TW200529817A

TW200529817A - Stabilized pharmaceutical compositions

Info

Publication number: TW200529817A
Application number: TW093133929A
Authority: TW
Inventors: Mark Robert Mecadon; Qin Ji; Abu T M Serajuddin; Erika Aina Zannou
Original assignee: Novartis Ag
Priority date: 2003-11-06
Filing date: 2004-11-05
Publication date: 2005-09-16
Also published as: PE20050487A1; WO2005044255A1; AR046320A1

Abstract

A composition comprising a dibenzo-oxepine and an acidulant in an amount effective for stabilization.

Description

200529817 九、發明說明：【發明所屬之技術領域】本發明係關於穩定化之醫藥組合物，例如係關於醫藥組合物中之醫藥活性二苯并噁庚的穩定化作用。【先前技術】醫藥組合物應確保在長時期内的高及可再產生之穩定性。例如，顯示醫藥活性（例如抗神經退化活性）之二苯并噁庚在調配於醫藥組合物中時可適用於特定降解類型。吾人現已驚奇地發現組合物中之二苯并噁庚可經穩定化，例如可預防降解。在一態樣中，本發明提供一種組合物（例如醫藥組合物），其包含（例如）作為活性成份之二苯并噁庚及有效穩定化數量（例如，如與不存在酸化劑之組合物相比，有效降低或預防二苯并噁庚之降解程度的數量）之酸化劑。本發明組合物所包含之二苯并噁庚在本文中亦表示為 “（根據）本發明之二苯并噁庚”。本發明之二苯并噁庚包括醫藥活性二苯并噁庚。本發明之醫藥活性二苯并噁庚包括（例如）如GB M79241、GB 1098347、US 3 100207、US 3928383、GB 1449297、US 3641056、GB 1302624、GB 1237386、EP 726265、WO 9745422所述之化合物。例如，如EP 726265或WO 9745422 所述，本發明之二苯并噁庚較佳包括10-胺基脂基-二苯并 (b，f)-噁庚，例如10-胺基-((^4)伸烷基-二苯并（b，f>噁庚。如EP 726265及WO 9745422所述之二苯并噁庚包括下式之 96608.doc -6- 200529817 化合物： alk"200529817 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a stabilized pharmaceutical composition, for example, to the stabilization of a medicinal active dibenzoxanthine in a pharmaceutical composition. [Prior art] The pharmaceutical composition should ensure high and reproducible stability over a long period of time. For example, dibenzoxanthine, which exhibits medicinal activity (such as anti-neurodegenerative activity), may be suitable for a particular type of degradation when formulated in a pharmaceutical composition. We have now surprisingly found that dibenzoxanthine in the composition can be stabilized, for example to prevent degradation. In one aspect, the present invention provides a composition (eg, a pharmaceutical composition) comprising, for example, dibenzoxanthine as an active ingredient and an effectively stabilized amount (eg, a composition with no acidifying agent present) In contrast, acidifiers that effectively reduce or prevent the degree of degradation of dibenzoxanthine. The dibenzoxanthine contained in the composition of the present invention is also referred to herein as "(according to) the dibenzoxanthine of the present invention". The dibenzoxanthine of the present invention includes pharmaceutically active dibenzoxanthine. The pharmaceutically active dibenzoxanthine of the present invention includes, for example, compounds described in GB M79241, GB 1098347, US 3 100207, US 3928383, GB 1449297, US 3641056, GB 1302624, GB 1237386, EP 726265, WO 9745422. For example, as described in EP 726265 or WO 9745422, the dibenzoxanthine of the present invention preferably includes 10-aminolipid-dibenzo (b, f) -oxheptane, such as 10-amino-((^ 4) Alkyl-dibenzo (b, f > oxoheptane. Dibenzooxane as described in EP 726265 and WO 9745422 includes compounds of the formula 96608.doc -6- 200529817: alk "

^4^ 4

Ri R 其中 a· alk為二價脂族基 R為未經取代或經單價脂族基及/或芳脂族基單取代或二取代或經二價脂族基、芳脂族基或雜芳基脂族基二取代之胺基，且Ri R wherein a · alk is a divalent aliphatic group R is unsubstituted or monosubstituted or disubstituted with a monovalent aliphatic group and / or an araliphatic group or with a divalent aliphatic group, an araliphatic group, or a heteroaromatic group An aliphatic di-substituted amino group, and

