TW200800195A - Organic compounds - Google Patents

Abstract

The present invention relates to microparticle pharmaceutical compositions in which the active agent is a topoisomerase I inhibitor, in particular, 7-t-butoxyiminomethylcamptothecin, that is useful for the treatment and prevention of proliferative diseases including cancer.

Description

200800195 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a particulate composition in which an active agent is used, and a isomerase I inhibitor, and the composition containing the microparticles is used for r ^ ^ ^ ^ „ A pharmaceutical composition for treating and preventing proliferative diseases including cancer. [Prior Art] A class of camptothecin derivatives is described in U.S. Patent No. 6,242, 4"

Chemical waste. The sulphate derivatives (e.g., the ones of the Japanese Patent No. 6,242,457) are usually extremely difficult to handle at the time of administration and especially when the 盍俭 组合 composition is administered, especially the sputum The problem of bioavailability is due to the extremely poor solubility of these derivatives. SUMMARY OF THE INVENTION Further in accordance with the present invention, it has now surprisingly been found that a stable microparticle pharmaceutical composition comprising 7-t-butoxyiminomethylcamptothecin has an extremely interesting bioavailability. It has been found that these novel compositions can solve or greatly reduce the previously encountered difficulties, namely the poor biological systems observed in the dry formulations of the crystallization of the camptotheca and the observations in the microemulsion preconcentration formulations. Limited drug content. Thus, the present invention achieves effective treatment by tolerizing a dose level of 7-second butoxyiminomethylcamptothecin, and can bring the daily dose requirement of each individual closer to standardization and optimization. Thus, the occurrence of potentially harmful side effects is reduced and the total cost of treatment can be reduced. [Embodiment] The present invention relates to a microparticle composition comprising a topoisomerase I inhibitor as an active agent in a vehicle, in particular, 7·t-butoxyimine 113088.doc 200800195 Mercapto camptothecin. The present invention also relates to a microparticle composition comprising a topoisomerase z inhibitor as an active agent in a vehicle, specific +, 7-t-butoxyiminomethylcamptothecin and The case comprises at least one surface stabilizer. The vehicle is selected from the group consisting of an oil vehicle, a hydrophilic non-aqueous vehicle or a self-microemulsification vehicle. In one embodiment, the self-microemulsifiable vehicle further comprises an excipient. The particulate compositions may further comprise a sedimentation inhibitor and further comprise an excipient. φ The present invention is also directed to a pharmaceutical composition comprising the particulate composition of the present invention and a pharmaceutically acceptable carrier and any desired excipient. Unit dosage forms of the invention are, for example, capsules, coated and uncoated lozenges, ampoules, vials or bottles. An example is a capsule containing from about 1 gram to about 5 milligrams of 7-second butoxyiminomethyl-Xi Shu. The present invention provides a method of treating an individual having a condition treatable with 7-t-butoxyiminomethylcamptothecin, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a medicament of the invention combination. The term 'effective amount, or I, pharmaceutically effective amount' as used herein, refers to an amount of the particulate formulation that is non-toxic but sufficient to provide the desired response and corresponding therapeutic effect in an amount sufficient to achieve treatment. Individuals, as defined below, as will be noted below, depending on the species, age and general condition of the individual, the severity of the condition to be treated, the mode of administration, the exact dose required between the subject and the subject may vary. Suitable "effective" dosages in any individual case can be determined by routine experimentation by those skilled in the art. Phrase, pharmaceutically acceptable or "pharmacologically acceptable", refers to material H material that is biologically unaffected by 113088.doc 200800195 or otherwise harmful. #四) granule formulations are administered together to the individual without Any undesired biological effect or in a detrimental manner interacts with any of the components contained in the composition. I. Active Agent As used herein, "active agent" refers to a 't-butoxyiminomethylcamptothecin having the following compound A: °

The preferred active agent can be in the form of a free or pharmaceutically acceptable salt.

Possible forms of enantiomers, diastereomers and related mixtures, polycrystals, amorphous, partially amorphous, solvates, active metabolites and prodrugs thereof. According to the present invention, the active agent may be present in an amount of from about 1% to about 30% by weight of the composition of the present invention. Preferably, the active agent is present in an amount of from about 1% to about 10%, optimally from about 1% to about 5% by weight of the composition. The term "microparticle" as used herein refers to an active ingredient particle having a diameter of up to about 15 microns, more preferably from about 5 microns to about 5 microns in diameter, and an optimum diameter of from about 10 microns to about 3 microns. The particle size can be readily determined by laser diffraction and/or scanning electron microscopy, which are well known in the art. 113088.doc 200800195 The term "microsuspension" as used herein refers to a medium containing an enzyme I inhibitor, a scorpion, a sulphate, a succinimide, a Kexishu is used as an inerting agent and, as the case may be, a micro-pure compound containing at least a surface stabilizer. The granule composition may further comprise a sedimentation inhibitor and further comprise an excipient. IL Surface Stabilizer I....Heart』a ------1 Heart Dispense Ya Hanliang Dispersibility of these county floats in contact with aqueous (for example) gastrointestinal fluids. The surface elixirs also help to inhibit crystal growth of the active agent in the microsuspension. The surface stabilizer can be improved

Further preferred surface stabilizers of the invention include, but are not limited to, cellulose derivatives, polyethylene ratios.无g, vinyl pyrrolidine g and a random copolymer of vinyl acetate, sodium lauryl sulfate, sodium dioctyl sulfonate, colloidal or sinking emulsification (such as Aerosil® from Desussa) Or Zeopharm® from Huber, poloxamers (eg, piur〇nics F688 and fi〇88, which are block copolymers of emulsified ethylene and propylene oxide), or combinations thereof. Examples of non-limiting flH of cellulose include (but are limited to) propylmethylcellulose, hydroxypropylcellulose. Other surface stabilizers for use in the present invention include, but are not limited to, conventional organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low knives, natural products, and surfactants. Surface stabilizers also include ion ion, ion and zwitterionic surfactants. Other examples of surface stabilizers include gelatin, casein, lecithin (phosphorus), dextran, gum arabic, cholesterol, sulfonate, stearic acid, benzoquinone, calcium stearate, and glycerin alone. Fatty acid ester, cetearyl alcohol, 113088.doc 200800195 cetomacrogol emulsifying wax, sorbitan ester, polyoxyalkylene linkage (such as polyethylene glycol ether, such as cetomacrogol 1000), polyoxyethylene Castor oil derivatives, polyoxyethylene ethyl sorbitan fatty acid esters (for example, commercially available Tweens®, for example, Tweeil 2®® & Tween 80® (ICI Specialty Chemicals)), Polyethylene B Glycols (eg Carb〇waxs 35508 and 9348 (Union Carbide)), polyoxyethylidene ethyl stearate, phosphate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sulfhydryl cellulose, hydroxyethyl Cellulose, hydroxypropyl methylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), and ethylene oxide and methyl 4-(1,1 , 3,3-tetradecylbutyl)-benzoquinone polymer (also known as tetrabutyl phenolic, supine (super Ione) and triton, poloxamine (eg Tetronic 908®, also known as p〇i〇xamine 9088) obtained by sequential addition of propylene oxide and ethylene oxide to ethylenediamine Tetrafunctional block copolymer (BASF Wyandotte, Parsippany, NJ·), Tetronic 1 5088 (T_ 1 508) (BASF Wyandotte), Tritons X-200® (which is an alkyl aryl polyether sulfonate) (R〇hπι and Haas)), Crodestas F-1008 (which is a mixture of sucrose stearate and sucrose distearate (Croda)), p-isodecylphenoxy poly-(glycidol) (also known as 01 in-10G® or Surfactant 10-G® (Olin Chemicals, Stamford, CT)), Crodestas SL-40® (Croda, Inc.), and SA9 0HC0 (which is C18H37CH2 (CON (CH3) )-CH2(CH0H)4(CH20H)2 (Eastman Kodak)), bromo-N-methylglucosamine, n-decyl &bgr; -D-glucopyranoside, n-decyl & Bgr D-maltopyranoside, n-dodecyl group &bgr; -D-glucopyranose 113088.doc -10· 200800195

Glycosides, n-dodecyl &bgr; -D-maltopyranoside, heptyl-N-decyl glucosamine, n-heptyl-&bgr;-D-glucopyranoside, n-heptyl &bgr;-D-thioglucoside, n-hexyl &bgr; -D-glucopyranoside, decyl-N-methylglucamine, η-mercapto &bgr; -D-pyran Glucoside, octyl-N-mercaptoglucosamine, n-octyl-β-D-glucopyranoside, octyl-β-D-thiopyranoside, PEG-phospholipid, PEG·cholesterol, PEG·cholesterol , PEG·vitamin A, PEG-vitamin E, lysozyme, random copolymer of vinylpyrrolidone and vinyl acetate, and the like. Exemplary cationic surface stabilizers are described in Cross and Singer's Cationic Surfactants: Analytical and Biological Evaluation, Marcel Dekker (1994); Rubingh Edited by Cationic

Surfactants: Physical Chemistry, Marcel Dekker (1991); and Richmond's Cationic Surfactants: Organic Chemistry, Marcel Dekker (1990). Most of these surface stabilizers are conventional pharmaceutical excipients and are described in detail in the Handbook of Medicines, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain. (The Pharmaceutical Press (2000)] in the Handbook of Pharmaceutical Excipients, which is expressly incorporated herein by reference. Such surface stabilizers are commercially available and/or can be prepared by techniques well known in the art. The surface stabilizer according to the present invention is present in an amount of from about 3% by weight to about 30% by weight (by weight) of the composition of the present invention. The surface stabilizer is preferably present in an amount from about 1% to about 15% by weight of the composition. 113088.doc -11 - 200800195 πι·agent The agent of the present invention may be an oily vehicle. Hydrophilic non-aqueous vehicle, or self-microemulsion according to the present invention, the composition of the present invention is from about 70% to about 99 垔/〇 The sputum needle, left 80 〇 / $ έ. ~ vehicle is preferably present in an amount of from about 80 / to about 98% by weight of the composition, in the most alumina in an amount of about 90 to 98%.

