TW200816987A - Nanoparticulate kinase inhibitor formulations - Google Patents

Nanoparticulate kinase inhibitor formulations Download PDF

Info

Publication number
TW200816987A
TW200816987A TW096121317A TW96121317A TW200816987A TW 200816987 A TW200816987 A TW 200816987A TW 096121317 A TW096121317 A TW 096121317A TW 96121317 A TW96121317 A TW 96121317A TW 200816987 A TW200816987 A TW 200816987A
Authority
TW
Taiwan
Prior art keywords
less
composition
nanoparticle
ammonium
chloride
Prior art date
Application number
TW096121317A
Other languages
Chinese (zh)
Inventor
Elaine Liversidge
Greta Cary
William H Bosch
Janine Keller
Niels Ryde
Original Assignee
Elan Pharma Int Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Elan Pharma Int Ltd filed Critical Elan Pharma Int Ltd
Publication of TW200816987A publication Critical patent/TW200816987A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention is directed to compositions comprising at least one nanoparticulate kinase inhibitor, such as LS104 or a salt or derivative thereof, having improved dissolution rate providing a faster onset of drug availability. The nanoparticulate kinase inhibitor particles, such as LS104, have an effective average particle size of less than about 2000 nm and are useful in the treatment of cancers, such as leukemia, myeloproliferative disorders and related diseases.

Description

200816987 九、發明說明： 【發明所屬之技術領域】 相關申請案 * 本發明係申明美國專利暫時申請案號60/812,960，於 5 2006年6月13日提申，之優先權，其内文在此併入本案以作 為參考資料。 發明領域 本發明係相關於一種激酶抑制劑化合物，以及用於治 療或預防疾病或病症，如骨髄增生疾病'白血病與相關疾 10病或症狀之組成物。更特別的是，本發明係相關於一種奈 米顆粒激酶抑制劑組成物，如奈米顆粒tLS1〇4組成物，具 有一有效平均粒徑小於約2000 nm。本發明亦相關於一種製 造與使用此奈米顆粒化組成物之方法。 t iltr Jt 15 發明背景 Α·有關LS104之背景說明 不正常之激酶活性已發現與數種疾病相關。白血病為 一種骨髓與金液之癌症。特徵為不正常血液細胞無法控制 地堆積。範例包括急性淋巴母細胞白血病（ALL)、慢性骨髓 20性白血病（CML)，以及急性骨髓性白血病（AML)。最常見的 白血病為疾病骨髓性白血病（AML)，每年在美國預計會新 增12,0〇〇個病例。AML僅發生於超過4〇歲之成人，平均發 生年齡為65歲。癌症如AML代表了高度無法滿足之醫療需 求區塊；目前對於AML之治療特徵為不良之長期反應速 200816987 率，在診斷出之後，僅有低於20%之成人病患存活率。數 種突變已發現於AML中；單一突變並不會有問題，至少需 要二突變才會引發疾病。然而，在受器酪胺酸激酶FLT3上 之突變係發生於約三分之一之AML病患身上，且預後通常 5 很差。FLT3會傳遞增生訊號，且通常會在骨髓幹細胞發育 早期表現，但在其突變形式中，會維持活性並幫助白細胞 繁衍。數個研究團隊已辨識出可抑制FLT3之化合物。 CML與數種ALLs之特徵為染色體轉位發生於染色體 22與染色體9之間，導致染色體22之改變，其已知為‘‘費氏 10 染色體(Philadelphia chromosome)”。費氏染色體為染色體9 之一部分’其包括Abelson原致癌基因（Abl)，轉移至染色 體22上。雖然染色體9上之斷裂點可變化，但染色體22上之 斷裂點卻相對地聚集。染色體22上之此區域稱之為“斷裂點 聚集區域（“Bcr”），且由轉位產生之融合基因稱之為 I5 “Bci*-Abl”。所有形式之融合蛋白包括一部份之Ab咖仙蛋 白，具有酪胺酸激酶活性。該酪胺酸激酶活性係為Bcr_Abi 融合蛋白之基本特性；此活性之負向調節並未在此融合蛋 白上發揮功用。此基本激酶活性已顯示可活化各種訊息傳 遞路控，導致無法控制之細胞生長與分裂(如，藉由促進細 20胞增生與抑制細胞凋亡）。例如，Bcr-Abl可導致未分化之血 球細胞大量增生，並無法成熟。 非-CML骨髓增生疾病（MpDs)，如真性多红 ㈣、原發性到、板增多症㈣與難特發性㈣纖= (IMF)，以及未分類之骨朗生疾病_D_Nc)，特徵為血 200816987 液細胞之不正常增加。請見，如Vainchenker and200816987 IX. INSTRUCTIONS: [Technical field to which the invention pertains] Related Applications* The present invention claims the priority of U.S. Patent Application Serial No. 60/812,960, filed on June 13, 2006, the priority of which is incorporated herein by reference. This is incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to a kinase inhibitor compound, and a composition for treating or preventing a disease or condition, such as an osteophyte hyperplasia disease leukemia and related diseases. More particularly, the present invention relates to a composition of a nanoparticulate kinase inhibitor, such as a nanoparticle tLS1〇4 composition, having an effective average particle size of less than about 2000 nm. The invention is also related to a method of making and using the nanoparticulate composition. t iltr Jt 15 Background of the Invention 背景·Background description of LS104 Abnormal kinase activity has been found to be associated with several diseases. Leukemia is a cancer of bone marrow and gold. It is characterized by abnormally uncontrolled accumulation of blood cells. Examples include acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). The most common form of leukemia is myeloid leukemia (AML), which is expected to increase by 12,0 in the United States each year. AML occurs only in adults over 4 years of age with an average age of 65 years. Cancers such as AML represent a highly unmet medical need block; current treatments for AML are characterized by poor long-term response rates of 200816987, and after diagnosis, only less than 20% of adult patients survive. Several mutations have been found in AML; a single mutation is not a problem, and at least two mutations are required to cause disease. However, mutations on the receptor tyrosine kinase FLT3 occur in about one-third of AML patients, and the prognosis is usually very poor. FLT3 delivers a proliferative signal and usually manifests itself in the early stages of bone marrow stem cell development, but in its mutant form, it maintains activity and helps leukocytes multiply. Several research teams have identified compounds that inhibit FLT3. CML and several ALLs are characterized by chromosomal translocation occurring between chromosome 22 and chromosome 9, resulting in a change in chromosome 22, which is known as ''Philadelphia chromosome''. The Fibonacci chromosome is chromosome 9 Part of 'which includes the Abelson proto-oncogene (Abl), which is transferred to chromosome 22. Although the breakpoint on chromosome 9 can vary, the breakpoint on chromosome 22 is relatively concentrated. This region on chromosome 22 is called " The breakpoint aggregation region ("Bcr"), and the fusion gene produced by translocation is referred to as I5 "Bci*-Abl". All forms of fusion proteins include a portion of Abcaine protein with tyrosine kinase activity. The tyrosine kinase activity is a fundamental property of the Bcr_Abi fusion protein; the negative regulation of this activity does not play a role in this fusion protein. This basic kinase activity has been shown to activate a variety of message transfer pathways leading to uncontrolled cell growth and division (e. g., by promoting cell proliferation and inhibiting apoptosis). For example, Bcr-Abl can cause undifferentiated blood cells to proliferate in a large amount and fail to mature. Non-CML myeloproliferative diseases (MpDs), such as true redness (4), primary to, hyperplasia (4) and difficult idiopathic (four) fibrosis (IMF), and unclassified bone disease (_D_Nc), characteristics An abnormal increase in blood cells for blood 200816987. See, for example, Vainchenker and

Constantinescu, Hematology (American Society of Hematology) 195-200 (2005)。此增加一般起使於位於骨髓 中之多潛能造血幹細胞自發性突變。由於突變，該幹細胞 5 會產生過多特定品系之血液細胞，與正常量相較，導致細 胞如原紅細胞、巨核細胞、顆粒細胞與單核細胞之過度製 造。某些MPD病患之共通症狀包括脾腫大、肝腫大、白血 球、紅血球及/或血小板細胞量上升、血凝塊(血拾）、衰弱、 暈眩與頭痛。疾病如PV、ET與IMF可預知白血病，然而轉 10 型之速率（如至急性轉化期），則每一種疾病皆不同。 對應許多MPDs之特定基因與伴隨之突變尚不清楚。然 而，目前已在數種MPDs中主要辨識出Janus激酶2 (JAK2)，一種細胞質内、非受器性酪胺酸激酶，基因上大 量的功能性突變。例如，此突變已報導發現於至多97%之 15 PV病患中，以及大於40%之ET或IMF病患中。請見如 Baxter等人，Lancet 365:1054-1060 (2005) ; James等人， Nature 438:1144-1148 (2005) ; Zhao等人，J· Biol· Chem· 280(24):22788-22792 (2005) ; Levine 等人，Cancer Cell 7:387-397 (2005) ; Kralovics 等人，New Eng· J· Med. 20 352(17):1779-1790 (2005); Jones等人，Blood 106:2162-2168 (2005) ; Steensma等人，Blood 106:1207-2109 (2005)。Constantinescu, Hematology (American Society of Hematology) 195-200 (2005). This increase generally results in a spontaneous mutation of pluripotent hematopoietic stem cells located in the bone marrow. Due to the mutation, the stem cells 5 produce excessive blood cells of a specific strain, which leads to excessive production of cells such as erythrocytes, megakaryocytes, granulosa cells and monocytes as compared with normal amounts. Common symptoms of certain MPD patients include splenomegaly, hepatomegaly, white blood cells, increased red blood cells and/or platelet counts, blood clots (blood pick-up), weakness, dizziness, and headache. Diseases such as PV, ET, and IMF predict leukemia, whereas the rate of metastasis (eg, to acute conversion) varies from disease to disease. The specific genes associated with many MPDs and the accompanying mutations are unclear. However, Janus kinase 2 (JAK2), a cytoplasmic, non-mediated tyrosine kinase, is genetically recognized in several MPDs. For example, this mutation has been reported to be found in up to 97% of 15 PV patients and in more than 40% of ET or IMF patients. See, for example, Baxter et al., Lancet 365: 1054-1060 (2005); James et al, Nature 438: 1144-1148 (2005); Zhao et al, J. Biol Chem. 280(24): 22788-22792 ( 2005); Levine et al., Cancer Cell 7:387-397 (2005); Kralovics et al., New Eng J. Med. 20 352(17):1779-1790 (2005); Jones et al., Blood 106:2162 -2168 (2005); Steensma et al., Blood 106: 1207-2109 (2005).

Janus激酶為一酪胺酸激酶家族，其在細胞激素訊息傳 遞中扮演重要角色。例如，JAK2激酶係作用為一中間物， 介於細胞膜連結之細胞激素受器如促紅血球生成素受器 200816987 (EpoR)，以及訊息傳遞路徑下游分子如STAT5 (Signal Transducers and Activators of Transcription protein 5)之間。 請見如 Schindler，C.W·，J. Clin Invest. 109:1133-1137 (2002); Tefferi and Gilliland, Mayo Clin. Proc. 80:947-958 5 (2005); Giordanetto and Kroemer, Protein Engineering 15(9):727-737 (2002)。當細胞激素受器/配位體錯合物磷酸 化其連結之JAK2激酶時，MK2會被活化。JAK2之後可磷 酸化並活化其受質分子，如STAT5，其可進入細胞核並與 其他調節蛋白作用，而影響轉錄。 10 白血病與骨髓增生疾病之治療涉及藥物療法（如化 療）、骨髓移植、放射療法，或其組合。可用於治療此種疾 病之一組藥物包括激酶抑制劑。例如，一激酶抑制劑稱之 為“伊瑪替尼甲磧酸鹽（imatinib mesylate)，，（^^11571 或2-苯基胺基嘧啶）已證實可有效治療CML與ALL。伊瑪替尼為 15 上市樂物’商品名稱為“Gleevec”或“Glivec”。 另一組激酶抑制劑包括LSI 04，一種苯乙浠丙烯腈 (styrylacrylonitirle)化合物，其化學組成為（E，E)_2-(节基胺 甲醯基)_3-(3,4-二羥基苯乙烯基）丙烯腈。LS1〇4之化學式為 C19H16O3N2，其分子量320.34。 LS104之化學構造如下：Janus kinase is a family of tyrosine kinases that play an important role in the transmission of cytokine messages. For example, the JAK2 kinase acts as an intermediate, a cell membrane-linked cytokine receptor such as erythropoietin receptor 200816987 (EpoR), and a signal transduction pathway downstream molecule such as STAT5 (Signal Transducers and Activators of Transcription protein 5) between. See, for example, Schindler, CW, J. Clin Invest. 109: 1133-1137 (2002); Tefferi and Gilliland, Mayo Clin. Proc. 80: 947-958 5 (2005); Giordanetto and Kroemer, Protein Engineering 15 (9) ): 727-737 (2002). MK2 is activated when the cytokine receptor/ligand complex phosphorylates its linked JAK2 kinase. JAK2 can then phosphorylate and activate its receptor molecules, such as STAT5, which can enter the nucleus and interact with other regulatory proteins to affect transcription. 10 Treatment of leukemia and myeloproliferative diseases involves drug therapy (eg, chemotherapy), bone marrow transplantation, radiation therapy, or a combination thereof. One group of drugs that can be used to treat such diseases include kinase inhibitors. For example, a kinase inhibitor called "imatinib mesylate," (^^11571 or 2-phenylaminopyrimidine) has been shown to be effective in the treatment of CML and ALL. Imatinib For 15 listings, the trade name is 'Gleevec' or 'Glivec'. Another group of kinase inhibitors includes LSI 04, a styrenel acrylonitrile compound, whose chemical composition is (E,E)_2-(节 胺 醯 ))) 3-(3,4-dihydroxystyryl) acrylonitrile. The chemical formula of LS1〇4 is C19H16O3N2, and its molecular weight is 320.34. The chemical structure of LS104 is as follows:

20 200816987 苯乙烯丙烯腈化合物例如LS104可用於治療多種細胞 增生性病症如癌症。苯乙烯丙稀腈化合物如所揭示，舉例 而言’美國專利號6,800,659揭不之“Compoimds for Modulating Cell Proliferation” ； 7,012,095 揭示之 5 “Compounds for Modulating Cell Proliferation” ；美國公開申 請案號2006/0058554，標題為“Novel Compounds Useful For Modulating Abnormal Cell Proliferation” ；美國公開申請案 號 2006/0058297，標題為 “Novel Compounds Useful For Modulating Abnormal Cell Proliferation” ；美國公開申請案 10 號2005/0085538，標題為“Compounds For Modulating Cell Proliferation” ；美國公開申請案號2005/0014690，標題為 uStyryl Acrylonitrile Compounds And Their Use To Promote Myelopoiesis” ；美國公開申請案號2004/0247592，標題為 “Ephrin And EPH Receptor Mediated Immune Modulation” ； 15 美國公開申請案號2004/0209845，標題為“Novel20 200816987 Styrene acrylonitrile compounds such as LS104 are useful in the treatment of a variety of cellular proliferative disorders such as cancer. A styrene acrylonitrile compound is disclosed, for example, in 'Compoimds for Modulating Cell Proliferation'; The title is "Novel Compounds Useful For Modulating Abnormal Cell Proliferation"; U.S. Published Application No. 2006/0058297, entitled "Novel Compounds Useful For Modulating Abnormal Cell Proliferation"; U.S. Published Application No. 10/2005/0085538, entitled "Compounds For Modulating Cell Proliferation; U.S. Published Application No. 2005/0014690, entitled UStyryl Acrylonitrile Compounds And Their Use To Promote Myelopoiesis; U.S. Published Application No. 2004/0247592, entitled "Ephrin And EPH Receptor Mediated Immune Modulation"; Published application number 2004/0209845, entitled "Novel

Compounds For Modulating Cell Proliferation” ；美國公開申 請案號2004/0006777，標題為 “Human Lymphoid Protein Tyrosine Phosphatases” ；美國公開申請案號2003/0113328， 標題為“Methods Of Modulation Of The Immune System”，以 20 上全部在此併入本案以作為參考資料。 苯乙細丙細猜化合物例如LS 104，一般而言’其作用為 抑制異常之細胞訊息傳導，其為癌細胞生長所需。LS104 可作為小分子激酶抑制劑，特別的是，可作為酪胺酸激酶 抑制劑。藉由阻斷特定激酶之作用，LS104之標的為癌細胞 200816987 訊息途徑’其不同於許多化療化合物，可攻擊癌性與非癌 性細胞，並產生嚴重副作用。 LS104為一種新型態合成、小分子、非-ATP競爭型激 酶抑制劑之成員。目前大多數發展中之激酶抑制劑，均以 5競爭細胞能量來源三磷酸腺苷(ATP)而達到治療目的。因 此，LS104具備有效抑制癌症發展之潛力，且產生之毒性明 顯低於目前之癌症化學療法。 這類化合物已知可用於治療急性淋巴癌例如急性骨髓 白血病（AML)、急性淋巴母細胞白血病（all)、慢性骨髓 10性白血病（CML)，且亦有利於其骨髓增生疾病或病症，例 如真性多紅血球症(PV)、原發性血小板增多症(ET)、骨魏 纖維化併發骨髓異常增生（MMM)與特發性骨髓纖維化 (IM)。舉例而吕，已知LS104可抑制Janus激酶2 (“JAK2”） 活性，其為許多骨髓增生疾病之主要激活突變（gain of 15 function mutation)位置，以及Bcr_Abl酿胺酸激酶活性，其 為所谓‘‘費氏染色體(Philadelphia Chromosome)，，轉位作用 之產物’並存在於各種淋巴癌病患體内。此外，Lgj 1 已證 實對於正常細胞具有極低或無毒效應。 然而在投藥時，LSI04可能無法立即被吸收。因此， 20必須配製成更具生物可吸收形式之LS104激酶抑制劑。此配 方可快速作用，因此可舒緩病患因酪胺酸激酶失調、過度 活化所產生之疾病或症狀。白血病、骨髓增生疾病或其他 血液相關癌症或疾病，為這類症狀之範例。此一配方亦可 解決傳統藥物配方有關之其他問題。本發明滿足這些需求。 200816987 本發明係相關於-種奈米顆粒激酶抑制劑組成物，例 如奈米顆粒LS1G4’或其鹽類或衍生物，用於治療血液癌症 與相關疾病、病症、症狀與症候。 B·有關奈米顆粒活化試劑組成物之背景說明 5 奈米顆粒活化試劑組成物，最初揭示於美國專利號 5，145,684 (即“ ‘684專利”），係含有溶解度差之治療或診斷 試劑顆粒’可將非交聯性表面穩定劑吸附於其表面。該‘684 專利並未揭示奈米顆粒組成物激酶抑制劑例如Ls 1 〇4。Compounds For Modulating Cell Proliferation; US Published Application No. 2004/0006777, entitled "Human Lymphoid Protein Tyrosine Phosphatases"; U.S. Published Application No. 2003/0113328, entitled "Methods Of Modulation Of The Immune System", on 20 All of which are incorporated herein by reference. Phenylpropionate compounds such as LS 104, in general, act to inhibit abnormal cellular signaling, which is required for cancer cell growth. LS104 acts as a small molecule kinase Inhibitors, in particular, act as tyrosine kinase inhibitors. By blocking the action of specific kinases, LS104 is labeled as cancer cell 200816987 message pathway 'which differs from many chemotherapeutic compounds in attacking cancerous and non-cancerous Cells, and produce serious side effects. LS104 is a member of a novel synthetic, small molecule, non-ATP competitive kinase inhibitor. Most of the developing kinase inhibitors currently compete with the cellular energy source of adenosine triphosphate (ATP). To achieve therapeutic goals. Therefore, LS104 has the potential to effectively inhibit the development of cancer. The resulting toxicity is significantly lower than current cancer chemotherapy. Such compounds are known to be useful in the treatment of acute lymphoid cancers such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and It is also beneficial for its myeloproliferative diseases or conditions, such as true polyerythrocytosis (PV), essential thrombocythemia (ET), osteofibrillary dysplasia (MMM) and idiopathic myelofibrosis (IM). For example, LS104 is known to inhibit Janus kinase 2 ("JAK2") activity, which is the position of the gain of 15 function mutation in many myeloproliferative diseases, and the Bcr_Abl tyrosine kinase activity, which is called ''Philadelphia Chromosome, a product of translocation' is present in a variety of lymphoma patients. In addition, Lgj 1 has been shown to have very low or no toxic effects on normal cells. However, at the time of administration, LSI04 It may not be absorbed immediately. Therefore, 20 must be formulated into a more bioabsorbable form of the LS104 kinase inhibitor. This formulation works quickly because It can relieve the disease or symptoms caused by dysregulation and overactivation of tyrosine kinase in patients. Leukemia, myeloproliferative diseases or other blood-related cancers or diseases are examples of such symptoms. This formula can also be used to solve traditional drug formulas. Other problems. The present invention satisfies these needs. 200816987 The present invention relates to a nanoparticle granule kinase inhibitor composition, such as nanoparticle LS1G4' or a salt or derivative thereof, for use in the treatment of hematological cancer and related diseases, disorders, symptoms and symptoms. B. Background of Nanoparticle Activating Reagent Composition 5 Nanoparticle Activating Reagent Composition, originally disclosed in U.S. Patent No. 5,145,684 ("the '684 patent"), is a therapeutic or diagnostic reagent particle having poor solubility. 'A non-crosslinkable surface stabilizer can be adsorbed to its surface. The '684 patent does not disclose a nanoparticle composition kinase inhibitor such as Ls 1 〇4.

製造奈米顆粒活化試劑組成物之方法揭示於，舉例而 10言，美國專利號5,518，187與5,862,999，兩者標題為“Method of Grinding Pharmaceutical Substances” ；美國專利號 5,718,388 揭示之 “Continuous Method of Grinding Pharmaceutical Substances”；以及美國專利號 5,5i〇，ii8 揭 示之 “Process of Preparing Therapeutic Compositions 15 Containing Nanoparticles”。 奈米顆粒活化試劑組成物，舉例而言，亦可見於美國 專利號5,298,262揭示之“Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilizatioii” ； 5,302,401 揭示之“Method to Reduce Particle Size Growth 20 During Lyophilization” ； 5,318,767揭示之 “X-Ray Contrast Compositions Useful in Medical Imaging” ； 5,326,552揭示 之 “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants” ； 5,328,404揭示之“Method of X-Ray 200816987A method of making a nanoparticle activating reagent composition is disclosed, for example, in U.S. Patent Nos. 5,518,187 and 5,862,999, both entitled "Method of Grinding Pharmaceutical Substances"; U.S. Patent No. 5,718,388, "Continuous Method of Grinding" Pharmaceutical Substances"; and "Process of Preparing Therapeutic Compositions 15 Containing Nanoparticles" disclosed in U.S. Patent No. 5,5i, ii8. The Nanoparticle Activating Agent Composition, for example, is also disclosed in "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilizatioii", US Patent No. 5,298,262; "Method to Reduce Particle Size Growth 20 During Lyophilization", 5,302,401 5,318,767, "X-Ray Contrast Compositions Useful in Medical Imaging"; 5,326,552, "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants"; 5,328,404, "Method of X-Ray 200816987

Imaging Using lodinated Aromatic Propanedioates” ； 5,336,507揭示之“Use of Charged phospholipids to Reduce Nanoparticle Aggregation” ； 5,340,564揭示之“Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability” ； 5,346,702 揭示之“Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization” ； 5,349,957 揭示之 “Preparation and Magnetic Properties of Very Small Magnetic-Glucose Particles” ； 5,352,459 揭示之 “Use of 10 Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization” ； 5,399,363 與 5,494,683 所揭示之 “Surface Modified Anticancer Nanoparticles” ； 5,401，492揭 示之“Water Insoluble Non-Magnetic Manganese Particles as5,336,507, "Use of Charged phospholipids to Reduce Nanoparticle Aggregation"; 5,340,564, "Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability"; 5,346,702, "Use of Non-Ionic Cloud 5,349,957, "Preparation and Magnetic Properties of Very Small Magnetic-Glucose Particles"; 5,352,459, "Use of 10 Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization"; 5,399,363 and 5,494,683 "Surface Modified Anticancer Nanoparticles"; 5,401,492 reveals "Water Insoluble Non-Magnetic Manganese Particles as

Magnetic Resonance Enhancement Agents” ； 5,429,824揭示 15 之“Use of Tyloxapol as a Nanoparticulate Stabilizer” ； 5,447,710揭示之“Method for Making Nanoparticulate X_Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants” ； 5,451，393揭示之“X-Ray Contrast Compositions Useful in Medical Imaging” ； 5,466,440揭示 20 之“Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays” ； 5,470,583揭示之“Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation” ； 5,472,683揭示之 12 200816987 "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging” ； 5,500,204 揭示之 “Nanoparticulate5,429,824 discloses "Use of Tyloxapol as a Nanoparticulate Stabilizer"; 5,447,710 discloses "Method for Making Nanoparticulate X_Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants"; 5,451,393 discloses "X - "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation"; 5, 466, 440 discloses "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays"; 5,472,683 discloses 12 200816987 "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; 5,500,204 Reveals "Nanoparticulate

Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool 5 and Lymphatic System Imaging” ； 5，518,738 揭示之 “Nanoparticulate NSAID Formulations” ； 5,521,218揭示之 ''Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents” ； 5,525,328 揭示之 “NanoparticulateDiagnostic Dimers as X-Ray Contrast Agents for Blood Pool 5 and Lymphatic System Imaging; 5,518,738, "Nanoparticulate NSAID Formulations"; 5,521,218, "Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents"; 5,525,328 "Nanoparticulate

Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for 10 Blood Pool and Lymphatic System Imaging” ； 5,543,133揭示 之 “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles” ； 5,552,160 揭示之 “Surface Modified NSAID Nanoparticles” ； 5,560,931 揭示之 “Formulations of Compounds as Nanoparticulate Dispersions 15 in Digestible Oils or Fatty Acids” ； 5,565，188 揭示之 “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles” ； 5,569,448揭示之“Sulfated Non-ionic Block5,543,133, "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles"; 5,552,160, "Surface Modified NSAID Nanoparticles"; 5,560,931 Revealing "Formulations of Compounds as Nanoparticulate Dispersions 15 in Digestible Oils or Fatty Acids; 5,565,188, "Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles"; 5,569,448, "Sulfated Non-ionic Blocks"

Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions” ·，5,571，536 揭示之 “Formulations of 20 Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids” ； 5,573,749 揭示之 “Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging” ； 5,573,750 揭示之 “Diagnostic Imaging X-Ray Contrast 13 200816987"Numparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool", 5,571,536, "Formulations of 20 Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids", 5,573,536 And Lymphatic System Imaging"; 5,573,750 Revealing "Diagnostic Imaging X-Ray Contrast 13 200816987

Agents” ； 5,573,783 揭示之 “Redispersible Nanoparticulate Film Matrices With Protective Overcoats” ； 5,580,579揭示之 “Site-specific Adhesion Within the GI Tract Using"Redispersible Nanoparticulate Film Matrices With Protective Overcoats", 5, 573, 783, "Site-specific Adhesion Within the GI Tract Using

Nanoparticles Stabilized by High Molecular Weight, Linear 5 Poly(Ethylene Oxide) Polymers” ； 5,585，108 揭示之Nanoparticles Stabilized by High Molecular Weight, Linear 5 Poly (Ethylene Oxide) Polymers"; 5,585,108 Reveal

“Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays” ； 5,587，143 揭示之“Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for 10 Nanoparticulate Compositions” ； 5,591，456 揭示之“Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer” ； 5,593,657 揭示之 “Novel Barium Salt"Billylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for 10 Nanoparticulate Compositions"; 5,591,456, "Milled Naproxen with Hydroxypropyl Cellulose as", 5, 591, 456, "Milled Naproxen with Hydroxypropyl Cellulose as "Milled Naproxen with Hydroxypropyl Cellulose as" Dispersion Stabilizer"; 5,593,657 Revealing "Novel Barium Salt