Ri、R2、R3及r4彼此獨立為氮、低碳數烧基、低碳數烧氧基、鹵素或三氟甲基，例如其中低碳數烷基包括（(^_4) 烷基且低碳數烷氧基包括（Cl-4)烷氧基， b· alk為二價脂族基， R為未經取代或經單價脂族基及/或芳脂族基單取代或二取代或經二價脂族基二取代之胺基，且Ri、r2、1及r4 彼此獨立為氫、低碳數烷基、低碳數烷氧基、鹵素或三氣甲基’例如其中低碳數烷基包括（Ci 4)烷基且低碳數烷氧基包括（Ci-4)烷氧基， c· alk為（Ci_4)伸烧基， R為胺基；該胺基係未經取代或經脂族基（例如（Cw)脂族基或芳脂族基，例如芳基(Ck4)脂族基，例如苯基（Cm) 脂族基）單取代或二取代，且 I、R2、R3及r4彼此獨立為氫、（Ci 4)烷基、（Ci 4)烷氧 96608.doc 200529817 基、鹵素或三氟曱基， d. alk為亞曱基， R係由下列各基組成之群中選出· -胺基；或經烷基 -苯基-(G·4)烧基胺基，其係未經取代 (C〗·4)烷氧基、鹵素或三氟甲基取代； ’其係未經取代二氣甲基取代，基 -N-苯基-(C〗_4)院基-N_(Ci·4)烷基胺基或經（Cw)烷基、（Cl-4)烷氧基、自素1 或 (C2-7)炔基胺基、N-(C2.7)烯 -(C2-7)烯基胺基 -N-(Ci_4)烧基胺基或n_(c2-7)快基且 ι、R2、r3及r4彼此獨立為氫、（Ci 4)烷基、（Cm)烷氧基、鹵素或三氟甲基，且 e· alk為二價脂族基， R為經單價脂族基單取代或二取代之胺基，至少一個單價基團為經取代或未經取代之低碳數炔基，且Ri、R2、 R3及R4彼此獨立為氫、低碳數烷基、低碳數烷氧基、鹵素或二氣甲基，例如其中低碳數烷基包括烷基且低碳數烷氧基包括（C^)烷氧基，例如’下式之化合物N_(二苯并（b，f)噁庚_1〇_基甲基）_Ν· 甲基丙-2·块基胺·· 96608.doc 200529817Ri, R2, R3, and r4 are independently of each other nitrogen, a low carbon number alkyl group, a low carbon number alkyl group, a halogen, or a trifluoromethyl group, for example, where the low carbon number alkyl group includes ((^ _4) alkyl group and low carbon number The number of alkoxy groups includes (Cl-4) alkoxy, b · alk is a divalent aliphatic group, and R is unsubstituted or mono-substituted or di-substituted or substituted with a mono-valent aliphatic group and / or araliphatic group. Valent aliphatic di-substituted amine groups, and Ri, r2, 1 and r4 are independently of each other hydrogen, lower alkyl, lower alkyl alkoxy, halogen or trimethyl, for example lower alkyl Including (Ci 4) alkyl and low carbon number alkoxy includes (Ci-4) alkoxy, c · alk is (Ci_4) elongation group, and R is amine group; the amine group is unsubstituted or aliphatic (Eg, (Cw) aliphatic or araliphatic, such as aryl (Ck4) aliphatic, such as phenyl (Cm) aliphatic) mono- or di-substituted, and I, R2, R3, and r4 Independently of each other, hydrogen, (Ci 4) alkyl, (Ci 4) alkoxy 96608.doc 200529817, halogen or trifluorofluorenyl, d. Alk is fluorenyl, R is selected from the group consisting of the following groups · -Amino group; or via alkyl-phenyl- (G · 4) alkylamino group, It is unsubstituted (C) · 4) alkoxy, halogen, or trifluoromethyl; "It is unsubstituted difluoromethyl, substituted -N-phenyl- (C〗 _4) N_ (Ci · 4) alkylamino or via (Cw) alkyl, (Cl-4) alkoxy, autogen 1 or (C2-7) alkynylamino, N- (C2.7) ene- (C2-7) alkenylamino-N- (Ci_4) alkenylamino or n_ (c2-7) quick group and ι, R2, r3, and r4 are each independently hydrogen, (Ci 4) alkyl, (Cm ) Alkoxy, halogen or trifluoromethyl, and e · alk is a divalent aliphatic group, R is a mono- or di-substituted amine group substituted with a mono-valent aliphatic group, and at least one mono-valent group is substituted or unsubstituted Substituted low-carbon alkynyl, and Ri, R2, R3, and R4 are independently of each other hydrogen, low-carbon alkyl, low-carbon alkoxy, halogen, or dimethyl, for example, where low-carbon alkyl includes alkane And low-carbon alkoxy groups include (C ^) alkoxy groups, for example, a compound of the formula N_ (dibenzo (b, f) oxohept_1-10_ylmethyl) _N · methylpropan-2 · Blockamine · 96608.doc 200529817