The short-chain single component of the oily vehicle comprises: ^ The oily agent of the invention comprises corn oil, eucalyptus oil, stone oil, soybean oil, cotton oil, long bond, medium and... triglycerol, alone or in combination. Vinegar and other suitable lipophilic! And share. Suitable lipophilic 1) Mono-C6_CM-Fatty Acid Glycerides These are obtained by (4) oil glycerin followed by molecular steaming. Monoglycerides suitable for use in the compositions of the present invention include both symmetric monoglycerides (i.e., beta-monoglycerols) and asymmetric monoglycerides (alpha monoglycerides). It also includes both homoglycerides (wherein the fatty acid component consists essentially of one fatty acid) and mixed glycerides (i.e., wherein the fatty acid component is composed of a plurality of fatty acids). The fatty acid component may comprise a chain length of, for example, (^ to (14) both saturated and unsaturated fatty acids. Particularly suitable are, for example, those under the trade name Imwit〇r® 308 or Imwii〇r® 312, respectively. Available from, for example, sas〇i octanoic acid or lauric acid monoglycerol. For example, Imwitor® 308 contains at least 80% monoglycerol g and exhibits the following additional characterization data. · Free glycerol up to 6%, acid The maximum value is 113088.doc •12· 200800195 3, the saponification value is 245 to 265, the maximum moth value, the maximum water content is ι%. Usually it contains 1% free glycerin, 9〇% monoglyceride, 7% diglyceride, 1% triglyceride (H. Fiedler, 1〇c. cit, Dijon, p. 798). Another example was purchased from Abitec's Capmul MCM C8. 2) C6 to Cu fatty acid mono- and diglycerides Mixtures of these include both symmetrical mono- and diglycerol vinegar (ie, β-monoglycerol g and φ α, α1_diglyceride), as well as asymmetric mono- and diglycerides (ie, alpha-monoglycerol) Esters and α,β-diglycerides) and acetylated derivatives thereof, which also include homoglycerides (wherein the fatty acid component is mainly composed of one The fatty acid composition) further comprises a mixed glyceride (ie, wherein the fatty acid component is composed of a plurality of fatty acids) and all derivatives thereof with lactic acid or citric acid. The fatty acid component may include a chain length of, for example, <:8 to <:: 1(s) both saturated and unsaturated fatty acids. Particularly suitable are, for example, the trade name of Imwitor 8742 or Imwitor 928, for example, from sol mixed octanoic acid and citric acid. Diglyceride. For example,

Imwito, 742 contains at least 45% monoglyceride and exhibits the following additional table data: free glycerol up to 2%, acid number up to 2, saponification value 250 to 280, iodine value up to 1, water up to 2 〇 / 〇 (H · Fiedler, 1〇c· cit., Vol. 1, p. 798). Other suitable mixtures include the octanoic acid/capric acid mono/diglyceride present in glycerol, for example, under the trade name Capmul8MCM, for example, from Abitec. Capmul MCM exhibits the following additional characterization data: acid value up to 2·5 'α-mono (in oleate form) minimum, free glycerol up to 113088.doc -13- 200800195 2·5%, iodine value up to 1, chain length Distribution ·············································· /〇, Humidity (measured by Karl Fisher) 〇·5% (manufacturer information). Suitable examples of mono-/di-glycerols further derived from lactic acid or citric acid are commercially available from sasol under the tradename Imwit(R) 375, 377 or 380. Further, the fatty acid component may include both saturated and unsaturated fatty acids having a chain length (e.g., W 6 to C 8). Suitable φ examples are Tegin® 〇 (oleic acid glycerin) which exhibits the following additional characterization data: Monoglyceride content 55 to 65%, maximum peroxide value 10, water maximum 1%, acid value 2, moth 70 to 76, yield value 15 8 to 175, free glycerin up to 2% (Manufacturer Information 3) '一^ C 6 - C 1 8 · fatty acid glycerol, which includes symmetrical (ie, α,α1-diglyceride) and asymmetric diglyceride (ie, α,β-diglycerol) And its acetylated derivatives. It also includes both homoglycerides (wherein the fatty acid component consists essentially of one fatty acid) φ and mixed glycerides (i.e., wherein the fatty acid component is composed of a plurality of fatty acids) and all of its acetylated derivatives. The fatty acid component may include both saturated and unsaturated fatty acids having a chain length of (6 to Cu (for example, (6 to C! 6, for example, (8 to c1G, for example, cs). Diglyceride, which can be, for example, under the trade name Sunfat® GDC-S from, for example, Taiyo Kagaku Co., Ltd. Sunfat® GDC-S has an acid number of about 3, about 28.8% diglyceride and about &9 single vinegar content. 4) Intermediate fatty acid triglyceride 1113088.doc -14- 200800195 These include saturated fatty acid triglycerides having 6 to 12 (for example 8 to 10) carbon atoms. Fatty acid triglycerides are known by the trade names Acomed®, Myritol8, Captex8,