Formulations Stabilized by Non-ionic and Anionic Stabilizers” ； 5,622,938揭示之“Sugar Based Surfactant for 15 Nanocrystals” ； 5,628,981 for “Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents” ； 5,643,552揭示之 “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic 20 System Imaging” ； 5,718,388揭示之“Continuous Method of Grinding Pharmaceutical Substances” ； 5,718,919 揭示之 “Nanoparticles Containing the R(-)Enantiomer of Ibuprofen” ·，5,747,001 揭示之 “Aerosols Containing Beclomethasone Nanoparticle Dispersions” ； 5,834,025揭示 g 14 200816987 之“Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions” ·， 6,045,829揭示之“Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using 5 Cellulosic Surface Stabilizers” ； 6,068,858揭示之“Methods5,622,938 discloses "Sugar Based Surfactant for 15 Nanocrystals"; 5,628,981 for "Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents"; 5,643,552 discloses "Nanoparticulate Diagnostic" "Nanoparticles Containing the R(-) Enantiomer of Ibuprofen", 5, 747, 919 "Aerosols Containing Beclomethasone Nanoparticle Dispersions"; 5,834,025 discloses "Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions" by g 14 200816987, "Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using 5 Cellulosic Surface Stabili "Zers"; 6,068,858 reveals "Methods

of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic 表面穩定劑”；6，153,225 揭示之 “Injectable Formulations of Nanoparticulate Naproxen” ； 6,165,506揭示 10 之“New Solid Dose Form of Nanoparticulate Naproxen” ； 6,221，400 揭示之 “Methods of Treating Mammals UsingOf Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers; 6, 153, 225, "Injectable Formulations of Nanoparticulate Naproxen"; 6,165,506, revealing "New Solid Dose Form of Nanoparticulate Naproxen"; 6,221,400 Revealing "Methods of Treating Mammals Using

Nanocrystalline Formulations of Human Immunodeficiency Vims (HIV) Protease Inhibitors” ； 6,264,922 揭示之 “Nebulized Aerosols Containing Nanoparticle Dispersions” ； 15 6,267,989揭示之 “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions” ； 6,270,806揭示之“Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions” ； 6,316,029揭 示之 “Rapidly Disintegrating Solid Oral Dosage Form” ； 20 6,375,986揭示之“Solid Dose Nanoparticulate Compositions"Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions"; 6,270, 989, "Use of PEG- disclosed by Nanocrystalline Formulations of Human Immunodeficiency Vims (HIV) Protease Inhibitors"; 6,264,922, "Nebulized Aerosols Containing Nanoparticle Dispersions"; Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions; 6, 316, 029, "Rapidly Disintegrating Solid Oral Dosage Form"; 20 6,375,986, "Solid Dose Nanoparticulate Compositions

Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate” ； 6,428,814揭示之“Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers” ； 6,431,478 揭示之 15 200816987 “Small Scale Mill” ；以及6,432,381 揭示之“Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract” ； 6,592,903揭示之 “Nanoparticulate Dispersions Comprising a Synergistic Combination of a 5 Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate” ； 6,582,285揭示之 “Apparatus for sanitary wet milling” ； 6,656,504 揭示之 “NanoparticulateComprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate"; 6,428,814, "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers"; 6,431,478 discloses 15 200816987 "Small Scale Mill"; and 6,432,381 discloses "Methods for Targeting Drug Delivery to "Nanoparticulate Dispersions Comprising a Synergistic Combination of a 5 Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate"; 6, 582, 285, "Apparatus for sanitary wet milling"; 6,656, 504, "Nanoparticulate disclosed in the Upper and/or Lower Gastrointestinal Tract";

Compositions Comprising Amorphous Cyclosporine” ； 6,742,734 揭示之 “System and Method for Milling 10 Materials” ； 6,745,962揭示之“Small Scale Mill and Method Thereof’ ； 6,811,767 揭示之 “Liquid droplet aerosols of nanoparticulate drugs” ； 6,908,626 揭示之 “Compositions having a combination of immediate release and controlled release characteristics” ； 6,969,529揭示之“Nanoparticulate 15 compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers” ； 6,976,647揭示之 “System and Method for Milling Materials” ； 6,991，191 揭示 之“Method of Using a Small Scale Mill” ； 7,101，576揭示之 “Nanoparticulate Megestrol Formulation，’ ； 7，198,795揭示之 20 uIn vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions” ；上述全部在此併入本案以作為參考 資料。 此外，美國專利公開號20070122486据示之 16 200816987Compositions Comprising Amorphous Cyclosporine; 6,742,734, "Systems and Methods for Milling 10 Materials"; 6,745,962, "Small Scale Mills and Methods Thereof"; 6,811,767, "Liquid droplets of nanoparticulate drugs"; 6,908,626, "Compositions having a "Nanoparticulate 15 composition comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers"; 6,969,647, "System and Method for Milling Materials"; 6,991,191, "Method of Method of Milling Materials" The use of a small scale Mill"; 7,101,576, "Nanoparticulate Megestrol Formulation, '; 7,198,795, 20 uIn vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions"; Incorporate this case as a reference. In addition, U.S. Patent Publication No. 20070122486 is shown as 16 200816987

“Nanoparticulate insulin” ；美國真利公開號20070110776揭 示之“In vitro methods for evaluating the in vivo effectivness of dosage forms of microparticulate or nanoparticulate active agent compositions” ；美國專#»J 公開號20070104792揭示之 “Nanoparticulate tadalafil formulations” ；美國專 f公開號 200700988051¾ 示之“Methods of making and using novel griseofulvin compositions” ；美國專泮j 公開號20070065374 揭示之 “Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations” ;美國專寿j 公開號 10 20070059371 揭 示之 “Nanoparticulate ebastine fomiulations” ；美國專利公開號20070048378揭示之 “Nanoparticulate anticonvulsant and immunosuppressive compositions” ； 美國專利公開號20070042049揭示之 “Nanoparticulate benidipine compositions” ；美國專公開 15 號 20070015719 揭示之 “Nanoparticulate clarithromycin formulations” ； 美國專利公開號20070003628揭示之 “Nanoparticulate clopidogrel formulations” ；美國專公開 號 20070003615 揭示之 “Nanoparticulate clopidogrel and aspirin combination formulations” > 美國專矛公開號 20 20060292214 福示之"Nanoparticulate acetaminophen formulations” ； 美國專利公開號20060275372揭示之 “Nanoparticulate imatinib mesylate formulations” ；美國專 利公開號 20060246142 揭示之 “Nanoparticulate quinazoline derivative formulations” ；美國專利公開號20060246141 揭 17 200816987"Nanoparticulate insulin" is disclosed in "In vitro methods for evaluating the in vivo effectivness of dosage forms of microparticulate or nanoparticulate active agent compositions"; "Nanoparticulate tadalafil formulations" disclosed in U.S. Patent No. 2,070,104,792 "Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations" disclosed in U.S. Patent Publication No. 20070065374; U.S. Patent Publication No. 10 20070059371, the disclosure of which is incorporated herein by reference. "Nanoparticulate anticonvulsant and immunosuppressive compositions" as disclosed in U.S. Patent Publication No. 20070048378; "Nanoparticulate benidipine compositions" as disclosed in U.S. Patent Publication No. 20070042049; "Nanoparticulate clarithromycin formulations" disclosed in U.S. Patent No. 1520070015719; No. 20070003628 reveals "Nanoparticulate clopidogrel and formulations", US Patent Publication No. 20070003615, "Nanoparticulate clopidogrel and aspirin combination formulations" > US Spears Publication No. 20 20060292214 "Nanoparticulate acetaminophen formulations"; U.S. Patent Publication No. 20060275372 discloses "Nanoparticulate imatinib" "Nanoparticulate quinazoline derivative formulations" as disclosed in U.S. Patent Publication No. 20060246142; U.S. Patent Publication No. 20060246141 discloses 17 200816987

示之 “Nanoparticulate lipase inhibitor formulations” ；美國 專利公開號 20060216353 揭示之 “Nanoparticulate corticosteroid and antihistamine formulations” ；美國專寿1J 公 開號 20060210639 揭示之 “Nanoparticulate bisphosphonate 5 compositions” ；美國專利公開號20060210638揭示之 “Injectable compositions of nanoparticulate immunosuppressive compounds” ；美國專利公開號 20060204588 揭示之 “Formulations of a nanoparticulate finasteride，dutasteride or tamsulosin hydrochloride，and 10 mixtures thereof’ ；美國專利公開號20060198896揭示之 “Aerosol and injectable formulations of nanoparticulate benzodiazepine” ;美國專利公開號20060193920揭示之 “Nanoparticulate Compositions of Mitogen-Activated (MAP) Kinase Inhibitors” ；美國專利公開號20060188566揭示之 15 “Nanoparticulate formulations of docetaxel and analogues thereof’ ；美國專利公開號20060165806揭示之 “Nanoparticulate candesartan formulations” ；美國專利公開 號 20060159767 揭示之 “Nanoparticulate bicalutamide fbrmulations” ；美國專利公開號20060159766揭示之 20 “Nanoparticulate tacrolimus formulations” ；美國專利公開 號 20060159628 揭示之 “Nanoparticulate benzothiophene formulations” ；美國專利公開號20060154918揭示之 “Injectable nanoparticulate olanzapine formulations” ；美國 專利公開號20060121112揭示之“Topiramate pharmaceutical 18 200816987 composition” ；美國專利公開號20020012675 A1揭示之 “Controlled Release Nanoparticulate Compositions” ；美國 專利公開號 20040195413 Al，揭示之 “Compositions and method for milling materials” ；美國專利公開號 5 20040173696 A1 揭示之 “Milling microgram quantities of"Nanoparticulate lipase inhibitor formulations"; "Nanoparticulate corticosteroid and antihistamine formulations" as disclosed in U.S. Patent Publication No. 20060216353; "Nanoparticulate bisphosphonate 5 compositions" disclosed in U.S. Patent Publication No. 2,060,210,639; "America and injectable formulations of nanoparticulate benzodiazepine"; US Patent Publication No. 2006020496, "Aerosol and injectable formulations of nanoparticulate benzodiazepine"; US Patent Publication No. 20060204588, "Formulations of a nanoparticulate finasteride, dutasteride or tamsulosin hydrochloride, and 10 mixtures thereof"; "Nanoparticulate Compositions of Mitogen-Activated (MAP) Kinase Inhibitors", as disclosed in U.S. Patent Publication No. 20060188566, "Nanoparticulate formulations of docetaxel and analogues thereof"; U.S. Patent Publication No. 20060165806 discloses "Nanoparticulate candesa" U.S. Patent Publication No. 20060159767 discloses "Nanoparticulate bicalutamide fbrulations"; U.S. Patent Publication No. 20060159766 discloses "Nanoparticulate tacrolimus formulations"; U.S. Patent Publication No. 20060159628 discloses "Nanoparticulate benzothiophene formulations"; U.S. Patent Publication No. 20060154918 discloses "Injectable nanoparticulate olanzapine formulations"; "Topiramate pharmaceutical 18 200816987 composition", which is disclosed in U.S. Patent Publication No. 2,060,121,112; "Controlled Release Nanoparticulate Compositions", U.S. Patent Publication No. 20040012675 A1; Method for milling materials"; US Patent Publication No. 5 20040173696 A1 discloses "Milling microgram quantities of

nanoparticulate candidate compoimds” ；美國專利公開號 20020012675 A1，公開於 January 31，2002，揭示 “Controlled Release Nanoparticulate Compositions” ；美國 專利公開號20050276974揭示之“Nanoparticulate Fibrate 10 Formulations” ；美國專利公開號20050238725揭示之 "Nanoparticulate compositions having a peptide as a surface stabilizer” ；美國專利公開號20050233001揭示之 “Nanoparticulate megestrol formulations” ；美國專利公開號 20050147664 揭示之 “Compositions comprising antibodies 15 and methods of using the same for targeting nanoparticulate active agent delivery” ；美國專利公開號20050063913揭示 之 “Novel metaxalone compositions” ;美國專利公開號 20050042177揭示之“Novel compositions of sildenafil free base”；美國專利公開號20050031691 揭示之“Gel stabilized 20 nanoparticulate active agent compositions” ；美國專利公開 號20050019412揭示之” Novel glipizide compositions” ；美 國專利公開號 20050004049 揭示之 “Novel griseofulvin compositions” ；美國專利公開號20040258758揭示之 “Nanoparticulate topiramate formulations” ；美國專利公開 19 200816987"Nanoparticulate Fibrate 10 Formulations", "Nanoparticulate Fibrate 10 Formulations", and "Disclosed by US Patent Publication No. 20050238725", which is disclosed in US Patent Publication No. 20040012675 A1, which is incorporated herein by reference. "Nanoparticulate megestrol formulations" as disclosed in U.S. Patent Publication No. 20050233001; "Compositions include antibodies 15 and methods of using the same for targeting nanoparticulate active agent delivery"; "Novel composition of sildenafil free base" as disclosed in U.S. Patent Publication No. 20050063913; "Gel stabilized 20 nanoparticulate active agent compositions"; U.S. Patent Publication No. 20050031691; Revised 20050019412" Novel glipizide c "Novoparticulate topiramate formulations"; U.S. Patent Publication No. 20040049, entitled "Nanoparticulate topiramate formulations"; U.S. Patent Publication No. 20040987

號 20040258757揭示之” Liquid dosage compositions of stable nanoparticulate active agents” ；美國專利公開號 20040229038 揭示之 “Nanoparticulate meloxicam formulations” ；美國專利公開號20040208833揭示之“Novel 5 fluticasone formulations” ；美國專利公開號20040195413揭 示之” Compositions and method for milling materials” ；美 國專利公開號 20040156895 揭示之 “Solid dosage fonns comprising pullulan” ；美國專利公開號美國專利公開號 20040156872揭示之“Novel nimesulide compositions” ；美國 10 專利公開號 20040141925 揭示之 “Novel triamcinolone compositions” ；美國專利公開號20040115134揭示之“Novel nifedipine compositions” ；美國專利公開號20040105889揭 示之“Low viscosity liquid dosage forms” ；美國專利公開號 20040105778 揭示之 “Gamma irradiation of solid 15 nanoparticulate active agents” ；美國專利公開號 20040101566 揭示之 “Novel benzoyl peroxide compositions” ；美國專利公開號20040057905揭示之 “Nanoparticulate beclomethasone dipropionate compositions” ；美國專利公開號20040033267揭示之 20 “Nanoparticulate compositions of angiogenesis inhibitors” ； 美國專利公開號20040033202揭示之“Nanoparticulate sterol formulations and novel sterol combinations” ；美國專利公開 號 20040018242 揭示之 “Nanoparticulate nystatin formulations” ；美國專利公開號20040015134揭示之“Drug 20 200816987 delivery systems and methods” ；美國專利公開號 20030232796 揭示之 “Nanoparticulate polycosanol formulations & novel polycosanol combinations” ；美國專矛！I 公開號20030215502揭示之“Fast dissolving dosage forms 5 having reduced friability” ；美國專利公開號20030185869揭 示之“Nanoparticulate compositions having lysozyme as a surface stabilizer” ；美國專利公開號20030181411揭示之"Nanoparticulate meloxicam formulations" as disclosed in U.S. Patent Publication No. 20040229038; "Novel 5 fluticasone formulations"; U.S. Patent Publication No. 20040195413, the disclosure of which is incorporated herein by reference. """""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""" "Lam viscosity liquid dosage forms", "Gamma irradiation of solid 15 nanoparticulate active agents", as disclosed in U.S. Patent Publication No. 20040105, 778; "Novel benzoyl pe" disclosed in U.S. Patent Publication No. 20040101566 "Nanoparticulate beclomethasone dipropionate compositions"; U.S. Patent Publication No. 20040033267 discloses "Nanoparticulate compositions of angiogenesis inhibitors"; U.S. Patent Publication No. 20040033202 discloses "Nanoparticulate sterol formulations and novel sterol combinations". "Nanoparticulate nystatin formulations" as disclosed in U.S. Patent Publication No. 20040018242; "Drug 20 200816987 delivery systems and methods", US Patent Publication No. 20040015134; "Nanoparticulate polycosanol formulations & novel polycosanol combinations"; Special spear! The disclosure of "Nanoparticulate compositions having lysozyme as a surface stabilizer" is disclosed in U.S. Patent Publication No. 20030214, 502, the disclosure of which is incorporated herein by reference.

“Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors”；美國專利公開號20030137067揭 10 示之 “Compositions having a combination of immediate release and controlled release characteristics” ；美國專利公 開號 20030108616 揭示之 “Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers”；美國專利公開號20030095928 揭示 15 之“Nanoparticulate insulin” ；美國專利公開號20030087308 揭示之“Method for high through put screening using a small scale mill or microfluidics’’ ；美國專利公開號20030023203 揭示之“Drug delivery systems & methods” ；美國專利公開 號 20020179758 揭不之 “System and method for milling 20 materials ;以及美國專利公開號20010053664揭示之 “Apparatus for sanitary wet milling，，；其中揭示奈米顆粒活 化試劑組成物在此併入本案以作為參考資料。 非晶形小顆粒組成物如所揭示，舉例而言，美國專利 號 4,783,484 揭不之 Particulate Composition and Use"Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors; "Compositions having a combination of immediate release and controlled release characteristics", US Patent Publication No. 20030108616, "Nanoparticulate compositions comprising copolymers" US Patent Publication No. 20030095928 discloses "Nanoparticulate insulin" of 15; "Method for high through put screening using a small scale mill or microfluidics" by US Patent Publication No. 20030087308; "Drug delivery systems & methods", which is disclosed in the publication No. 20030023203; "System and method for milling 20 materials; and "Apparatus for sanitary wet milling," disclosed in U.S. Patent Publication No. 20010053664 Nanoparticle activating reagent compositions are incorporated herein by reference. Amorphous Small Particles As it was disclosed as, for example, U.S. Patent No. 4,783,484 does not expose the Particulate Composition and Use

21 20081698721 200816987

Thereof as Antimicrobial Agent” ； 4,826,689揭示之“Method for Making Uniformly Sized Particles from Water-InsolubleThereof as Antimicrobial Agent"; 4,826,689, "Method for Making Uniformly Sized Particles from Water-Insoluble

Organic Compounds” ； 4,997,454揭示之“Method for Making Uniformly-Sized Particles From Insoluble Compounds” ； ， 5 5,741，522 揭示之 “Ultrasmall，Non-aggregated Porous v Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods”，以及 5,776,496揭示之 “Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter”。在此亦併 入本案以作為參考貪料。 10 雖然在習知技藝中激酶抑制劑例如LS104被視為具有 高度治療價值，但其為水溶性差之抑制劑，於口服或注射 給藥時，會侷限其生物可吸收性，且較難或無法配製成安 全與有效之他種給藥劑型。因此，必須在技術上配製成一 種包含激酶抑制劑並改善其生物可吸收性，以增加藥效與/ 15或適合投藥例如非經腸胃給藥。本發明符合此需求。 本發明係關於含有激酶抑制劑例如L S10 4之奈米顆粒 組成物’可用於治療與預防疾病及病症，例如、趙^、 ALL、骨髓增生疾病與其他血液相關癌症與疾病。 L 明内容;j 20 發明概要 本發明係相關於-種奈米顆粒激酶抑制劑組成物，包 含有-激ϋ抑制劑’如Ls刚或其細或衍生物，以及至少 一表面穩定劑。在某些實施例中，該表面穩定劑可與顆粒 表面結合，例如，表面穩定劑可吸附至ls104顆粒之表面。 22 200816987 一般而言，該藥物奈米顆粒具一有效平均粒徑小於約2000 nm ° 該組成物可包括LS104顆粒，其為結晶相、非晶相、半 晶相、半非晶相或其混合物。 5 該組成物可包括一或多種表面穩定劑。例如，某些組 成物可包括至少一主要表面穩定劑與至少一次要表面穩定 劑。示範性表面穩定劑包括，但不侷限於，非離子表面穩 定劑、離子表面穩定劑、陰離子表面穩定劑、陽離子表面 穩定劑與兩性離子表面穩定劑，及其組合。 10 本發明亦相關於一種組成物，包含奈米顆粒激酶抑制 劑如LS104或其鹽類或衍生物、至少一表面穩定劑，以及 選擇地，一或多種醫藥上可接受之賦形劑、載體，以及選 擇！'生地或多種活性試劑，用於治療癌症，如白金病、骨 髓增生疾病，與相關疾病，或其組合。 15 本舍明之組成物包含一奈米顆粒激酶抑制劑，如LS104 或其鹽類或衍生物，係被認為具有增進之藥物動力學性 質’與一般激酶抑制劑組成物相較(如LS1〇4)。例如，奈米 顆粒組成物之°^狀及/或AUC可大於一般組成物之Cmax及/或 AUC，在投以相同劑量情況下，而1^^則較低，奈米顆粒 2〇 LS014組成物具有增進之(：蘿、Αυ(^τ·之組合 ，與一般 LS104組成物相較。在其他實施例中，該lsi〇4組成物並不 t產生明顯不同之吸收量，當齡狀態與禁食狀態投藥相 較時。 在某些實施例中，奈米顆粒LS104組成物具有增進之生 t 23 200816987 物可獲得性，與一般LS104組成物相較。例如，在投藥至一 哺乳動物情況下，奈米顆粒LS1〇4組成物可重新分散，使得 該顆粒具一有效平均粒徑小於約2微米。 本發明亦相關於一種製造奈米顆粒組成物，包括激酶 5抑制劑，如LS1〇4或鹽類或其衍生物。在某些實施例中，該 方法可包括將LS104顆粒與至少一表面穩定劑接觸一段時 間’在足以提供具一有效平均粒徑小於約2〇〇〇 ηπι之奈米顆 粒LSI 04組成物之條件下。 本發明亦相關於使用奈米顆粒LS104組成物之治療 10方法。在某些方法中，一組成物係包含奈米顆粒LS104或 其鹽類或衍生物，具一有效平均粒徑小於約2〇〇〇 ηιη，以及 至少一表面穩定劑，可投藥至一個體中。在某些方法中， 该組成物可配製為非經腸胃注射（如靜脈内、肌肉内或皮 下），於醫療有效劑量下。在某些實施例中，該可注射配方 15可提供高1^140濃度於欲注射之小體積中。在其他實施例 中，该投藥可包含激轉抑制劑如LS140之團注法，以及一連 續式快速注射，而非藥物之緩慢注入。舉例而言，該組成 物可投藥以治療骨髓增生病症、疾病、症候或與骨髓增生 疾病相關之症狀，以及癌症如白血病，如CML、八“匕與 20 ALL。在某些實施例中，該個體患有此類疾病、病症、症 候或症狀。其他使用本發明奈米顆粒組成物之治療方法為 熟習此技術領域者所熟知。 本發明前述之摘要與後述之詳細說明，皆為示範性與 解釋用，而提供本發明更詳細之說明。其他目的、優點與 24 200816987 新穎之特徵，此技術領域者將由下列詳細說明而得知。 C 方式]14,997,454, "Method for Making Uniformly-Sized Particles From Insoluble Compounds"; , 5,741,522, "Ultrasmall, Non-aggregated Porous v Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods", and 5,776,496 The disclosure of "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter" is also incorporated herein by reference. 10 Although in the prior art, kinase inhibitors such as LS104 are considered to be highly therapeutic, they are poorly water soluble. The inhibitor, when administered orally or by injection, limits its bioabsorbability and is difficult or impossible to formulate into a safe and effective dosage form. Therefore, it must be technically formulated to contain a kinase. Inhibiting the agent and improving its bioabsorbability to increase the efficacy of the drug and/or suitable for administration, such as parenteral administration. The present invention meets this need. The present invention relates to a nanoparticle composition comprising a kinase inhibitor such as L S10 4 ' can be used to treat and prevent diseases and conditions, for example, Zhao ^, A LL, myeloproliferative diseases and other blood-related cancers and diseases. L Ming content; j 20 SUMMARY OF THE INVENTION The present invention relates to a nanoparticle kinetic kinase inhibitor composition comprising a stimulating inhibitor such as Ls Gang or a fine or derivative, and at least one surface stabilizer. In certain embodiments, the surface stabilizer can bind to the surface of the particle, for example, a surface stabilizer can adsorb to the surface of the ls 104 particle. 22 200816987 In general, the drug The nanoparticle has an effective average particle size of less than about 2000 nm. The composition may comprise LS 104 particles which are crystalline phase, amorphous phase, semicrystalline phase, semi-amorphous phase or a mixture thereof. 5 The composition may comprise a Or a plurality of surface stabilizers. For example, certain compositions may include at least one primary surface stabilizer and at least one primary surface stabilizer. Exemplary surface stabilizers include, but are not limited to, nonionic surface stabilizers, ionic surface stabilizers Anionic surface stabilizers, cationic surface stabilizers and zwitterionic surface stabilizers, and combinations thereof. 10 The invention is also related to a composition comprising nanoparticles A kinase inhibitor such as LS104 or a salt or derivative thereof, at least one surface stabilizer, and, optionally, one or more pharmaceutically acceptable excipients, carriers, and a choice of 'skin or multiple active agents for treatment Cancer, such as platinum disease, myeloproliferative disease, and related diseases, or a combination thereof. 15 The composition of Benben contains a nanoparticle kinase inhibitor, such as LS104 or a salt or derivative thereof, which is considered to have improved pharmacokinetic properties' compared to a general kinase inhibitor composition (eg LS1〇4) ). For example, the shape and/or AUC of the nanoparticle composition may be greater than the Cmax and/or AUC of the general composition, and the same dose is applied, while 1^^ is lower, and the nanoparticle 2〇LS014 is composed. The material has an improved (: combination of radish and lanthanum (^τ· compared with the general LS104 composition. In other embodiments, the lsi〇4 composition does not produce a distinctly different amount of absorption, the age state and In the fasted state, the drug is administered in comparison. In certain embodiments, the nanoparticle LS104 composition has improved availability of t 23 200816987 compared to a typical LS 104 composition. For example, when administered to a mammal Next, the nanoparticle LS1〇4 composition can be redispersed such that the particles have an effective average particle size of less than about 2 microns. The invention is also related to a composition for making nanoparticles, including kinase 5 inhibitors, such as LS1〇. Or a salt or a derivative thereof. In certain embodiments, the method can include contacting the LS 104 particles with at least one surface stabilizer for a period of time sufficient to provide an effective average particle size of less than about 2 〇〇〇ηπι Nanoparticle LSI 04 composition The present invention is also related to the method of treatment 10 using a composition of nanoparticle LS104. In some methods, a composition comprising nanoparticle LS104 or a salt or derivative thereof, having an effective average particle size Less than about 2 〇〇〇ηηη, and at least one surface stabilizer, can be administered to a body. In some methods, the composition can be formulated for parenteral injection (such as intravenous, intramuscular or subcutaneous). In a medically effective dose, in certain embodiments, the injectable formulation 15 can provide a high concentration of 1 ^ 140 in a small volume to be injected. In other embodiments, the administration can include a regiment of a violent inhibitor such as LS140. Injection, and a continuous rapid injection, rather than slow injection of the drug. For example, the composition can be administered to treat myeloproliferative disorders, diseases, symptoms or symptoms associated with myeloproliferative diseases, as well as cancers such as leukemia, such as CML, eight "匕 and 20 ALL. In certain embodiments, the individual has such a disease, condition, symptom or symptom. Other treatments using the nanoparticle composition of the present invention are cooked The foregoing summary of the invention is intended to be illustrative and illustrative of the embodiments of the invention It will be known from the following detailed description. C Mode]1

較佳實施例之詳細說明 本發明係相關於一種組成物’包含至少^—奈米顆粒激 5 酶抑制劑，如LS104或其鹽類或衍生物，以及至少一表面穩 定劑。該表面穩定劑可吸附至或與藥物表面結合。一般而 言’該藥物奈米顆粒或其鹽類或衍生物，具一有效平均粒 徑小於約2000 nm。 10 15DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to a composition comprising at least a nanoparticle granulating enzyme inhibitor such as LS104 or a salt or derivative thereof, and at least one surface stabilizer. The surface stabilizer can be adsorbed to or bound to the surface of the drug. Generally, the drug nanoparticle or a salt or derivative thereof has an effective average particle diameter of less than about 2000 nm. 10 15