【發明内容】本發明之二苯并噁庚包括任何形式之二苯并噁庚，例如呈游離形式、呈鹽形式、呈溶劑合物形式及呈鹽與溶劑合物形式之二苯并噁庚。鹽包括金屬鹽或酸加成鹽，較佳為酸加成鹽。酸加成鹽包括二苯并噁庚與無機或有機酸形成之鹽。式I化合物之鹽為（例如）其與諸如氫鹵酸、硫酸或嶙酸之適當無機酸所形成的醫藥學上可接受之酸加成鹽（例如氫氯酸鹽、氫溴酸鹽、硫酸鹽、硫酸氫鹽或磷酸鹽），或為與醫藥學上可接受之有機酸形成的鹽，例如與下列有機酸所形成的鹽： -視情況羥基化之（C!·7)鏈烷酸，例如包括乙酸、丙酸、特戊酸、乙醇酸、焦乙酸（pyroacernic acid)、乳酸、葡萄糖酸， -視情況羥基化、胺化及/或氧取代之（C2.7)烷二竣酸，例如包括草酸、丙二酸、丁二酸、麩胺酸、天冬胺酸、酒石酸、蘋果酸， -視情況羥基化及/或氧取代之（Co7)烷三羧酸，例如包括檸檬酸、烏頭酸， -視情況羥基化及/或氧取代之（Co7)烯二羧酸，例如包括反丁烯二酸、順丁烯二酸、甲叉丁二酸， 96608.doc -9- 200529817 -視情況羥基化及/或氧取代之（C4·7)炔二羧酸，例如包括乙炔二羧酸， -苯甲酸、水楊酸、鄰苯二曱酸、苯乙酸、扁桃酸、肉桂酸、於驗酸， •月曰私或方族％酸或N -取代胺基確酸，例如包括曱續酉曼脂、苯磺酸脂、對曱苯磺酸脂或N-環己基胺磺酸脂（環己胺基續酸S旨）。本發明之二苯并噁庚較佳呈鹽形式，例如包括式Ia化合物之式I化合物呈與順丁烯二酸（順丁烯二酸脂）所形成之鹽形式。游離形式之本發明二笨并噁庚可轉化為相應之鹽形式化合物；且反之亦然。游離形式或鹽形式及溶劑合物形式之本發明二苯并噁庚可轉化為相應之游離形式化合物或非溶合形式之鹽形式化合物；且反之亦然。本發明之二苯并噁庚可以純異構體或其混合物之形式存在例如以光學異構體、非對映異構體、順/反異構體形式存在。本發明之二苯并σ惡庚可（例如）含有不對稱碳原子且 = 此以對映異構體或非對映異構體及其混例疑體）形式存在。 4/月 σ 、適田方式（例如，根據（例如，類似於）如習知 :離異構*合物《獲得純異構 : 包括呈任何異構形式及在任何異構混合物中之：= 庚，例如# w + 本并°惡在另互變異構體’則亦包括互變異構體。 L ’ ，本發明提供本發明組合物，其中該一— 96608.doc 200529817 R2、R3及R4係如上并°惡庚為式1化合物，其中alk、R、Ri、所界定，例如視情況呈鹽(例如郴4夕斗、τ 貝丁知二酸所形成之鹽）形式之式la化合物，例如呈順一物 „ 烯—酸脂形式之式I化合猶uT —本开°惡庚可以適當方式(例如，根據(例如，之方法）而製得。本發明之二苯并喔庚亦可 :(:如m據(例如，類似於)如習知之方法(例如藉由研磨來降低粒子尺寸）製得的微米尺寸化形式存在。在另-態樣中，本發明提供本發明組合物，其中諸如包括式h化合物的式!化合物之二笨并嚼庚係以微形式存在。用於本發明組合物之適當酸化劑包括有機㈣，例如包括諸如以上所揭示者之羧酸，較佳為視情況羥基化、胺化及/或氧取代之（C2·7)烷二羧酸，例如視情況羥基化之（Cw)烷二羧酸，例如包括丁二酸、酒石酸； -視情況羥基化及/或氧取代之（Cq)烷三羧酸，例如羥基化之（C4-7)烷三羧酸，例如包括檸檬酸； -視情況羥基化及/或氧取代之（C4·7)烯二羧酸，例如 (C4·7)晞二魏酸，例如包括順丁浠二酸；例如檸檬酸、順丁浠二酸、酒石酸及丁二酸，較佳為轉檬酸。在另一態樣中，本發明提供本發明組合物，其中該酸化 96608.doc 200529817 劑為諸如檸檬酸之有機羧酸。在另一態樣中，本發明提供本發明組合物，其中該二苯并噁庚為與順丁烯二酸所形成的鹽形式之式la化合物且其中該酸化劑為檸檬酸。在本發明組合物中，本發明二苯并噁庚之數量在醫藥組合物中為適量，例如以該組合物之總重量計佔 -約 0.25% w/w至約 3 0°/。w/w，例如 0.25% w/w至 3 0% w/w， -約 0.75% w/w至約 25°/。w/w，例如 0.75% w/w至 25% w/w， -約 0.75% w/w至約 20% w/w，例如 0.75% w/w至 20% w/w 5 •約 0.75% w/w至約 1 5% w/w，例如 0.75% w/w至 15% w/w 〇在本發明組合物中，酸化劑之數量並不重要，儘管該量至少必須足以穩定地（例如）降低或預防本發明組合物中之二苯并噁庚的降解，且以該組合物之總重量計較佳為至少約 0.5% w/w(例如0.5% w/w)，例如以該組合物之總重量計為 -約 0.5% w/w至約 25% w/w，例如 0.5% w/w至 25% w/w， -約 1 % w/w至約 20% w/w，例如 1 % w/w至 20% w/w， -約 1 % w/w至約 1 5% w/w，例如 1 % w/w至 1 5% w/w， -約 1 % w/w至約 10% w/w，例如 1 % w/w至 1 0% w/w， -約 1 % w/w至約 5% w/w，例如 1 % w/w至 5% w/w。藉由預測試可發現適當之穩定化數量。 96608.doc •12- 200529817 本發明之二苯并噁庚與酸化劑的重量比可如習知方法來加以測定，且包括本發明二苯并噁庚與酸化劑之下列重量比：約 5·5 : 1至約 1 : 7，例如 5.5 : 1至 1 : 7，約2 ·· 1至約1 : 2，例如2 ·· 1至1 : 2。在另一態樣中，本發明提供本發明組合物，其中 -本發明二苯并噁庚之存在量以該組合物之總重量計為約 0.25¾ w/w至約 30% w/w(%);及/或 -该酸化劑之存在量以該組合物之總重量計為約 0.5°/。至約25% ;及/或 •本發明之二苯并噁庚與酸化劑之重量比為約5.5:1 至約1 : 7。 2發明組合物可進一步包含適當賦形劑，例如包括諸如込田載d及/或稀釋劑之醫藥賦形劑，該賦形劑為醫藥學上所接受。該賦形劑必須與所選酸化劑才目容以便不干擾本發明一苯并噁庚之穩定化官能且（例如）包括 /閏滑劑’例如滑石粉及驗土金屬硬脂酸鹽（例如硬脂酸鎂與硬月曰酸詞）及氫化植物油（例如氫化棉子油與氣化蓖麻油）；晶纖維素、交聯聚乙烯吡咯啶酮及海黏口剤，例如聚乙烯吡咯啶酮及明膠；崩解劑，例如微藻酸，填充劑、流量調節劑、濕潤劑及/或乳化劑、水淨化劑緩衝劑、防腐劑、抗氧化劑、著色劑、調味劑（芳香劑） 96608.doc 200529817 糖及甜味劑、增溶劑及/或調節渗透壓之鹽。該賦形劑對關於本發明_ .. 一本开％庚之酸化劑穩定化官能這成的干擾可在預測試中 y 以測疋。大體而言，適當之賊升> 劑包括不含有會嚴重干捧设本發明二苯并噁庚或酸化劑的土團之化合物且視情況包括、匕枯作為穩定化組份之潤滑劑。如，諸如乳糖、蔗糖、甘露嬙路糖知及山梨糖醇之糖完全適合；諸：玉米贏叙及木薯贏粉之澱粉、諸如羧甲基纖維素鈉及 ”何生物之纖維素及其；^生物（例如竣甲基纖維素鈉、乙基纖維素及曱基纖維素）、談1 ^ 黑，下）如磷酸二鈣之磷酸鈣、硫酸鈉及聚乙稀醇亦適合°賦形劑在本發明組合物中之存在量以节[Summary of the Invention] The dibenzoxanthine of the present invention includes any form of dibenzoxanthine, such as dibenzoxanthine in free form, salt form, solvate form, and salt and solvate form. . The salt includes a metal salt or an acid addition salt, and is preferably an acid addition salt. Acid addition salts include salts of dibenzoxanthine with inorganic or organic acids. Salts of compounds of formula I are, for example, pharmaceutically acceptable acid addition salts (e.g., hydrochloride, hydrobromide, sulfuric acid) formed with a suitable inorganic acid such as hydrohalic acid, sulfuric acid, or osmic acid Salt, bisulfate or phosphate), or salts with pharmaceutically acceptable organic acids, such as those formed with the following organic acids:-(C! · 7) alkanoic acid, optionally hydroxylated , Including, for example, acetic acid, propionic acid, pivalic acid, glycolic acid, pyroacernic acid, lactic acid, gluconic acid,-optionally (C2.7) alkanedicarboxylic acid, which is hydroxylated, aminated, and / or oxygen substituted Including, for example, oxalic acid, malonic acid, succinic acid, glutamic acid, aspartic acid, tartaric acid, malic acid,-optionally hydroxylated and / or oxygen-substituted (Co7) alkanetricarboxylic acids, such as citric acid Aconitic acid,-optionally hydroxylated and / or oxygen substituted (Co7) enedicarboxylic acids, such as fumaric acid, maleic acid, mesuccinic acid, 96608.doc -9- 200529817 -Optionally hydroxylated and / or oxygen-substituted (C4 · 7) acetylene dicarboxylic acids, including, for example, acetylene dicarboxylic acid,-benzyl Acids, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, and citric acid, • Private or cubic% acid or N-substituted amino acids, including, for example, tritium , Benzene sulfonate, p-toluene sulfonate or N-cyclohexylamine sulfonate (cyclohexylamino acid). The dibenzoxanthine of the present invention is preferably in the form of a salt. For example, the compound of the formula I including the compound of the formula Ia is in the form of a salt formed with maleic acid (maleic acid ester). The dibenzylloxane of the present invention in free form can be converted into the corresponding salt form compound; and vice versa. The dibenzoxanthine of the invention in free form or salt form and solvate form can be converted into the corresponding free form compound or unsolvated salt form compound; and vice versa. The dibenzoxanthine of the present invention may exist as a pure isomer or a mixture thereof, for example, as an optical isomer, a diastereomer, a cis / trans isomer. The dibenzosigmaoxane of the present invention may, for example, contain asymmetric carbon atoms and = this is present as an enantiomer or a diastereomer and a mixed example thereof. 4 / month σ, Shida method (for example, according to (for example, similar to) as is known: Isomeric * compounds "to obtain pure isomerism: including in any isomeric form and in any isomeric mixture: = Geng, for example, #w + Benzo is also a tautomer. It also includes tautomers. L ', the present invention provides the composition of the present invention, wherein the one-96608.doc 200529817 R2, R3 and R4 As mentioned above, oxegen is a compound of formula 1, wherein alk, R, Ri, are defined, for example, a compound of formula la in the form of a salt (such as a salt formed by 郴 4 郴, τbedine diacid), such as The compound I in the form of a cis-acid ester is synthesized in the form of a compound UT. The present invention can be prepared in an appropriate manner (for example, according to (for example, the method). The dibenzooxazene of the present invention can also be :( : Micron-sized forms exist according to (e.g., similar to) conventional methods (e.g., to reduce particle size by grinding). In another aspect, the invention provides compositions of the invention, such as Compounds of the formula! 2, including compounds of formula h, exist in micro-forms. Suitable acidifying agents in the composition of the present invention include organic hydrazones, including, for example, carboxylic acids such as those disclosed above, preferably (C2 · 7) alkanedicarboxylic acids, optionally hydroxylated, aminated and / or oxygen substituted, For example, optionally hydroxylated (Cw) alkanedicarboxylic acids, including, for example, succinic acid, tartaric acid;-optionally, hydroxylated and / or oxygen substituted (Cq) alkanetricarboxylic acids, such as hydroxylated (C4-7) Alkanetricarboxylic acids, including, for example, citric acid;-optionally hydroxylated and / or oxygen-substituted (C4 · 7) enedicarboxylic acids, such as (C4 · 7) sulfonic acid, including, for example, maleic acid; For example, citric acid, maleic acid, tartaric acid, and succinic acid, preferably transcitric acid. In another aspect, the present invention provides the composition of the present invention, wherein the acidification agent 96608.doc 200529817 is such as citric acid In another aspect, the present invention provides the composition of the present invention, wherein the dibenzoxanthane is a compound of formula la in the form of a salt with maleic acid and wherein the acidifying agent is lemon In the composition of the present invention, the amount of the dibenzoxanthine of the present invention is in the pharmaceutical composition. A suitable amount, for example, from about 0.25% w / w to about 30 ° / .w / w based on the total weight of the composition, such as 0.25% w / w to 30% w / w, -about 0.75% w / w to about 25 ° /. w / w, such as 0.75% w / w to 25% w / w, -about 0.75% w / w to about 20% w / w, such as 0.75% w / w to 20% w / w 5 • about 0.75% w / w to about 15% w / w, such as 0.75% w / w to 15% w / w 〇 In the composition of the present invention, the amount of acidifying agent is not important, although the amount is at least Must be sufficient to stably, for example, reduce or prevent the degradation of dibenzoxanthine in the composition of the invention, and preferably at least about 0.5% w / w (eg, 0.5% w / w) based on the total weight of the composition , For example, based on the total weight of the composition, from about 0.5% w / w to about 25% w / w, such as from 0.5% w / w to 25% w / w, from about 1% w / w to about 20% w / w, such as 1% w / w to 20% w / w, -about 1% w / w to about 15% w / w, such as 1% w / w to 15% w / w, -about 1 % w / w to about 10% w / w, such as 1% w / w to 10% w / w, -about 1% w / w to about 5% w / w, such as 1% w / w to 5% w / w. The appropriate amount of stabilization can be found by pre-testing. 96608.doc • 12- 200529817 The weight ratio of the dibenzoxanthane to the acidifying agent of the present invention can be determined according to a conventional method, and includes the following weight ratio of the dibenzoxanthane to the acidifying agent of the present invention: about 5. · 5: 1 to about 1: 7, such as 5.5: 1 to 1: 7, about 2 ·· 1 to about 1: 2, such as 2 ·· 1 to 1: 2. In another aspect, the present invention provides a composition of the present invention, wherein-the present dibenzoxanthine is present in an amount of about 0.25 ¾ w / w to about 30% w / w (based on the total weight of the composition) %); And / or-the acidulant is present in an amount of about 0.5 ° / based on the total weight of the composition. To about 25%; and / or • the weight ratio of dibenzoxanthine to the acidifying agent of the present invention is about 5.5: 1 to about 1: 7. 2 The composition of the invention may further comprise suitable excipients, including, for example, pharmaceutical excipients such as Putianzai and / or diluents, which excipients are pharmaceutically acceptable. The excipient must be compatible with the chosen acidulant so as not to interfere with the stabilizing functionality of the monobenzoxanthine of the present invention and, for example, include / slip agents such as talc and earth metal stearates (such as Magnesium stearate and hard moon acid words) and hydrogenated vegetable oils (such as hydrogenated cottonseed oil and gasified castor oil); crystalline cellulose, cross-linked polyvinyl pyrrolidone, and sea urn, such as polyvinyl pyrrolidone And gelatin; disintegrating agents, such as microalginic acid, fillers, flow regulators, wetting agents and / or emulsifiers, water purifying agent buffers, preservatives, antioxidants, colorants, flavoring agents (fragrances) 96608. doc 200529817 Sugars and sweeteners, solubilizers and / or salts that regulate osmotic pressure. The interference of this excipient on the stability of the functionalizing agent of the present invention _... Can be measured in a preliminary test. In general, suitable agents include lubricants that do not contain compounds that would seriously dry the soil clumps of the dibenzoxanthine or acidifying agent of the present invention, and optionally, dagger as a stabilizing component. For example, sugars such as lactose, sucrose, mannose, and sorbitol are perfectly suitable; various: corn starch and cassava starch, starches such as sodium carboxymethylcellulose, and cellulose of Hebi and its; ^ Biological (such as sodium methylcellulose, ethylcellulose and fluorenyl cellulose), Tan 1 ^ Black, bottom) such as dicalcium phosphate, calcium phosphate, sodium sulfate and polyvinyl alcohol are also suitable as excipients. The amount present in the composition of the present invention