Neobee® Μ 5 F, MiglyoP 810, Miglyol® 812 'Miglyol® 818, Mazol®, Sefsol® 860, Sefsol® 870 are available, Miglyol 8812 is the best. Miglyol 8812 is a refined coconut oil comprising octane oxime-癸S夂 diglycerol _ and a molecular weight of about 520 Daltons. Fatty acid composition = C6 up to about 3%, 〇8 about 50 to 65%, C! 〇 about 30 to 4 5 % 'C〗 2 up to 5%; acid value about 〇 · 1; saponification value about 33 0 to 345; The maximum iodine value is 1. New §17〇1<|)812 is available from (:〇11(16& Neobee® Μ 5 F-based refined octanoic acid-triglyceride available from coconut oil, with the highest acid value 〇·2 Saponification value is about 335 to 36 〇, angstrom value is maximum 0.5, water content is 〇·ι5%, d.20 0.930 to 〇.96 〇, HD20 1.448 to 1.451 (manufacturer information). Neobe, M 5 F is available from Stepan Another example is Miglyol 829 which additionally contains an ester formed with succinic acid. 5) Mono-C16-C18-fatty acid glycerides These are obtained by esterifying glycerol with vegetable oil followed by molecular steaming crane. The monoglyceride of the composition of the invention includes both symmetric monoglycerides (i.e., β-monoglycerides) and asymmetric monoglycerides (cardia monoglycerides), which also include homoglycerides (wherein the fatty acid component is mainly composed of a fatty acid) The composition and the mixed glyceride (that is, wherein the fatty acid component is composed of a plurality of fatty acids). The fatty acid component may include both a saturated and an unsaturated fatty acid having a bond length (for example, to ^1. Doc -15· 200800195 Examples include Eastman's GMOrphic, Da Nisco Ingredients Rylo MG20 hot distilling glycerin, or Henkel's Monomuls 90-018. For example, GM Orphic®-80 (monoolein) exhibits the following additional characterization data: a minimum of 94% monoglyceride, C18 :1 content minimum 75%, peroxide value maximum 2.5, Cis:2+C18:3 maximum 15%, C16:0+C18:0+C20:0 maximum 1〇〇/0, water up to 2%, maximum acid value 3, iodine value 65 to 75, saponification value 155 to 165, free glycerol most φ more than 1%, hydroxyl number 300 to 330 (manufacturer information). 6) mixed mono-, di-, triglyceride The trade name Maisine® is a mixed mono-, di-, and triglyceride from Gattefossd, which is a transesterification product of corn oil and glycerin. These products are mainly composed of linoleic acid and oleic acid mono-, di- and triglycerol. The ester is composed with a small amount of palmitic acid and stearic acid mono-, di- and triglycerides (corn oil itself is composed of about 56% by weight linoleic acid, 3% oleic acid, about 10% palmitic acid and about 3% hard). The composition of the fatty acid component. Physical Φ is: free glycerin up to 10%, monoglyceride about 40%, diglyceride about 40%, triglyceride about i 0% and free The acid content is about i%. Other physical properties are: acid value of 2, 峨85 to 丨〇5, saponification value of 150 to 175, inorganic acid content = 〇. Maisir^i fatty acid content is usually: palmitic acid about 11% , about 2.5% stearic acid, about 29% oleic acid, about 56% linoleic acid and about 1.5% other (H. Fiedler, loc. cit, Vol. 2, p. 958, manufacturer information). The mixed mono-, di-, and triglycerides preferably comprise a mixture of C8sCw or Cu to Cm fatty acid mono-, di-, and triglycerides, especially 113088.doc -16-200800195 and C16 to c18- Fatty acid mono-, di-, and triglycerin I. The fatty acid components of the mixed mono-, di-, and triglycerides may comprise both saturated and unsaturated fatty acid residues. Preferably, however, it consists essentially of unsaturated fatty acid residues, especially cu unsaturated fatty acid residues. Suitably, the mono-, di-, triglyceride comprises at least 60%, preferably at least 75%, more preferably at least 85% by weight of Ci8 unsaturated fatty acids (eg, linoleic acid, linoleic acid) And oleic acid) mono-, di- and tri-glyme oil esters. Suitably the mixed mono-, di-, triglycerides comprise less than 20%, for example about 15% or 10% by weight or less of saturated fatty acids (eg, palmitic acid and stearic acid) mono-, di - and triglycerides. The mixed mono-, di-, and triglycerides are preferably mainly composed of mono- and diglycerides, for example, mono- and diglycerides account for at least 50%, more preferably at least 70% of the total weight of the lipophilic phase or component. . More preferably, the mono- and diglycerol vinegar comprise at least 75% by weight of the lipophilic component, for example about 8% or 85%. Preferably, the monoglyceride comprises from about 25% to about 50% (based on the total weight of the lipophilic component) of the mixed mono-, di-, and triglyceride esters. More preferably, there is about 30. /. Up to about 401⁄4 (eg 35 to 40%) monoglyceride. Preferably, the diglycerol is present in an amount of from about 30% to about 60% by weight based on the total weight of the lipophilic component of the mixed mono-, di-, and triglycerides. More preferably, from about 40% to about 55% (e.g., from 48 to 50%) of the diglyceride is present. The triglyceride preferably comprises at least 5% but less than about 25% (based on the total weight of the lipophilic component) of the mixed mono-, di-, triglyceride. More preferably, from about 7.5% to about 15% (e.g., from about 9 to 12%) of the triglyceride is present. The mixed mono-, di-, and triglyceride esters can be prepared by blending the mono-, di- or tri-glycan 113088.doc -17-200800195 oil ester in a suitable relative proportion. However, it may conveniently be converted from vegetable oils such as almond oil, peanut oil, olive oil, peach oil, palm oil, or preferably corn oil, hollyhed oil or safflower oil, and preferably corn oil, with glycerin. _ chemical product composition. Such transesterification products are generally obtained as described in GB 2 257 359 or WO 94/09211. Preferably, when a soft gelatin capsule is to be prepared, a portion of the glycerin is first removed to obtain a "substantially glycerin-free batch'. The purified transesterified product of corn oil and glycerol provides a particularly suitable combination of mono-, di- and triglycerides, hereinafter referred to as, "purified oil" and according to British Patent Specification No. GB 2,257,359 or International Patent Publication WO Prepared by the procedure described in 94/09211. 7) Acetylated monoglyceride (C18) These include Myvacet 9-45. 8) Propylene glycol mono-fatty acid ester The fatty acid component may include both saturated and unsaturated fatty acids having a chain length of, for example, CS to c12. Particularly suitable are, for example, the trade names φ Sefs〇l8 218, Capryol® 90 or Lauroglycol 8 90 available from, for example, Nikko Chemicals Ltd. or octanoic acid available from Abitec under the trade name GattefossS or Capmul PG-8. And propylene glycol monoester of lauric acid. For example, Lauroglycol 890 exhibits the following additional characterization data: maximum acid number 8, saponification value 200 to 220, maximum magnetic value 5, free propylene glycol content up to 5%, and monoester content at least 90%; Sefsol 8218 exhibits the following additional characterization data: The acid value is a maximum of 5 and the hydroxyl value is 220 to 280 (H. Fiedler, loc. cit, Vol. 2, p. 906, manufacturer information). M3088.doc -18- 200800195 9) Propylene glycol mono- and di-fatty acid esters These include Lauroglycol FCC and Capryol PGMC 〇10) propylene glycol di-ester propylene glycol di-fatty acid esters, such as propylene glycol dicaprylate (which can be trademarked Miglyol® 840 is available from, for example, sasol, H. Fiedler, l〇c. cit., Vol. 2, p. 1008) or from Abitec under the trade name Captex 200.

11) propylamine 3 acetal acid and propylene glycol diacetate 12 12) transesterified ethoxylated vegetable oils which include transesterified ethoxylated vegetable oils, for example, by suitable catalysts In the presence of various natural vegetable oils (eg, corn oil, corn germ oil, castor oil, nuclear oil, almond oil, peanut oil, eucalyptus oil, soybean oil, sunflower oil, safflower oil, and palm oil or mixtures thereof) with an average molecular weight of A polyethylene glycol reaction of 200 to 800 is obtained. Such procedures are described in U.S. Patent No. 3,288,824. Transesterified ethoxylated corn oil is preferred. Transesterified ethoxylated vegetable oils are conventionally available and are commercially available under the tradename Labrafil® (H. Fiedler, loc. cit., Vol. 2, p. 88). Examples are Labrafil® Μ 2125 CS (obtained from corn oil and having an acid number of less than about 2, a saponification value of 155 to 175, an HLB value of 3 to 4, and a enthalpy value of 90 to 110) and Labrafil 8Μ 1944 CS (obtained from nuclear oil and The acid value is about 2, the saponification value is 145 to 175, and the iodine value is 60 to 90). Labrafil® Μ 2130 CS (which is a transesterification product of a C12 to C18 glyceride and polyethylene glycol and having a melting point (mp·) of about 35 to 40 ° C and an acid value of less than 113088.doc 19 200800195 about 2 can also be used. The saponification value is 185 to 200 and the iodine value is less than about 3). The preferred transesterified ethoxylated vegetable oil is Labrafil 8 Μ 2125 CS, which is available, for example, from Gattefoss 6, Saint-Priest Cedex, France. 13) Sorbitol fatty acid esters These esters include, for example, the sorbitan mono-CuSCu-fatty acid ester, or sorbitan tri-fatty acid ester, available under the trade name Span® from, for example, Uniqema. Especially such products (eg _) Span® 20 (sorbitan monolaurate) 4Span® 8〇 (sorbitan monooleate) (Fiedler, loc·cit, Volume 2, Page 1430, Handbook of Pharmaceutical Excipients, loc. cit, p. 473). 14) Esterified compounds of fatty acids and monohydric alcohols These include esterified compounds having a fatty acid having 8 to 20 carbon atoms and a monohydric alcohol having 2 to 3 carbon atoms (for example, isopropyl myristate, palm Isopropyl oleate, ethyl linoleate, ethyl oleate, Beans 酉 乙 曰 ) ) ' 且 且 且 linoleic acid and ethanol Isopropyl acrylate is also preferred. 15) Triacetin or (1,2,3)-triacetin This is obtained by esterifying glycerol with acetic anhydride. Triacetin can be obtained, for example, from Wriacetin® 1580 from Uniqema International, or from EastmanTM Trig, from Eastman, or from Courtaulds Chemicals, Inc. Triacetin exhibits the following additional characterization data: Molecular Weight 21 8.03 , D.2q.3 1,159 to 1.163, nD20 1.43 0 to 1.344, maximum water content 〇·2%, viscosity (25.) 17.4 mPa s, maximum acid value 〇1, saponification value about 766 to 774, triacetin Contents up to 113088.doc -20 - 200800195 97% less (Η·Fiedler, loc·cit, vol. 2, p. 1580; Handbook of Pharmaceutical Excipients, l〇c_cit, page 534, manufacturer information). 16 Ethyltriethyl citrate is obtained by separately esterifying citric acid with ethanol followed by acetonitrile with acetic anhydride. Ethyl triethyl citrate can be, for example, trade name

Citroflex A-2 is available from, for example, Morflex Corporation.

17) 彳 彳 : 酸 : : : : : : : : : : : : : : : : : 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 The fatty acid component may include a chain length of, for example, (saturated and unsaturated fats of from 8 to c18). Particularly suitable is, for example, Plurol from Gattefoss S.