20 該組成物之優點係包含至少一奈米顆粒激酶抑制劑， 如LS104，與該相同激酶抑制劑（如LS1〇句之一般非-奈米顆 粒(微結㈣或轉性括，但不侷祕：⑴較小 之藥旋或其他固體藥劑形式尺寸；（2)較小之藥物劑量，為 達到相同藥物作用所需；（3)增加之生物可獲得性；⑷增進 之藥物動力學；（5)實質上類似之藥物動力學，在餵食^ 食狀態下投藥時；⑹生物等效性，在餵食與禁食狀態下： 樂時；⑺奈米顆粒組成物吸收速率增加；⑻溶解速率辦 加；以及(9)激酶抑咖組成物可與另—活性試劑结合曰 於治療骨髓增生疾病、痒症如白 瓦症如白血病，與相關之病症、疾 病、症候或症狀。 本發明亦包括-組成物，包含至少—奈米顆粒激酶抑 制心如LSHM或其鹽類或衍生物，以及—或多種非毒性醫 2接受韻、佐劑或為載體。如成物可配 衣為非經^注射(如靜脈内、肌肉内或皮下）、η服投藥， 為固體、親錢溶膠形式、生物騎物、陰道、鼻内、 25 200816987 直腸内、眼内、局部(粉末、藥膏或滴劑）、口頰、蛛網膜下 腔、腹膜内或局部投藥，及類似方式。 在某些實施例中，本發明之較佳藥劑形式為可注射藥 _ 劑形式，雖然任一藥學可接受之藥劑形式皆可使用。在某 ^ 5些實施例中，該可注射配方可提供高LS140濃度於待注射之 -小劑量中。在其他實施例中，該投藥包括激酶抑制劑如 LS140之團注法，以及一連續式快速注射，而非藥物之緩慢 注入。 _ 示範性之固體藥劑形式包括，但不侷限於，藥錠、膠 10囊、小袋、菱片鍵、粉末、藥丸或顆粒，且該固體藥劑形 式可為，如快熔藥劑形式、控制釋放藥劑形式、冷陳乾燥 藥劑形式、延遲釋放藥劑形式、持續釋放藥劑形式、脈衝 釋放藥劑形式、混合立即釋放與經控制釋放藥劑形式，或 其組合。 15 本發明係於下描述數種定義，用於本份申請書全文。 術語“有效平均粒徑”，使用於此係指至少約50%奈米顆 • 粒激酶抑制劑顆粒，如LSI04，具有粒徑小於約2〇〇〇 nm (使 用重量或其他適當之測量方法，如體積、數量等），當以， 如沈降流動分離法、光子相關光譜法、光散射法、盤式離 20 心，以及其他此領域已知之技術，测量時。 使用於此，“约”為此技術領域者所瞭解者，且依據所 使用之内文而有不同。若使用之術語在内文中為此技術領 域者所不清楚，則“约”代表至多特定術語之10%上下範圍。 於此使用奈米顆粒激酶抑制劑如LS104A之穩定顆 26 200816987 粒，“穩定”意指，但不侷限於一或多種下列參數：（i)無法 明顯成團或聚集之顆粒，由於顆粒間之吸引力所造成，或 隨時間粒徑明顯增加；（2)該顆粒之物理結構並不會隨時間 而改變，如由非晶形轉變為結晶形；(3)該顆粒為化學性穩 5 定;及/或(4)其中激酶抑制劑並未置於一加熱步驟於或高於 激酶抑制劑顆粒之熔點，在製備本發明奈米顆粒時。 術語“一般”或“非-奈米顆粒活性試劑”係指一活性試 劑，其已溶解，或其具一有效平均粒徑大於約2000 nm。奈 米顆粒活性試劑以定義為具有一有效平均粒徑小於約2000 10 nm 〇 術語“水難溶性藥物”使用於此係指具有水中溶解度小 於約30 mg/ml、小於約20 mg/ml、小於約10 mg/ml，或小於 約1 mg/ml之藥物。 使用於此，術語“醫療有效劑量”係指該藥物劑量可提 15 供特定之藥物反應，當該藥物投至需此治療之明顯數量之 個體中時。需強調的是，在一特定情況下，投以一特定醫 療有效劑量至一特定個體，並非可永遠有效治療此述之該 症狀/疾病，即使此劑量為此技術領域者所定義之醫療有效 劑量。 20 術語“骨髓增生疾病”或“骨髓增生病症”係包括非淋巴 發育不良或新生瘤症狀，由於造血幹細胞或其後代所引 起。“MPD病患”包括診斷患有MPD之病患。“骨髓增生疾病” 係包括特定、分類形式之骨髓增生疾病，包括真性多紅血 球症(PV)、原發性血小版增多症氏乃與特發性骨髓纖維化 27 200816987 (IMF)。亦包括嗜酸性粒細胞增多症(HES)、慢性嗜中性粒 細胞白血病（CNL)、伴隨骨髓異常增生之骨髓纖維化 (MMM)、慢性骨髓單核球白血病（CMML)、青少年骨髓單 核球白血病、慢性嗜驗性粒細胞白血病、慢性嗜酸性粒細 5 胞白血病，及系統性肥大細胞增生症（SM)。“骨髓增生疾病” 亦包括任一未分類之骨髏增生疾病（UMPD或MPD-NC)。 A·本發明奈米顆粒激酶抑制劑組成物之特徵 1·生物可獲得性增加 本發明之組成物包含至少一激酶抑制劑，如Lsi〇4，本 1〇發明具有增加之生物可獲得性，與相同之非-奈米顆粒激酶 抑制劑相較。此外，本發明之組成物預期需要較小劑量， 以及較小藥錠與其他固體藥劑形式尺寸，與先前相同激酶 抑制劑之一般非-奈米顆粒配方相較，達到相同藥物作用。 增加之生物可獲得性相當明顯，由於其代表此奈米顆 15粒激酶抑制劑之藥劑形式具有明顯較大之藥物吸收。 2·增進之藥物動力學 本發明亦包含-組成物，其包含至少一奈米顆粒激酶 抑制劑，如LS104，具有希望之藥物動力學性質，當投至哺 乳動物體中時。包含奈米顆粒激酶抑制劑刚之組成物 20所希望之藥物動力學包括，但不侷限於··⑴一激酶抑制劑 如LS104之Cmax，當於投藥後之哺乳動物體血漿中試驗時， 較佳大於投以相同藥劑之相同激酶抑制劑非奈米顆粒配方 之Cmax，及/或(2) —激酶抑制劑如LSl〇42Auc，當於投藥 後之哺乳動物體血漿中試驗時，較佳大於投以相同藥劑之 28 200816987 相同激酶抑制劑非奈米顆粒配方之AUC;及/或(3)—激酶抑 制劑如LS104之Tmax，當於投藥後之哺乳動物體血漿中試驗 時，較佳小於投以相同藥劑之相同激酶抑制劑非奈米顆粒 配方之Tmax。所希望之藥物動力學狀態，使用於此，為在激 5 酶抑制劑如LS104起始劑量時測量之藥物動力學狀態。 在一實施例中，一組成物包含一奈米顆粒激酶抑制 劑，如LS104，具有可比較之藥物動力學試驗，使用相同激 酶抑制劑之非·奈米顆粒配方，投以相同劑量，Tmax不大於 約90%、不大於約80%、不大於約70%、不大於約60%、不 10 大於約50%、不大於約30%、不大於約25%、不大於約20%、 不大於約15%、不大於約10%，或不大於約5%之非-奈米顆 粒激酶抑制劑配方之Tmax。 在另一實施例中，該組成物包含一奈米顆粒激酶抑制 劑如LS104,具有可比較之藥物動力學試驗，使用相同激酶 15 抑制劑之非·奈米顆粒配方，Cmax至少約50%、至少約1 〇0%、 至少約200%、至少約300%、至少約400%、至少約5〇〇〇/0、 至少約600%、至少約700%、至少約800%、至少約900%、 至少約1000%、至少約1100%、至少約1200%、至少約 1300%、至少約1400%、至少約1500%、至少約1600%、至 20少約1700%、至少約1800%，或至少約1900%大於非·奈米顆 粒激酶抑制劑配方之cmax。 在另一實施例中，該組成物包含一奈米顆粒激酶抑制 劑如LS104,具有可比較之藥物動力學試驗，使用相同激酶 抑制劑之非-奈米顆粒配方，AUC至少約25%、至少約5〇%、 29 200816987 至少約75%、至少約100%、至少約125%、至少約150%、至 少約175%、至少約200%、至少約225%、至少約250%、至 少約275%、至少約300%、至少約350%、至少約400%、至 少約450%、至少約500%、至少約550%、至少約600%、至 5 少約750%、至少約700%、至少約750%、至少約800%、至 少約850%、至少約900%、至少約950%、至少約1000%、至 少約1050%、至少約1100%、至少約1150%，或至少約1200% 大於非-奈米顆粒激酶抑制劑配方之AUC。 在本發明之一實施例中，激酶抑制劑如LS104iTmax， 10 當試驗於哺乳動物血漿中，係小於約6至約8小時。在本發 明之另一實施例中，LS104之Tmax小於約6小時、小於約5小 時、小於約4小時、小於約3小時、小於約2小時、小於約1 小時，或小於約30分鐘，投藥後。 所希望之藥物動力學狀態，使用於此，為在激酶抑制 15劑如LS104起始劑量時測量之藥物動力學狀態。該組成物可 以任何方式配製，以於此描述之方式或是此技術領域者所 熟知之方法。 3·本發明組成物之激酶抑制劑之藥物動力學不會受到餵 食或禁食狀態攝入該組成物而影箏 2〇 本發明係包含一組成物，包含至少一奈米顆粒激酶抑 制劑，如LS104,其中該激酶抑制劑之藥物動力學狀態，實 質上不會受到餵食或禁食狀態攝入該組成物而影響。此代 表在藥物吸收量(AUC)、藥物吸收速率（Cmax)，，或達到c max 之¥間長度(Tmax)方面並無實質上之不同，t該奈米顆粒激 30 200816987 酶抑制劑組成物於餵食或禁食狀態下投藥。 本發明奈米顆粒激酶抑制劑組成物（如LS1〇4組成物） 之吸收度(AUC)或Cmax之差異，當比較餵食與禁食狀態下投 藥，較佳小於約100%、小於約9〇%、小於約8〇%、小於約 5 7〇%、小於約60%、小於約55%、小於約5〇y0、小於約45%、 小於約40%、小於約35%、小於約3〇%、小於約25%、小於 約20%、小於約15%、小於約1〇%、小於約5%，或小於約3%。 4·本發明激酶抑制劑組成物之生物等效性，當比較餵食或 禁食狀態下投藥時 本發明亦包含一組成物，其包含一奈米顆粒激酶抑制 劑，如LS104，其中於餵食狀態下投藥至一個體時，係與於 禁食狀態下投藥具生物等效性。 在本發明之一實施例中，本發明係包含一組成物，其 包含一奈米顆粒激酶抑制劑，如LS104,其中於餵食狀態下 15投藥至一個體時，係與於禁食狀態下投藥具生物等效性， 尤其是Cmax與AUC所定義者，該準則係由美國食品與藥物 管理局與對應之歐洲規範局（EMEA)所提供。基於u s. fda 規範，二產物或方法為生物等效性，若AUC與Cmax之90%信 賴區間（CI)介於〇·8〇與ι·25之間（Tmax之測量並不與一般目 20的之生物等效性相關）。為了顯示二化合物或投藥條件具有 生物等效性，依據歐洲EMEA規範，AUC之90% CI必須介 於0.80至1.25，且Cmax之90%CI必須介於0.70至1.43。 S·本發明激酶抑制劑組成物之溶解狀態 該組成物包含至少一奈米顆粒激酶抑制劑，如LS1〇4 31 ί -t > 200816987 或其鹽類或衍生物，係假設具有未預期之劇烈溶解狀態。 才又藥之活性試劑較佳為快速溶解，快速溶解一般可導致較 佳之生物可獲得性，且可較快啟動作用。為了增進激酶抑 制劑之溶解狀態與生物可獲得性，可增加該藥物之溶解 ' 5 度，使其達到接近100%。 本發明之激酶抑制劑如LS104組成物較佳具有溶解狀 態，其中在約5分鐘内至少有約20%之該組成物溶解。在本 發明之另一實施例中，至少約3〇%或至少約4〇%之激酶抑制 瞻劑組成物，係於約5分鐘内溶解。在另一實施例中，較佳至 1〇少約4G%、至少約5G%、至少約_、至少約7()%，或至少 約80%之激酶抑制劑組成物，在約1〇分鐘内溶解。最後， 在本發明之另一實施例中，較佳至少約7〇%、至少約8〇%、 至少約90%，或至少約100%之激酶抑制劑組成物係於約2〇 分鐘内溶解。 15 溶解度較佳係於一介質中測量，其具可分別性。且分 # 雜之溶解介質為可對於二產物產生二非常不同之溶解1 線，該二產物在胃液中具有非常不同之溶解狀態，即，該 溶解介質預測可於體内溶解一組成物。一示範性之溶解^ 質為-含有0.025 Μ之界面活性劑月桂基硫酸納之水性: 扣質。溶解量之測量可以光譜法進行。轉紫法 Pharmacopoeia)可用於測量溶解度。 6·本發明激酶抑制劑組成物之再分散性 該级成物係包含至少-奈米顆粒激酶抑制劑，如讓 或其鹽類或衍生物，其-額外特徵為該組成物重新分散， 32 200816987 使得再分散之激酶抑制劑顆粒之有效平均粒徑小於約2微 米。此在投藥時相當明顯，若本發明組成物之激酶抑制劑 顆粒聚集，或未分散至實質上奈米顆粒大小，該藥劑便^ 失去配製為奈米顆粒大小之激酶抑制劑所擁有之優點。 5 此係因為奈米顆粒活性試劑組成物，具有活性試劑小 顆粒尺寸之優點。若活性試劑並未分散為小顆粒尺寸^投 藥後便會“結塊”或聚集該活性試劑顆粒，歸因於奈米顆粒 系統之高表面能量，與熱動力驅動力，而達到自由能之麴 降低。具有此種結塊顆粒配方，此藥劑形式之生物可獲得 10性會降低，與奈米顆粒活性試劑之液體分散形式相較。 此外，本發明組成物包含至少一奈米顆粒激酶抑制 劑，如LS104,具有奈米顆粒激酶抑制劑顆粒之劇烈再分散 性，基於投藥至哺乳動物，如人體或動物體，以生物相關 介質重新配製/重新分散，使得該重新分散之激酶抑制劑顆 5粒之平均粒控小於約2微米。此生物相關水性介質可為任竹 水性介質，其具有希望之離子強度與pH，形成該介質之生 物相關性之基礎。所希望之pH與離子強度，為人體生理條 件之代表。此生物相關水性介質可為，如水性電解質溶液， 或任一鹽類、酸或鹼或其組合物之水溶液，具有希望之 20 值與離子強度。 生物相關pH為技術上已知。例如，在胃中，pH範圍微 小於2 (但一般大於1)，至多至4或5。在小腸中，pH範圍為 4至6，在直腸中範圍為6至8。生物等效性離子強度亦為技 衔上已知。禁食狀恶之胃液具離子強度約0· 1Μ，而禁食狀 33 200816987 態之小腸具離子強度約0.14。請見如Lindahl ei α/.， ^Characterization of Fluids from the Stomach and Proximal20 The advantage of this composition is that it contains at least one nanoparticle kinase inhibitor, such as LS104, and the same kinase inhibitor (such as the general non-nanoparticle of LS1 haiku (micro-junction (four) or transgenic, but not Secret: (1) smaller drug spin or other solid dosage form size; (2) smaller drug dose required to achieve the same drug effect; (3) increased bioavailability; (4) enhanced pharmacokinetics; 5) Substantially similar pharmacokinetics when administered under fed conditions; (6) Bioequivalence, in fed and fasted state: Leh; (7) Increase in absorption rate of nanoparticle composition; (8) Dissolution rate And (9) the kinase inhibitor composition may be combined with another active agent for the treatment of myeloproliferative diseases, itch such as white blood such as leukemia, and related disorders, diseases, symptoms or symptoms. The present invention also includes - The composition comprising at least - nanoparticle kinetic kinase inhibiting heart such as LSHM or a salt or derivative thereof, and - or a plurality of non-toxic medicinal agents, adjuvants or carriers, such as the composition can be coated as a non-injection (eg intravenous, intramuscular or Subcutaneous), η service, solid, pro-sol, sol, vaginal, intranasal, 25 200816987 rectal, intraocular, topical (powder, ointment or drops), buccal, subarachnoid, Intraperitoneal or topical administration, and the like. In certain embodiments, preferred forms of the invention are in the form of injectables, although any pharmaceutically acceptable pharmaceutical form may be employed. In embodiments, the injectable formulation provides a high LS140 concentration in the small dose to be injected. In other embodiments, the administration includes a bolus injection of a kinase inhibitor such as LS140, and a continuous bolus injection, rather than Slow injection of the drug. _ Exemplary solid dosage forms include, but are not limited to, tablets, gel 10 capsules, sachets, pellets, powders, pills or granules, and the solid dosage form can be, for example, a fast-melting agent Form, controlled release pharmaceutical form, cold dry pharmaceutical form, delayed release pharmaceutical form, sustained release pharmaceutical form, pulsed release pharmaceutical form, mixed immediate release and controlled release pharmaceutical form, Combinations of the Invention 15 The invention is described below in terms of several definitions for use in this application. The term "effective average particle size" as used herein refers to at least about 50% nanoparticle granule kinase inhibitor particles, such as LSI04, having a particle size of less than about 2 〇〇〇 nm (using weight or other suitable measurement methods such as volume, quantity, etc.), such as sedimentation flow separation, photon correlation spectroscopy, light scattering, disc separation 20 hearts, as well as other techniques known in the art, when measured. As used herein, "about" is known to those skilled in the art and varies depending on the context in which they are used. It is not clear to those skilled in the art that "about" represents the upper and lower ranges of up to 10% of the specific terms. Here, a nanoparticle kinase inhibitor such as LS104A stable 26 200816987 is used, "stable" means, but not limited to, Or a plurality of the following parameters: (i) particles that are not clearly agglomerated or aggregated, due to the attraction between the particles, or a significant increase in particle size over time; (2) the physical structure of the particles does not change over time Change, such as from amorphous to crystalline; (3) the particles are chemically stable; and/or (4) wherein the kinase inhibitor is not placed in a heating step at or above the melting point of the kinase inhibitor particles In the preparation of the nanoparticles of the invention. The term "general" or "non-nanoparticle active agent" means an active agent which has been dissolved or which has an effective average particle size of greater than about 2000 nm. The nanoparticle active agent is defined as having an effective average particle size of less than about 2000 10 nm. The term "water poorly soluble drug" is used herein to mean having a solubility in water of less than about 30 mg/ml, less than about 20 mg/ml, less than about 10 mg/ml, or less than about 1 mg/ml. As used herein, the term "medical effective dose" means that the dosage of the drug provides for a particular drug response when the drug is administered to a significant number of individuals in need of such treatment. It is emphasized that, in a particular situation, administration of a particular medically effective dose to a particular individual is not always effective in treating the symptom/disease described herein, even if the dose is a medically effective dose as defined by the skilled artisan. . 20 The term "myeloproliferative disorder" or "myeloproliferative disorder" includes non-lymphocytosis or neoplastic symptoms caused by hematopoietic stem cells or their progeny. "MPD patients" include patients diagnosed with MPD. "Myocardial proliferative disorders" include specific, classified forms of myeloproliferative disorders, including true polycythemia (PV), primary hyperplasia, and idiopathic myelofibrosis 27 200816987 (IMF). Also includes eosinophilia (HES), chronic neutrophilic leukemia (CNL), myelofibrosis associated with myelodysplasia (MMM), chronic myelomonocytic leukemia (CMML), adolescent bone marrow mononuclear ball Leukemia, chronic myelocytic leukemia, chronic eosinophilic 5-cell leukemia, and systemic mastocytosis (SM). "Myoblastic disease" also includes any unclassified osteophyte hyperplasia (UMPD or MPD-NC). A. Characteristics of Nanoparticle Kinase Inhibitor Compositions of the Invention 1. Bioavailability Increase The compositions of the present invention comprise at least one kinase inhibitor, such as Lsi〇4, which has increased bioavailability, Compared to the same non-nanoparticulate kinase inhibitor. In addition, the compositions of the present invention are expected to require smaller dosages, as well as smaller dosages of tablets and other solid dosage forms, which achieve the same pharmaceutical effect as compared to conventional non-nanoparticle formulations of the same kinase inhibitors. The increased bioavailability is quite significant due to the significantly greater drug uptake due to its agent form representing the nanoparticle 15 kinase inhibitor. 2. Improved pharmacokinetics The present invention also encompasses a composition comprising at least one nanoparticulate kinase inhibitor, such as LS104, having the desired pharmacokinetic properties when administered to a mammalian body. The desired pharmacokinetics of the composition comprising the nanoparticle kinase inhibitor just 20 include, but are not limited to, (1) a Cmax of a kinase inhibitor such as LS104, when tested in mammalian plasma after administration, Preferably, it is greater than the Cmax of the same kinase inhibitor non-nanoparticle formulation administered with the same agent, and/or (2) a kinase inhibitor such as LSl〇42Auc, which is preferably greater than when tested in the plasma of the mammalian body after administration. Administration of the same agent 28 200816987 The same kinase inhibitor non-nanoparticle formulation AUC; and / or (3) - kinase inhibitor such as LS104 Tmax, when tested in the mammalian body plasma after administration, preferably less than The Tmax of the same kinase inhibitor non-nanoparticle formulation of the same agent was administered. The desired pharmacokinetic state, as used herein, is the pharmacokinetic state measured at the initial dose of the kinase inhibitor, such as LS104. In one embodiment, a composition comprising a nanoparticle kinase inhibitor, such as LS104, has comparable pharmacokinetic assays, using a non-nanoparticle formulation of the same kinase inhibitor, administered at the same dose, Tmax not More than about 90%, no more than about 80%, no more than about 70%, no more than about 60%, no more than about 50%, no more than about 30%, no more than about 25%, no more than about 20%, no more than A Tmax of about 15%, no more than about 10%, or no more than about 5% of the non-nanoparticulate kinase inhibitor formulation. In another embodiment, the composition comprises a nanoparticulate kinase inhibitor such as LS104, having comparable pharmacokinetic assays, using a non-nanoparticle formulation of the same kinase 15 inhibitor, having a Cmax of at least about 50%, At least about 1%, at least about 200%, at least about 300%, at least about 400%, at least about 5〇〇〇/0, at least about 600%, at least about 700%, at least about 800%, at least about 900% At least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, to less than about 1700%, at least about 1800%, or at least About 1900% is greater than the cmax of the non-nanoparticle kinase inhibitor formulation. In another embodiment, the composition comprises a nanoparticulate kinase inhibitor such as LS104 having comparable pharmacokinetic assays using a non-nanoparticle formulation of the same kinase inhibitor with an AUC of at least about 25%, at least About 5%, 29 200816987 at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275 %, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, to less than about 750%, at least about 700%, at least About 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than AUC of non-nanoparticle kinase inhibitor formulations. In one embodiment of the invention, a kinase inhibitor such as LS104iTmax, 10, when tested in mammalian plasma, is less than about 6 to about 8 hours. In another embodiment of the invention, the LS 104 has a Tmax of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes, administered. Rear. The desired pharmacokinetic state, as used herein, is the pharmacokinetic state measured at the initial dose of kinase inhibitor 15 such as LS104. The composition can be formulated in any manner, as described herein or in a manner well known to those skilled in the art. 3. The pharmacokinetics of the kinase inhibitor of the composition of the present invention does not ingest the composition in a fed or fasted state and the kite 2) The present invention comprises a composition comprising at least one nanoparticle kinase inhibitor, For example, LS 104, wherein the pharmacokinetic state of the kinase inhibitor is substantially unaffected by ingestion of the composition in a fed or fasted state. This represents no substantial difference in the amount of drug absorbed (AUC), the rate of drug absorption (Cmax), or the length of time (Tmax) to reach cmax, t the nanoparticle granules 30 200816987 enzyme inhibitor composition Dosing in a fed or fasted state. The difference in absorbance (AUC) or Cmax of the nanoparticulate kinase inhibitor composition of the present invention (e.g., LS1〇4 composition) is preferably less than about 100% and less than about 9 比较 when administered in a fed and fasted state. %, less than about 8%, less than about 5.7 %, less than about 60%, less than about 55%, less than about 5 〇 y0, less than about 45%, less than about 40%, less than about 35%, less than about 3 〇 %, less than about 25%, less than about 20%, less than about 15%, less than about 1%, less than about 5%, or less than about 3%. 4. Bioequivalence of a kinase inhibitor composition of the invention, when administered in a comparatively fed or fasted state, the invention also comprises a composition comprising a nanoparticle kinase inhibitor, such as LS 104, wherein in a fed state When administered to a single body, it is bioequivalent to administration in the fasted state. In one embodiment of the present invention, the present invention comprises a composition comprising a nanoparticle kinase inhibitor such as LS104, wherein when administered to a body in a fed state, 15 is administered in a fasted state Bioequivalence, especially as defined by Cmax and AUC, is provided by the US Food and Drug Administration and the corresponding European Regulatory Authority (EMEA). Based on the u s. fda specification, the second product or method is bioequivalent, if the 90% confidence interval (CI) of AUC and Cmax is between 〇·8〇 and ι·25 (the measurement of Tmax is not related to the general purpose) 20 is related to bioequivalence). In order to show that the two compounds or the conditions of administration are bioequivalent, according to the European EMEA specification, 90% CI of AUC must be between 0.80 and 1.25, and 90% CI of Cmax must be between 0.70 and 1.43. S. The dissolution state of the kinase inhibitor composition of the invention. The composition comprises at least one nanoparticulate kinase inhibitor, such as LS1〇4 31 ί -t > 200816987 or a salt or derivative thereof, which is assumed to have an unexpected Drastically dissolved. Preferably, the active agent of the drug is rapidly dissolved, and rapid dissolution generally results in better bioavailability and faster start-up. In order to increase the solubility and bioavailability of the kinase inhibitor, the dissolution of the drug can be increased by 5 degrees to nearly 100%. The kinase inhibitor of the present invention, such as the LS104 composition, preferably has a dissolved state wherein at least about 20% of the composition dissolves in about 5 minutes. In another embodiment of the invention, at least about 3% or at least about 4% of the kinase inhibitory composition is dissolved within about 5 minutes. In another embodiment, preferably up to about 4 G%, at least about 5 G%, at least about _, at least about 7 (%), or at least about 80% of the kinase inhibitor composition, in about 1 minute. Dissolved inside. Finally, in another embodiment of the invention, preferably at least about 7%, at least about 8%, at least about 90%, or at least about 100% of the kinase inhibitor composition is dissolved in about 2 minutes. . 15 Solubility is preferably measured in a medium with separability. And the dissolving medium of the miscellaneous is such that two very different dissolution lines can be produced for the two products, the two products having very different dissolution states in the gastric juice, i.e., the dissolution medium is predicted to dissolve a composition in the body. An exemplary dissolution is - a surfactant containing 0.025 Μ of surfactant sodium lauryl sulfate: a buckle. The measurement of the amount of dissolution can be carried out by spectrometry. Transfer purple method Pharmacopoeia) can be used to measure solubility. 6. Redispersibility of the kinase inhibitor composition of the invention The graded product comprises at least a nanoparticulate kinase inhibitor, such as or a salt or derivative thereof, which is additionally characterized by redispersion of the composition, 32 200816987 The re-dispersed kinase inhibitor particles have an effective average particle size of less than about 2 microns. This is quite evident at the time of administration, and if the kinase inhibitor particles of the composition of the present invention aggregate or are not dispersed to a substantially nanoparticle size, the agent loses the advantage of being formulated as a nanoparticle size kinase inhibitor. 5 This is because of the nanoparticle active reagent composition, which has the advantage of the small particle size of the active reagent. If the active agent is not dispersed to a small particle size, it will "cluster" or accumulate the active agent particles after administration, due to the high surface energy of the nanoparticle system and the thermal power driving force, and the free energy is reached. reduce. With such agglomerated particle formulation, the organism in this form of the agent can be reduced in selectivity to the liquid dispersed form of the nanoparticle active agent. Furthermore, the compositions of the present invention comprise at least one nanoparticulate kinase inhibitor, such as LS104, having a vigorous redispersibility of nanoparticles of granule kinase inhibitors, based on administration to a mammal, such as a human or animal body, with a biologically relevant medium. Formulated/re-dispersed such that the average particle size of the 5 of the redispersed kinase inhibitor particles is less than about 2 microns. The biologically relevant aqueous medium can be a bamboo aqueous medium having the desired ionic strength and pH to form the basis for the biological dependence of the medium. The desired pH and ionic strength are representative of the physiological conditions of the human body. The biologically relevant aqueous medium can be, for example, an aqueous electrolyte solution, or an aqueous solution of any of the salts, acids or bases or combinations thereof, having a desired value of 20 and ionic strength. Biologically relevant pH is known in the art. For example, in the stomach, the pH range is slightly less than 2 (but generally greater than 1), up to 4 or 5. In the small intestine, the pH ranges from 4 to 6, and in the rectum ranges from 6 to 8. Bioequivalence ionic strength is also known in the art. The fasting stomach has an ionic strength of about 0.1 Μ, while the fasting shape of the small intestine has a ionic strength of about 0.14. See, for example, Lindahl ei α/., ^Characterization of Fluids from the Stomach and Proximal

Jejumim in Men and Women,” Pharm· Res” 14 (4): 497-502 (1997) 〇 5 一般相信待測溶液之p H與離子強度較特定化學成分更 重要。因此，適當之pH與離子強度值可經由數種強酸、強 鹼、鹽類、單一或多種共軛酸_鹼對（即弱酸與該酸相對應之 鹽類），單質子與多質子電解質等組合而成。 代表性電解質溶液可為，但不侷限於，HC1溶液，濃度 10範圍自約0.001至約0·1 Μ，以及NaC1溶液，範圍自濃度約 0.001至約0·1 Μ，及其混合物。例如，電解質溶液可為，但 不限制於，約0·1 MHC1或更低，〇 〇1 MHC1或更低，約〇 〇〇1 MHC1或更低，〇·ΐ MNaCl或更低，約〇_G1 MNaC1或更低， 約0.001 M NaCl或更低，及其混合物。在這些電解質溶液 !5中，〇.〇1 Μ肥及/或(U M NaC1，為最具禁食人體生理狀 態之代紐’自於其pH與科強度最接近上端腸胃道。 0.001 MHQ、G.G1 MHC1 與(U MHC1 之電解 f 濃度係 分別相對應於PH 3、PH 2與阳i。因此，〇 〇1 M肥溶液係 模擬在胃中發現之典顧條件。CU M NaC1溶㈣提供人 2〇體内離子強度之合理模擬，包括腸胃液，雖然濃度高於^ Μ係用於模㈣食狀態之人體腸胃道。 鹽類、酸'驗或其組合溶液，其具有希望之ΡΗ與離子 強度，包括，但不侷限於，鱗酸續酸鹽+氯化納、卸㈣ 鹽、醋酸/醋酸鹽+氯化納、㈣舰、碳崎酸氫鹽+氯化Jejumim in Men and Women,” Pharm·Res” 14 (4): 497-502 (1997) 〇 5 It is generally believed that the p H and ionic strength of the solution to be tested are more important than the specific chemical composition. Thus, suitable pH and ionic strength values can be via several strong acids, strong bases, salts, single or multiple conjugate acid-base pairs (ie, salts of weak acids corresponding to the acid), single protons and multi-proton electrolytes, etc. Combined. A representative electrolyte solution can be, but is not limited to, an HCl solution having a concentration ranging from about 0.001 to about 0.1 Torr, and a NaC1 solution ranging from about 0.001 to about 0.1 Torr, and mixtures thereof. For example, the electrolyte solution may be, but is not limited to, about 0.1 MHC1 or lower, 〇〇1 MHC1 or lower, about M1 MHC1 or lower, 〇·ΐ MNaCl or lower, about 〇_ G1 MNaC1 or lower, about 0.001 M NaCl or less, and mixtures thereof. In these electrolyte solutions! 5, 〇.〇1 Μ fertilizer and / or (UM NaC1, is the most fasting physiological state of the dynasty's since its pH and family strength is closest to the upper gastrointestinal tract. 0.001 MHQ, G .G1 MHC1 and (U MHC1 electrolysis f concentration system correspond to PH 3, PH 2 and yang i respectively. Therefore, 〇〇1 M fertilizer solution simulates the conditions found in the stomach. CU M NaC1 solution (4) provides A reasonable simulation of the ionic strength in human sputum, including gastrointestinal fluids, although the concentration is higher than that of sputum used in the gastrointestinal tract of the human (four) food state. Salt, acid 'test or combination solution, it has hope and Ionic strength, including, but not limited to, squaric acid hydrochloride + sodium chloride, unloaded (tetra) salt, acetic acid / acetate + sodium chloride, (four) ship, carbonic acid hydrogen salt + chlorination

34 -¾ .S 200816987 鈉、_與約鹽，以及擰檬酸/檸檬酸鹽+氯化納、鉀與#弓鹽。34 -3⁄4 .S 200816987 Sodium, _ and about salt, and citric acid / citrate + sodium, potassium and # bow salts.