醫藥組合物之總重量計可為約5% w/w至約9〇% w/w(例如X 5〇/〇 w/w至 90% w/w)、較佳約 1〇% w/w至約 8〇% w/w(例如 10% w/w至 80% w/w) 〇在另一態樣中，本發明提供本發明組合物，其進一步包含至少一種醫藥賦形劑。吾人已驚可地發現使用氫化蓖麻油作為潤滑劑可優化酸化劑之穩定化效果，例如若在本發明組合物中將氫化蓖麻油用作潤滑劑，則可在處理及儲存時降低二苯并噁庚之氧化降解產物的形成。在另一態樣中，本發明提供本發明組合物，其進一步包含諸如氫化蓖麻油之潤滑劑。潤滑劑在本發明組合物中之適當數量可藉由預測試來發現且包括下列數量：以該組合物之總重量計， -約〇_5% w/w至約 10% w/w，例如 0.5% 〜&至 10% w/w， 96608.doc -14- 200529817 -約 1% w/w至約 5% w/w，例如 1% w/w至 5°/。w/w。本發明組合物中之可選賦形劑總量與本發明二苯并噁庚、酸化劑、視情況存在的潤滑劑及視情況存在的醫藥學上可接受之載劑的數量一致，意即總量將與該等組合物之剩餘物相等。在另一態樣中’本發明提供本發明組合物，其中二苯并心庚為與順丁烯一酸形成的鹽形式之式ia化合物，其中酸化劑為檸檬酸，其進一步包含： -諸如氫化蓖麻油之潤滑劑及/或 -黏合劑及/或 -崩解劑；例如進一步包含填充劑、流量調節劑、濕潤劑及/或乳化劑、水淨化劑、緩衝劑、防腐劑、抗氧化劑、著色劑、調味劑（芳香劑）、糖及甜味劑、增溶劑及/或調節滲透壓之鹽。在另一態樣中，本發明提供包含式Ia化合物、檸檬酸、甘露糖醇、微晶纖維素、聚乙烯咄咯啶酮及氫化蓖麻油之組合物。雖然含有本發明組合物（包括醫藥組合物）之二苯并嚼庚可呈任何形式，但其較佳為諸如錠劑、膠囊、小丸或藥囊之固體形式。在另一態樣中，本發明提供呈固體形式（例如呈錠劑、膠囊、小丸或藥囊形式）之本發明組合物（例如醫藥組合物其視情況為經塗覆之錠劑，例如經羥丙基甲基纖維素 (HPMC)塗料塗覆之錠劑。 96608.doc 15 200529817 本發明組合物可以適當方式 1仔’例如由任何處理括 (例如習知方法）製得。处里技術為了達到本發明二苯并σ牵洛心句勻分佈及酸化劑在二苯开噁庚粒子上或在苴中之妁冬 …"二分佈’較佳使用濕式造粒。The total weight of the pharmaceutical composition may be about 5% w / w to about 90% w / w (e.g., X 50 / 〇w / w to 90% w / w), preferably about 10% w / w To about 80% w / w (eg, 10% w / w to 80% w / w). In another aspect, the invention provides a composition of the invention, further comprising at least one pharmaceutical excipient. I have been surprised to find that the use of hydrogenated castor oil as a lubricant can optimize the stabilizing effect of the acidifier. For example, if hydrogenated castor oil is used as a lubricant in the composition of the present invention, dibenzo Formation of oxidative degradation products of oxetine. In another aspect, the invention provides a composition of the invention, further comprising a lubricant such as hydrogenated castor oil. The appropriate amount of lubricant in the composition of the present invention can be found by pre-testing and includes the following amount: -about 0-5% w / w to about 10% w / w, based on the total weight of the composition, for example 0.5% to & to 10% w / w, 96608.doc -14- 200529817-about 1% w / w to about 5% w / w, such as 1% w / w to 5 ° /. w / w. The total amount of optional excipients in the composition of the present invention is consistent with the amount of the dibenzoxanthine, acidifying agent, optionally lubricant, and optionally pharmaceutically acceptable carrier of the present invention, meaning that The total amount will be equal to the remainder of these compositions. In another aspect, the invention provides the composition of the invention, wherein dibenzoxin is a compound of formula ia in the form of a salt with maleic acid, and the acidifying agent is citric acid, which further comprises:-such as Lubricants and / or-binders and / or-disintegrating agents for hydrogenated castor oil; for example, further including fillers, flow regulators, wetting agents and / or emulsifiers, water purifying agents, buffering agents, preservatives, antioxidants , Colorants, flavors (fragrances), sugars and sweeteners, solubilizers and / or salts to adjust osmotic pressure. In another aspect, the present invention provides a composition comprising a compound of Formula Ia, citric acid, mannitol, microcrystalline cellulose, polyvinylpyrrolidone, and hydrogenated castor oil. Although the dibenzochrysene containing the composition of the present invention (including the pharmaceutical composition) may be in any form, it is preferably in a solid form such as a lozenge, capsule, pellet, or sachet. In another aspect, the present invention provides a composition (eg, a pharmaceutical composition) of the present invention in a solid form (eg, in the form of a tablet, capsule, pellet, or sachet) (eg, a coated tablet, such as Hydroxypropyl methylcellulose (HPMC) coating-coated tablets. 96608.doc 15 200529817 The composition of the present invention can be prepared in an appropriate manner, for example, by any processing method (such as a conventional method). To achieve the homogeneous distribution of dibenzo [sigma] and dioxin in the present invention and the winterization of acidifiers on the dibenzocarboxane particles or in the radon ... " The second distribution 'is preferably using wet granulation.