Oleique CC497, which has a saponification value of 133 to 155 and a turbidity value of 196 to 244. Other suitable polyglycerol fatty acid esters include diglycerol monooleate (DGMO) and the well-known and commercially available Hexaglyn-5-O from, for example, Nikko Chemicals Co., Ltd. 19) PEG-fatty alcohol ether This includes Brij 3〇tm polyoxyethyl (4) lauryl ether. 20) Fatty alcohols and fatty acids Fatty acids can be obtained by hydrolyzing various animal and vegetable fats or oils (e.g., olive oil) and then isolating the liquid acids. The fatty acid/alcohol component can include both saturated and mono- or diunsaturated fatty acids/alcohols having a chain length of, for example, C6 to C2G. Particularly suitable are, for example, oleic acid, oleyl alcohol, linoleic acid, citric acid, octanoic acid, caproic acid, tetradecyl alcohol, dodecanol or n-nonanol. Oleohydrin is commercially available under the trade name HD-Eutanol 8V (for example) 113088.doc -21 - 200800195

Henkel KGaA. Oleic alcohol exhibits the following additional characterization data: acid value maximum 11, hydroxyl value about 210, iodine value about 95, saponification value maximum 1, D·20 about 0.849, nD20 1.462, molecular weight 268, viscosity (20°) about 35 mPa s (manufacturer information). Oleic acid exhibits the following additional characterization data: molecular weight 282.47, D.20 0.895, nD20 1.45823, acid number 195 to 202, iodine value 85 to 95, viscosity (25°) 26 mPa s [H· Fiedler, loc·cit·, Volume 2, page 1112, Handbook of Pharmaceutical Excipients, 2nd ed., Wade and Weller, Eds. (1994), American Pharmaceutical Assoc., Washington, USA, and The Pharmaceutical Press, London, England, pp. 325 ]. 21) Tocopherol and its derivatives, such as acetate, including Coviox T-70, Copherol 1250, Copherol F-1300, Covitol 1360 and Covitol 1100 〇22) pharmaceutically acceptable oils or the lipophilic components include For example, a commercially acceptable oil, such as a vegetable oil, preferably containing an unsaturated component. 23) Excipient-based polyols or esters These include C3 to Cy alkylene triols, especially glycerols, ethers or esters. Suitable C3 to Cy alkylene triol ethers or esters include mixed ethers or esters, ie components comprising other ether or ester components, such as c3 to alkylene triols, with other mono-, di- or poly-components The alcohol is converted to a acetonitrile reaction product. Especially suitable for alkyl alcohol ether or ester mixed c3 to c5-alkylene triol / poly-(C: 2 to C4_alkylene) glycol fatty acid ester, especially mixed glycerin / polyethylene Alcohol fatty acid ester or polypropylene glycol fatty acid 113088.doc -22- 200800195 ester. ^ Its suitable alkyl alcohol ethers or esters including by glycerides (such as triglycerin) with ? The product obtained by the transesterification of a diol (e.g., polyethylene glycol and, if appropriate, glycerol) of a Mc2 to c4. Such conversions are usually obtained by alcoholysis of glycerol (eg, triglyceride) in the presence of a diol (eg, ethylene-alcohol and optionally glycerol) (ie, ie, It is achieved by poly(ethylene glycol)/glycerol solution • from #油自意至聚1烧基: transesterification of alcohol/glycerol component). In general, this reaction is achieved by reacting the components (glycerol-, poly-alkylene glycol and optionally glycerol) at a high temperature in an inert atmosphere with continuous stirring. Preferred glyceride fatty acid triglycerides, such as (CiGsC22-fatty acid) triglycerides, including natural and hydrogenated oils, especially vegetable oils. Suitable vegetable oils include, for example, olive oil, almond oil, peanut oil, coconut oil, palm oil, large Soybean oil and wheat germ oil, and specifically, natural or hydrogenated oil containing (C12 to C) fatty acid ester residue. Preferred polyalkylene glycol material is polyethylene glycol, specifically s ' molecular weight A polyethylene glycol of from about 500 to 4,000 (e.g., from about 1,000 to 2,000). Suitable alkylene polyol ethers or esters include C3 to C5-alkyltriol esters (e.g., in variable relative amounts) Mono-, di- and tri-esters, and poly(C2 to C4_stretched) mono- and di-branched, and a small amount of free c3 to C5_-trimethanol and free poly-(C2 to C5) a mixture of -alkylene diols. As described above, the preferred alkylene triol moiety Glycerin, compared to 113088.doc -23· 200800195 The preferred polyalkylene glycol moiety includes, in particular, a molecular weight of from about 5 Å to 4, (10) oxime, and preferably a fatty acid moiety. (9) to 匕^ fatty acid ester Residues, especially saturated c1G to c22-fatty acid ester residues. Particularly suitable for extender-based polyol ethers or esters including natural or hydrogenated vegetable oils with polyethylene glycol and optionally transesterification of glycerol, or Glycerol mono-, di- and tri-CiG to C22_fatty acid esters and polyethylene glycol mono- and di-C1G to Cn-fatty esters (as appropriate, for example with small amounts of free glycerol and free polyethylene glycol) Compositions consisting of or consisting of. Preferred vegetable oils, polyethylene glycol or polyethylene glycol moieties and fatty acid moieties as defined above are as described above. Particularly suitable for use in the present invention are as described above. Polyol ethers or vinegars including those available under the trade name Gelucire® (for example)

GattefossS, specifically, the following products: a) Geiucir, 3 3/01 'the melting point = about 33 to 37 (and the saponification value is about 23 〇 to 255; b) Gelucire® 39/01, melting point = about, Saponification value = Φ about 225 to 245; and c) Gelucire 8 43/01, melting point = about 42 to 46 ° C, saponification value = about 220 to 240. The above products a) to c) all have an acid value of at most 3. The compositions of the present invention may comprise a mixture of such ethers or esters. 0 24) Hydrocarbons These include, for example, squalene available from, for example, Nikko Chemicals Co., Ltd. 25) Ethylene Glycol Ester is specifically included in Monthyle 8 (Glycol 113088.doc -24-200800195 early stearate) available from, for example, Gattefoss0. 26) Isopentyl alcohol fatty acid and the poly(alkylene diol) scales include, for example, pentaerythritol-dioleate, -distearate, and a single month t S text, _ poly Alcohols, and "monostearate, and pentaerythritol fatty acid esters (Fiedler, l.c. Ch, Vol. 2, pp. 1158 to 1160, which is incorporated herein by reference). Some of the sides (e.g., 1 to 3, 5 to 6, 8 to 9, 12 to 13, 19) exhibit surfactant-like properties and may also be referred to as co-surfactants. B. Hydrophilic Nonaqueous Agents These hydrophilic nonaqueous vehicles include, but are not limited to, the following excipients, either alone or in combination: 1) Polyethylene glycol glycerol (^ to C10-fatty acid ester, the fatty acid ester) It may include mono- and/or di- and/or tri-fatty acid esters, which may optionally include a chain length of, for example, (a) to a saturated and unsaturated fatty acid of Cig. There may be, for example, 5 to 10 [CII2-CH^O]monoindoles, for example 7 units. One particularly suitable fatty acid ester is polyethylene glycol (7) glycerol monocoa, which may, for example, be a trademark name