在本發明之另一實施例中，激酶抑制劑如LS104或其鹽 類或衍生物之重新分散顆粒（重新分散於水中、生物相關介 質或任一適當之重新分散介質中），具有一有效平均粒徑小 5 於約1900 nm、小於約1800 nm、小於約1700 nm、小於約1600 nm、小於約1500 nm、小於約1400 nm、小於約1300 nm、 小於約 1200 nm，less than about 1100 nm、小於約 1000 nm、小於約990 nm、小於約980 nm、小於約970 nm、小於 約960 nm、小於約950 nm、小於約940 nm、小於約930 nm、 10 小於約920 nm、小於約910 nm、小於約900 nm、小於約890 nm、小於約880 nm、小於約870 nm、小於約860 nm、小於 約850 nm、小於約840 nm、小於約830 nm、小於約820 nm、 小於約810 nm、小於約800 nm、小於約790 nm、小於約780 nm、小於約770 nm、小於約760 nm、小於約750 nm、小於 15 約740 nm、小於約730 nm、小於約720 nm、小於約71〇11111、 小於約700 nm、小於約690 nm、小於約680 nm、小於約670 nm、小於約660 nm、小於約650 nm、小於約640 nm、小於 約630 nm、小於約620 nm、小於約610 nm、小於約600 nm、 小於約590 nm、小於約580 nm、小於約570 nm、小於約560 20 nm、小於約550 nm、小於約540 nm、小於約530 nm、小於 約520 nm、小於約510 nm、小於約500 nm、小於約490 nm、 小於約480 nm、小於約470 nm、小於約460 nm、小於約450 nm、小於約440 nm、小於約430 nm、小於約420 nm、小於 約410 nm、小於約400 nm、小於約390 nm、小於約380 nm、 35 200816987In another embodiment of the invention, a kinase inhibitor such as LS104 or a salt or derivative thereof is redispersed (re-dispersed in water, in a biologically relevant medium or in any suitable redispersing medium) having an effective average The particle size is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, Less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm Less than about 900 nm, less than about 890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm Less than about 800 nm, less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 nm, less than 15 about 740 nm, less than about 730 nm, less than about 720 nm, less than about 71 〇11111, less than about 700 nm, less than about 690 nm, Less than about 680 nm, less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, Less than about 580 nm, less than about 570 nm, less than about 560 20 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm Less than about 480 nm, less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm , less than about 380 nm, 35 200816987

小於約370 nm、小於約360 nm、小於約350 nm、小於約340 nm、小於約330 nm、小於約320 nm、小於約310 nm、小於 約300 nm、小於約290 nm、小於約280 nm、小於約270 nm、 小於約260 nm、小於約250 nm、小於約240 nm、小於約230 5 nm、小於約220 nm、小於約210 nm、小於約200 nm、小於 約190 nm、小於約180 nm、小於約170 nm、小於約160 nm、 小於約150 nm、小於約140 nm、小於約130 nm、小於約120 nm、小於約110 nm、小於約1〇〇、小於約7511111，或小於約 50 nm，使用光散射法、顯微鏡或其他適當之方法測量。此 10 種適用於測量有效平均粒徑之方法為熟習此技術領域者已 知。 重新分散性可使用任何技術上已知之方法測量。請見 如美國專利號 6,375,986，“Solid Dose NanoparticlulateLess than about 370 nm, less than about 360 nm, less than about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, Less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 5 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm Less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 1 Torr, less than about 75,111,111, or less than about 50 Nm, measured using light scattering, microscopy or other suitable method. These 10 methods suitable for measuring the effective average particle size are known to those skilled in the art. Redispersibility can be measured using any method known in the art. See, for example, US Patent No. 6,375,986, "Solid Dose Nanoparticlulate

Composition Comprising a Synergistic Combination of a 15 Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate”之範例一節。 7·用於與其他活性試劑結合之奈米顆粒激酶抑制劑組成物 該組成物係包含至少一奈米顆粒激酶抑制劑，如L s i 〇 4 或其鹽類或衍生物，可額外地包含一或多種用於治療癌症 20如白血病或其他相關疾病、病症、症狀或症候之化合物， 或該激酶抑制劑組成物可與此種化合物結合投藥。奈米顆 粒激酶抑制劑組成物，如LS104，可提供多種機會，與其他 激_抑制劑組合使用，如Gieevec®，以及目前標準化學治 療、骨髓移植等。Example of Composition Comprising a Synergistic Combination of a 15 Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate. 7. Nanoparticle Kinase Inhibitor Composition for Combination with Other Active Agents This Composition Contains At least One Nanoparticle Kinase Inhibition An agent, such as L si 〇 4 or a salt or derivative thereof, may additionally comprise one or more compounds for the treatment of cancer 20 such as leukemia or other related diseases, conditions, symptoms or symptoms, or the kinase inhibitor composition may In combination with such compounds, nanoparticulate kinase inhibitor compositions, such as LS104, offer a variety of opportunities for use in combination with other agonists such as Gieevec®, as well as current standard chemotherapy, bone marrow transplantation, and the like.

36 i S 200816987 Β·奈米顆粒激酶抑制劑組成物 本發明係提供-種組成物，包含至少一激酶抑制 LS104或其鹽類或衍生物之顆粒，以及至少_表面释定; 該表面穩定劑較佳係吸附於或結合於£§1〇4顆粒之表面= 面穩定劑尤其可物雜地吸㈣或結合於奈米軸激酶^ 制劑顆粒之表面上，但理想上並非化學性地與激酶抑制劑 (如LS104)顆粒或其本身反應。該表面穩定劑分別吸附之分 子實質上不含分子間交聯。36 i S 200816987 Β·Nago granule kinase inhibitor composition The present invention provides a composition comprising at least one kinase inhibiting particles of LS 104 or a salt or derivative thereof, and at least _ surface release; the surface stabilizer Preferably, it is adsorbed or bound to the surface of the £§1〇4 particle = surface stabilizer, especially in the surface of the nanoparticle kinase compound particles, but ideally not chemically and kinase The inhibitor (such as LS104) particles or the reaction itself. The molecules adsorbed by the surface stabilizer are substantially free of intermolecular crosslinks.

本發明亦包括激酶抑制劑如LS1〇4 (或其鹽類或衍生 10物）’該組成物結合一或多種非毒性生理可接受之载體、佐 劑或載劑’通稱為載體。該組成物可配製為非經腸胃注射(如 靜脈内、肌内或皮下）、口服投藥，為固體、液體或氣溶膠 形式、陰道内、鼻内、直腸、眼部、局部（粉末、藥膏或滴 劑）、口頰、蛛網膜下腔、腹膜内或局部投藥，及類似方式。 15 I激酶抑制劑顆粒 本發明该組成物包含至少一激酶抑制劑如或其 鹽類或衍生物之顆粒。該顆粒可為結晶相、非晶相、半晶 相、半非晶相或其混合物。 2.表面穩定荆 該激酶抑制劑如LS104之表面穩定劑之選擇亦相當重 要。因此，本發明係相關於令人驚訝的發現，可製造出奈 米顆粒激酶抑制劑組成物。 大於一種表面穩定劑之組合可使用於本發明。可使用 於本發明之表面穩定劑包括，但不侷限於，已知之有機與 37 200816987 無機醫藥用賦形劑。此類賦形劑包括各種聚合物、低分子 量养合物、天然產物與界面活性劑。示範性之表面穩定劑 包括非離子性與離子性(如陰離子性、陽離子性與兩性離子 性)界面活性劑或化合物。 5 表面穩定劑之代表性範例包括白蛋白，包括但不侷限 於人類血清白蛋白與牛白蛋白、羥基丙基曱基纖維素(現稱 之為hypromellose)、羥基丙基纖維素、聚乙醯基吡咯酮、 月桂基硫酸鈉、琥ίό酸二辛醋石黃酸鹽、明膠、酪蛋白、即 磷脂(磷脂質）、葡聚醣、阿拉伯膠、膽固醇、特拉佳康膠、 10硬脂酸、苯札氣銨、硬脂酸飼、單硬脂酸甘油酯、西托硬 月曰醇（cetostearyl alcohol)、聚西托醇（cetomacrogol)乳化堪、 山梨醇S曰、聚氧基乙稀基烧基鍵（如聚乙二醇謎，如聚西 托醇1000)、聚氧基乙烯基蓖麻油衍生物、聚氧基乙烯基山 梨醇脂肪酸酯(如商業上可購得之Tween®產物，如Tween 15 20⑧與Tween 80® (ICI Speciality Chemicals));聚乙二醇（如The present invention also encompasses kinase inhibitors such as LS1〇4 (or a salt or derivative thereof). The composition is combined with one or more non-toxic physiologically acceptable carriers, adjuvants or carriers. The composition can be formulated as a parenteral injection (such as intravenous, intramuscular or subcutaneous), orally, in solid, liquid or aerosol form, intravaginal, intranasal, rectal, ocular, topical (powder, ointment or Drops), buccal, subarachnoid, intraperitoneal or topical administration, and the like. 15 I kinase inhibitor granules The composition of the present invention comprises at least one kinase inhibitor such as a granule of a salt or derivative thereof. The particles may be a crystalline phase, an amorphous phase, a semicrystalline phase, a semi-amorphous phase or a mixture thereof. 2. Surface Stabilization The choice of the surface stabilizer for this kinase inhibitor such as LS104 is also important. Thus, the present invention is related to the surprising discovery that a nanoparticulate kinase inhibitor composition can be made. Combinations greater than one surface stabilizer can be used in the present invention. Surface stabilizers which can be used in the present invention include, but are not limited to, those known to be organic and 37 200816987 inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight nutrients, natural products and surfactants. Exemplary surface stabilizers include nonionic and ionic (e.g., anionic, cationic, and zwitterionic) surfactants or compounds. 5 Representative examples of surface stabilizers include albumin, including but not limited to human serum albumin and bovine albumin, hydroxypropyl fluorenyl cellulose (now called hypromellose), hydroxypropyl cellulose, polyethyl hydrazine Pyrrolidone, sodium lauryl sulfate, succinic acid dioctyl sulphate, gelatin, casein, ie phospholipids (phospholipids), dextran, gum arabic, cholesterol, trajaya gum, 10 stearin Acid, benzalkonium chloride, stearic acid, glyceryl monostearate, cetostearyl alcohol, cetomacrogol, sorbitol S曰, polyoxyethylene A base group (such as a polyethylene glycol mystery such as polycetitol 1000), a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester (such as the commercially available Tween®). Products such as Tween 15 208 and Tween 80® (ICI Speciality Chemicals); polyethylene glycol (eg

Carbowaxs 355(^與934® (Union Carbide))、聚氧基乙烯基 硬脂酸酯、膠體二氧化矽、磷酸鹽、羧基甲基纖維素鈣、 緩基曱基纖維素鈉、甲基纖維素、羥基乙基纖維素、羥丙 甲基纖維素酞酸酯、非結晶型纖維素、矽酸鎂鋁、三乙醇 20 胺、聚乙烯醇(PVA)、4-(1，1，3,3·四甲基丁基)-酚聚合物，具 有環氧乙稀與甲酸（亦已知為tyloxapol、superione與 trit〇n)、普絡沙姆（poloxamers)(如卩1111>〇1^8卩68(§)與 F108® ’其為乙烯氧化物與丙烯氧化物之嵌段共聚物”普 絡沙胺（p〇l〇xamines)(如Tetronic 908⑧，亦已知為 38 200816987Carbowaxs 355 (^ and 934® (Union Carbide)), polyoxyethylene stearate, colloidal cerium oxide, phosphate, carboxymethylcellulose calcium, sodium thioglycolate, methylcellulose , hydroxyethyl cellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanol 20 amine, polyvinyl alcohol (PVA), 4-(1,1,3,3 · Tetramethyl butyl)-phenol polymer with ethylene oxide and formic acid (also known as tyloxapol, superione and trit〇n), and poloxamers (eg 卩1111>〇1^8卩) 68 (§) and F108® 'which are block copolymers of ethylene oxide and propylene oxide, p〇l〇xamines (eg Tetronic 9088, also known as 38 200816987)

Poloxamine 908®，其為衍生自依序添加丙烯氧化物與乙烯 氧化物至乙烯基二胺之四官能基嵌段共聚物（BASF Wyandotte Corporation，Parsippany，N.J·)) ; Tetronic 1508® ' (Τ· 1508) (BASF Wyandotte Corporation)、Tritons X-200®， 。 5 其為一烧基芳基聚醚石黃酸i旨（Rohm and Haas) ; Crodestas — F-110®，其為蔗糖硬脂酸鹽與蔗糖二硬脂酸鹽之混合物 (Croda Inc·) ; p-異壬基苯氧基聚-(縮水甘油），亦已知為 Olin-IOG®，或 Surfactant 10-G®(Olin Chemicals, Stamford, • CT) ; Crodestas SL-40⑧（Croda，Inc·);以及SA90HC0， 10 其為 C18H37CH2(C0N(CH3)-CH2(CH0H)4(CH20H)2 (Eastman Kodak Co·);癸醯基-N-甲基葡醣醯胺；η·癸基β-D-吡喃葡萄醣苷；η-癸基β-D·吡喃麥芽醣苷；η-十二烷基β-D-吡喃葡萄醣苷；η-十二烷基β-D-麥芽醣苷；庚醯基-Ν-甲基 葡醣醯胺；η-庚基-β-D-吡喃葡萄醣苷；η•庚基_p-D_硫代葡 15萄醣苷；η_己基β-D·吡喃葡萄醣苷；壬醯基-Ν-甲基葡醣醯 胺；η-壬基β-D-吡喃葡萄醣苷；辛醯基-N-曱基葡醣醯胺； 镛 η_辛基-β-D-吡喃葡萄醣苷；辛基β-D-硫代吡喃葡萄醣苷； PEG-磷脂質、PEG-膽固醇、peg-膽固醇衍生物、PEG_維 生素A、PEG-維生素E、溶菌酶(iys〇Zyme)、乙酸乙稀g旨與 2〇乙―基11比σ各酮之隨機共聚物，及其類似物。 若希望，本發明之奈米顆粒激酶抑制劑如ls1〇4組成物 可配製為不含磷脂質。 可使用之陽離子性表面穩定劑包括，但不侷限於，聚 合物、生物聚合物、多醣體、纖維素、海藻膠、磷脂質與 39 200816987 非聚合性化合物，如兩性離子穩定劑V聚-n-曱基吡唆鏽、 蒽基吡啶鑌氯、陽離子性磷脂質、幾丁質、聚離胺酸、聚 乙烯基咪唑、凝聚胺(polybrene)、聚甲基甲丙烯酸酯三甲基 溴化銨溴（PMMTMABr)、己基二苯乙酮基三甲基溴化銨 5 (HDMAB)，以及聚乙烯基吡咯綱_2_二甲基胺基乙基曱基丙 烯酸酯二甲基硫酸酯。 其他可使用之陽離子性穩定劑包括，但不侷限於，陽 離子性脂質、锍基、鱗基，與四級銨化合物，如硬脂基三 甲基氯化銨、苄基-二(2-氣乙基）乙基溴化銨、椰子三甲基 10氯化銨或溴化銨、椰子甲基二羥基乙基氯化銨或溴化銨、 癸基三乙基氯化銨、癸基二甲基羥基乙基氣化銨或溴化 ^ x Ci2-i5一甲基沒基乙基氣化錢或溴化敍、挪子二甲基_ 基乙基氣化銨或溴化銨、肉菫蔻基三甲基曱基硫酸銨、月 私基甲基下基氣化叙或〉臭化錢、月桂基二曱基（氧乙稀美)4 15氯化銨或溴化銨、N-烷基(Cnw)二甲基苄基氯化銨、N—烷 基(Cu-u)二甲基-苄基氣化鈹、]Si-十四院基二甲基节基氯化 銨單水合物、二甲基二癸基氯化銨、N_烷基與(C1214)二甲 基1-萘基曱基氯化銨、三甲基_化銨、烧基_三甲基銨鹽， 與二烷基-二甲基銨鹽、月桂基三甲基氯化銨、乙氧基化烷 20基醯胺烷基二烷基銨鹽，及/或乙氧基化三烷基銨鹽、二烷 基笨一烧基氯化銨、二癸基二甲基氯化銨、四烧基 二甲基苄基氣化銨單水合物、N-烷基(cu_14)二甲基^萘基 甲基氣化叙，與十一烧基一甲基节基氯化銨、二烧基苯烧 基氣化銨、月桂基三甲基氯化銨、烷基节基甲基氯化銨、 40 200816987 烷基苄基二曱基溴化銨、c12, c15, c17三曱基溴化銨、十二 烷基节基三乙基氣化銨、聚·二烯丙基二曱基氣化銨 (DADMAC)、二甲基氯化鏔、烧基二甲基鹵化銨、三魚京堪 基甲基氯化銨、癸基三甲基溴化銨、十二烧基三乙基溴化 5 銨、十四烷基三甲基溴化銨、甲基三辛基氯化銨(ALIQUAT 336TM)、P〇LYQUAT 10™、四丁基溴化銨、苄基三甲基溴 化銨、膽鹼酯類（如脂肪酸之膽鹼酯）、苯札氣銨、硬脂基氣 化銨（stearalkonium chloride)化合物（如硬脂基三氯化銨與 二-硬脂基二氣化銨）、鯨蠟基吼啶鑌溴或氣、四級化聚氧基 10 乙基烷基胺之鹵化鹽類、MIRAPOL™與ALKAQUAT™ (Alkaril Chemical Company)、烷基吡啶鑌鹽類；胺類如烧 基胺、二烷基胺、醇胺、聚乙烯基聚胺、N，N-二烷基胺基 烷基丙烯酸酯，以及乙烯基吡啶、胺基鹽類，如月桂基胺 醋酸鹽、硬脂基胺基醋酸鹽、烷基吡啶鏽鹽，以及烷基咪 15 唑鹽類，及胺基氧化物；醯胺偶氮鹽；質子化四級丙烯醯 胺；曱基化四級聚合物，如聚[二烯丙基二甲基氯化銨]與聚 -[N-甲基乙烯基吡啶氯化鏽];以及陽離子性瓜爾膠(gUar)。 此示範性之陽離子性表面穩定劑，與其他可使用之陽 離子性表面穩定劑係描述於J. Cross and E. Singer, Cai/omY 20 Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic iSW/aciimb:尸C/ze/mWrj； (Marcel Dekker，1991);以 及 J. Richmond，Cationic Surfactants: Organic Chemistry, (Marcel Dekker，1990)。 41 200816987 非聚合性表面穩定劑為任一非離子性化合物，如苯札 氯銨，一種碳陽離子性化合物、鱗化合物，——種氧鏽化合 物、鹵鑌化合物、陽離子性有機金屬化合物、四級構化合 4 物、吡啶鑌化合物、苯銨離子化合物、銨化合物、羥基銨 * 5 化合物、一級胺化合物、二級胺化合物、三級胺化合物， - 以及四級胺化合物，具式Nmi⑴。就式Nmi⑴ 之化合物而言： (i) H4無一為 CH3 ; Φ (ii) RrlU之一為 CH3 ; 10 (iii) RrR4之三者為 CH3 ; (iv) RrR4所有皆為CH3 ; (v) RrR4之二者為 CH3、RrlU 之一者為 C6H5CH2， 及1^-114之一者為具七個或更少碳原子之烷基鏈； (vi) R〗-R4之二者為 CH3、RrR4之一者為 C6H5CH2， 15 以及Ri-R4之一者為具19個或更多碳原子之烷基鏈； (vii) Ri-R4之·一者為CH3 ’以及R1-R4之*^者為 ^ C6H5(CH2)n基團，其中 η>1 ; (viii) !^·!^之二者為 CH3，Ri-IU之一者為 C6H5CH2， 以及R4-R4之一者包含至少一雜原子； 20 (ix) RrR4之二者為 CH3、之一者為 C6H5CH2， 以及Ri-R4之一者包含至少一鹵素； (X) RrlU之二者為 CH3、R「R4之一者C6H5CH2，以 及1-114之一者係包含至少一環狀片段； (xi) RrR4之二者為CH3，以及RrR4之一者為苯環；或 42 200816987 (xii) Ri-R4之二者為CH3，及K-R4之二者為純脂肪族片 段。 此化合物包括，但不侷限於，苯漢氯化錢 (behenalkonium chloride)、苄索氯銨、鯨蠟基吡啶氯化 5 鏽、苯漢三氯化銨（behentrimonimn chloride)、勞拉氯錢 (lauralkonium chloride)、西他氣銨（cetaik〇nium Chl0ride)、Poloxamine 908®, a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to vinyl diamine (BASF Wyandotte Corporation, Parsippany, NJ·); Tetronic 1508® ' (Τ· 1508) (BASF Wyandotte Corporation), Tritons X-200®, . 5 It is a aryl aryl polyether tartaric acid (Rohm and Haas); Crodestas - F-110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); P-isodecylphenoxy poly-(glycidol), also known as Olin-IOG®, or Surfactant 10-G® (Olin Chemicals, Stamford, • CT); Crodestas SL-408 (Croda, Inc.) And SA90HC0, 10 which is C18H37CH2(C0N(CH3)-CH2(CH0H)4(CH20H)2 (Eastman Kodak Co.); mercapto-N-methylglucamine; η·decyl β-D -glucopyranoside; η-mercapto β-D·maltopyranoside; η-dodecyl β-D-glucopyranoside; η-dodecyl β-D-maltoside;醯-Ν-methyl glucoside; η-heptyl-β-D-glucopyranoside; η•heptyl_p-D_thioglucosamine; η-hexyl β-D·pyridyl Glucosinolate; fluorenyl-hydrazine-methyl glucoside; η-mercapto β-D-glucopyranoside; octyl-N-mercaptoglucosamine; 镛η_octyl-β-D -glucopyranoside; octyl β-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, peg-cholesterol derivative, PEG_vitamin A, PE a random copolymer of G-vitamin E, lysozyme (iy〇Zyme), ethyl acetate, and 2 〇 ethyl-yl 11 σ ketone, and the like. If desired, the nanoparticle kinase inhibition of the present invention Agents such as the ls1〇4 composition can be formulated to be free of phospholipids. Cationic surface stabilizers that can be used include, but are not limited to, polymers, biopolymers, polysaccharides, cellulose, algin, phospholipids and 39 200816987 Non-polymerizable compounds, such as zwitterionic stabilizers V poly-n-mercaptopyrene, pyrithione chloride, cationic phospholipids, chitin, polylysine, polyvinylimidazole, polycondensed amines Polybrene), polymethylmethacrylate trimethylammonium bromide bromide (PMMTMABr), hexyldiphenethyl ketone trimethylammonium bromide 5 (HDMAB), and polyvinylpyrrolidine-2-dimethylamine Base ethyl methacrylate dimethyl sulfate. Other cationic stabilizers that can be used include, but are not limited to, cationic lipids, sulfhydryl groups, squara groups, and quaternary ammonium compounds such as stearyl trimethacrylate Ammonium chloride, benzyl-bis(2-vaporethyl)ethylammonium bromide, coconut three Base 10 ammonium chloride or ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride or ammonium bromide, mercapto triethyl ammonium chloride, mercapto dimethyl hydroxyethyl ammonium hydride or bromination ^ x Ci2-i5-monomethyl-ethylated gas or bromide, chloroform-methyl carbamide or ammonium bromide, triterpene trimethylsulfonium sulphate, monthly Methyl subgroup gasification or > stinky money, lauryl dimercapto (oxyethylene) 4 15 ammonium chloride or ammonium bromide, N-alkyl (Cnw) dimethyl benzyl ammonium chloride, N-alkyl (Cu-u) dimethyl-benzyl vaporized hydrazine,] Si-fourteen yards dimethyl benzyl ammonium chloride monohydrate, dimethyl dimercapto ammonium chloride, N_ Alkyl and (C1214) dimethyl 1-naphthylfluorenyl ammonium chloride, trimethyl-ammonium, alkyl-trimethylammonium salt, dialkyl-dimethylammonium salt, lauryl trimethyl Ammonium chloride, ethoxylated alkane 20 decylamine alkyl dialkylammonium salt, and / or ethoxylated trialkyl ammonium salt, dialkyl stupid ammonium chloride, dimercapto Methyl ammonium chloride, tetraalkyl dimethyl benzyl ammonium carbonate monohydrate, N-alkyl (cu_14) dimethyl phthalyl methyl sulfonate, and ten Anthracyl monomethyl ammonium chloride, dialkyl benzoate ammonium hydride, lauryl trimethyl ammonium chloride, alkyl benzyl methyl ammonium chloride, 40 200816987 alkyl benzyl dimercapto bromide Ammonium, c12, c15, c17 tridecyl ammonium bromide, dodecyl succinyl triethyl ammonium hydride, poly-diallyl dimercapto ammonium hydride (DADMAC), dimethyl ruthenium chloride , mercapto dimethyl ammonium halide, trisyl kylin methyl ammonium chloride, decyl trimethyl ammonium bromide, dodecyl triethyl bromide 5 ammonium, tetradecyl trimethyl bromide Ammonium, methyl trioctyl ammonium chloride (ALIQUAT 336TM), P〇LYQUAT 10TM, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters (eg choline esters of fatty acids), Benzene gas, stearalkonium chloride compound (such as stearyl ammonium trichloride and di-stearyl diammonium hydride), cetyl pyridinium bromide or gas, quaternized Halogenated salts of polyoxyl 10 ethylalkylamines, MIRAPOLTM and ALKAQUATTM (Alkaril Chemical Company), alkylpyridinium salts; amines such as alkylamines, dialkylamines, alcoholamines, polyvinyls Polyamine, N, N-dioxane Aminoalkyl acrylate, and vinyl pyridine, amine salts such as laurylamine acetate, stearyl amide acetate, alkyl pyridine rust salt, and alkyl amide 15 azole salts, and amines Base oxide; indoleamine azo salt; protonated fourth-grade acrylamide; thiolated quaternary polymer, such as poly[diallyldimethylammonium chloride] and poly-[N-methylvinyl Pyridine chloride; and cationic guar (gUar). This exemplary cationic surface stabilizer is described in J. Cross and E. Singer, Cai/omY 20 Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); And D. Rubingh (Editor), Cationic iSW/aciimb: corpse C/ze/mWrj; (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990). 41 200816987 Non-polymeric surface stabilizers are any nonionic compounds such as benzalkonium chloride, a carbocation compound, scale compounds, species of rust compounds, halogen compounds, cationic organometallic compounds, grade 4 A compound, a pyridinium compound, a benzammonium ion compound, an ammonium compound, a hydroxylammonium*5 compound, a primary amine compound, a secondary amine compound, a tertiary amine compound, and a quaternary amine compound having the formula Nmi(1). For compounds of the formula Nmi(1): (i) none of H4 is CH3; Φ(ii) one of RrlU is CH3; 10 (iii) three of RrR4 are CH3; (iv) RrR4 is all CH3; (v) RrR4 is either CH3, one of RrlU is C6H5CH2, and one of 1^-114 is an alkyl chain having seven or fewer carbon atoms; (vi) R--R4 are both CH3, RrR4 One of them is C6H5CH2, 15 and one of Ri-R4 is an alkyl chain having 19 or more carbon atoms; (vii) one of Ri-R4 is CH3' and R1-R4* ^ a C6H5(CH2)n group, wherein η>1; (viii) !^·!^ are both CH3, one of the Ri-IUs is C6H5CH2, and one of R4-R4 comprises at least one heteroatom; 20 (ix) RrR4 is either CH3, one is C6H5CH2, and one of Ri-R4 contains at least one halogen; (X) RrlU is both CH3, R "R4 is one of C6H5CH2, and 1- One of 114 comprises at least one cyclic segment; (xi) both RrR4 are CH3, and one of RrR4 is a benzene ring; or 42 200816987 (xii) Ri-R4 is both CH3, and K-R4 Both are pure aliphatic fragments. This compound includes, but is not limited to, Benzene chlorinated money (behenalkonium chloride), benzethonium chloride, cetylpyridine chloride 5 rust, behentrimonimn chloride, lauralkonium chloride, cetaik〇nium Chl0ride,