Ik Ρ 例如在鬲矣切造粒製程中將_ / 口表枉干將酸化劑用作造粒液體，二苯并°惡庚粒子處理之水溶液形式。包含本發明二苯并喔庚及酸化劑之所製粒子可進—步由形劑以適當方式進行處理，例如，如習知方法（例如由作匕合、造粒、摻合、塗覆、掣復裏叙或封入膠囊製程）進行虛理以（例如）獲得錠劑、膠囊、小丸或藥囊。· 在另一態樣中，本發明提供·· -:化劑在穩定化諸如醫藥組合物之組合物中的二苯并噁庚上的用途。 --種用於穩定化諸如醫藥組合物之組合物中的二苯并。惡庚之方法’其包含添加有效穩定化數量之酸化劑。本發明組合物可適料（例蝴於治療本發明二苯并喔庚可適於治療的疾病之藥劑，該等疾病包括（例如）已知二苯并噪庚適於治療之疾病。該等疾病包括（例如）神經退化性病症、大腦局部缺血、青光眼、亨廷頓氏病、阿兹海默症、帕金森氏症、减縮性財硬化、乡發性硬化、視網膜退化（例如色素性視網膜炎）' 普通或糖尿病性周邊神經病、雙極症及精神分裂症，較佳為諸如肌萎縮性側索硬化、帕金森氏症及阿m默症之神經退化性疾病。$了醫藥用 96608.doc -16- 200529817 :’存在於本發明組合物中之：苯㈣庚包括—或多種（較佳一種）二苯并噁庚，例如兩種或兩種以上二苯并噁庚之組合0 —在另悲樣中，本發明提供用於製造醫藥品之本發明醫藥組合物’該醫藥品係用於治療神經退化性病症、大腦局部缺血、青光眼、亨廷頓氏病、阿兹海默症、帕金森氏症、肌萎縮性財硬化、乡發性硬化、視賴退化⑽如色素性視網膜炎）、普通或糖尿病性周邊神經病、雙極症及精神分裂症’較㈣m㈣如轉縮性財硬化、帕金森氏症及阿茲海默症之神經退化性疾病。在另先、樣中，本潑 B月提供一種治療神經退化性病症、大腦局部缺企、青光眼、亨廷頓氏疾病、阿兹海默症、帕金森氏症、肌萎縮性財硬化、多發性硬化、視網膜退化（例如色素性視賴炎）m糖尿錢周邊神經病、雙極症精神刀裂症之方法，其較佳係用於治療諸如肌萎縮性側索硬化、帕金森氏症及阿兹海默症之神經退化性疾病，其包含對需要該治療之受檢者施以本發明醫藥組合物，該組合物中存在有效數量之二苯并。惡庚。治療包括治療及預防。，為了該治療’適當劑量當然將視(例如)所用本發明二苯并噁庚之化學性質及筚物裔τ +風·欠丨丨梁物動力學資料、個別宿主、用藥模式及所治療病症之性質及嚴重性而變化1而，為了在大型哺乳動物(例如人類)中得到令人滿意的結果，所干之每曰劑量-般介於(約)0.01 §至(約)l5 g範圍内，例如 96608.doc 200529817 (”勺）〇·〇3 g至（約）〗〇g化合物存在於本發明醫藥組合物現p以（例如）分次給藥直至一天四次來用_。如上所示，Ik PF For example, in the process of cutting and granulating, an acid solution is used as a granulating liquid, and an aqueous solution of dibenzo-heptane particles is used. The granules comprising the dibenzoxaheptan of the present invention and an acidulant can be further processed in a suitable manner by a dosage form, for example, by conventional methods (for example, by daggering, granulating, blending, coating, (Controlling or encapsulation process) to perform hypotheses to obtain, for example, tablets, capsules, pellets or sachets. In another aspect, the present invention provides the use of a chelating agent to stabilize dibenzoxanthine in a composition such as a pharmaceutical composition. A dibenzo used in stabilizing a composition such as a pharmaceutical composition. The method of dioxin 'comprises adding an effective stabilizing amount of an acidifying agent. The composition of the present invention is suitable (for example, a medicament for treating a disease in which the dibenzooxagen of the present invention is suitable for treatment, which includes, for example, a disease in which dibenzonogen is suitable for treatment. Such Diseases include, for example, neurodegenerative disorders, cerebral ischemia, glaucoma, Huntington's disease, Alzheimer's disease, Parkinson's disease, shrinking fiscal sclerosis, rural sclerosis, retinal degeneration (such as pigmented retina Inflammation) 'Ordinary or diabetic peripheral neuropathy, bipolar disorder and schizophrenia, preferably neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease and Ammer disease. $ 96608 for medicine. doc -16- 200529817: 'Phenazepine present in the composition of the present invention includes-or more (preferably one) dibenzoxanthine, for example a combination of two or more dibenzoxanthine 0- In another aspect, the present invention provides a pharmaceutical composition of the present invention for use in the manufacture of a pharmaceutical product. The pharmaceutical product is used to treat a neurodegenerative disorder, cerebral ischemia, glaucoma, Huntington's disease, Alzheimer's disease, Parkinson Disease, amyotrophic sclerosis, sclerosis, visual degeneration (such as pigmented retinitis), common or diabetic peripheral neuropathy, bipolar disorder and schizophrenia, such as atrophic sclerosis, Parkinson Neurodegenerative diseases of Alzheimer's disease and Alzheimer's disease. Among other things, this month provides a treatment for neurodegenerative disorders, local brain deficiency, glaucoma, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic sclerosis, multiple sclerosis Retinal degeneration (such as pigmented optic retinitis) m diuretic peripheral neuropathy, bipolar schizophrenia, which is preferably used for the treatment of such factors as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's A degenerative neurodegenerative disease comprises administering to a subject in need of the treatment a pharmaceutical composition of the present invention in which an effective amount of dibenzo is present. Evil geng. Treatment includes treatment and prevention. For this treatment, the proper dosage will, of course, depend on, for example, the chemical properties of the dibenzoxanthine used in the present invention and the species τ + wind · owed 丨 beam physicokinetic data, individual hosts, medication patterns, and conditions to be treated The nature and severity varies1 and, in order to obtain satisfactory results in large mammals (such as humans), the doses per day-generally between (about) 0.01 § to (about) 15 g For example, 96608.doc 200529817 ("spoon) 0.03 g to (approximately) 0 g of the compound is present in the pharmaceutical composition of the present invention, and is administered in divided doses, for example, up to four times a day. As described above. Show,