Cetiol HE is available, for example, from Henkel KGaA. Cetiol® HE has a D·(20°) of 1.05' acid value of less than 5, a saponification value of about 95, a base value of about 18 〇 and an angstrom value of less than 5 (Η·Fiedler, l〇c·cit, Volume 1, Page 337) or Lipestrol E-8 10 〇 2) N-Alkylpyrrolidone is especially suitable (for example) under the trade name PharmasolveTM from 113088.doc -25 - 200800195 (for example) International Specialty Products (ISP) (for example) N-mercapto-2-pyrrolidone. N-methylpyrrolidone exhibits the following additional characterization data: molecular weight: 991, D.25: 1 · 〇 27 to 1.028, purity (expressed as % by area measured by gc) (including methyl isomers) At least 99.85% (Η. Fiedler, loc. cit, vol. 2, p. 1004, manufacturer information). 3) Benzyl alcohol _ This is commercially available, for example, from Merck or can be obtained by distillation of benzyl gas with potassium carbonate or sodium carbonate. Benzyl alcohol exhibited the following additional characterization data: molecular weight 108.14, D·1·〇43 to 1.049, nD 1.538 to 1.541. (H. Fiedler, l〇c. Cit, Vol. 1, p. 238; Handbook of Pharmaceutical Excipients, loc. cit, p. 35). 4) Triethyl citrate It is obtained by esterifying citric acid and ethanol. Triethyl citrate can be purchased, for example, from the trade name Citroflex 82 or at the pharmaceutical grade under the trade name TEC-PG/N 10 from, for example, Morflex Corporation. Particularly suitable is triethyl citrate, its molecular weight is 276.3, specific gravity 1.135 to 1.139, refractive index 1.439 to 1.441, viscosity (25 ° C) 35.2 mPa s, analysis (based on anhydrous materials): 99.0 to 100.5%, Water up to 0.25% (H. Fiedler, be. cit, Vol. 1, p. 371; Handbook of Pharmaceutical Excipients, loc. cit, p. 540). Other suitable hydrophilic compounds include ethylene glycol monoethyl ether ((: 2115-[〇-(CH2)2]2-〇H), polyethylene glycol tetra-perylene methyl ether (also known as tetrahydrofurfuryl alcohol) Glycol ether), 1,2-propanediol, dimethylisosorbide 113088.doc -26- 200800195 (eg Arlasolve from Uniqema), polyethylene glycol (eg 200, 300, 400, _, etc.) , triethylene glycol, ethyl acetate and ethyl acetate lactic acid C. Self-microemulsifying agent The advantages of self-dispersing system can be combined with the advantages of microparticles by using self-microemulsifying medium as a grinding medium instead of simple oil. The "徼 emulsion preconcentrate" used refers to in an aqueous medium such as water (e.g., 1:1 to • I: 300, preferably I: 1 to 1: 70, but especially 1:1 to ι: ι〇) Dilution) or a composition for spontaneously forming a microemulsion in gastric juice after oral administration. In certain embodiments of the compositions of the present invention the self-microemulsifying vehicle comprises one or more of the following lipophilic components and one or more of the following The following surfactants. In other embodiments, the self-microemulsifying vehicle comprises one or more of the following pro-monthly group injuries, one or more The following hydrophilic components and one or more of the following surfactants described below. (I) Surfactants # Surfactants may be complex mixtures containing by-products or unreacted starting products associated with their preparation, for example by polymerization Surfactants prepared by oxyethylation may contain another by-product such as polyethylene glycol. Each surfactant preferably has a hydrophilic lipophilic balance (hlb) value of from 8 to 17, especially from 10 to 17. The HLB value is preferably the average HLB value. Suitable surfactants include: 1) the reaction product of natural or hydrogenated castor oil with ethylene oxide. The natural or hydrogenated castor oil can be oxidized at a molar ratio of from about 1:35 to about 1:60. Ethylene reaction, and optionally polyethylene glycol 113088.doc -27- 200800195 components are removed from the product. A variety of these surfactants are commercially available. Particularly suitable surfactants include those available under the trade name Cremophor®. Polyethylene glycol-deuterated castor oil, Cremophor® RH 40 has a saponification value of about 50 to 60, an acid value of less than about 1, a water content (Fischer) of less than about 2%, η〇6ί) of about 1.453 to 1.457 and HLB is approximately 14 to 16; and Cremophoi* RH 60 has a saponification value of about 40 to 50, an acid value of less than about 1, an iodine value of less than about 1, a water content (Fischer) of about 4.5% to 5.5%, nD6, about 1.453 to 1.457, and an HLB of about 15 to 17. Such products are Cremophor® RH40. Other beneficial products are available under the trade names Nikkol® (eg, Nikkol 8HCO-40 and HCO-60), Mapeg 8 (eg, Mapeg 8 CO-40h),

Incrocas® (for example, Incrocas 8 40), Tagat® (for example, polyoxyethylidene-glycerol-fatty acid esters such as Tagat® RH 40) and Simulsol OL-50 (PEG-40 castor oil, which have a saponification value of about 55 To 65, the acid value is 2, the iodine value is 25 to 35, the water content is at most 8%, and the HLB is about 13, which is commercially available from Seppic. These surfactants are further described in H. Fiedler, loc. cit. Other suitable such surfactants include, for example, polyethylene glycol castor oil available under the trade name Cremophor® EL having a molecular weight (measured by vapor osmometry) of about 1630 and a saponification value of about 65 to 70. The acid number is about 2, the iodine value is about 28 to 32, and the nD25 is about 1.471. 2) Polyoxyethylidene-sorbitan-fatty acid esters These include the conventional type and can be purchased from Uniqema's single- and three-laurels under the trade name Tween® (H. Fiedler, loc. cit, p. 1615).酉,, 113088.doc -28- 200800195 Brown, stearyl S| and oil, which include the following products: Tween® 20 [polyoxyethylene (tetra) sorbitol = monolaurate], • Tween821 [polyoxy-extension ethyl (4) mountain plow ^ rice glycol monolaurate], • Tween 840 [polyoxy-extended ethyl (2 〇) mountain plough, tantosan monopalmitate], • Tween® 60 [polyoxy-extended ethyl (2〇) sorbitol sterol monostearate], • Tween® 65 [polyoxy-extended ethyl (20) sorbose Hit tristearate], • Tween ® 聚 polyoxoethyl (2 〇) sorbitan monooleic acid brewing], • Tween, [polyoxyethylene (5) sorbitol liver monooleic acid brewing], and • Tween® 85 [poly Oxygen extended ethyl (2 〇) sorbitan trioleate]. Such products are Tween820 and Tween880. 3) Polyoxyethylidene esters These include the well-known types and are available under the trade name Myrj8 from Uniq (10) (Η·Fiedler, 1〇c., Vol. 2, p. (10): p.). Stearate. More preferably, such product 852 has a D25 of about 1.1, a melting point of about 4{^44〇c, a hlb of about 16.9, an acid number of about 0 to 1, and a saponification value of about 25 to 35. 4) Polyoxy-extension ethyl-polyoxyl-propyl copolymers and block copolymers or poloxamers These include conventional types and are available under the trade name plur〇ni, & EmkalyX® 113088.doc -29- 200800195 Purchased (H_Fiedler, loc. cit., vol. 2, p. 1203). This product is available from BASF's Pluronic® F68 (poloxamer 18 8) with a melting point of about 52 ° C and a molecular weight of about 6,800 to 8,975. Other preferred such products are available from Uniqema's Synperonic® PE L44 (Polosham 124). 5) Saturated C10 to C22 polyoxyethylene monoesters These include, for example, PEGi C1S-substituted (for example) hydroxy fatty acids having a molecular weight of, for example, 600 to 900, for example, 660 φ Daltons (for example, 12 hydroxystearate) Acid) PEG esters, for example from BASF, Ludwigshafen,

Solutol® HS 15 from Germany. According to the BASF technical leaflet MEF 1 5 1E (1986) comprises about 70% by weight of polyethoxylated 12-hydroxystearate and about 30% by weight of unesterified polyethylene glycol. S〇lut〇l HS 15 has a hydrogenation number of 90 to 110, a saponification value of 53 to 63, a maximum acid number of 1, and a maximum water content of 0.5% by weight. 6) Polyoxyethylidene ether This special test includes polyoxyethylene ethylene glycol of C 1 2 to C 8-8 alcohol, for example

Polyoxyl 2-, 10- or 20-hexadecyl ether or Poly0xyl 23_ lauryl bond, or Polyoxyl 20-oleyl ether, or p〇lyOXyi 2-, 1 oxime, 20- or 100-stearyl ether, It is known in the industry and can be purchased from Uniqema under the trade name Brij®. Such products are, for example, Brij® 35 (Polyoxyl 23 lauryl ether) or Brij 8 98 (p〇ly〇xyl 2 〇 oil based ϋ) (Η·Fiedler, loc. cit, Volume 1 '259 Page; Handbook of Pharmaceutical Excipients, loc·cit, p. 367). Similar suitable products include polyoxyethylene ethyl-polyoxyl-propyl-alkyl ethers, such as polyoxyl I13088.doc -30- 200800195 exoethyl-polyoxyl-propyl-ether of Ci2 to 〇18-alcohol, for example It is known in the art and can be purchased, for example, from the trade name Nikkd PBC834. Polyoxyethylene Ethyl-20-Polyoxypropyl _4_hexadecyl ether of Chemicals Co., Ltd. (F. Fiedler, l〇c. cit, Vol. 2, p. 1239). Polyoxyalkyl fatty acid ethers such as Acconon® E are also suitable. 7) Sodium sulphate and sodium sulphate, and sodium aryl sulfonate These include sodium lauryl sulfate, also known as sodium lauryl sulfate and • can be purchased, for example, from Henkel under the trade name Texapon K12® KGaA. 8) Water-soluble tocopheryl polyethylene glycol succinate (TPGS) These include a polymerization number of about 15 〇 00 or 4 〇〇 (for example) purchased from Eastman