十六烷基三甲基溴化銨、十六烷基三甲基氯化銨、十六烧 基胺基氟化氫、氯化浠丙基甲胺氣化物（季銨鹽_15 (Qimternium_15))、二硬脂基二曱基氯化銨（季銨鹽_5 10 (Quaternimn-5))、十二烷基二甲基乙基苄基氯化銨（季銨鹽 14 (Quaternmm-14))、季銨鹽-22 (Quaternimn-22)、季銨 鹽-26 (Quaternium-26)、季銨鹽-18 (Quaternium-18)石夕酸鎮 經、二曱基胺基乙基氣氣化氫、半胱胺酸氣化氫、二乙醇 銨POE(IO)油基醚磷酸鹽、二乙醇銨p〇E(3)油基醚磷酸 15鹽、牛脂氯化烷基、二甲基三十六烷基銨矽酸鎂鋰、硬脂 基氯化銨（stearalkonium chloride)、杜米分溴化物 (domiphen bromide)、苯甲地那銨（denatonium benzoate)、 肉莖蔻基二曱基苄基氯化銨、月桂基三曱基氯化銨、乙二 胺基二氯化氫、胍氯化氫、吼σ多醇(pyrid〇xine)HCl、歐非 20 他胺氯化氫（iofetamine hydrochloride)、葡曱胺（meglumine) 氯化氫、曱基苄索氯銨、肉莖蔻基三甲基溴化銨、油酸基 二甲基氣化銨、聚季銨鹽-1 (polyquaternium-1)、普魯卡因 氣化氫（procainehydrochloride)、 椰子甜菜驗 (cocobetaine)、硬脂基砍酸鎮|f(stearalkonium bentonite)、Cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, hexadecylamino hydrogen fluoride, cesiumpropylmethylamine hydride (quaternary ammonium salt _15 (Qimternium_15)), Distearyl diammonium chloride (quaternary ammonium salt _5 10 (Quaternimn-5)), dodecyl dimethyl ethyl benzyl ammonium chloride (quaternary ammonium salt 14 (Quaternmm-14)), Quaternium-22, Quaternium-26, Quaternium-18, oxalate acid, dimercaptoethylamine gas, Cysteine gasification hydrogen, diethanolammonium POE (IO) oleyl ether phosphate, diethanol ammonium p〇E (3) oleyl ether phosphate 15 salt, tallow alkyl chloride, dimethyl trihexadecane Lithium magnesium citrate, stearalkonium chloride, domiphen bromide, denatonium benzoate, diterpene benzyl ammonium chloride , lauryl tridecyl ammonium chloride, ethylenediamine dihydrogen chloride, hydrazine hydrogen chloride, pyridin xine HCl, iofetamine hydrochloride, meglumine, hydrogen chloride, Mercaptobenzyl Ammonium, meat stem sulfhydryl trimethyl ammonium bromide, oleic acid dimethyl ammonium sulfate, polyquaternium-1 (polyquaternium-1), procaine hydrogenation (procainehydrochloride), coconut beet test ( Cocobetaine), stearic acid base acid | f (stearalkonium bentonite),

43 200816987 stearalkoniumliectonite、硬脂基三羥基乙基丙二胺二氟化 氫、牛脂氯化三烷基，以及六癸基三甲基溴化銨。 在某些實施例中，該表面穩定劑可為一共聚維酮 (copovidone)(如Plasdone S630，其為乙酸乙烯酯與乙浠基 5 吼嘻酮之隨機共聚物），及/或多庫酯（docusate)納。 該表面穩定劑為商業上可購得，及/或可以技術上已知 之方法製備。大部分這些表面穩定劑為已知之醫藥賦形 歡，生詳細插遂於 Handbook of Pharmaceutical Excipients， 美國藥學協會與英國醫藥協會共同發行（The 10 Pharmaceutical Press，2000)，在此併入本案以作為參考資 料。 3·其他醫藥用賦形劑 本發明醫藥用組成物亦可包含一或多種黏著劑、填充 劑、潤滑劑、懸浮劑、增甜劑、香味劑、防腐劑、緩衝劑、 Ϊ5 濕潤劑、分解劑、發泡劑，與其他賦形劑。此賦形劑為技 術上已知。 填充劑之範例包括乳醣單水合物、乳醣無水物，以及 各種澱粉；黏著劑之範例包括各種纖維素，與交聯聚乙烯 基°比咯酮、微結晶纖維素，如Avicel® ΡΉ101與Avicel® 2〇 PH102、微結晶纖維素，以及矽化微結晶纖維素(ProSolv SMCCTM) 〇 適當之潤滑劑，包括可作用於待壓縮之粉末之流動性 試劑，可包括膠體二氧化矽，如Aerosil® 200、滑石、硬脂 酸、硬脂酸鎂、硬脂酸鈣，及矽膠。 44 200816987 增甜劑之範例可包括任一天然或人工增甜劑，如蔗 糖、木糖醇、糖精鈉、環磺酸鹽、阿斯巴甜與安賽蜜 (acsulfame)。香味劑之範例(MAFCO之商標 名）、泡泡糖香味，以及水果香味，及類似物。 5 防腐劑之範例包括山梨醇基鉀、對-羥基苯曱酸甲酯、 對-羥基苯甲酸丙酯、苯甲酸與其鹽類、對羥基苯甲酸之其 他酯類，如對-羥基苯曱酸丁酯、醇類如乙基或苄基醇、酚 類化合物，如紛，或四級化合物如苯札氯銨。 適當之稀釋劑包括醫藥上可接受之惰性填充劑，如微 10 結晶纖維素、乳糖、二鹼基磷酸鈣、糖精，及/或前述任一 混合物。稀釋劑之範例包括微結晶纖維素，如Avicel@ PH101 與Avicel® PH102 ;乳糖如乳糖單水合物、乳糖針，與 Pharmatose。DCL21，一驗基麟酸转如Emcompress@ ;甘露 醇；澱粉、山梨醣醇；蔗糖；與葡萄糖。 15 適當之分解劑包括微交聯聚乙稀基吼哈酮、小麥澱 粉、馬鈴薯澱粉、玉米澱粉，及經修飾澱粉、交聯經甲基 纖維素鈉、交聯-聚維酮、羧甲基澱粉鈉，及其混合物。 發泡劑之範例包括發泡耦合物，如有機酸或碳酸鹽或 碳酸氫鹽。適當有機酸包括，例如，擰檬酸、酒石酸、蘋 20 果酸、反丁浠二酸、己二酸、琥珀酸與海藻酸與酸酐及其 鹽類。適當之碳酸鹽與碳酸氫鹽包括，例如，礙酸鈉、碳 酸氫納、碳酸鉀、碳酸氫卸、碳酸鎂、甘胺酸破酸鈉、L-離胺酸碳酸鹽，及精胺酸碳酸鹽。此外，僅有碳酸氫鈉成 分之發泡麵合物可存在。 45 & 200816987 4.奈米顆粒激酶抑制劑之顆粒尺寸43 200816987 stearalkoniumliectonite, stearyltrihydroxyethylpropanediamine dihydrogen fluoride, tallow trialkyl chloride, and hexamethyltrimethylammonium bromide. In certain embodiments, the surface stabilizer can be a copovidone (eg, Plasdone S630, which is a random copolymer of vinyl acetate and ethyl ketone), and/or docusate (docusate). The surface stabilizers are commercially available and/or can be prepared by methods known in the art. Most of these surface stabilizers are known as the pharmaceutical formulas, which are detailed in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the British Medical Association (The 10 Pharmaceutical Press, 2000), which is incorporated herein by reference. data. 3. Other pharmaceutical excipients The pharmaceutical composition of the present invention may further comprise one or more adhesives, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffering agents, Ϊ5 humectants, decomposition Agents, foaming agents, and other excipients. This excipient is known in the art. Examples of fillers include lactose monohydrate, lactose anhydrate, and various starches; examples of the adhesive include various celluloses, with crosslinked polyvinylpyrrolidone, microcrystalline cellulose such as Avicel®® 101 and Avicel® 2〇PH102, microcrystalline cellulose, and deuterated microcrystalline cellulose (ProSolv SMCCTM) 〇 Suitable lubricants, including flowable agents that act on the powder to be compressed, may include colloidal cerium oxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silicone. 44 200816987 Examples of sweeteners may include any natural or artificial sweeteners such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame and acsulfame. Examples of fragrances (trade name of MAFCO), bubble gum fragrance, and fruit flavors, and the like. 5 Examples of preservatives include potassium sorbitol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid and its salts, and other esters of p-hydroxybenzoic acid, such as p-hydroxybenzoic acid. Butyl esters, alcohols such as ethyl or benzyl alcohol, phenolic compounds, such as, or quaternary compounds such as benzalkonium chloride. Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharin, and/or any of the foregoing. Examples of diluents include microcrystalline cellulose such as Avicel@PH101 and Avicel® PH102; lactose such as lactose monohydrate, lactose needle, and Pharmatose. DCL21, a test of basal acid to transfer such as Emcompress@; mannitol; starch, sorbitol; sucrose; and glucose. 15 Suitable decomposers include micro-crosslinked polyethylene heptahexanone, wheat starch, potato starch, corn starch, and modified starch, cross-linked methylcellulose sodium, cross-linking-povidone, carboxymethyl Sodium starch, and mixtures thereof. Examples of blowing agents include foaming couplings such as organic acids or carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, citric acid, butyl succinic acid, adipic acid, succinic acid and alginic acid with anhydrides and salts thereof. Suitable carbonates and bicarbonates include, for example, sodium, sodium bicarbonate, potassium carbonate, hydrogencarbonate, magnesium carbonate, sodium glycinate, L-isoamine carbonate, and arginine carbonate. salt. Further, a foamed dough having only a sodium hydrogencarbonate component may be present. 45 & 200816987 4. Particle size of nanoparticle kinase inhibitors

本發明之組成物包含至少一奈米顆粒激酶抑制劑，如 LS104 (或其鹽類或衍生物)顆粒，其具有效平均粒徑小於約 2000 nm (即2微米）、小於約1900 urn、小於約1800 nm、小 5 於約1700 nm、小於約1600 nm、小於約1500 nm、小於約1400 nm、小於約 1300 nm、小於約 1200 nm，less than about 1100 nm、小於約1000 nm、小於約990 nm、小於約980 nm、小 於約970 nm、小於約960 nm、小於約950 nm、小於約940 nm、小於約930 nm、小於約920 nm、小於約910 nm、小於 10 約 900 nm、小於約 890 nm、小於約88〇11111、小於約87〇11111、 小於約860 nm、小於約850 nm、小於約840 nm、小於約830 nm、小於約820 nm、小於約810 nm、小於約800 nm、小於 約790 nm、小於約780 nm、小於約770 nm、小於約760 nm、 小於約750 rnn、小於約740 nm、小於約730 nm、小於約720 15 nm、小於約710 nm、小於約700 nm、小於約690 nm、小於 約680 nm、小於約670 nm、小於約660 nm、小於約650 nm、 小於約640 nm、小於約630 nm、小於約620 nm、小於約610 nm、小於約600 nm、小於約590 nm、小於約580 nm、小於 約570 nm、小於約560 nm、小於約550 nm、小於約540 nm、 20 小於約530 nm、小於約520 nm、小於約510 nm、小於約500 nm、小於約490 nm、小於約48〇11111、小於約47〇11111、小於 約460 nm、小於約450 nm、小於約440 nm、小於約430 rnn、 小於約420 nm、小於約410 nm、小於約400 nm、小於約390 nm、小於約380 rnn、小於約370 nm、小於約360 nm、小於 46 200816987 約350 nm、小於約340 nm、小於約330 nm、小於約320 nm、 小於約310 nm、小於約300 nm、小於約290 nm、小於約280 nm、小於約270 nm、小於約260 nm、小於約250 nm、小於 約240 nm、小於約230 nm、小於約220 nm、小於約210 nm、 5 小於約200 nm、小於約190 nm、小於約180 nm、小於約170 nm、小於約160 nm、小於約150 nm、小於約140 nm、小於 約130 nm、小於約120 nm、小於約110 nm、小於約100、小 於約75 nm，或小於約50 nm，以光散射法、顯微鏡或其他 適當方法測量。 10 “有效平均粒徑小於約2000 nm’，，係指至少50%之激酶 抑制劑顆粒，如LS104，具有粒徑小於有效平均值，依據重 量，（或藉由其他適當之測量技術，如體積、數量等），即， 小於約2000 nm、1900 nm、1800 nm等，當以上述技術測量 時。在本發明之其他實施例中，至少約6〇%、至少約7〇%、 15至少約、至少約90%、至少約95°/〇，或至少約99%之激 酶抑制劑顆粒’如LS104具粒徑小於該有效平均粒徑，即小 於約2000 麵、1900 nm、1800 nm、1700 nm等。 在本發明中，奈米顆粒激酶抑制劑如组成物之 D50值，為低於50%之激酶抑制劑顆粒所落之粒徑範圍，依 20據重i類似地，D9〇為低於5〇%之激酶抑制劑顆粒所落之 粒徑範圍，依據重量。 5·激酶抑制劑受器拮抗劑舆表面穩定劑之濃度 敖酶抑帝】劑如LS104或其鹽類或衍生物，以及一或多種 表面穩定劑之相對量可變化。各成分之最佳量可依據，如， 47 200816987 所選擇之特定激酶抑制 點，以及穩定劑水溶液之表面張力等私性平衡卿、炼 0。。：酶抑制劑(如_)之濃度可自約 。自約95%至約〇.1%，或自約9〇%至約〇 5%，依據 里，以激酶抑制劑與至少一表面穩定劑，不包含 形劑之乾燥重量為基準。 軾The compositions of the present invention comprise at least one nanoparticulate kinase inhibitor, such as LS 104 (or a salt or derivative thereof) particles having an effect average particle size of less than about 2000 nm (i.e., 2 microns), less than about 1900 urn, less than About 1800 nm, small 5 at about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 Nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 10 to about 900 nm, less than about 890 nm, less than about 88〇11111, less than about 87〇11111, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, Less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 rnn, less than about 740 nm, less than about 730 nm, less than about 720 15 nm, less than about 710 nm, less than about 700 nm , less than about 690 nm, less than about 680 nm, less than about 670 nm, less than about 6 60 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm, less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, 20 less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm, less than about 48〇11111, less than about 47〇11111 Less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 rnn, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm, less than about 380 rnn, less than about 370 nm Less than about 360 nm, less than 46 200816987 about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, 5 less than about 200 nm, less than about 190 nm, less than about 180 nm, less than About 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, Less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, or less than about 50 nm, measured by light scattering, microscopy, or other suitable method. 10 "effective average particle size less than about 2000 nm', means that at least 50% of the kinase inhibitor particles, such as LS104, have a particle size less than the effective average, depending on the weight, (or by other suitable measurement techniques such as volume , number, etc., ie, less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured by the above techniques. In other embodiments of the invention, at least about 6%, at least about 7%, 15 at least about At least about 90%, at least about 95°/〇, or at least about 99% of the kinase inhibitor particles, such as LS104, have a particle size less than the effective average particle size, i.e., less than about 2,000, 1900, 1800, and 1700 nm. In the present invention, the D50 value of the nanoparticulate kinase inhibitor such as the composition is less than 50% of the particle size range of the kinase inhibitor particles, and the D9〇 is lower than the weight according to the weight I. The particle size range of 5〇% of the kinase inhibitor particles, depending on the weight. 5. The concentration of the kinase inhibitor receptor antagonist, the surface stabilizer, the enzyme, such as LS104 or its salts or derivatives, and The relative amount of one or more surface stabilizers can vary. The amount can be based on, for example, the specific kinase inhibition point selected by 47 200816987, and the surface tension of the aqueous solution of the stabilizer, such as the private balance, and the concentration of the enzyme inhibitor (such as _) can be self-contained. % to about 0.1%, or from about 9% to about 5%, based on the dry weight of the kinase inhibitor and at least one surface stabilizer, excluding the agent.

10 至少一表面穩定劑之濃度為約0.5%至約99.999%，自 約5:0%至約99.9%，或自約1〇%至約99 5%，依據重量，以 ，酶抑制劑與至少—表面穩定劑，不包含其他賦形劑之乾 無重量為基準。 不範性奈未顆粒LS104藥健配方 、數種示範性LS104藥錠配方提供如下。彡些範例並非用 於限制中請專利範圍，而是提供示範性之LS1G4藥錠配方， 其可用於本發明。此示範性藥錠亦可包括一包覆試劑。 不範性奈米顆粒 一~^ —^ LS104藥錠配方#1 成分 ------ g/Kg ~' LSI 04 ^----- 約50至約500 經丙甲基纖維素(Hypromellose)，USP 約10至約70 多庫酯鈉(Docusate sodium)，USP 約1至約tio 蔗糖，NF 約100至約500 月桂基硫酸鈉，NF 約1至約40 乳糖單水合物，NF 約50至約400 矽化微結晶纖維素 約50至約300 交聯聚維酮(Crospovidone)，NF 約20至約300 硬脂酸鎂，NF 約0.5至約5 48 20081698710 at least one surface stabilizer having a concentration of from about 0.5% to about 99.999%, from about 5:0% to about 99.9%, or from about 1% to about 99%, by weight, to the enzyme inhibitor and at least - Surface stabilizer, based on no dry weight of other excipients. The non-standard Naiwei granule LS104 medicinal formula, several exemplary LS104 medicinal formulations are provided below. These examples are not intended to limit the scope of the patent application, but rather to provide an exemplary LS1G4 tablet formulation that can be used in the present invention. The exemplary tablet may also include a coating reagent. Irregular Nanoparticles~~^^ LS104 Medicinal Formula #1 Ingredients ------ g/Kg ~' LSI 04 ^----- About 50 to about 500 by propylmethylcellulose (Hypromellose USP from about 10 to about 70 Docusate sodium, USP from about 1 to about tio sucrose, NF from about 100 to about 500 sodium lauryl sulfate, NF from about 1 to about 40 lactose monohydrate, NF about 50 Up to about 400 deuterated microcrystalline cellulose from about 50 to about 300 crospovidone (Crospovidone), NF from about 20 to about 300 magnesium stearate, NF from about 0.5 to about 5 48 200816987

示範性奈米顆粒 LS104藥錠配方#2 成分 g/Kg LSI04 約100至約300 經丙曱基纖維素(Hypromellose)，USP 約30至約50 多庫酯鈉(Docusate sodium)，USP 約0.5至約10 蔗糖，NF 約100至約3 00 月桂基硫酸鈉，NF 約1至約30 乳糖單水合物，NF 约100至約300 矽化微結晶纖維素 約50至約200 交聯聚維酮(Crospovidone)，NF 約50至約000 硬脂酸鎂，NF 約0.5至約5 示範性奈米顆粒 LS104藥錠配方#3 成分 g/Kg LSI 04 約200至約225 經丙甲基纖維素(Hypromellose)，USP 約42至約46 多庫醋納(Docusate sodium)，USP 約2至約6 蔗糖，NF 約200至約225 月桂基硫酸鈉，NF 約12至約18 乳糖單水合物，NF 約100至約205 矽化微結晶纖維素 約130至約135 交聯聚維酮(Crospovidone)，NF 約112至約118 硬脂酸鎂，NF 約0.5至約3Exemplary Nanoparticle LS104 Formulation #2 Ingredient g/Kg LSI04 From about 100 to about 300 by Hyporomellose, USP about 30 to about 50 Docusate sodium, USP about 0.5 to About 10 sucrose, NF from about 100 to about 300 sodium lauryl sulfate, NF from about 1 to about 30 lactose monohydrate, NF from about 100 to about 300 deuterated microcrystalline cellulose from about 50 to about 200 crospovidone (Crospovidone ), NF of about 50 to about 000 magnesium stearate, NF of about 0.5 to about 5 exemplary nanoparticle LS104 formulation formula #3 ingredient g/Kg LSI 04 about 200 to about 225 by propylmethylcellulose (Hypromellose) USP from about 42 to about 46 Docusate sodium, USP from about 2 to about 6 sucrose, NF from about 200 to about 225 sodium lauryl sulfate, NF from about 12 to about 18 lactose monohydrate, NF from about 100 to About 205 deuterated microcrystalline cellulose from about 130 to about 135 crospovidone (Crospovidone), NF from about 112 to about 118 magnesium stearate, NF from about 0.5 to about 3

49 200816987 示範性奈米顆粒 LS104藥錠配方#4 成分 g/Kg LSI 04 約119至約224 羥丙甲基纖維素(Hypromellose)，USP 约42至約46 多庫酯納(Docusate sodium)，USP 約2至約6 蔗糖，NF 約119至約224 月桂基硫酸鈉，NF 约12至約18 乳糖單水合物，nf 約119至約224 砍化微結晶纖維素 約129至約134 交聯聚維酮(Crospovidone)，NF 約112至約118 硬脂酸鎂，NF 约0.5至約3 7·示範性注射用奈米顆粒LS104配方 本發明係提供一種注射用組成物，包含至少一奈米顆 粒小分子激酶抑制劑，如LS1〇4，其可包括低注射體積之高 藥物濃度’使用快速藥物溶解投藥。此外，本發明注射用 奈米顆粒激酶抑制劑，如ls104配方可減少助溶劑之使用需 要，如聚烴氧60氫化蓖麻油（HCO_60)。示範性注射用組成 物係包含下列化合物，依據％ w/w : 10 5-50% 0.1-50% 0.05 -0.25% pH約6至約7 q.s. 小分子、合成激酶抑制劑如LS104 聚維酮聚合物： 防腐劑： pH調整劑： 注射用水： 50 15 200816987 不範性防腐劑包括對-羥基苯甲酸曱酯（約018〇/〇，基於 % w/w)、對-經基苯曱酸丙酯（約〇 〇2%，基於％ w/w)、酚（約 〇·5%，基於％ w/w)，以及苯曱醇(至多2% v/v)。示範性pH 調整試劑為氫氧化鈉，以及一示範性液體載體為注射用無 5菌水。其他可使用之防腐劑、PH調整試劑與液體載劑為技 術上已知。 C·製造奈米顆粒激酶抑制劑組成物之方法 該組成物包含至少一奈米顆粒激酶抑制劑，如LS104 (或其鹽類或衍生物），可使用如磨碎或研磨（包括，但不侷 10限於溼式研磨），均質化、沈殺、冷凍、模板乳化技術、超 臨界流體顆粒產生技術、奈米-電灑技術，或其任一組合方 法製造。製造奈米顆粒組成物之示範方法係描述於‘684號 專利中。製造奈米顆粒組成物之方法亦描述於美國專利號 5,518，187“Method of Grinding Pharmaceutical 15 Substances”，美國專利號5,718,388 “Continuous Method of Grinding Pharmaceutical Substances” ；美國專利號5,862,999 “Method of Grinding Pharmaceutical Substances” ；美國專利 號 5,665,331 “Co-Microprecipitation of Nanoparticle Pharmaceutical Agents with Crystal Growth Modifiers” ；美國 20 專利號 5,662,883 “Co-Microprecipitation of Nanoparticle Pharmaceutical Agents with Crystal Growth Modifiers” ；美國 專利號 5,560,932 “Microprecipitation of Nanoparticle Pharmaceutical Agents” ；美國專利號5,543,133 “Process of Preparing X-Ray Contrast Composition Containing 51 20081698749 200816987 Exemplary Nanoparticle LS104 Ingot Formulation #4 Ingredient g/Kg LSI 04 From about 119 to about 224 Hypomylose, USP from about 42 to about 46 Docusate sodium, USP From about 2 to about 6 sucrose, NF from about 119 to about 224 sodium lauryl sulfate, NF from about 12 to about 18 lactose monohydrate, nf from about 119 to about 224, chopped microcrystalline cellulose from about 129 to about 134 cross-linked poly-dimensional Crospovidone, NF from about 112 to about 118 magnesium stearate, NF from about 0.5 to about 37. Exemplary injectable nanoparticle LS104 formulation The present invention provides an injectable composition comprising at least one nanoparticle small Molecular kinase inhibitors, such as LS1〇4, can include high drug concentrations in low injection volumes' using rapid drug dissolution administration. In addition, the injectable nanoparticulate kinase inhibitor of the present invention, such as the ls 104 formulation, reduces the need for use of a co-solvent such as polyoxyl 60 hydrogenated castor oil (HCO_60). Exemplary injectable compositions comprise the following compounds according to % w/w : 10 5-50% 0.1-50% 0.05 -0.25% pH about 6 to about 7 qs small molecule, synthetic kinase inhibitor such as LS104 povidone polymerization Preservative: pH adjuster: Water for injection: 50 15 200816987 Non-standard preservatives include decyl-hydroxybenzoate (about 018 〇/〇, based on % w/w), p-parabens Ester (about 2% based on % w/w), phenol (about 5%, based on % w/w), and phenyl sterol (up to 2% v/v). An exemplary pH adjusting agent is sodium hydroxide, and an exemplary liquid carrier is a non-bacterial water for injection. Other preservatives, pH adjusting agents and liquid carriers which can be used are known in the art. C. Method of Making a Nanoparticle Kinase Inhibitor Composition The composition comprises at least one nanoparticulate kinase inhibitor, such as LS104 (or a salt or derivative thereof), which may be used, such as grinding or grinding (including, but not Bureau 10 is limited to wet milling), homogenization, immersion, freezing, template emulsification techniques, supercritical fluid particle generation techniques, nano-electric shower technology, or any combination thereof. An exemplary method for making nanoparticle compositions is described in the '684 patent. A method of making a nanoparticle composition is also described in U.S. Patent No. 5,518,187, "Method of Grinding Pharmaceutical 15 Substances", U.S. Patent No. 5,718,388, "Continuous Method of Grinding Pharmaceutical Substances"; U.S. Patent No. 5,862,999 "Method of Grinding Pharmaceutical Substances" US Patent No. 5,665,331 "Co-Microprecipitation of Nanoparticle Pharmaceutical Agents with Crystal Growth Modifiers"; US Patent No. 5,662,883 "Co-Microprecipitation of Nanoparticle Pharmaceutical Agents with Crystal Growth Modifiers"; US Patent No. 5,560,932 "Microprecipitation of Nanoparticle Pharmaceutical Agents"; US Patent No. 5,543,133 "Process of Preparing X-Ray Contrast Composition Containing 51 200816987