本發明二苯并嚼庚及其在治療諸如神經退化性疾病之疾病上的用途已為吾人所知且其用藥模式及適當劑獻中有所記載。 U 本發明醫藥組合物可以任何習知路徑來用藥，例如用藥(例如，包括經鼻、經頰、經直腸、經口用藥)、非妳腸用樂(例如’包括經靜脈内、經肌肉内、經皮局部用藥(例如’包括經表皮、經鼻内、經氣管内用率)：例如，以經塗覆或未經塗覆錠劑、膠囊、小丸或藥囊形式用樂’以可注射溶㈣懸浮液形式（例如以安瓶、小玻璃瓶形式)用藥’以乳膏、凝膠、糊狀物、吸入劑散劑、發泡體、釘、唇棒、滴劑、喷霧形式或以检劑形式（較佳以固體形式）用藥。本發明醫藥組合物可以醫藥學上可接受之鹽（例如酸加成鹽或金屬鹽)形式…游離形式；視情況以溶劑合物形式來用藥。在本發明組合物或醫藥细合物中存在之越形 =的本發明二苯并嗔庚與在本發明組合物或醫藥組合物中存在之游離形式（視情況為溶劑合物形式）的二苯并喔庚展現相同活性等級。 '本發明組合物或醫藥製劑可單獨或與一或多種其它醫藥活性劑組合用於根據本發明之醫藥治療。此組合包括：固定組合’其中兩種或兩種以上醫藥活性劑位於相同調配物中；套組’其中仅於獨立調配物中之兩 96608.doc •18· 200529817 以相同封裝（例如）與共同用竣The dibenzopyrene of the present invention and its use in treating diseases such as neurodegenerative diseases are well known to us and documented in its mode of administration and appropriate dosing. U The pharmaceutical composition of the present invention can be administered by any conventional route, such as medication (e.g., including nasal, buccal, rectal, oral administration), non-enteral entertaining (e.g., 'including intravenous, intramuscular Percutaneous topical application (eg 'including transepidermal, intranasal, intratracheal use): For example, in the form of coated or uncoated tablets, capsules, pellets, or sachets, injectable Dosing in the form of a lysing suspension (for example in the form of ampoules, vials) in the form of creams, gels, pastes, inhalants, foams, nails, lip sticks, drops, sprays or in the form of The drug is used in the form of a test agent (preferably in a solid form). The pharmaceutical composition of the present invention may be in the form of a pharmaceutically acceptable salt (such as an acid addition salt or a metal salt) ... free form; and may be used in the form of a solvate as appropriate. The presence of the cross-cut in the composition or the pharmaceutical composition of the present invention = the dibenzopyrene of the present invention and the two (in the solvate form) of the free form of the present invention or the pharmaceutical composition Benzohexene exhibits the same level of activity. 'The composition or pharmaceutical preparation of the present invention can be used alone or in combination with one or more other pharmaceutically active agents for the medical treatment according to the present invention. This combination includes: a fixed combination' in which two or more pharmaceutically active agents are located in the same formulation Medium; set 'of which only two of the independent formulations 96608.doc • 18 · 200529817 in the same package (for example) and common use