Fine Chemicals Kingsport, TX, USA. 9) Polyglycerol fatty acid esters These include, for example, one from 1 to 2 (e.g., 1) glycerol units. The fatty acid component may include a chain length of, for example, (8: to 18: both saturated and unsaturated fatty acids. Especially suitable for (for example) 癸 Φ Φ oil monolaurate or glycerol mono phthalate It is known in the industry and can be purchased under the trade name Decaglyn® 1-L or Decaglyn® 1_M or Decaglyn 1-0, respectively (for example) by Nikko Chemicals Co., Ltd. (η Fiedler, loc. cit, Vol. 2, No. 1228 Page) 10) Stretching base polyol ethers or esters These include C3 to Cy alkylene triols, especially glycerols, ethers or esters. Suitable C3 to c" alkylene triol ethers or esters including mixing An ether or ester 'is a component comprising other ether or ester components, such as a transesterification reaction of a Cs to a decyl glycol ester with other mono-, di- or polyhydric alcohols. 113088.doc • 31 - 200800195 product. Suitable for alkyl alcohol ether or ester mixed ^ to ^ alkyl alkyl triol / poly-(c: 2 to C4_alkylene) glycol fatty acid ester, especially ... δ glycerol / polyethylene glycol Fatty acid brewed or polypropylene glycol fatty acid ester. Particularly suitable for alkyl alcohol ethers or esters comprising glycerides (eg digan a product obtained by transesterification of an oil ester) with a poly-(C:2 to Cr alkylene) glycol such as polyethylene glycol and optionally glycerol. _ These transesterification products are usually a poly-(C2 to c4-alkylene) diol (for example, polyethylene glycol and optionally glycerol) in the presence of an alcoholysis glyceride (eg, a diglyceride) to obtain (ie, via a poly-alkylene group) The alcoholysis/glycerol solution is effected from the glycerol to the trans-acetalization of the polyalkylene glycol/glycerol component. In general, the plants are obtained by stirring at an elevated temperature in an inert atmosphere under continuous stirring. Indicates the reaction of the component (glyceride, polyalkylene glycol and optionally glycerol) to achieve this reaction. Car glycerin fatty acid triglyceride, such as Ci❹ to fatty acid® diglyceride, including natural and hydrogenated oils (especially vegetable oils). Suitable vegetable oils include, for example, eucalyptus oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and wheat germ oil, and natural or hydrogenated, especially rich in C12 to c18-fatty acid ester residues. The preferred poly(alkylene glycol) material is polyethylene glycol, especially Amounts of from about 500 to 4,000 (e.g., from about L000 to about 2 Torr) of polyethylene glycol. Suitable extended alkyl polyol ethers or esters include C3SC5_alkylene triol esters (e.g., present in variable relative amounts) Mono-, di- and tri-esters, and poly(C:2 to Cr); diol mono- and di-esters, with a small amount of free c3sc5_ 113088.doc -32- 200800195 a mixture of an alcohol and a free poly-(c: 2 to Cyalkyl) diol. As described above, preferably the alkyltriol moiety is glycerol, and preferably the polyalkylene glycol moiety comprises, in particular, a molecular weight of about 500. Polyethylene glycol up to 4,000, and preferred fatty acid moieties are particularly saturated (: 1 () to c22 - fatty acid ester residues.

Particularly suitable for alkyl alcohol ethers or esters including natural or hydrogenated vegetable oils and polyethylene glycols and, as the case may be, the transesterification reaction product of glycerol, or glycerol/from mono- and di-Cio to C22-fatty acids And a composition comprising or consisting of a polyethylene glycol mono- and di-C1G to C22-fatty ester (as appropriate, for example with a small amount of free glycerol and free polyethylene glycol). Preferred vegetable oil, polyethylene glycol or polyethylene glycol moieties and fatty acid moieties associated with the above definitions are as set forth above. 11) Polyethylene glycol glycerin fatty acid ester The fatty acid ester may include mono- and/or di- and/or tri-fatty acid esters.

The fatty acid component may include both saturated and unsaturated fatty acids having a chain length of, for example, C12 to c18. The polyethylene glycols may have, for example, 10 to 40 [CHrCI^O] units, for example 15 or 3 units. Particularly suitable are polyethylene glycol (15) glyceryl monostearate, which is commercially available, for example, under the tradename TGMS®-15 from, for example, Nikk® Chemicals Co., Ltd. Other suitable glycerin fatty acid esters include polyethylene glycol (3〇) glycerol monooleate, which can be purchased, for example, under the trade name hgat®® from, for example, G〇ldschmidt (H. Fiedler l〇c, 2nd) Volumes 15 〇 2 pp. to 1503) 'and under the trade name Tagat 〇 2 (polyethylene glycol glycerol monooleate vinegar and Tagat L (polyethylene glycol (10) glycerol monolauric acid 113088.doc -33 - 200800195 and Tagat L2 (Polyethylene glycol (20) glycerol monolaurate) is commercially available, for example, from Goldschmidt (H. Fiedler, loc. Ch, Vol. 2, pp. 1502 to 1503). Ethylene glycol glycerol fatty acid esters are Tagat TO., 12) sterols and their derivatives. These include cholesterol and its derivatives, especially phytosterols, for example, containing sitosterol, rapeseed alcohol or soybean alcohol and its oxidation. Ethylene adducts • (eg, soy sterols) and derivatives thereof (eg, polyethylene glycol sterols such as polyethylene glycol phytosterols or polyethylene glycol soy sterols). There may be, for example, 1 to 4 units of [CH2_CH2_〇], such as 25 or 30 units. It is commercially available, for example, under the trade name Nikkol BPS^O from, for example, polyethylene glycol (3〇) phytosterol of Nikk〇 Chemicals Co., Ltd. Other suitable persons can be purchased, for example, under the trade name Generol® 122 e 25 From, for example, polyethylene glycol (25) soy sterol (H. Fiedler, l〇c. cit, vol.: vol., p. 680). 13) Transesterification, polyoxyethylated octane Acidic glycerides These include those available under the trade name Labras® 1®, for example. Labrasol® has the highest acid value! The saponification value is 9 〇 to 11 〇, and the iodine value is the largest 1 (H·Fiedler, loc. cit, Vol. 2, p. 88). 14) Sugar fatty acid esters These include (: 12 to <: 18-fatty acids, such as sucrose monolaurate, for example, available from, for example, Mitsubishi-Kasei Foods, Tokyo, japaniRy〇t. L-1695® I13088.doc -34 - 200800195 15) PEG sterol ethers These include, for example, 5 to 35 [CH2-CH2-0] units (eg 20 to 30 units), For example, it can be purchased from, for example, Amerchol

Solulan® C24 〇 16) Sodium dioctyl sulfosuccinate This is available under the trade name Aerosol OT® (for example) from American

Cyanamid Corporation (Η·Fiedler, l〇c. cit, Vol. 1, p. 118 10)' or a-[2-ethylhexyl]••j-white acid salt (H. Fiedler, loc. cit, p. Volume 1, page 487). 17) Phospholipids These include, inter alia, lecithin (H. Fiedler, loc. cit, Vol. 2, p. 910 pp. 1184). Suitable lecithins include, in particular, soy egg dish 113088.doc -35- 200800195 Examples of hydrophilic components of the invention include, but are not limited to: 1) polyethylene glycol glycerol C6 to c10 fatty acid esters And / or di- and / or tri-fatty acid esters. It may optionally include both chain saturated and unsaturated fatty acids having a chain length of, for example, 8 to C1 G. The polyethylene glycols may have, for example, 5 to CH^O units, for example, 7 units. Suitable fatty acid esters are polyethylene glycol (7) glycerol monocoa, which may, for example, be trade name

Cetiol® HE is available, for example, from Henkel KGaA. Cetiol8 HE has a D. (20.) of 1·〇5, an acid value of less than 5, a saponification value of about 95, a hydroxyl value of about 18 及, and an iodine value of less than 5 (Η·Fiedler, 1〇c·ch, Volume 1, 337 pages). Or the Lipestrol E-810. 2) N-alkyl. Bilo bites are especially suitable, for example, from Pharmas〇lveTM, available from, for example, International Specialty Products (ISP), for example, N-methyl-2-pyrrolidone. N-methylpyrrolidone exhibits the following additional characterization data: molecular weight: 99.1, D.25: 1·〇27 to 1.028, purity (expressed as % by area measured by GC) (including methyl isomers): At least 99.85% (Η·Fiedler, loc·cit, vol. 2, p. 1004, manufacturer information). 3) Benzyl alcohol This is commercially available, for example, from Meixk or can be obtained by distilling benzyl chloride with potassium carbonate or sodium carbonate ^ ^ ^ ν Γ . Benzyl alcohol exhibits the following additional characterization data. · Molecules · 108.14 ' D. · 1·〇43 to 1.049, nD: 1.538 to 1.541 (Η· Fiedler, loc·ch, vol. vol., p. 238, Pharmacy Excipient hand 113088.doc -36- 200800195, loc. cit, page 35). 4) Triethyl citrate

