inc. | Asenapine Prodrugs |
WO2011084848A2 (en) | 2010-01-07 | 2011-07-14 | Alkermes, Inc. | Prodrugs of heteraromatic compounds |
US9274048B2 (en) | 2010-02-16 | 2016-03-01 | Hamamatsu Photonics K.K. | Gas concentration calculation device and gas concentration measurement module |
NZ603268A (en) | 2010-05-04 | 2015-02-27 | Alkermes Pharma Ireland Ltd | Process for synthesizing oxidized lactam compounds |
CA2802733C (en) | 2010-06-24 | 2017-11-21 | Alkermes Pharma Ireland Limited | Prodrugs of nh-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
ES2604558T3 (es) | 2011-03-18 | 2017-03-07 | Alkermes Pharma Ireland Limited | Composiciones farmacéuticas inyectables que comprenden un antipsicótico insoluble en agua, laurato de sorbitán y polisorbato 20 |
ES2765036T3 (es) | 2012-03-19 | 2020-06-05 | Alkermes Pharma Ireland Ltd | Composiciones farmacéuticas que comprenden esteres de ácidos grasos |
EP2827867B1 (en) | 2012-03-19 | 2019-11-06 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising glycerol esters |
NZ630428A (en) | 2012-03-19 | 2017-02-24 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising benzyl alcohol |
EP2897592B1 (en) | 2012-09-19 | 2020-02-19 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
MX2016012041A (es) | 2014-03-20 | 2017-01-19 | Alkermes Pharma Ireland Ltd | Formulaciones de aripiprazol que tienen mayores velocidades de inyeccion. |
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JP2015529237A (ja) | 2015-10-05 |
US10639376B2 (en) | 2020-05-05 |
EP2897592A2 (en) | 2015-07-29 |
AU2013349388A1 (en) | 2015-03-26 |
US10342877B2 (en) | 2019-07-09 |
US20140088115A1 (en) | 2014-03-27 |
WO2014080285A3 (en) | 2014-09-04 |
US11969469B2 (en) | 2024-04-30 |
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HK1210033A1 (en) | 2016-04-15 |
NZ748572A (en) | 2020-07-31 |
US20200268891A1 (en) | 2020-08-27 |
WO2014080285A2 (en) | 2014-05-30 |
US20240307542A1 (en) | 2024-09-19 |
US9193685B2 (en) | 2015-11-24 |
JP2018090629A (ja) | 2018-06-14 |
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