Nanoparticles” ；美國專利號 5,534,270 “Method of Preparing Stable Drug Nanoparticles” ；美國專利號 5,510,118 “Process of Preparing Therapeutic Composition * Containing Nanoparticles” ；以及美國專利號 5,470,583 ， 5 ''Method of Preparing Nanoparticle Composition Containing - Charged Phospholipids to Reduce Aggregation”，在此併入本 案以作為參考資料。 所得奈米顆粒激酶抑制劑組成物或分散物，可用於固 Φ 體或液體藥劑配方中，如注射用形式、液體分散液、凝膠、 10 氣溶膠、藥膏、乳液、控制釋放藥劑形式、快熔藥劑形式、 冷凍乾燥藥劑形式、藥錠、膠囊、延遲釋放藥劑形式、持 續釋放藥劑形式、脈衝釋放藥劑形式、混合立即釋放與經 控制釋放藥劑形式等。 1·研磨以獲得奈米顆粒激酶抑制劑分散物 15 研磨激酶抑制劑如LS104或其鹽類或衍生物，以獲得奈 米顆粒激酶抑制劑分散物，包含分散該激酶抑制劑顆粒於 液體分散介質中，其中該激酶抑制劑為難溶性，之後施加 機械裝置，在研磨介質存在下，以縮小激酶抑制劑之粒徑 至希望之有效平均粒徑。該分散介質可為，如， 广 不、紅化 20油、乙醇、第三-丁醇、甘油、聚乙二醇(PEG)、己烷或乙 二醇。在某些實施例中，較佳之分散介質為水。 激酶抑制劑顆粒可縮小尺寸，在至少一表面穩定劑存 在下。此外，_抑制劑顆粒可與一或多種表面穩定二接 觸，在研磨之後。其他化合物，如稀釋劑，可加至該激酶 52 200816987 抑制劑/表面穩定劑組成物中，在粒徑縮小過程中。分散物 可連續製造或以批次模式製造。 研磨介質可包括顆粒，較佳為實質上球狀，如微珠， 實質上係由I合性或共聚合性樹脂組成。此外，該研磨介 5質可包含-核心，具有-外衣，有聚合性或共聚合性樹脂 黏附於其上。 一般而έ，適當之聚合性或共聚性樹脂為化學或物理 性惰性，貝貝上不含金屬、溶劑與單體，具有足夠之硬度 與脆性，使其能預防在研磨過程中被切碎或壓碎。適當之 10聚合性或共聚性樹脂包括交聯性聚苯乙烯，如與二乙烯基 苯父聯之聚笨乙烯，聚苯乙烯共聚物、聚碳酸酯；聚甲醛， 如 DelrmTM (Ε·Ι· du Pont de Nemours and Co·);乙烯基氣聚 合物與共聚物，聚胺酯；聚醯胺；聚（四氟乙烯），如Tefl〇n⑧ (Ε·Ι· du Pont de Nemours and Co·)，以及其他氟化聚合物； 15咼始、度聚乙烯；聚丙烯；纖維素醚與酯類，如纖維素醋酸 酯；聚羥基甲丙烯酸酯；聚羥基乙基丙烯酸酯，與含二氧 化矽聚合物，如聚矽氧烷及類似物。該聚合物為生物可分 解。示範性之生物可分解聚合物或共聚物包括聚（乳酸）、 聚(經基乙酸）、乳酸與減乙酸之共聚物、聚酸針、聚(經 2〇基乙基甲丙烯酸酯）、聚（亞胺基碳酸酯）、聚(N-醯基羥基脯 胺1)¾類、聚(N-棕櫚基羥基脯胺酸)酯、亞乙基·乙烯基醋 酸酯共聚物、聚(原酸酯）、聚（異喹啉酮），以及聚(磷偶氮）。 就生物可分解聚合物或共聚物而言，來自介質本身之污染 物可占優勢地於體内代謝為生物可接受之產物，其可自體 53 200816987 内清除。 S研磨’I貝之尺寸較佳範圍為約〇 〇1至約3画^。就微 細研磨而言，該研磨介質較佳為約0·02至約2腿，更佳自 約0·03至約1 mm。 〜水口 I*生或共聚合樹脂可具有一密度自約〇.8至約 g/cm3。 f 研磨製程中，該顆粒可連續製造。此方法包 3連、貝式引入本發明之組成物至—研磨室中，在研磨室中 將本發明組成物與研磨介質接觸，以縮小本發明組成物之 10粒徑，並自該研磨室中連續地移出本發明之奈米顆粒組成 物。 該研磨介質係與本發明之奈米顆粒分離，使用一般分 離技術’在第-製程中，如簡單過渡、經^^罔狀過渡器或 筛網篩選，及類似方法。其他分離技術如離心亦可使用。 15 2·沈激以獲得奈米顆粒㈣抑制劑組絲 希主、、且成物，其包含奈米顆粒激酶抑制劑，如LS104 或其鹽類或何生物，之另一形成方法為微沈殿。此為一製 備難溶性活性試劑之穩定分散物方法，在一或多種表面穩 定劑，以及一或多種膠體穩定增強界面活性劑存在下，不 20含任何微量毒性溶劑或可溶性重金屬不純物。此一方法包 含，如：⑴溶解該激酶抑制劑於—適當溶劑中；⑺將一含 有至少一表面穩定劑之溶液加入步驟（1)之配方中；（3)沈澱 步驟(2)之配方，使用適當之非溶劑。該方法之後可移除任 -形成之鹽類，若存在，藉由透析或稀釋祕，並以一般 54 200816987 方法濃縮該分散物。 3.均質化以獲得奈米顆粒激酶抑制劑組成物 製備活性試劑奈米顆粒組成物之示範性均質化方法係 描述於美國專利號 5,510，118，“Process of Preparing 5 Therapeutic Composition Containing Nanoparticles”。此一 方法係包含分散LS104(或其鹽類或衍生物）之顆粒於一液 體分散介質中，之後將該分散物均質化，以縮小該激酶抑 制劑之粒徑，以達到希望之有效平均粒徑。該顆粒可在至 少一表面穩定劑存在下縮小粒徑。此外，該激酶抑制劑可 10與一或多種表面穩定劑接觸，在研磨之前或之後。其他化 合物，如一稀釋劑，可加至該激酶抑制劑/表面穩定劑組成 物中’在粒徑縮小製程之前、當時或之後。分散物可以連 續式或批次式模式製造。 4·冷凍法以獲得奈米顆粒激酶抑制劑組成物 15 另一形成希望之奈米顆粒激酶抑制劑如LS104 (或其鹽 類或衍生物）組成物之方法為，喷霧冷凍至液體中（SFL)。此 技術包含一激酶抑制劑之有機或有機水性溶液，具有穩定 劑，其可注射至冷凍用液體中，如液態氮。LSl〇4溶液冷凍 物’以足以使結晶與顆粒成長最小化之速率滴入，因此可 20形成奈米結構之LSI04顆粒。取決於所選用之溶液系統與加 工條件’該奈米顆粒激酶抑制劑顆粒可具有各種顆粒型 態。在分離步驟中，該氮氣與溶劑可在防止激酶抑制劑顆 粒結塊或熟化之條件下移除。 作為SFL之互補技術，超快速冷束(URF)亦可用於產生 55 200816987 等=之不米結構激酶抑侧齡，具有增強之表面積。咖 酶抑制劑之有機或有機水性溶液，具有穩定劑於 一冷凍受體上。 、 •乳化法以獲得奈㈣粒激酶抑糊組成物 7成所希望奈米顆粒激酶抑制劑如LS104組成物之另 方法’係藉由模板乳化法。模板乳化會產生奈米結構之 为卩制J或衍生物顆粒，具有經控制之粒徑分佈與快速 广解之表現。該方法包含一水包油乳化，其係經製備、之 1、匕3激酶抑制劑與穩定劑之非水性溶液膨脹。激酶抑 u之粒；^分佈料m狀寸之直減果，在載入激 酶抑制叙$ ’為此製程中可控制且最佳化之特性。此外， ^由師選n用途’可達到乳化穩定性，不具或抑制 ^stwald热化。之後，移除溶劑與水，回收經穩定之奈米 、、^冓激酶抑制劑顆粒。各種激酶抑制劑顆粒之型態可藉由 加工條件之適當控制而達到。 6·超臨界流艘法製造奈米顆粒 奈米顆粒組成物亦可利用超臨界流體之方法製造。在 此方法中，激酶抑制劑如LS104,係溶於一溶液或載劑中， 可έ有至少一表面穩定劑。溶液與超臨界流體之後可共 =入至齡形絲中H面穩定舰未先添加至該 载J中，則可加至該顆粒形成管中。溫度與壓力係經控制， 使得該載劑之分散與萃取實質上同時發生，藉由超臨界流 一之作用。可作為超臨界流體之化學物質包括二氧化碳、 1化氮、六Ι化硫、氣、乙烯、三氟甲烧基氯、乙烧，US Patent No. 5,534,270, "Method of Preparing Stable Drug Nanoparticles"; U.S. Patent No. 5,510,118, "Process of Preparing Therapeutic Composition * Containing Nanoparticles"; and U.S. Patent No. 5,470,583, 5 ''Method of Preparing Nanoparticle Composition Containing - Charged Phospholipids to Reduce Aggregation, which is incorporated herein by reference. The resulting nanoparticulate kinase inhibitor composition or dispersion can be used in solid body or liquid formulation, such as injectable form, liquid dispersion, gel, 10 aerosol, ointment, lotion, controlled release form, fast The form of the melt, the form of the lyophilized drug, the tablet, the capsule, the form of the delayed release agent, the form of the sustained release agent, the form of the pulse release agent, the immediate release of the mixture, the form of the controlled release agent, and the like. 1 grinding to obtain a nanoparticle kinase inhibitor dispersion 15 a grinding kinase inhibitor such as LS104 or a salt or derivative thereof to obtain a nanoparticle kinase inhibitor dispersion comprising dispersing the kinase inhibitor particles in a liquid dispersion medium Wherein the kinase inhibitor is poorly soluble, followed by application of a mechanical device in the presence of a milling medium to reduce the particle size of the kinase inhibitor to the desired effective average particle size. The dispersion medium may be, for example, broad, red 20 oil, ethanol, tri-butanol, glycerin, polyethylene glycol (PEG), hexane or ethylene glycol. In certain embodiments, the preferred dispersion medium is water. The kinase inhibitor particles can be downsized in the presence of at least one surface stabilizer. In addition, the _inhibitor particles can be in contact with one or more surface stabilization contacts after milling. Other compounds, such as diluents, can be added to the kinase 52 200816987 inhibitor/surface stabilizer composition during particle size reduction. The dispersion can be manufactured continuously or in batch mode. The grinding media can comprise particles, preferably substantially spherical, such as microbeads, consisting essentially of an I- or copolymeric resin. Further, the abrasive media may comprise a core having an outer coat to which a polymerizable or copolymerizable resin is adhered. Generally, the appropriate polymerizable or copolymerizable resin is chemically or physically inert. The babe is free of metals, solvents and monomers, and has sufficient hardness and brittleness to prevent it from being chopped during the grinding process. crush. Suitable 10 polymerizable or copolymerizable resins include crosslinkable polystyrene, such as polystyrene, polystyrene copolymer, polycarbonate, and polyoxymethylene, such as DelrmTM (Ε·Ι· Du Pont de Nemours and Co·); vinyl gas polymers and copolymers, polyurethanes; polyamines; poly(tetrafluoroethylene), such as Tefl〇n8 (Ε·Ι· du Pont de Nemours and Co·), and Other fluorinated polymers; 15 Å, polyethylene; polypropylene; cellulose ethers and esters, such as cellulose acetate; polyhydroxy methacrylate; polyhydroxyethyl acrylate, and cerium oxide containing polymer Such as polyoxane and the like. The polymer is biodegradable. Exemplary biodegradable polymers or copolymers include poly(lactic acid), poly(transacetic acid), copolymers of lactic acid and acetic acid reduction, polyacid needles, poly(2,ylethyl methacrylate), poly (Imino carbonate), poly(N-decyl hydroxy decylamine 1) 3⁄4, poly(N-palmityl hydroxy phthalic acid) ester, ethylene vinyl acetate copolymer, poly (ortho acid) Ester), poly(isoquinolinone), and poly(phosphorazo). In the case of biodegradable polymers or copolymers, contaminants from the medium itself can be predominantly metabolized in vivo to biologically acceptable products which can be removed from the body 53 200816987. The size of the S-milled 'I shell is preferably from about 〇1 to about 3 Å. In the case of fine grinding, the grinding medium is preferably from about 0. 02 to about 2 legs, more preferably from about 0. 03 to about 1 mm. ~Water I* Raw or copolymerized resin may have a density from about 〇8 to about g/cm3. f The granules can be produced continuously in the grinding process. The method comprises introducing the composition of the present invention into a grinding chamber, contacting the composition of the present invention with a grinding medium in a grinding chamber to reduce the particle size of the composition of the present invention, and from the grinding chamber. The nanoparticle composition of the present invention is continuously removed. The grinding media is separated from the nanoparticle of the present invention using a general separation technique 'in a first process, such as a simple transition, a chromatographic transition through a sieve or a screen, and the like. Other separation techniques such as centrifugation can also be used. 15 2·Throwing to obtain the nanoparticle (4) inhibitor group, and the inclusion of a nanoparticle kinase inhibitor, such as LS104 or its salts or organisms, another method of formation is the micro-suppressed temple . This is a method of preparing a stable dispersion of a poorly soluble active agent, in the presence of one or more surface stabilizers, and one or more colloidal stability enhancing surfactants, without any traces of toxic or soluble heavy metal impurities. The method comprises, for example: (1) dissolving the kinase inhibitor in a suitable solvent; (7) adding a solution containing at least one surface stabilizer to the formulation of step (1); (3) formulating the precipitation step (2), Use a suitable non-solvent. The method can then remove any of the formed salts, if present, by dialysis or dilution, and concentrate the dispersion by the general method of 54 200816987. 3. Homogenization to obtain a nanoparticulate kinase inhibitor composition. An exemplary homogenization process for preparing an active agent nanoparticle composition is described in U.S. Patent No. 5,510,118, "Process of Preparing 5 Therapeutic Composition Containing Nanoparticles." The method comprises dispersing particles of LS 104 (or a salt or a derivative thereof) in a liquid dispersion medium, and then homogenizing the dispersion to reduce the particle size of the kinase inhibitor to achieve a desired effective average particle. path. The particles can be reduced in particle size in the presence of at least one surface stabilizer. Additionally, the kinase inhibitor can be contacted with one or more surface stabilizers, either before or after milling. Other compounds, such as a diluent, may be added to the kinase inhibitor/surface stabilizer composition before, during or after the particle size reduction process. The dispersion can be manufactured in a continuous or batch mode. 4. A method of freezing to obtain a nanoparticulate kinase inhibitor composition 15 Another method of forming a composition of a desired nanoparticle kinase inhibitor such as LS104 (or a salt or a derivative thereof) is spray-freezing into a liquid ( SFL). This technique comprises an organic or organic aqueous solution of a kinase inhibitor with a stabilizer which can be injected into a liquid for freezing, such as liquid nitrogen. The LSl〇4 solution frozen material was dropped at a rate sufficient to minimize crystal growth and particle growth, and thus the nanostructured LSI04 particles were formed. The nanoparticulate kinase inhibitor particles can have various particle types depending on the solution system and processing conditions selected. In the separation step, the nitrogen and solvent can be removed under conditions which prevent the kinase inhibitor particles from agglomerating or ripening. As a complementary technology to SFL, ultra-fast cold bundles (URF) can also be used to produce 55 200816987 and other non-structural kinase inhibitors with enhanced surface area. An organic or organic aqueous solution of a protease inhibitor having a stabilizer on a frozen receptor. • Emulsification to obtain a neat (tetra) cytokinase inhibiting composition. Another method of forming a desired nanoparticle kinetic kinase inhibitor such as LS104 is by template emulsification. The emulsification of the template produces a nanostructured J or derivative granule with controlled particle size distribution and rapid broadening. The method comprises an oil-in-water emulsification which is prepared by swelling a non-aqueous solution of a 匕3 kinase inhibitor and a stabilizer. The kinase-inhibited granules; the distribution material m-shaped direct-reducing fruit, can be controlled and optimized in the process of loading the enzyme inhibition. In addition, ^ is used by the teacher to achieve emulsification stability, without or inhibiting the heating of the ^stwald. Thereafter, the solvent and water are removed, and the stabilized nanoparticles, and the kinase inhibitor particles are recovered. The type of various kinase inhibitor particles can be achieved by appropriate control of the processing conditions. 6. Supercritical flow boat method for producing nano particles The nano particle composition can also be produced by a method using a supercritical fluid. In this method, a kinase inhibitor such as LS104 is dissolved in a solution or carrier and may contain at least one surface stabilizer. The solution and the supercritical fluid may be added to the age-formed wire. The H-side stable ship is not added to the load J first, and may be added to the particle forming tube. The temperature and pressure are controlled such that the dispersion and extraction of the carrier occur substantially simultaneously, by supercritical flow. Chemicals that can be used as supercritical fluids include carbon dioxide, nitrogen, sulfur, gas, ethylene, trifluoromethyl chloride, and ethylene.

S 56 200816987 及三氟甲烷。 已知製造奈米顆粒之超臨界方法包括國際專利申請號 WO 97/144407 to Pace et al.，公開於 1997年4月 24 日，其說 明水難溶性生物活性化合物顆粒，具平均粒徑1〇〇 nm至3〇〇 . 5 11111，製備自溶解該化合物於一溶液中，之後喷灑該溶液至 、壓縮氣體、液體或超臨界流體中，在適當之表面穩定劑存 在下。 類似地，美國專利號6,4〇6,718，Cooper etal·係描述 _ 一種形成顆粒氟替卡松(fluticasone)丙酸酯產物之方法，包 10含共同引入一超臨界流體與一載劑，其包含有至少一氟替 卡松(fluticasone)丙酸酯於溶液或懸浮液中，至〆顆粒形成 管中，溫度與壓力係經控制，使得該載劑之分散與萃取可 實質上同時發生，藉由超臨界流體之作用。可作為超臨界 流體之化學物質包括二氧化碳、一氧化氮、六氟化硫、氙、 15乙烯、三氟甲烷基氯、乙烷，及三氟甲烷。超臨界流體玎 選擇性地包含一或多種修飾劑，如甲醇、乙醇、乙酸乙酯、 ^ 丙酮、乙腈或其任一混合物。超臨界流體修飾刻（或共溶劑) 為一化學物，當加至超臨界流體中時，會改變該超臨界流 體之本質，在臨界點或附近時。依據Co0per etal·，使用超 20 臨界流體所產生之氟替卡松(fluticasone)丙酸_顆粒，具有 粒徑範圍1至10微米，較佳為1至5微米。 7·用於獲得奈米顆粒組成物之奈米電灌技術 在電灑離子化過程中，一液體係經由非常小之帶電， 通常為金屬之毛細管噴出。此液體含有所希望之物質，如’ 57 200816987 一激酶抑制劑（或“分析物，，)係溶於大量溶劑中，其通常較分 析物更具揮發性。揮發性酸、鹼或緩衝液通常會加入此溶 液中。該分析物以溶液中之離子形式存在，不論是質子化 或陰離子形式。由於電荷相斥，液體會將其本身推離毛細 5 ^ ’形成務氣或氣務’具小滴液約1 〇 μΐϋ橫截面。此氣霧滴 液之噴射至少部分由涉及Taylor圓錐，以及由此圓錐尖端噴 射之過程產生。一中性載體氣體，如氮氣，有時係用於幫 助霧化該液體，並幫助該中性溶劑蒸發為小滴液。由於小 滴液揮發、懸浮於空氣中，該帶電之分析物分子遂彼此趨 10近。該滴液變得不穩定，由於帶電分子彼此接近，該滴液 又開始分裂。此稱之為庫侖分裂(C〇ul〇mbic fissi〇n)，由於 帶電分析物分子之間之庫侖排斥力驅動。此過程會重複， 直至分析物不含溶劑並為單一離子。 在奈米技術中’電灑法可用於沈積單一顆粒至一表面 15上，如激酶抑制劑顆粒。此可藉由噴灑膠體並確認每一滴 沒有超過一顆粒而達成。結果，周圍溶劑之乾燥會產生希 望形式之單一顆粒之氣霧流。在此，該製程之離子化性質 並非絕對，但可用於顆粒之靜電沈殿。 D·使用本發明奈米顆粒激酶抑制劑組成物之方法 2 0 本發明係提供一種增加激酶抑制劑如L S10 4 (或其鹽類 或衍生物）生物謂得性之枝(如增加讀巾含量）=一' 個體中。此方法包含口服投藥一有效劑量之組成物至一個 體，包含奈米顆粒激酶抑制劑。 在本發明之-實施例中，該奈米顆粒激酶抑制劑組成 58 200816987 物’如LSI04 ’依據標準藥物動力學，預期具有生物可獲得 性約50%大於、約40%大於、約30%大於、約20%大於，或 約10%大於一般劑量形式。 • 在本發明之另一實施例中，當個體依據標準藥物動力 ^ 5 學實施禁食時，該組成物係假設可產生最大血漿中濃度小 - 於約6小時、小於約5小時、小於約4小時、小於約3小時、 小於約2小時、小於約1小時，或小於約3〇分鐘，在組成物 初始投藥後。 # 本發明組成物可用於治療細胞增生疾病，如癌症，例 10如白企病如CML與ALL，以及骨髓增生疾病，如pv、ET與 IMF 〇 本發明組成物包含至少一奈米顆粒激酶抑制劑，如 LS104(或其鹽類或衍生物），可投至一個體中，經由一般方 法包括’但不偈限於，口服、直腸、眼部、非經腸胃（如靜 15脈内、肌内，或皮下）、蛛網膜下腔、肺部、陰道内、腹腔 内、局部（如粉末、藥膏或滴液），或口頰或鼻部喷液。在 、⑩ 某些實施例中，較佳為非經腸胃投藥。使用於此，術語“個 體係指一動物，較佳為一哺乳動物，包括人類或非人類。 術語病患與個體可互相交換使用。 20 適用於非經腸胃注射之組成物可包含生理上可接受之 無菌水溶液或非水溶液、分散液、懸浮液或乳化物，以及 無菌粉末，可重新配製為無菌注射用溶液或懸浮液。適當 之水性或非水性載體、稀釋劑、溶劑或載劑之範例包括水、 乙醇來一醇（丙二醇、聚乙二醇、甘油及類似物），其適當 59 200816987 曹 ' 5 η • 之混合物、蔬菜油(如撖欖油)與注射用有機酷，如油酸乙 醋。適當之錢性可_，例如，藉由使科衣如卵填脂、 错由維持分散液所需粒徑，以及藉由使用界面活性劑。 該組成物包含至少一奈米顆粒激酶抑制：，如 LS104(或其鹽類或衍生物），亦可包含佐劑，如防腐劑、濕 满劑、乳化劑與分散劑。微生物體生長之預防可以各種抗 細菌與抗黴菌劑確保，如對_羥基苯甲酸酯、氯化丁醇、酚、 山梨酸及類似物。亦希望包含等張試劑，如蔗糖、氯化鈉， 及類似物。可使用延長吸收之注射用藥劑形式，藉由使用 10 延遲吸收之試劑，如單硬脂酸鋁與明膠。 用於口服投藥之固體藥劑形式包括，但不侷限於，膠 囊、藥錠、藥丸、粉末與顆粒。在此固體藥劑形式中，該 活性試劑係與下列至少一者混合：（a) 一或多種惰性賦形劑 (或載體）’如捧橡酸鈉或構酸二約；（b)填充物或延展物， 15 • 如澱粉、乳糖、蔗糖、葡萄糖、山梨糖醇與矽酸；（c)黏著 劑，如羧基甲基纖維素、海藻膠鹽、明膠、聚乙烯基吼咯 酮、蔗糖與阿拉伯膠；（d)濕潤劑，如甘油；（e)分解劑， 如瓊脂、碳酸鈣、馬鈐薯或樹薯澱粉、海藻酸、某些錯合 物矽酸鹽，以及碳酸鈉；（f)溶液延遲劑，如石蠟；（g)吸收 20 加速劑，如四級銨化合物；(h)濕潤劑，如綠堪基醇與單硬 脂酸甘油酯；⑴吸收劑，如高嶺土與皂土；以及⑴潤滑劑， 如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫 酸納，或其混合物。就膠囊、藥鍵、與藥丸而言，該藥劑 形式亦可包含缓衝試劑。 60 200816987 用於口服投藥之液體形式包括醫藥上可接受之乳化 物、溶液、懸浮液、糖漿與酏劑。除了激酶抑制劑如LS104 之外，該液體藥劑形式尚包含此技術領域一般使用之惰性 稀釋劑，如水或其他溶劑、助溶劑與乳化劑。示範性乳化 5 劑為乙醇、異丙醇、乙基碳酸_、乙酸乙自旨、苯甲醇、节 基苯甲酸酯、丙二醇、1，3-丁二醇、二曱基甲醯胺、油類， 如棉籽油、花生油、玉米胚芽油、撖欖油、蓖麻油與芝麻 油、甘油、四氫糠醇(tetrahydrofurfuryl alcohol)、聚乙二醇、 山梨糖醇之脂肪酸酯，或這些物質之混合物，及類似物。 10 除了此種惰性稀釋劑外，該組成物亦可包括佐劑，如 濕潤劑、乳化劑與懸浮劑、增甜劑、香味劑與香料。 “醫療有效劑量”使用於此，如激酶抑制劑如LSl〇4之劑 Ϊ： ’係指其可提供特定醫療反應之劑量，當此1 〇4投藥至 需要此治療之明顯數量之個體。重點為“醫療有效劑量’，係 15投至一特疋個體，在一特定情況下，並非總是可有效治療 於此描述之疾病，即使此劑量被此技術領域者認為“醫療有 效劑量’’。更進一步瞭解到，；lS104之劑量為，在特定案例 中，口服投藥之測量，或是測量血液中之藥物量。 此技術領域者應瞭解到激酶抑制劑如LS 1〇4之有效劑 2〇量可依經驗決定，並可以純化形式使用，或此形式係以醫 藥上可接^：鹽類、g旨類或前藥形式存在。激酶抑制劑如 LS104在奈米顆粒組成物中之實際劑量可變化，以獲得可有 效達到希酉療反應之激酶抑制劑如⑽之量，就特定組 成物與投藥方法而言。因此，所選擇之劑量係依據希望之 61 200816987 5 • 療效、投藥路捏、待投藥之激酶抑制劑如LS104之藥效、希 望之治療期間，與其他因素。 藥劑單位组成物可包含此劑量之此多重物，可使用作 為每曰劑ΐ。然而，應瞭解到，任一特定病患之特定劑量 應依據多種因素：欲達到之細胞與生理反應之程度與種 類’所使用之特定試劑或組成物之活性；病患之年齡、體 重、一般健康狀況、性別與病患飲食；投藥時間、投藥路 #'試劑排出速率；治療期間；用於與特定試劑組合或同 時使用之藥物；及藥學領域中熟知之類似因素。 10 Ε.範例 15 下列範例係用於詳細說明本發明。然而，應瞭解到， 其並非用於將本發明限制於這些範例之特定條件或細節。 在本份說明書中，所有可公開獲得之文獻，包括美國專利， 皆在此併入本案以作為參考資料。 範例1 暑 20 本範例之目的係製備LS104奈米顆粒配方，以作為靜脈 注射之用。如下所示，係一成功之奈米顆粒分散配方 (“NCD”)範例，内含i〇〇/〇 LS104、2.5%聚維酮Κ-12 PF與0.1% 去氧膽酸鈉(sodium deoxycholate)。 配方之初步篩選係利用一低能滾磨（low energy roller mill)(Stoneware)進行。所使用之研磨介質為〇·8 mm經氧化 釔(yittrium)處理之氧化锆(zirc〇nia) (Tosoh)。所有配方以 170 rpm研磨。研磨時間如下表1所示。以光學顯微鏡觀 察，係採用Leica光學顯微鏡之ΙΟΟχ物鏡。所有顆粒以Horiba 62 200816987 LA 910測量粒徑，係以去離子水(DI)為稀釋劑並超音波震 盪30秒。 進行四種配方之篩選，内容如表1所示。第一種配方包 含以Poloxamer 338 (Plunmic F108)作為穩定劑。過程結束 5時可觀察到大的晶體產生。由於晶體生長的結果(〇stwaid 熟化），顯示此穩定劑在某些研磨參數下可能不理想（亦即， 使用特定藥物濃度與表面穩定劑濃度）。第二種配方包含聚 山梨醇酯80 (Tween 80)。過程結束時可觀察到小且均勻分 散之顆粒產生。第二種配方包含經基丙基纖維素 10 (HPC-SL)。此配方亦產生小且均勻分散之顆粒。第四種配 方包含聚維酮K-12 (PlasdoneK-12,低分子量等級之聚乙稀 吡咯烷酮)與去氧膽酸鈉混合物。此配方於過程結束時亦產 生小且均勻分散之顆粒。結果摘錄於下表1。S 56 200816987 and trifluoromethane. A supercritical process for the manufacture of nanoparticles is known, including International Patent Application No. WO 97/144407 to Pace et al., issued Apr. 24, 1997, which describes the granules of the water-insoluble bioactive compound having an average particle size of 1 〇〇. Nm to 3〇〇. 5 11111, prepared by dissolving the compound in a solution, followed by spraying the solution into a compressed gas, liquid or supercritical fluid in the presence of a suitable surface stabilizer. Similarly, U.S. Patent No. 6, 4, 6, 718, Cooper et al., describes a method of forming a fluticasone propionate product, the package 10 comprising a co-introduction of a supercritical fluid and a carrier comprising at least Fluticasone propionate in solution or suspension, into the granule forming tube, temperature and pressure are controlled, so that the dispersion and extraction of the carrier can occur substantially simultaneously, by the action of supercritical fluid . Chemicals that can act as supercritical fluids include carbon dioxide, nitrogen monoxide, sulfur hexafluoride, ruthenium, 15 ethylene, trifluoromethyl chloride, ethane, and trifluoromethane. The supercritical fluid 玎 selectively comprises one or more modifying agents such as methanol, ethanol, ethyl acetate, ^acetone, acetonitrile or any mixture thereof. A supercritical fluid modification engraving (or cosolvent) is a chemical that, when added to a supercritical fluid, alters the nature of the supercritical fluid, at or near the critical point. According to Co0per et al., fluticasone propionic acid granules produced using a supercritical fluid having a particle size ranging from 1 to 10 microns, preferably from 1 to 5 microns. 7. Nano-electric irrigation technology for obtaining nanoparticle composition In the electrospray ionization process, a liquid system is ejected through a very small charged, usually metal capillary. This liquid contains the desired material, such as '57 200816987. A kinase inhibitor (or "analyte,") is soluble in a large amount of solvent, which is generally more volatile than the analyte. Volatile acids, bases or buffers are usually Will be added to this solution. The analyte is present in the form of ions in solution, either protonated or anionic. The liquid will push itself away from the capillary 5 ^ 'to form a gas or gas service' because of the charge repellent The drip is about 1 〇μΐϋ cross section. The spray of this aerosol droplet is generated at least in part by the process involving the Taylor cone and thus the tip of the cone. A neutral carrier gas, such as nitrogen, is sometimes used to aid atomization. The liquid, and helps the neutral solvent to evaporate into small droplets. Since the droplets are volatilized and suspended in the air, the charged analyte molecules tend to be close to each other. The droplet becomes unstable due to charged molecules to each other. Close, the droplet begins to split again. This is called Coulomb splitting (C〇ul〇mbic fissi〇n), driven by the Coulomb repulsion between the charged analyte molecules. This process repeats until analysis The solvent is free of solvent and is a single ion. In nanotechnology, the electrospray method can be used to deposit a single particle onto a surface 15, such as a kinase inhibitor particle. This can be done by spraying the colloid and confirming that each drop does not exceed one particle. As a result, drying of the surrounding solvent produces a stream of aerosols of a single particle in a desired form. Here, the ionization properties of the process are not absolute, but can be applied to the electrostatic sink of the particles. D·Inhibition using the nanoparticle kinase of the present invention Method of Agent Composition 20 The present invention provides an increase in the biologically deficient branch of a kinase inhibitor such as L S10 4 (or a salt or a derivative thereof) (e.g., increasing the amount of reading towel) = one in an individual. A composition comprising an effective dose of an oral administration comprising a nanoparticle kinase inhibitor. In the present invention, the nanoparticle kinase inhibitor composition 58 200816987 'such as LSI04' is based on standard pharmacokinetics. It is expected that the bioavailability is about 50% greater than, about 40% greater than, greater than about 30% greater than, greater than about 20% greater than, or greater than about 10% greater than the general dosage form. In the example, when the individual is fasted according to standard pharmacokinetics, the composition is assumed to produce a maximum plasma concentration of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, Less than about 2 hours, less than about 1 hour, or less than about 3 minutes after the initial administration of the composition. # The composition of the invention can be used to treat cell proliferative diseases, such as cancer, such as white disease such as CML and ALL, And myeloproliferative diseases, such as pv, ET, and IMF. The compositions of the present invention comprise at least one nanoparticulate kinase inhibitor, such as LS104 (or a salt or derivative thereof), which can be administered to a body, including by general methods. However, it is not limited to oral, rectal, ocular, parenteral (such as static 15 intrapulmonary, intramuscular, or subcutaneous), subarachnoid, pulmonary, intravaginal, intraperitoneal, topical (such as powder, ointment or Drops), or buccal or nasal sprays. In some embodiments, it is preferred to administer parenterally. As used herein, the term "system" refers to an animal, preferably a mammal, including human or non-human. The terms patient and individual are used interchangeably. 20 A composition suitable for parenteral injection may comprise a physiologically acceptable A sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and sterile powder may be reconstituted as a sterile injectable solution or suspension. Examples of suitable aqueous or nonaqueous vehicles, diluents, solvents or carriers Including water, ethanol, monool (propylene glycol, polyethylene glycol, glycerol and the like), suitable for the mixture of 2008 2008987 Cao ' 5 η •, vegetable oil (such as eucalyptus oil) and organic cool for injection, such as oleic acid Ethyl vinegar. Appropriate money can be, for example, by making the coating such as egg fat, by the particle size required to maintain the dispersion, and by using a surfactant. The composition comprises at least one nanoparticle kinase. Inhibition: For example, LS104 (or its salts or derivatives) may also contain adjuvants such as preservatives, wetters, emulsifiers and dispersing agents. The prevention of microbial growth can be various antibacterial and The mold agent ensures, for example, p-hydroxybenzoate, butyl chloride, phenol, sorbic acid, and the like. It is also desirable to include isotonic agents such as sucrose, sodium chloride, and the like. In the form of a medicament, by using a delayed absorption agent such as aluminum monostearate and gelatin. Solid dosage forms for oral administration include, but are not limited to, capsules, troches, pills, powders and granules. In a solid pharmaceutical form, the active agent is admixed with at least one of: (a) one or more inert excipients (or carriers) such as sodium oleate or acid; (b) filler or extension , 15 • such as starch, lactose, sucrose, glucose, sorbitol and citric acid; (c) adhesives such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (d) a humectant such as glycerin; (e) a decomposing agent such as agar, calcium carbonate, mash or tapioca starch, alginic acid, certain complex citrate, and sodium carbonate; (f) solution delay Agent, such as paraffin; (g) absorb 20 accelerators, a quaternary ammonium compound; (h) a wetting agent such as chloromercaptan and glyceryl monostearate; (1) an absorbent such as kaolin and bentonite; and (1) a lubricant such as talc, calcium stearate, stearic acid Magnesium, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. The capsule form, the drug bond, and the pill may also contain a buffering agent. 60 200816987 Liquid form for oral administration includes medicinal Acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to kinase inhibitors such as LS104, the liquid dosage form also contains inert diluents commonly used in the art, such as water or other solvents, co-solvents and emulsifiers. Exemplary emulsification 5 agents are ethanol, isopropanol, ethyl carbonate _, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimercaptocarboxamide , oils, such as cottonseed oil, peanut oil, corn germ oil, eucalyptus oil, castor oil and sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, sorbitol fatty acid ester, or these substances mixture , and the like. In addition to such an inert diluent, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes. A "medical effective dose" is used herein, such as a kinase inhibitor such as LSl4, Ϊ: ' refers to a dose that provides a particular medical response, when administered to a significant number of individuals in need of such treatment. The focus is on "medical effective doses", which are 15 to one individual, and in a particular case, are not always effective in treating the disease described herein, even if the dose is considered by the skilled artisan as "medical effective dose" . It is further understood that the dose of lS104 is, in a specific case, a measure of oral administration or a measure of the amount of drug in the blood. It should be understood by those skilled in the art that the amount of the kinase inhibitor such as LS 1〇4 can be determined empirically and can be used in a purified form, or the form can be pharmaceutically acceptable: salt, g or The prodrug form exists. The actual dosage of a kinase inhibitor such as LS 104 in the nanoparticle composition can be varied to achieve an amount of a kinase inhibitor such as (10) that is effective to achieve a therapeutic response, in terms of the particular composition and method of administration. Therefore, the dose chosen is based on the desired efficacy, the administration of the drug, the pharmacokinetics of the kinase to be administered, such as LS104, the desired duration of treatment, and other factors. The pharmaceutical unit composition may comprise such a multiplicity of the dose which may be used as a sputum per sputum. However, it should be understood that the specific dosage of any particular patient should be based on a number of factors: the degree of cellular and physiological response to be achieved and the activity of the particular agent or composition used in the species'; age, weight, and general Health status, gender and patient diet; dosing time, dosing route #'reagent expulsion rate; treatment period; drugs for use in combination with or concurrent with specific agents; and similar factors well known in the pharmaceutical arts. 10 Ε. Example 15 The following examples are provided to illustrate the invention in detail. However, it should be understood that the invention is not limited to the specific conditions or details of the examples. In this specification, all publicly available documents, including U.S. patents, are incorporated herein by reference. Example 1 Summer 20 The purpose of this example was to prepare a LS104 nanoparticle formulation for intravenous use. As shown below, a successful nanoparticle dispersion formulation ("NCD") example containing i〇〇/〇LS104, 2.5% povidone Κ-12 PF and 0.1% sodium deoxycholate . The initial screening of the formulation was carried out using a low energy roller mill (Stoneware). The grinding media used were 〇·8 mm yittrium-treated zirconia (Tosoh). All formulations were ground at 170 rpm. The polishing time is shown in Table 1 below. Observed by an optical microscope, the objective lens of the Leica optical microscope was used. All particles were measured for particle size with Horiba 62 200816987 LA 910 using deionized water (DI) as a diluent and ultrasonically oscillated for 30 seconds. The screening of the four formulations was carried out as shown in Table 1. The first formulation contains Poloxamer 338 (Plunmic F108) as a stabilizer. At the end of the process, a large crystal formation was observed at 5 o'clock. As a result of crystal growth (〇stwaid ripening), it has been shown that this stabilizer may not be ideal under certain milling parameters (i.e., using a particular drug concentration and surface stabilizer concentration). The second formulation contains polysorbate 80 (Tween 80). Small, evenly dispersed particles are observed at the end of the process. The second formulation contains propylcellulose 10 (HPC-SL). This formulation also produces small, uniformly dispersed particles. The fourth formulation contains a mixture of povidone K-12 (Plasdone K-12, low molecular weight grade polyethylpyrrolidone) and sodium deoxycholate. This formulation also produces small, uniformly dispersed particles at the end of the process. The results are summarized in Table 1 below.