It is obtained by esterifying citric acid and ethanol. Triethyl citrate can be purchased, for example, under the trade name Citroflex® 2 or at the pharmaceutical grade under the trade name TEc_pG/N from, for example, Morflex. Particularly suitable is as follows: citric acid diethyl@@'s molecular weight is 276.3, specific gravity is 1.135 to 1.139, refractive index is 1.439 to 1.441, viscosity (25. 〇 is 35.2 mPa s, analysis (based on anhydrous materials): 9 9 · 0 to 10 0 · 5 %, water up to 2 · 2 5 % (Fiedler, loc· Cit, Volume I, page 371; Handbook of Pharmaceutical Excipients, loc·cit, page 540) Other suitable hydrophilic The compound includes ethylene glycol monoethyl ether (CH2) 2] 2-〇H), polyethylene glycol tetrahydrofurfuryl methyl ether (also known as tetra-sterol polyglycol ether), 1,2-propanediol , Diterpene isosorbide (for example, Arlasolve from Uniqema), polyethylene glycol (for example, 200, 300, 400, 600, etc.), triethylene glycol, ethyl acetate, and ethyl lactate. An example of a self-microemulsifying medium includes hydrogenated poiyoxy1 castor oil, corn oil, mono-, di-, triglyceride, propylene glycol 1, 2 and ethanol. Examples of the self-microemulsifying medium include hydrogenated ρ〇1 castor oil, corn oil, mono-, di-, triglycerin® and propanol 1,2. Another example of a self-microemulsifying vehicle includes hydrogenated polyoxylt sesame oil, corn oil, mono-, di- and tri-glycerol vinegar, polyethylene glycol 400, and ethanol. Another example of a self-microemulsifying vehicle includes nitriding P〇ly〇Xyl sesame oil, corn oil, mono-, di- and triglycerides, and polyethylene glycol 400. 113088.doc -37- 200800195 Another example of a self-microemulsifying vehicle includes vitamin E TPGS, dimercaptoisosorbide, triethyl citrate, and ethanol. Another example of a self-microemulsifying vehicle includes vitamin E TpGs, dimethyl isosorbide, and triethyl citrate. Another example of a self-microemulsifying vehicle includes hydrogenated polyoxyl castor oil, Cs/ClG. monoterpene diglyceride, triethyl citrate, and ethanol. Still another example of the self-microemulsifying medium includes hydrogenated p〇ly〇xyl castor oil, C8/C1 (r mono-/diglyceride, and triethyl citrate. Another example of the self-U emulsification medium includes hydrogenated p〇ly〇 Xy castor oil, linoleyl polyethylene glycol -6 glyceride, propylene glycol and ethanol. Another example of self-emulsified emulsification medium includes hydrogenated p〇ly〇xyl castor oil, linoleyl PEG _ 6 Glycerin and propylene glycol IV. Sedimentation inhibitor The microparticle composition of the present invention may further comprise a sedimentation inhibitor which significantly increases the viscosity. Examples of the sedimentation inhibitor are oil gel formers including, but not limited to, precipitated or colloidal Cerium dioxide (for example, Aerosii 2® or 300®), bentonite, zinc/aluminum stearate and certain copolymers, such as ethylene/propylene/styrene copolymer, butene/ethylene/styrene copolymer (eg, Versagel® MP), hydrogenated styrene/isoprene copolymer, and hydrogenated stupid ethylene/butadiene copolymer. Another example of a settling inhibitor is a wax and a solid excipient, such as a surfactant, Lipophilic or hydrophilic excipients, such as high molecular weight (2, 〇〇〇, Polyethylene glycol or alkylene polyol ether or ester of 4,000, ...) (eg Gelucire 44/14) 〇113088.doc -38- 200800195 The sedimentation inhibitor may be added during or after the grinding procedure. Pharmaceutical Compositions and Methods of Treatment The pharmaceutical compositions of the present invention comprising the particulate compositions of the present invention can be administered in the form of an oral suspension in a multi-dose or single-dose container or in a hard or soft gelatin capsule. It can be adsorbed onto a carrier and pressed into a hard ingot. Examples of suitable carriers are precipitated and colloidal cerium oxide (for example, derived from

Hubei*'s Zeopharm 808, 6008 or 5170® from Degussa

Aerosil 20 (^ or 300®, Aer〇perl 3〇〇®), and a sugar sphere or a derivative ball (for example, Celpher from Asahi_Kasei, or from

Syntapharm's Cellets®). Certain embodiments of the pharmaceutical compositions of the present invention include additives such as antioxidants, antibacterial agents, enzyme inhibitors, elixirs, preservatives, humectants, sweeteners, and other ingredients, as described, for example, in H. Fiedler, 1 〇c. d of them. Preferred antioxidants include palmitic acid ascorbic vinegar, butyl benzophenone (BHA), butyl hydroxytoluene (BHT), and heart tocopherol. Preferred stabilizers include organic acids such as the selected acid, tartaric acid, ascorbic acid and scaly acid. Malay The dosage of the active agent in the compositions of the present invention is the same or at most half the dosage used in the conventional compositions containing the active agent. The compositions of the present invention have an active agent concentration of about. From milligrams to about 4 mg/day, preferably from about 1 mg to about 20 dg/day, for example, the active agent preferably exhibits good activity from about 0.1 mg to about 5 mg/day. The active agent is used to treat a proliferative disease or is associated with sustained angiogenesis or the usual dosage system of the disease caused by it 1 to 10 mg/day.

Proliferative diseases are primarily caused by oncological diseases (or cancer) (and/or any metastasis). The composition of the present invention is especially suitable for treating the following tumors: breast cancer, lung cancer, intestinal cancer (including esophageal cancer, gastric cancer, small intestine cancer, colorectal cancer and colorectal cancer), glioma, sarcoma (for example, involving bone, cartilage, soft tissue) , muscle, blood and lymphatic vessels), ovarian cancer, myeloma, cervical cancer, endometrial cancer, head and neck cancer, mesothelioma, kidney cancer, urethral, bladder and urethra cancer, Prostate cancer, skin cancer and melanoma. In particular, the compositions of the invention are particularly useful for the treatment of: (I) breast tumors, lung tumors (eg, non-small cell and small cell lung cancer), lunate tumors (eg, colorectal tumors), or genitourinary tumors (eg, prostate tumors) ). (II) Proliferative diseases that are difficult to treat with other chemotherapeutic agents, or (11) tumors that are difficult to treat with other chemotherapeutic agents due to multiple drug resistance. In a broader sense of the present invention, proliferative diseases may be further hyperproliferative Sexual diseases such as leukemia, lymphoma and multiple myeloma. The X 4 additive or ingredient may comprise from about 0.05 to 5% by weight based on the total weight of the composition. The antioxidant, antibacterial, enzyme inhibitor, stabilizer or preservative typically comprises up to about G() u 2% by weight based on the total weight of the composition. Sweeteners or humectants typically comprise up to about 05% by weight of the total weight of the composition. The particulate composition of the present invention may be subjected to a specific embodiment of the present invention by a grinding technique including, but not limited to, wet milling (including! ball milling), high pressure homogenization, microfluidization, or sinking. 113088.doc 200800195 An example of an example. The examples are given for illustrative purposes only and are not intended to limit the scope of the invention in any way. While trying to ensure that the variables used (eg, quantity, temperature, etc.) are accurate, certain experimental errors and deviations should be considered (of course). Example 1 Particulate Composition Wet co-milling was carried out in a ball mill using glass beads (0 is 3 mm). A 7 hour milling time was used at 3,200 rpm. Alternatively, the microsuspensions can be prepared using other mills and/or milling conditions (rotational speed, ingredient concentration, time, bead material, and size). Table 1: Description of the microparticle compositions of the invention Test drug content vehicle, % surface stabilizer, % 1 2% corn oil, 98% 2 2% corn oil, 92% HPMC 3 cps, 6% 3 2% corn oil, 96% colloidal cerium oxide, 2% 4 2% corn oil, 90% HPMC 3 cps, 6% Pluronic F68®, 2% 5 2% corn oil, 94% colloidal cerium oxide, 2% Pluronic F68® 5 2% 6 2% corn oil, 92% Povidone K30, 6% 7 2% corn oil, 90°/〇 Povidone K30, 6% SDS, 2% 8 2% Self-microemulsifying system 1*, 98% 9 2% Microemulsification system 1*, 92% HPMC 3 cps, 6% 10 2% corn oil, 87% + 3% Aerosil 200 (thickener) HPMC 3 cps, 6% Pluronic F68®, 2% 11 4% Self-microemulsifying System 1*, 93% + 3% Aerosil 200 (thickener) 12 4% corn oil, 88% HPMC 3 cps, 6% Pluronic F68® 5 2% 13 4% Self-microemulsifying system 2*, 96% 14 4 % Self-microemulsifying system 1*, 96%

* Ingredients (w/w,%): 113088.doc -41 - 200800195 Self-microemulsifying system 1 ·· 36% corn oil mono-, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 9% propylene glycol, 10% absolute ethanol. Self-microemulsifying system 2: 40% corn oil mono-, di- and triglycerides, 490 / 聚 polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 10% propylene glycol. The particle size distribution of the ground 7-t-butoxyiminoindenyl camptothecin was measured by laser light scattering or optical microscopy. The results are shown in Table 2.