小瓶，並進行 ，3個月、6個 最後以γ-輻射滅菌。將最終產物包裝成 最後照射。進行多個批次的穩定性研究(例如 月與12個月，不同溫度與濕度條件）。 63 200816987 範例2 以第二與第四配方進行進-步評估。過去經驗顯示 PVPK]2_aDQC：之結合可產生較小之減，可適用於第 四配方。因此，選擇PVPK12/去氧膽酸鈉結合物作為LS1〇4 5 穩定劑。 利用高能介質研磨機進行初步滚磨篩選，其以高度交 聯之聚苯乙烯微珠作為研磨介質。已知前驅配方可利用此 法製備，隨然高剪切環境有時會造成聚集(aggregati〇n)D以 含有相同穩定劑成分之配方進行高能流程。該配方包含有 10 5% LS104/1.25% PVP K-12/0.05% NaDOC，並可成功地於 高能研磨環境下進行評估。 產物粒徑以Horiba LA910粒徑分析儀測量，並採用標 準R&D步驟，其中樣本濃度目標為8〇%轉換，並使用一相 對錯合物折射率1·2-〇·1ζ·。結果如下表2所示。 表2前駆配方之高能研磨 配方 平均PS 光學顯微鏡 5%LS104/1.25%PVPK12 + 0.05%去氧膽酸鈉 107 nm 可接受 1週冷穩定性 112 nm 可接受Vials, and carried out, 3 months, 6 and finally sterilized by γ-radiation. The final product is packaged for final illumination. Conduct batch stability studies (eg monthly and 12 months, different temperature and humidity conditions). 63 200816987 Example 2 A further step-by-step evaluation with the second and fourth recipes. Past experience shows that the combination of PVPK]2_aDQC: produces a small reduction and is applicable to the fourth formulation. Therefore, the PVPK12/sodium deoxycholate conjugate was selected as the LS1〇4 5 stabilizer. A preliminary barrel screening was performed using a high energy media mill using highly crosslinked polystyrene beads as the grinding media. Precursor formulations are known to be prepared by this method, and the high shear environment sometimes causes agglomeration to carry out a high energy process with a formulation containing the same stabilizer component. The formulation contains 10 5% LS104/1.25% PVP K-12/0.05% NaDOC and can be successfully evaluated in high energy grinding environments. The particle size of the product was measured on a Horiba LA910 particle size analyzer and the standard R&D procedure was used with a sample concentration target of 8〇% conversion and a relative refractive index of 1·2-〇·1ζ·. The results are shown in Table 2 below. Table 2 High-energy grinding of the former formula. Average PS optical microscope 5% LS104/1.25% PVPK12 + 0.05% sodium deoxycholate 107 nm Acceptable 1 week cold stability 112 nm Acceptable

研究顯示含有5% LS 104/ 1.25% PVPK-12/ 0.05%去氧 膽酸鈉之配方適合高能流程。其後可增加活性醫藥成分 (API)濃度以評估效用，其中API/穩定劑比例仍相同。 下表3詳述了其他奈米顆粒LS104配方。所有該配方之 製備係利用 NanoMill_01 (NanoMill Systems，King of 64 200816987 ?!^8丨^?八，請見例如，美國專利號6,431，478)，並配合500 微米PolyMill®摩擦介質(Dow Chemical)。同樣地，光學顯 微鏡之觀察係採用Leica光學顯微鏡之ΙΟΟχ油鏡。所有顆粒 以HoribaLA910測量粒徑，以去離子水為稀釋劑並超音波 5震盪30秒。在表3中，第1攔為配方；第2攔為平均與D9〇粒 徑(PS);第3攔為顯微鏡觀察；第4欄為研磨時間；第5攔為 研磨粒徑，第6欄為研磨載入量；第7攔為研磨速度(mm speed);以及第8欄為配方之相關註釋。 表3· 配方 平均 粒樹 D90 光學 顯微鏡 研磨 時間 研磨 粒徑 載入 介質 研磨 轉 5%LS104/ 1.25%PVPK12 + 0.05%去氧膽酸納 107 nm/ 167 nm 非常小且一 致之均勻分 散顆粒 60分鐘 10 ml 光滑軸 89% 5500 理想 配方 5%LS104 + 1.25%PVPK12 + 0.05%去氧膽酸納 105 nm/ 159 nm 非常小且一 致之均勻分 散顆粒 60分鐘 10 m】 光滑軸 89% 5500 理想 配方 5%LS104 + 1.25%PVPK12 + 0.05%去氧膽酸納 102 nm/ 146 nm 非常小且一 致之均勻分 散顆粒 60分鐘 10ml 光滑轴 89% 5500 理想 配方 5%LS104 + l.25%PVPK12 + 0.05%去氧膽酸納 113 nm/ 182 nm 非常小且一 致之均勻分 散顆粒 60分鐘 100 ml 銷轴 89% 3430 rpm 理想 配方 5%LS104 + 1.25%PVPK12 + 0.05%去氧膽酸納 107 nm/ 160 nm 非常小且一 致之均勻分 散顆粒 60分鐘 100 ml 銷軸 89% 3430 rpm 理想 配方 5%LS104 + 1.25%PVPK12 + 0.05%去氧膽酸鈉 106 nm/ 168 nm 非常小且一 致之均勻分 散顆粒 60分鐘 100 ml 銷軸 89% 3430 rpm 理想 配方 10%LS104 + 2.5%PVPK12 + 0.1%去氧膽酸納 106 nm /168 nm 非常小且一 K均勻分 散顆粒 60分鐘 100 ml 銷軸 89% 3430 rpm 理想 配方 10%LS104 + 2.5%PVPK12 + 0.1%去氧膽酸鈉 121 nm/ 207 nm 非常小且一 &夂均勻分 散顆粒 60分鐘 100 ml 光滑轴 89% 2140 rpm 理想 配方 65 10 200816987 此技術領域者應瞭解到，本發明之組成物與方法皆可 進行各種修飾與變化，而不脫離本發明精神或範疇。因此， 本發明係涵蓋本發明可進行之修飾與變化，係依據後述申 請專利範圍與其等效物。 5 【圖式簡單說明】 【主要元件符號說明】 (無）Studies have shown that formulations containing 5% LS 104 / 1.25% PVPK-12 / 0.05% sodium deoxycholate are suitable for high energy processes. The active pharmaceutical ingredient (API) concentration can then be increased to assess utility, with the API/stabilizer ratio remaining the same. Table 3 below details other nanoparticle LS104 formulations. All formulations were prepared using NanoMill_01 (NanoMill Systems, King of 64 200816987 ?!^8丨^?8, see, for example, U.S. Patent No. 6,431,478) in combination with a 500 micron PolyMill® friction medium (Dow Chemical). Similarly, the observation of the optical microscope was performed using a Leica optical microscope. All particles were measured with Horiba LA910, deionized water was used as a diluent and ultrasonic 5 was shaken for 30 seconds. In Table 3, the first block is the formula; the second block is the average and D9 〇 particle size (PS); the third block is the microscope observation; the fourth column is the grinding time; the fifth block is the grinding particle size, column 6 For the grinding load; the seventh stop is the grinding speed (mm speed); and the eighth column is the relevant note of the formula. Table 3. Formulation average grain tree D90 Optical microscope grinding time Grinding particle size Loading medium grinding to 5% LS104/ 1.25% PVPK12 + 0.05% sodium deoxycholate 107 nm / 167 nm Very small and consistent uniform dispersion of particles for 60 minutes 10 ml smooth axis 89% 5500 ideal formula 5% LS104 + 1.25% PVPK12 + 0.05% sodium deoxycholate 105 nm / 159 nm Very small and consistent uniform dispersion of particles 60 minutes 10 m] smooth axis 89% 5500 ideal formula 5 %LS104 + 1.25% PVPK12 + 0.05% sodium deoxycholate 102 nm / 146 nm Very small and consistent uniform dispersion of particles 60 minutes 10 ml smooth axis 89% 5500 ideal formula 5% LS104 + l.25% PVPK12 + 0.05% Sodium oxycholate 113 nm / 182 nm Very small and consistent uniform dispersion of particles for 60 minutes 100 ml Pin 89% 3430 rpm Ideal formulation 5% LS104 + 1.25% PVPK12 + 0.05% sodium deoxycholate 107 nm / 160 nm Very Small and consistent uniform dispersion of particles for 60 minutes 100 ml Pin 89% 3430 rpm Ideal formulation 5% LS104 + 1.25% PVPK12 + 0.05% sodium deoxycholate 106 nm / 168 nm Very small and consistent uniform dispersion of particles 60 minutes 100 Ml pin 89% 3430 rpm Ideal formulation 10% LS104 + 2.5% PVPK12 + 0.1% sodium deoxycholate 106 nm / 168 nm Very small and one K uniformly dispersed particles 60 minutes 100 ml Pin 89% 3430 rpm Ideal formulation 10% LS104 + 2.5% PVPK12 + 0.1% sodium deoxycholate 121 nm / 207 nm very small and one & 夂 uniformly dispersed particles for 60 minutes 100 ml smooth axis 89% 2140 rpm ideal formulation 65 10 200816987 It is understood by those skilled in the art that the compositions of the present invention Various modifications and changes can be made without departing from the spirit and scope of the invention. Thus, the present invention is intended to cover such modifications and alternatives 5 [Simple description of the diagram] [Explanation of main component symbols] (none)

Claims (1)

200816987 十、申請專利範圍： l 種知疋之奈米顆粒激酶抑制劑組成物，包含有·· (a) LS104顆粒或其鹽類或衍生物，具備一有效平均 粒控小於約2000 nm ;以及 5 (b)至少一表面穩定劑。 2·如申請專利範圍第1項之組成物，其中該LS104為結晶 相 '非晶相、半晶相、半非晶相或其混合物。 3·如申請專利範圍第1或2項之組成物，其中該LS104顆粒 或其鹽類或衍生物之有效平均粒徑係選自於由約βοο 10 nm、小於約1800 nm、小於約1700 nm、小於約1600 nm、 小於約1500 nm、小於約1400 nm、小於約1300 nm、小 於約1200 nm、小於約11〇〇 nm、小於約1000 nm、小於 約990 nm、小於約980 nm、小於約970 nm、小於約960 nm、小於約95〇11111、小於約94〇11111、小於約93〇11111、 15 小於約920 nm、小於約910 nm、小於約900 nm、小於約200816987 X. Patent Application Range: l A known nanoparticle granule kinase inhibitor composition comprising (a) LS104 particles or a salt or derivative thereof having an effective average particle size of less than about 2000 nm; 5 (b) at least one surface stabilizer. 2. The composition of claim 1, wherein the LS 104 is a crystalline phase 'amorphous phase, semi-crystalline phase, semi-amorphous phase or a mixture thereof. 3. The composition of claim 1 or 2, wherein the effective average particle size of the LS 104 particles or salts or derivatives thereof is selected from the group consisting of about βοο 10 nm, less than about 1800 nm, and less than about 1700 nm. Less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 11 〇〇 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 95 〇 11111, less than about 94 〇 11111, less than about 93 〇 11111, 15 less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm、小於約880 nm、小於約870 nm、小於約860 nm、 小於約850 nm、小於約840 nm、小於約830 nm、小於約 820 nm、小於約810 nm、小於約800 nm、小於約790 nm、 小於約780 nm、小於約770 nm、小於約760 nm、小於約 20 750 nm、小於約740 nm、小於約730 nm、小於約720 nm、 小於約710 nm、小於約700 nm、小於約690 nm、小於約 680 nm、小於約670 nm、小於約660 nm、小於約650 nm、 小於約640 nm、小於約630 nm、小於約620 nm、小於約 610 nm、小於約600 nm、小於約590 nm、小於約580 nm、 67 200816987 小於約570 nm、小於約560 nm、小於約550 nm、小於約 540 nm、小於約530 nm、小於約520 nm、小於約510 nm、 小於約500 nm、小於約490 nm、小於約480 nm、小於約 470 nm、小於約460 nm、小於約450 nm、小於約440 nm、 小於約430 nm、小於約420 nm、小於約410 nm、小於約 400 nm、小於約390 nm、小於約380 nm、小於約370 nm、 小於約360 nm、小於約350 nm、小於約340 nm、小於約 330 nm、小於約320 nm、小於約310 nm、小於約300 nm、 小於約290 nm、小於約280 nm、小於約270 nm、小於約 10 260 nm、小於約250 nm、小於約240 nm、小於約230 nm、 小於約220 nm、小於約210 nm、小於約200 nm、小於約 190 nm、小於約 180 nm、小於約17〇11111、小於約16〇11111、 15890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 20 750 nm, less than about 740 nm, less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than About 690 nm, less than about 680 nm, less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than About 590 nm, less than about 580 nm, 67 200816987 less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm Less than about 490 nm, less than about 480 nm, less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm , less than about 390 nm, less than about 380 nm, less than about 370 nm, less than about 360 nm, At about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 10 260 nm Less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 17〇11111, less than about 16. 〇11111, 15 20 小於約150 nm、小於約140 nm、小於約130 nm、小於約 120 nm、小於約110 nm、小於約1〇〇、小於約75 nm，以 及小於約50 nm組成之族群。 4·如申請專利範圍第1、2或3項之組成物，其中該奈米顆 粒LS104組成物，相較於一般LS104組成物，具有增進 之生物可利用率(bioavailability)。 5·如申請專利範圍第1、2、3或4項之組成物，其中該組成 物係配製為： (a) 投藥方式係選自於由口服、肺部、靜脈、直腸、 眼睛、結腸、非經腸胃、蛛網膜下腔(intracisternal)、陰 道内、腹腔、局部、口頰、鼻内與局部投藥組成之族群； (b) 劑量形式係選自於由液體分散液、凝膠、氣溶 68 200816987 I、軟m藥之族群. 方2劑量種類係選自於由冷凌乾燥配方、，卜 ::放配方、延遲釋放配方、持續釋放配方： 5 15 20 (d)任何⑻、⑻與(C)之結合。 如申請專利範圍第！、2、 组成物更包含有一或更多醫藥二=組成物，其中讀 或其組合物。 μ W文賦形劑、載體， 10 7. 如申請專利範圍第卜2、3、 (a) LS104之含量係選自於由约9:組至：’其中： 約9-至約•與約9〇%至約· LS104與至少一表面穩定劑 里百刀比，以 燥重量為基準，組成之族群；"括其他賦形劑之總乾 (b) 至少_表面穩定劑之存 至_/。之重量百分比' 糸、自於由〇聊❶ 比、約0.5%至約9〇%之重量百八^約95%之重量百分 之重量百分比，與約1〇%至約吸5%之約= 至物外 —與至少-表面穩定劑，不包括其比，以 燥重量為基準，組成之族群；或者 '他Η形劑之總乾 (c) (a)與(b)之一組合。 8·如申請專利範圍第1、2、3、4、 包含有至少—主要表面穩定劑與之組成物’ 劑。 -人要表面穩定 ί § 69 200816987 9.如申請專利範圍第卜^卜㈠❹項之組成物， 其中該至少一表面穩定劑係選自於由非離子表面穩定 劑、離子表面穩定劑、陰離子表面穩定劑、陽離子表面 穩疋劑與兩性離子表面穩定劑組成之族群。 1 〇 ·如申請專利範圍第1、2、3、4、5、6 /、8或9項之組 成物，其中至少一表面穩定劑係選自於下列群組，包 含有鯨蠟基吨啶鏽氯、明膠、酪蛋白、碟脂類20 is less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 1 Å, less than about 75 nm, and less than about 50 nm. 4. The composition of claim 1, 2 or 3, wherein the nanoparticle LS104 composition has improved bioavailability compared to the general LS104 composition. 5. The composition of claim 1, 2, 3 or 4, wherein the composition is formulated as: (a) the method of administration is selected from the group consisting of oral, pulmonary, intravenous, rectal, ocular, colonic, a group consisting of parenteral, intrathecal (intracristal), intravaginal, intraperitoneal, topical, buccal, intranasal, and topical administration; (b) dosage forms are selected from liquid dispersions, gels, and aerosols. 68 200816987 I. Groups of soft m medicines. The formula for the 2 doses is selected from the formula of dry cooling, the formula: the formula, the delayed release formula, the sustained release formula: 5 15 20 (d) any (8), (8) and (C) combination. Such as the scope of patent application! 2, the composition further comprises one or more pharmaceutical two = composition, wherein the reading or its composition. μ W medium excipient, carrier, 10 7. The content of LS104 is selected from the group of about 9: to: 'where: about 9-to about and about 9〇%至约· LS104 with at least one surface stabilizer in a hundred-knife ratio, based on dry weight, composed of groups; " total dryness of other excipients (b) at least _ surface stabilizer to _ /. The weight percentage '糸, from about 0.5% to about 9% by weight, is about 95% by weight, about 95% by weight, and about 5% to about 5%. = to the outside - with at least - surface stabilizer, excluding the ratio, based on the dry weight of the group; or 'the total dryness of his bismuth agent (c) (a) combined with one of (b). 8. The scope of claims 1, 2, 3, and 4 includes at least a primary surface stabilizer and a composition agent. - The person is to be surface stable ί 69 § 69 200816987 9. The composition of claim 1, wherein the at least one surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an ionic surface stabilizer, an anionic surface. A group of stabilizers, cationic surface stabilizers, and zwitterionic surface stabilizers. 1 如A composition of claim 1, 2, 3, 4, 5, 6 /, 8 or 9 wherein at least one surface stabilizer is selected from the group consisting of cetyl tungidine Rust chlorine, gelatin, casein, dish grease 10 1510 15 (phosphatides)、葡聚醣、甘油、阿拉伯膠、膽固醇、 特拉佳康膠、硬脂酸、苯札氣銨、硬脂酸鈣、單硬脂 酸甘油酯、西托硬脂醇（cetostearylalc〇h〇1)、聚西托醇 (cetomacrogol)乳化蠟、山梨醇酯、聚氧基乙烯基烷基 鱗、水氧基乙炸基說麻油衍生物、聚氧基乙稀基山半 醇脂肪酸酯、聚乙二醇、十二烷基三甲基溴化銨、聚 氧基乙浠基硬脂酸酯、膠體二氧化石夕、碟酸鹽、十二 烧基硫酸鈉、叛基曱基纖維素妈、經基丙基纖維素、 羥丙甲基纖維素、羧基甲基纖維素鈉、甲基纖維素、 羥基乙基纖維素、羥丙甲基纖維素酜酸酯、非結晶型 纖維素、矽酸鎂鋁、三乙醇胺、聚乙烯醇、聚乙烯基 吡咯酮、4-(1，1，3,3·四甲基丁基)_酚聚合物，具有環氧 20 乙浠與甲駿、普絡沙姆（poloxamers);普絡沙胺 (poloxamines)、帶電磷脂質、琥珀酸二辛酯磺酸鹽、琥 珀酸鈉之二烷基酯、月桂基硫酸鈉、烷基芳基聚醚磺 酸鹽、蔗糖硬脂酸鹽與蔗糖二硬脂酸鹽之混合物、 C18H37CH2C(0)N(CH3)-CH2(CH0H)4(CH20H)2、P-異壬(phosphatides), dextran, glycerin, acacia, cholesterol, trajiakang, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearylalc〇 H〇1), cetomacrogol emulsifying wax, sorbitol ester, polyoxy vinyl alkyl squama, ethoxy bromide sesame oil derivative, polyoxyethylene succinyl alcohol ester , polyethylene glycol, dodecyl trimethyl ammonium bromide, polyoxyethylene sulphate, colloidal silica, sulphate, sodium lauryl sulfate, thioglycol fiber Su Ma, propyl propyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose phthalate, amorphous cellulose , magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3·tetramethylbutyl)-phenolic polymer, with epoxy 20 acetamidine and a jun , poloxamers; poloxamines, charged phospholipids, dioctyl succinate sulfonate, dialkyl esters of sodium succinate, Sodium lauryl sulfate, alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, C18H37CH2C(0)N(CH3)-CH2(CH0H)4(CH20H)2, P - Different 70 200816987 570 200816987 5 10 15 20 基苯氧基聚-(縮水甘油）、癸酿基甲基葡聽酿胺，n-癸基β-D-吡喃葡萄醣苷；η-癸基β-D-吡喃麥芽醣苷；n-十二烷基β-D-吡喃葡萄醣苷；η-十二烷基β-D-麥芽醣 苷；庚醯基-Ν-甲基葡醣醯胺；η-庚基-β-D-吡喃葡萄醣 苷；η-庚基-β-D-硫代葡萄醣苷；η-己基β-D-咣喃葡萄醣 苷；壬醯基-Ν·甲基葡醣醯胺；η-壬基β-D-吡喃葡萄醣 苷；辛醯基-Ν-甲基葡醣醯胺；η-辛基-β-D-n比喃葡萄醣 苷；辛基β-D-硫代°比喃葡萄醣苷；溶菌酶(lysozyme)、 PEG-磷脂質、PEG-膽固醇、PEG-膽固醇衍生物、溶菌 酶(lysozyme)、PEG·維生素A、PEG·維生素E、乙酸乙烯 酯與乙醯基吼咯酮之隨機共聚物、陽離子性共聚物、陽 離子性生物聚合物、陽離子性多醣、陽離子性纖維素、 陽離子性海藻酸鹽、陽離子性非聚合物性化合物、陽離 子性磷脂質、陽離子性脂質、聚甲基甲基丙烯酸酯三曱 基溴化銨、锍基化合物、聚乙烯基吡咯酮-2-二甲基胺基 乙基甲基丙烯酸酯二甲基硫酸酯、六癸基三甲基溴化 銨、鱗基化合物、四級胺化合物、苄基-二(2-氯乙基)乙 基溴化銨、椰子三甲基氯化銨、椰子三甲基溴化銨、椰 子甲基二羥基乙基氯化銨、椰子甲基二羥基乙基溴化 銨、癸基三乙基氯化銨、癸基二甲基羥基乙基氯化銨、 癸基二甲基羥基乙基氯溴化銨、C12_15二甲基羥基乙基氯 化銨、C12_15二甲基羥基乙基氯溴化銨、椰子二甲基羥基 乙基氯化銨、椰子二曱基羥基乙基溴化銨、肉莖蔻基三 曱基甲基硫酸銨、月桂基甲基节基氯化銨、月桂基二甲 71 .ί: .¾ 200816987 基苄基溴化銨、月桂基二甲基(氧乙烯基)4氯化銨、月桂 基二甲基(氧乙烯基)4溴化銨、N-烷基(C12_18)二甲基苄基 氯化錄、N-烧基(C14_18)二甲基-节基氯化铵、N-十四烧 基二甲基节基氯化銨單水合物、二甲基二癸基氯化銨、 5 N•烷基與(Cum)二甲基1-萘基甲基氯化銨、三甲基鹵 化銨、烷基-三甲基銨鹽、二烷基-二甲基銨鹽、月桂基 三甲基氯化銨、乙氧基化烷基醯胺烷基二烷基銨鹽、乙 氧基化三烷基銨鹽、二烷基苯二烷基氯化銨、N-二癸基 二甲基氯化銨、N-十四烷基二甲基苄基氣化銨單水合 10 物、N-烧基(Cn-M)二甲基1-萘基甲基氯化銨、十二烧基 一曱基节基氯化銨、二烧基苯烧基氯化録、月桂基三甲 基氯化銨、烷基节基甲基氯化銨、烷基节基二甲基溴化 銨、C!2三甲基溴化銨、Cm三曱基溴化铵、C17三甲基漠 化銨、十二烧基节基三乙基氣化銨、聚-二稀丙基二甲 15 基氣化銨(DADMAC)、二甲基氯化銨、烷基二甲基鹵化 銨、三鯨蠟基甲基氯化銨、癸基三甲基溴化銨、十二烧 基三乙基溴化銨、十四烷基三甲基溴化銨、甲基三辛基 氣化銨、POLYQUAT 10™、四丁基溴化銨、苄基三甲基 溴化銨、膽驗酯類、苯札氯錄、硬脂基氯化銨 20 (stearalkonium chloride)化合物、鯨蠟基吡啶鏘溴、鯨壤 基吡啶鏽氯、四級化聚氧基乙基烷基胺之南化鹽類、 MIRAPOL™、ALKAQUAT™、烷基吡啶鑌鹽類；胺類、 銨鹽、胺基氧化物、醯胺基偶氮陽離子鹽類（imide azolinium salts)、質子化四級丙稀醯胺、曱基化四級聚 72 200816987 合物’以及陽離子性瓜爾膠(guar)。 11.如申請專利範圍第1、2、3、4、5、6、7、8、9或10項 之組成物，額外地包含一或多種活性試劑，可用於治療 細胞增生疾病或病症。 12·如申請專利範圍第1、2、3、4、5、6、7、8、9、10或 11項之組成物，其中：10 15 20 phenoxy poly-(glycidol), mercapto methyl melamine, n-mercapto β-D-glucopyranoside; η-mercapto β-D-maltopyranoside N-dodecyl β-D-glucopyranoside; η-dodecyl β-D-maltoside; p-menthyl-fluorene-methylglucamide; η-heptyl-β- D-glucopyranoside; η-heptyl-β-D-glucosinolate; η-hexyl β-D-glucopyranoside; fluorenyl-fluorenylmethylglucosamine; η-fluorenyl β-D-glucopyranoside; octyl-indole-methylglucamide; η-octyl-β-Dn glucopyranoside; octyl β-D-thio-pyranoside; lysozyme Lysozyme), PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, lysozyme, PEG·vitamin A, PEG·vitamin E, random copolymer of vinyl acetate and acetylfuroxone, cation Copolymer, cationic biopolymer, cationic polysaccharide, cationic cellulose, cationic alginate, cationic non-polymeric compound, cationic phospholipid, cationic lipid, polymethyl methacrylate triterpene Bromine Ammonium, mercapto compound, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexamethyltrimethylammonium bromide, squara compound, quaternary amine compound, Benzyl-bis(2-chloroethyl)ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxy Ammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride, decyldimethylhydroxyethylammonium bromide, C12_15 dimethylhydroxyethylammonium chloride, C12_15 dimethyl hydroxyethyl ammonium chlorobromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimercapto hydroxyethyl ammonium bromide, meat stem sulfhydryl tridecyl methyl ammonium sulfate, lauryl methyl Alkyl ammonium chloride, lauryl dimethyl 71 . ί: .3⁄4 200816987 benzyl benzyl ammonium bromide, lauryl dimethyl (oxyethylene) 4 ammonium chloride, lauryl dimethyl (oxyethylene) 4 Ammonium bromide, N-alkyl (C12_18) dimethylbenzyl chloride, N-alkyl (C14_18) dimethyl-salt ammonium chloride, N-tetradecyl dimethyl sulfhydryl chloride Ammonium monohydrate, dimethyl Di-decyl ammonium chloride, 5 N•alkyl and (Cum) dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salt, dialkyl-di Methylammonium salt, lauryl trimethyl ammonium chloride, ethoxylated alkyl decylamine alkyl dialkyl ammonium salt, ethoxylated trialkyl ammonium salt, dialkyl benzene dialkyl ammonium chloride , N-dimercaptodimethylammonium chloride, N-tetradecyldimethylbenzyl ammonium sulfate monohydrate 10, N-alkyl (Cn-M) dimethyl 1-naphthylmethyl Ammonium chloride, dodecyl sulfhydryl hexyl ammonium chloride, dialkyl benzoate chloride, lauryl trimethyl ammonium chloride, alkyl benzyl methyl ammonium chloride, alkyl node Dimethylammonium bromide, C!2 trimethylammonium bromide, Cm tridecyl ammonium bromide, C17 trimethylammonium chloride, dodecapine sulfhydryl triethylammonium hydride, poly-diuret Propyl dimethyl 15-based ammonium hydride (DADMAC), dimethyl ammonium chloride, alkyl dimethyl ammonium halide, tri-cetyl methyl ammonium chloride, decyl trimethyl ammonium bromide, twelve burning Triethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctyl ammonium halide, POLYQUAT 10TM, tetrabutyl bromide , benzyltrimethylammonium bromide, cholesteryl ester, benzalkonium chloride, stearalkonium chloride compound, cetylpyridinium bromide, whale pyridine rust chloride, quaternization Nanhua salts of polyoxyethylalkylamines, MIRAPOLTM, ALKAQUATTM, alkylpyridinium salts; amines, ammonium salts, amine oxides, imide azolinium salts ), protonated quaternary amide, thiolated quaternary poly 72 200816987 compound 'and cationic guar (guar). 11. A composition according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 additionally comprising one or more active agents for the treatment of a cell proliferative disease or condition. 12. If the patent application covers the composition of items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, among them: 10 1510 15 (a)在投藥至一哺乳動物情況下，LS104或鹽類或其 衍生物之顆粒係重新分散，使得顆粒具一有效平均粒 徑，選自於由小於約2微米、小於約1900 nm、小於約1800 nm、小於約1700 nm、小於約1600 nm、小於約1500 nm、 小於約1400 nm、小於約1300 nm、小於約1200 nm、小 於約llOOnm、小於約1〇〇〇11111、小於約99〇11111、小於約 980 nm、小於約970 nm、小於約960 nm、小於約950 nm、 小於約940 nm、小於約930 nm、小於約920 nm、小於約 910 nm、小於約900 nm、小於約890 nm、小於約880 nm、 小於約870 nm、小於約860 nm、小於約850 nm、小於約 840 nm、小於約830 nm、小於約820 nm、小於約810 nm、 小於約800 nm、小於約790 nm、小於約780 nm、小於約 770 nm、小於約760 nm、小於約750 nm、小於約740 nm、 20 小於約730 nm、小於約720 nm、小於約710 nm、小於約 700 nm、小於約690 nm、小於約680 nm、小於約670 nm、 小於約660 nm、小於約650 nm、小於約640 nm、小於約 630 nm、小於約620 nm、小於約610 nm、小於約600 nm、 小於約590 nm、小於约580 nm、小於約570 nm、小於約 73 ΐ S 200816987(a) in the case of administration to a mammal, the particles of LS 104 or a salt or a derivative thereof are redispersed such that the particles have an effective average particle size selected from less than about 2 microns, less than about 1900 nm, less than About 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about llOOnm, less than about 1 〇〇〇 11111, less than about 99 〇 11111, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 Nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 Nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 nm, less than about 740 nm, 20 less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than about 690 nm, less than about 680 nm, less than about 670 nm, less than about 660 nm Less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm, less than about 570 nm, less than about 73 ΐ S 200816987 10 15 560 nm、小於約 550 nm、小於約54〇11]11、小於約53〇11111、 小於約520 nm、小於約510 nm、小於約50〇11111、小於約 490 nm、小於約480 nm、小於約470 nm、小於約460 nm、 小於約450 nm、小於約440 nm、小於約430 nm、小於約 420 nm、小於約410 nm、小於約400 nm、小於約3 90 nm、 小於約380 nm、小於約370 nm、小於約360 nm、小於約 350 nm、小於約340 nm、小於約330 nm、小於約320 nm、 小於約310 nm、小於約300 nm、小於約290 nm、小於約 280 nm、小於約270 nm、小於約260 nm、小於約250 nm、 小於約240 nm、小於約230 nm、小於約220 nm、小於約 210 nm、小於約200 nm、小於約190 nm、小於約180 nm、 小於約170 nm、小於約160 nm、小於約150 nm、小於約 140 nm、小於約130 nm、小於約120 nm、小於約110 nm、 小於約100、小於約75 nm，以及小於約50 nm組成之族 群；10 15 560 nm, less than about 550 nm, less than about 54〇11]11, less than about 53〇11111, less than about 520 nm, less than about 510 nm, less than about 50〇11111, less than about 490 nm, less than about 480 nm, Less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 3 90 nm, less than about 380 nm Less than about 370 nm, less than about 360 nm, less than about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm Less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm Less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, and less than about 50 nm a group of people; 20 (b)該組成物於一生物相關性(biorelevent)介質中重 新分佈，使得該LS104顆粒具一有效平均粒徑，選自於 由小於約2微米、小於約1900 nm、小於約1800 nm、小 於約1700 nm、小於約1600 nm、小於約1500 nm、小於 約1400 nm、小於約1300 nm、小於約1200 nm，小於約 1100 nm、小於約1000 nm、小於約990 nm、小於約980 nm、小於約97〇11111、小於約96〇11111、小於約95〇11111、 小於約940 nm、小於約930 nm、小於約920 nm、小於約 910 nm、小於約900 nm、小於約890 nm、小於約880 nm、 74 20081698720 (b) the composition is redistributed in a biorelevent medium such that the LS 104 particles have an effective average particle size selected from less than about 2 microns, less than about 1900 nm, less than about 1800 nm, Less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, Less than about 97〇11111, less than about 96〇11111, less than about 95〇11111, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 880 nm, 74 200816987 10 1510 15 20 小於約870 nm、小於約860 nm、小於約850 nm、小於約 840 nm、小於約830 nm、小於約820 nm、小於約810 nm、 小於約800 nm、小於約790 nm、小於約780 nm、小於約 770 nm、小於約760 nm、小於約750 nm、小於約740 nm、 小於約730 nm、小於約720 nm、小於約710 nm、小於約 700 nm、小於約690 nm、小於約680 nm、小於約670 nm、 小於約660 nm、小於約650 nm、小於約640 nm、小於約 630 nm、小於約620 nm、小於約610 nm、小於約600 nm、 小於約590 nm、小於約580 nm、小於約570 nm、小於約 560 nm、小於約550 nm、小於約540 nm、小於約530 nm、 小於約520 nm、小於約510 nm、小於約500 nm、小於約 490 nm、小於約480 nm、小於約470 nm、小於約460 nm、 小於約450 nm、小於約440 nm、小於約430 nm、小於約 420 nm、小於約410 nm、小於約400 nm、小於約390 nm、 小於約380 nm、小於約370 nm、小於約360 nm、小於約 350 nm、小於約34〇11111、小於約33〇11111、小於約32〇11111、 小於約310 nm、小於約300 nm、小於約290 nm、小於約 280 nm、小於約 270 nm、小於約26〇11111、小於約25〇11111、 小於約240 nm、小於約230 nm、小於約22〇11111、小於約 210 nm、小於約200 nm、小於約190 nm、小於約180 nm、 小於約170 nm、小於約160 nm、小於約150 nm、小於約 140 nm、小於約130 nm、小於約120 nm、小於約110 nm、 小於約100、小於約75 nm，以及小於約50 nm組成之族 群；或 75 200816987 (c) (a)與(b)之組合。 13·如申請專利範圍第12項之組成物，其中該生物相關性 (biorelevent)介質係選自於由水、電解質水溶液、鹽類 水溶液、酸之水溶液、鹼之水溶液，及其組合物組成 之族群。 14.如申請專利範圍第1、2、3、4、5、6、7、8、9、1〇、 11、12或13項之組成物，其中： 10 15 20 (a) 奈米顆粒LS104組成物之Tmax，當於投藥後之哺 乳動物體血漿中試驗時，係小於投以相同藥劑之相同非 奈米顆粒LS104組成物iTmax ; (b) 奈米顆粒LS104組成物之cmax，當於投藥後之哺 乳動物體血漿中試驗時，係大於投以相同藥劑之相同非 奈米顆粒LS104組成物之(：_ ; (c) 奈米顆粒LS104組成物之AUC，當於投藥後之哺 乳動物體血漿中試驗時，係大於投以相同藥劑之相同非 奈米顆粒LS104組成物之AUC;或 (d) (a)、（b)與⑷之任一組合。 15·如申請專利範圍第14項之組成物，其中： ⑻該Tmax係選自於由不大於約90%、不大於約 80%、不大於約70%、不大於約60%、不大於約5〇%、不 大於約30%、不大於約25%、不大於約20%、不大於約 15%、不大於約10%，以及不大於約5%之投以相同藥巧 之相同非奈米顆粒LS104組成物之Tmax組成之族_ . ⑻該Cmax係選自由至少約50%、至少約1〇〇%、至 76 200816987 少約200%、至少約300%、至少約400%、至少約500%、 至少約600%、至少約700%、至少約800%、至少約900%、 至少約1000%、至少約1100%、至少約1200%、至少約 1300%、至少約1400%、至少約1500%、至少約1600%、 5 至少約1700%、至少約1800%，或至少約1900%大於投 以相同藥劑之相同非奈米顆粒LS104組成物之Cmax組成 之族群； (c)該AUC係選自於由至少約25%、至少約50%、至 少約75%、至少約100%、至少約125%、至少約150%、 10 至少約175%、至少約200%、至少約225%、至少約250%、 至少約275%、至少約300%、至少約350%、至少約400%、 至少約450%、至少約500%、至少約550%、至少約600%、 至少約750%、至少約700%、至少約750%、至少約800%、 至少約850%、至少約900%、至少約950%、至少約 15 1〇〇〇°/〇、至少約1050%、至少約1100%、至少約1150%或20 less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 nm, less than about 780 nm Less than about 770 nm, less than about 760 nm, less than about 750 nm, less than about 740 nm, less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than about 690 nm, less than about 680 nm Less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm Less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm, less than about 480 nm Less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm, less than about 380 nm , less than about 370 nm, less than about 360 nm, less than about 350 nm, less than about 34〇11111, small About 33〇11111, less than about 32〇11111, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 26〇11111, less than about 25〇11111, less than about 240 nm, less than about 230 nm, less than about 22 〇 11111, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than a population of about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, and less than about 50 nm; or 75 200816987 (c) (a) and (b) The combination. 13. The composition of claim 12, wherein the biorelevant medium is selected from the group consisting of water, an aqueous electrolyte solution, a salt aqueous solution, an aqueous acid solution, an aqueous alkali solution, and a combination thereof. Ethnic group. 14. The composition of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 , 11, 12 or 13 of which: 10 15 20 (a) Nanoparticles LS104 The Tmax of the composition, when tested in the plasma of the mammalian body after administration, is less than the same non-nanoparticle LS104 composition iTmax administered with the same agent; (b) the cmax of the composition of the nanoparticle LS104, when administered The test in the plasma of the mammalian body is greater than the composition of the same non-nanoparticle LS104 administered with the same agent (: _; (c) the AUC of the nanoparticle LS104 composition, when the mammalian body is administered In the plasma test, it is greater than the AUC of the same non-nanoparticle LS104 composition administered with the same agent; or (d) any combination of (a), (b) and (4). The composition, wherein: (8) the Tmax is selected from no more than about 90%, no more than about 80%, no more than about 70%, no more than about 60%, no more than about 5%, no more than about 30%. No more than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, and no more than about 5% of the same medicinal phase The Tmax composition of the composition of the non-nanoparticle LS104. (8) The Cmax is selected from at least about 50%, at least about 1%, to about 76 200816987, about 200% less, at least about 300%, at least about 400%, At least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, At least about 1500%, at least about 1600%, 5 at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax composition of the same non-nanoparticle LS104 composition administered with the same agent; (c) The AUC is selected from at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, 10 at least about 175%, at least about 200%, at least about 225. %, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750 %, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 15 1 〇〇〇 ° / 〇, at least about 1050 %, at least about 1100%, at least about 1150% or 至少約1200%大於投以相同藥劑之相同非奈米顆粒 LS104配方之AUC組成之族群；或 (d) (a)、（b)與(c)之任一組合。 16·如申請專利範圍第1、2、3、4、5、6、7、8、9、10、 11 ' 12 ' 13、14或15項之組成物，當在餵食與禁食條件 下投藥時，並不會產生明顯不同之吸收量。 17·如申請專利範圍第16項之組成物，其中當於餵食狀態與 禁食狀態投藥相較時，本發明活性試劑組成物吸收度之 差異為選自於由小於約100%、小於約90%、小於約 77 ΐ Β 200816987 80%、小於約70%、小於約6〇%、小於約5〇%、小於約 40%、小於約3〇%、小於約25%、小於約2〇%、小於約 15%、小於約10%、小於約5%，以及小於約3%組成之族 m 群。 r 5 18·如申請專利範圍第1、2、3、4、5、6、7、8、9、10、 11 ' 12、13、14、15、16或17項之組成物，其中該組成 物投藥至一禁食狀態之人體時，係與該組成物投藥至_ 進艮狀恶之個體呈生物等量性(bi〇eqUivaient)。 _ 19.如申請專利範圍第18項之組成物，其中“生物等量性，，係 10 建立為： ⑻Cmax與AUC二者之90%信賴區間係介於〇 8〇與 1.25 間； (b)AUC之90%^賴區間係介於〇·8〇與ι·25間，以及 Cmax之90%信賴區間係介於〇·7〇與us之間。 奢15 20· 一種如申請專利範圍第1、2、3、4、5、6、7、8、9、 • 10、11、12、13、14、15、16、17、18或 19項之組成物 之用途，用於製造一藥物。 21·如申請專利範圍第2〇項之用途，其中該藥物係用於治療 白血症、骨髓增生性疾病，以及相關疾病或病症。 20 22·—種製備奈米顆粒LS104或其鹽類或衍生物之方法，包 含將LS104顆粒與至少一表面穩定劑接觸—段時間，在 足以提供具一有效平均粒徑小於約2〇〇〇 nm之奈米顆粒 LS104組成物之條件下。 23.如申請專利範ϋ第22項之方法，其中該_包括研磨、 78 - ^ 200816987 濕式研磨、均質化、沈澱、冷凍、超臨界流體顆粒產生 技術、乳化技術、奈米-電灑技術，或其任一組合。 200816987 七、指定代表圖： (一） 本案指定代表圖為：第（）圖。（無) (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：At least about 1200% greater than the group consisting of the AUC of the same non-nanoparticle LS104 formulation administered the same agent; or (d) any combination of (a), (b) and (c). 16. If the composition of the patent scope 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ' 12 ' 13, 14 or 15 is administered under feeding and fasting conditions At the time, there is no significant difference in absorption. 17. The composition of claim 16, wherein the difference in absorbance of the active agent composition of the present invention is selected from less than about 100% and less than about 90 when compared to administration in a fed state and a fasted state. %, less than about 77 ΐ Β 200816987 80%, less than about 70%, less than about 6%, less than about 5%, less than about 40%, less than about 3%, less than about 25%, less than about 2%, Groups of m groups of less than about 15%, less than about 10%, less than about 5%, and less than about 3%. r 5 18· The composition of items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ' 12, 13, 14, 15, 16 or 17 of the patent application, wherein the composition When the substance is administered to a human in a fasting state, it is biologically equivalent (bi〇eqUivaient) to the individual who is administered the composition to the sputum. _ 19. The composition of claim 18, wherein “biological equivalent,” is established as: (8) The 90% confidence interval between Cmax and AUC is between 〇8〇 and 1.25; (b) The 90% of the AUC range is between 〇·8〇 and ι·25, and the 90% confidence interval of Cmax is between 〇·7〇 and us. Luxury 15 20· One as the patent application scope 1 The use of a composition of items 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for the manufacture of a medicament. 21. The use of the second aspect of the patent application, wherein the medicament is for the treatment of leukotrix, myeloproliferative diseases, and related diseases or conditions. 20 22 - Preparation of nanoparticle LS104 or its salts or derivatives A method comprising contacting LS 104 particles with at least one surface stabilizer for a period of time sufficient to provide a nanoparticle LS 104 composition having an effective average particle size of less than about 2 Å. The method of claim 22, wherein the _ includes grinding, 78 - ^ 200816987 wet grinding, homogenization, precipitation, Frozen, supercritical fluid particle generation technology, emulsification technology, nano-electric shower technology, or any combination thereof. 200816987 VII. Designation of representative drawings: (1) The representative representative of the case is: () (None) ( b) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:
TW096121317A 2006-06-13 2007-06-13 Nanoparticulate kinase inhibitor formulations TW200816987A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US81296006P 2006-06-13 2006-06-13

Publications (1)

Publication Number Publication Date
TW200816987A true TW200816987A (en) 2008-04-16

Family

ID=38832788

Family Applications (1)

Application Number Title Priority Date Filing Date
TW096121317A TW200816987A (en) 2006-06-13 2007-06-13 Nanoparticulate kinase inhibitor formulations

Country Status (8)

Country Link
EP (1) EP2043606A2 (en)
JP (1) JP2009540010A (en)
KR (1) KR20090018864A (en)
CN (1) CN101500540A (en)
AU (1) AU2007257667A1 (en)
CA (1) CA2654909A1 (en)
TW (1) TW200816987A (en)
WO (1) WO2007146943A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9670334B2 (en) 2014-08-26 2017-06-06 Industrial Technology Research Institute Shear thickening formulation and composite material employing the same

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8685458B2 (en) 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
EP3181128B1 (en) 2012-01-13 2023-03-08 XSpray Pharma AB (publ) Nilotinib pharmaceuticalcomposition
ES2854751T3 (en) * 2012-01-13 2021-09-22 Xspray Microparticles Ab A process for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003531133A (en) * 2000-04-13 2003-10-21 エイチエスシー リサーチ アンド ディベロップメント リミテッド パートナーシップ Novel compounds that regulate cell proliferation
ATE385777T1 (en) * 2002-03-20 2008-03-15 Elan Pharma Int Ltd NANOPARTICLE COMPOSITIONS OF MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INHIBITORS

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9670334B2 (en) 2014-08-26 2017-06-06 Industrial Technology Research Institute Shear thickening formulation and composite material employing the same

Also Published As

Publication number Publication date
JP2009540010A (en) 2009-11-19
AU2007257667A1 (en) 2007-12-21
CN101500540A (en) 2009-08-05
WO2007146943A2 (en) 2007-12-21
WO2007146943A3 (en) 2008-05-29
CA2654909A1 (en) 2007-12-21
EP2043606A2 (en) 2009-04-08
KR20090018864A (en) 2009-02-23

Similar Documents

Publication Publication Date Title
TWI558422B (en) Reduction of flake-like aggregation in nanoparticulate active agent compositions
JP4611641B2 (en) Nanoparticle composition of MAP kinase inhibitor
US20210038585A1 (en) Niraparib formulations
EP1276465B1 (en) Improved water-insoluble drug particle process
TWI354568B (en) Insoluble drug particle compositions with improved
TW200811145A (en) Nanoparticulate posaconazole formulations
TW200820991A (en) Nanoparticulate sorafenib formulations
JP2018135351A (en) Abiraterone acetate formulation
US20210030735A1 (en) Pediatric niraparib formulations and pediatric treatment methods
TW200403079A (en) Nanoparticulate fibrate formulations
JP2010285451A (en) Fast dissolving dosage form having reduced friability
KR20080016952A (en) Nanoparticulate clopidogrel and aspirin combination formulations
JP2006514688A (en) Gel-stabilized nanoparticle active substance composition
BRPI0608771A2 (en) nanoparticulate clopidogrel formulations
AU2007221471A1 (en) Nanoparticulate carvedilol formulations
CN106794251B (en) Aripiprazole prodrug compositions
TW200816987A (en) Nanoparticulate kinase inhibitor formulations
JP6826167B2 (en) Aripiprazole prodrug composition
AU2018238136A1 (en) Sustained release olanzapine formulations