Table 2: Particle size distribution after grinding Test 1 6 7 xl〇 (micron) 0.5 0.5 0.4 2,4 0.4 4.1 3.7 Χ5〇 (micron) 1.2 1.3 12.2 1.3 13.8 13.5 x90 (micron) 3.0 3.2 2.9 51.5 4.4 25.8

26.6 Very fine particles, <1 to approximately 3 microns Very fine particles, <1 to approximately 3 microns, a few irregular shapes Particles, 0 to 120 microns**

The particle size distribution was determined by optical microscopy. ** It was confirmed that the larger irregular shaped particles were excipient particles, and the smaller particles were drug substance particles. Example 2 Dissolution rate/bioavailability: From the results of these technical tests and from in vivo canine studies, it can be clearly seen that the powder of the form U and the crystalline 7-t-butoxyiminomethylcamptothecin is mixed 113088. .doc •42, 200800195 Improve bioavailability compared to substances. 2) The same bioavailability can be obtained with a smaller dose of 7 v tert-butoxyiminomethylcamptothecin compared to the conventional form of the second butoxyimido-indenyl camptothecin. 3) The redispersibility of the 7-t-butoxyiminofluorenyl-containing crystals contained in the composition after oral administration is preferred. 4) The dissolution rate is increased as compared with the conventional crystalline form of 7_2,2-butoxyiminomethyl xylin. 5) Improved oral performance characteristics, such as higher dosage levels and therefore smaller formulation volumes, i.e., smaller capsules. Figure 1 of the present invention illustrates the in vitro dissolution rate curve (usp2, ι, 〇〇〇 milliliter, 0.3% SDS, 50 rpm, 37 °C). It can be seen that all of the microparticle formulations exhibit improved dissolution and resuspension properties compared to crystalline drug materials. For tests 4 and 5 containing corn oil and PlUronic %8 as surface stabilizers, and tests 8, 9, 11 and 13 using self-microemulsifying media as grinding media, the dissolution rate was observed to be extremely significant. Extracting the unground drug substance stored in a dry powder formulation (hard capsule) and administering the composition of the present invention by measuring the bioavailability of 7-t-butoxyimimylmethylcamptothecin Degrees are compared. Form of administration: 5 mg of 7-butoxymimeimine thioglycine in each capsule and each dog. The compositions of the invention correspond to Runs 4 and 8 of Example 1. The study was completed with six (6) dogs. Every dog accepts all three tones 113088.doc -43- 200800195

Third butoxyiminomethylcamptothecin.

The quantitation limit is 0.1 Ng/ml. ί Take blood samples for determination in plasma. The liquid-liquid extraction and the supernatant were used for each of the test-butoxyimidomethyl-methods by positive electrospray ionization (positive ESI-LC/MS-MS). Heparinized plasma samples were analyzed. Figures 2 and 3 of the present invention show the bioavailability in live dogs (〇 5 mg 7_ second butoxyimidate methyl camptothecin / dog, beagle, 6 dogs). The bioavailability observed in the two microparticle formulations (Fig. 2) was significantly improved compared to that observed for the dry mixture containing the crystalline compound quinone (Fig. 3). The particle suspension compositions tested correspond to Runs 4 and 8 in Table 1. Example 3 Amplification Test Φ To confirm the amplification test capability of the wet co-grinding method, a 2 liter batch was treated in a ball mill using glass beads (0 is 1 mm). The treatment time was 72 hours/batch in continuous mode and the suspension was maintained in the grinding chamber at 3,200 rpm for 7 hours. Alternatively, the microparticle formulation can be prepared using other mills and/or milling conditions (rotation speed, ingredient concentration, time, bead material, and size). Table 3: Description of the microparticle composition during the amplification test. Drug content vehicle, % corresponding small scale test 15 4% Self-microemulsifying system 1*, 96% 14 — 16 2% Self-microemulsifying system 1*, 98% 8 — 17 2% Self-microemulsifying system 2*, 98% 13 (4% drug content) 113088.doc -44- 200800195 * Ingredients (w/w, %) ·· Self-microemulsifying system 1 ·· 36% corn oil list -, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 9% propylene glycol, 10% absolute ethanol. Self-microemulsifying system 2: 40% jade oil-free early-, di- and triglycerin g, 49% polyethylene glycol 40 hydrogenated castor oil (Cpmophor RH40), 10% propylene glycol. The particle size distribution of the polished compound was measured using laser scattering. The results are shown in Table 4. The particle size of the small scale test and the 2 liter scale test batch are within the same range. Table 4: Particle size distribution test after grinding x10 (microns) Χ 50 (micrometers) Χ 90 (micrometers) ~ 15 0.8 L9 4.3 ~ 16 0.7 1.9 4.6 17 0.6 2.3 3.5 Figure 4 of the present invention illustrates the in vivo amplification test batch 15 and small The dissolution rate curve of the scale test batch 14 (USP2, ι, 〇〇〇 ml, 〇SDS' 5 rpm, 37. 〇. The dissolution rate curve is equivalent. Example 4 The final dosage form can also be used to prepare the ground. The self-microemulsifying system of the product, the diluted microparticles 16 and 17. In some cases, Aer〇sU 2〇〇 is added. The diluted microparticle formulation is filled in a soft gelatin capsule. 8, (9) or The composition of these dosage forms is summarized in Table 1. 113088.doc -45- 200800195 Table 5: Examples of Example Final Formulations Example 18 19 20 21 Microsuspension 1% Example 16 1 %Example 16 1 % Example 17 1% Example 17 Self-microemulsifying system 1* 9% 3% self-microemulsifying system containing Aerosil 200 1* 9% Self-microemulsifying system 2* 9% Containing 3% self-microemulsifying of Aerosil 200 System 2* 9% Total Filled Suspension 250 mg 250 mg 250 mg 250 mg Gelatin capsules (size 1) 250 mg of the diluted microparticle formulation / hard gelatin capsules 250 mg soft gelatin capsule formulation was diluted microparticle / soft gelatin capsule composition (w / w,%):

Self-microemulsifying system 1: 36% corn oil mono-, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated onion oil (Cremophor RH40), 9% propylene glycol, 10% absolute ethanol. Self-microemulsifying system 2 ·· 40% corn oil mono-, di- and triglycerin cool, 49% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 10% propylene glycol. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the in vitro dissolution rate curve. Figure 2 illustrates the bioavailability in living dogs. Figure 3 illustrates the bioavailability in living dogs. Figure 4 illustrates the in vitro dissolution rate curve. 113088.doc -46-

Claims (1)

200800195 X. Scope of application for patents··---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- The pharmaceutical composition of 1, wherein the vehicle is selected from the group consisting of an oily vehicle back, a hydrophilic nonaqueous vehicle or a self-microemulsifiable vehicle. 3. As requested! The pharmaceutical composition, wherein the microparticles are at most about _m0. 4. The pharmaceutical composition of claim 3, wherein the microparticles are from about 5 microns to about 5 microns. 5. The pharmaceutical composition according to claim 2, wherein the at least one surface stabilizer is i«•self-light propyl propyl hydride, polyethylene „ππ ketamine' F68, eleven alkyl sulphate Or a colloidal oxidative granule. 6. The pharmaceutical composition according to claim 2, wherein the oily vehicle is selected from the group consisting of corn oil, sesame oil, olive oil, stone butterfly oil, soybean oil, cottonseed oil, and long a chain, medium and short chain mono-, di-, triglyceride and other suitable lipophilic components. 7. The pharmaceutical composition of claim 2, wherein the hydrophilic non-aqueous vehicle comprises one or more of the following excipients. · Polyethylene glycol glycerol C6 to C1 〇-fatty acid g, N-alkyl group, butyl alcohol, glycerol or triethyl citrate. 8. The pharmaceutical composition of claim 2, wherein the self-microemulsifying The vehicle comprises one or more lipophilic components, one or more surfactants, and optionally one or more hydrophilic components. 9. The pharmaceutical composition of claim 8, wherein the self-microemulsifiable vehicle comprises a corn oil sheet -, di- and triglycerides, polyethylene glycol Polyoxyl 40 hydrogenated ramie 113088.doc 200800195 oil, propylene glycol and depending on the situation The pharmaceutical composition of θ length item 1 further comprises a sedimentation inhibitor. 11. The pharmaceutical composition of claim 9, wherein the sedimentation inhibitor is a superior state of the dioxide dioxide. 12· a microparticle of a third butoxyiminomethylcamptothecin. 13. The microparticle of claim 12 having a diameter of up to about 15 micrometers. 14. A microparticle according to claim 5, which is about 丨 micron to Approximately $micron. 15. The particle of claim 12 is prepared by grinding, high pressure homogenization or sinking technique. 16. : Use of the seed of the 7th third butoxyimidomethyl camptothecin It is used for the preparation of a medicament for the treatment of a proliferative disease in a patient having the need for the treatment of the present invention. 17. The use of claim 16, wherein the proliferative disease is breast cancer, lung cancer, intestinal cancer, large intestine And colorectal cancer, glioma, sarcoma, nest cancer, myeloma, cervical cancer, endometrial cancer, head and neck cancer, mesothelioma, kidney cancer, prostate cancer, uterus, pro- urethra cancer , skin cancer and melanoma. Q 113088.doc