但給出用於同時或相繼用藥於同時或相繼用藥之指令。本發明組合物可具有一些在的潤滑劑，例如氫化蓖添口物可具有一些優於不含酸化劑(及視情況存別，例如氫化蓖麻油）之組合物的優點。諸如式^ 二笨并噁庚實際上主要可避免任何類型之降種或兩種以上醫藥活性劑係指令一起。諸如式la 2之降解。化合物之二|丑此外’本發明組合物 -在正常儲存條件下可具有延長之存放期； •可對濕氣不敏感； -在有效時期内可具有即使有亦極微之變色； _在著色劑存在下使用時，可具有即使有亦極微之不穩定性。在另一態樣中，本發明提供一種使含有經受降解的二苯并噁庚化合物之醫藥組合物穩定的方法，其包含併入其中However, instructions are given for simultaneous or sequential medication. The composition of the present invention may have some existing lubricants, such as hydrogenated castor additives, which may have some advantages over compositions that do not contain an acidulant (and optionally, such as hydrogenated castor oil). Such as the formula ^ dibenzyl and oxegen can actually avoid any type of seeding or two or more pharmaceutically active agents being ordered together. Degradation such as formula la 2. Compound No. 2 | Ugly Also 'The composition of the present invention-may have an extended shelf life under normal storage conditions; • may be insensitive to moisture;-may have a slight discoloration, if any, within the effective period; _ in colorants When used in the presence, it can have very little instability. In another aspect, the present invention provides a method for stabilizing a pharmaceutical composition containing a dibenzoxanthane compound that is subject to degradation, comprising the incorporation therein

在另一態樣中，本發明提供一種使含有經受降解的二苯并°惡庚化合物之醫藥組合物穩定的方法，其包含將有效穩定化數量之酸化劑併入其中，例如，其中該二苯并噁庚化合物具有結構式I，In another aspect, the present invention provides a method for stabilizing a pharmaceutical composition containing a dibenzo ° oxan compound that is subject to degradation, comprising incorporating an effective stabilizing amount of an acidifying agent therein, for example, wherein the two Benzoxanthene compounds have structural formula I,

alk為二價脂族基； 96608.doc 19- 200529817 R為經單價脂族基單取代或二取代之胺基，至少一個該等單價基團為未經取代或經取代之低碳數炔基；且各Ri、R2、R3及R4獨立為氫、低碳數烧基、低碳數烧氧基、鹵基或三氟曱基；或醫藥學上可接受之鹽。【實施方式】下列實例說明本發明。實例1 表1列出呈ί定劑核心形式之根據本發明之組合物的組份。表1 組份數量(mg) 呈順丁烯二酸酯形式之式la化合物，經微米尺寸化 3.55 甘露糖醇Μ 200 90.70 微晶纖維素 19.50 聚乙烯吡咯啶酮Κ-30 2.60 檸檬酸 2.60 *純水 a.n. 聚乙嫦°比洛咬酮XL 5.20 氫化蓖麻油 5.85 總計= 130.00 *用於在濕式造粒製程中分散酸化劑且在流化床乾燥之後移除； a.n.:必要量。如下所述來進行錠劑之製備：alk is a divalent aliphatic group; 96608.doc 19- 200529817 R is an amine group mono- or di-substituted with a monovalent aliphatic group, and at least one of these monovalent groups is an unsubstituted or substituted low-carbon alkynyl group And each of Ri, R2, R3, and R4 is independently hydrogen, a low carbon number alkyl group, a low carbon number alkyl group, a halogen group, or a trifluorofluorenyl group; or a pharmaceutically acceptable salt. [Embodiments] The following examples illustrate the present invention. Example 1 Table 1 lists the components of a composition according to the invention in the form of a core formulation. Table 1 Number of components (mg) Compounds of the formula la in the form of maleic acid esters, micron-sized 3.55 mannitol M 200 90.70 microcrystalline cellulose 19.50 polyvinylpyrrolidone K-30 2.60 citric acid 2.60 * Pure water an Polyacetone ° Bilobitone XL 5.20 Hydrogenated castor oil 5.85 Total = 130.00 * For dispersing the acidulant in the wet granulation process and removing after drying in a fluidized bed; an: necessary amount. The preparation of tablets is performed as follows:

使呈順丁烯二酸酯形式且藉由研磨而微米尺寸化之式I 96608.doc -20- 200529817 化合物與甘露糖醇、微晶纖維素及聚乙烯吡咯啶酮Κ-30在高剪切混合器中預摻合以獲得預摻合物。使檸檬酸溶解於 Η20中且將該溶液添加至高剪切混合器中之預摻合物中。使所得濕式造粒產物在流化床乾燥器中乾燥，經由合適之篩網來篩選所得顆粒且使篩選出的顆粒與聚乙烯吡咯啶酮 XL及氫化蓖麻油摻合。將所得顆粒壓縮成錠劑。在40 °C /75%相對濕度下歷經180天，上述組合物具有 0.56%之總降解。實例2 表2中之下列組合物2 A及2B代表呈錠劑核心形式（=未經薄膜塗覆）之根據本發明之組合物，其係根據如實例1所述之方法製得。表2中之組合物2C係如對於組合物2A及2B所述而製得，但不含本發明之酸化劑。表2 組份數量(mg) 2A 2B 2C 呈順丁烯二酸酯形式之式(la)化合物，經微米尺寸化 3.55 3.55 3.55 甘露糖醇Μ 200 91.35 91.35 106.0 0 微晶纖維素 19.50 19.50 21.00 聚乙稀σ比洛°定酮Κ-30 2.60 2.60 2.80 檸檬酸 2.60 2.60 — *純水 a.n. a.n. a.n. 聚乙稀°比洛°定_XL 5.20 5.20 5.60 硬脂酸鎂 — 0.98 1.05 氫化蓖麻油 5.20 一一總計= 130.0 0 125.7 8 140.0 0 96608.doc -21 - 200529817 *用於在濕式造粒製程中分散酸化劑且在流化床乾燥之後移除。實例3 實例2之錠劑2A、2B及2C為在40°C及75%相對濕度下儲存 3個月之錄:劑核心’在儲存開始時及在三個月之後由Hplc 來測定呈順丁烯二酸酯形式之式la化合物在該等組合物中之含ΐ。计异在疑劑核心中之式I a化合物在3個月以後的檢定°/〇及降解％。結果列於表3中。表3 2Α 2Β 2C *檢定損耗（％) 0.00 0.25 7.44 總降解（％) 0.13 0.60 1.51 *式（la)化合物之順丁稀二酸鹽含量在初始檢料間零姜 3個月以後之間的差異百分比。Compounds of the formula I 96608.doc -20- 200529817 in the form of maleic acid and micronized by milling with mannitol, microcrystalline cellulose and polyvinylpyrrolidone K-30 at high shear Pre-blend in a mixer to obtain a pre-blend. The citric acid was dissolved in Rhenium 20 and the solution was added to a pre-blend in a high shear mixer. The obtained wet granulated product is dried in a fluidized bed dryer, the obtained granules are sieved through a suitable screen and the sieved granules are blended with polyvinylpyrrolidone XL and hydrogenated castor oil. The granules obtained are compressed into lozenges. After 180 days at 40 ° C / 75% relative humidity, the above composition had a total degradation of 0.56%. Example 2 The following compositions 2 A and 2B in Table 2 represent a composition according to the invention in the form of a lozenge core (= without film coating), which was prepared according to the method described in Example 1. Composition 2C in Table 2 was prepared as described for Compositions 2A and 2B, but did not contain the acidulant of the present invention. Table 2 Number of components (mg) 2A 2B 2C Compounds of the formula (la) in the form of maleates, micron-sized 3.55 3.55 3.55 Mannitol M 200 91.35 91.35 106.0 0 Microcrystalline cellulose 19.50 19.50 21.00 Poly Ethylene σ Bilo ° ketone ketone K-30 2.60 2.60 2.80 Citric acid 2.60 2.60 — * Pure water ananan Poly Bile º Bile ° _XL 5.20 5.20 5.60 Magnesium stearate — 0.98 1.05 Hydrogenated castor oil 5.20 One by one total = 130.0 0 125.7 8 140.0 0 96608.doc -21-200529817 * Used to disperse the acidulant in the wet granulation process and remove after drying in a fluidized bed. Example 3 The tablets 2A, 2B, and 2C of Example 2 were recorded at 40 ° C and 75% relative humidity for 3 months: the core of the agent was measured by Hplc at the beginning of storage and after three months. The halide content of the compounds of the formula la in the form of oxalates in these compositions. Examination of the compound of formula Ia in the core of the suspect after 3 months was performed to determine ° / 0 and% degradation. The results are shown in Table 3. Table 3 2A 2B 2C * Testing loss (%) 0.00 0.25 7.44 Total degradation (%) 0.13 0.60 1.51 * The content of maleic acid diacid of the compound of formula (la) is between 3 months after zero ginger in the initial sample room. Percent difference.

根據表3,在40/75狀況下3個月則麦，不含根據本發明戈酸化劑的錠劑核心2C顯然已有約75%之檢定損耗，而實畴According to Table 3, under the condition of 40/75 for 3 months, wheat, and the tablet core 2C without the acidifying agent according to the present invention obviously has about 75% of the verification loss, and the real domain

上錠劑核心2A無降解且鍵劑2B僅少量降解，該等兩種鍵齊 =為根據本發明之錢劑。此外，根據表3,錠劑核心2(：在健存期間的降解為錠劑枋The upper tablet core 2A is not degraded and the bonding agent 2B is degraded only slightly. These two kinds of bonds are equal to each other according to the present invention. In addition, according to Table 3, Lozenge Core 2 (: Degradation to Lozenges During Storage)

的…" 的1〇倍以上且為錠劑核心2E 的兩倍以上。實例4 96608.doc -22- 200529817 表4 組份數量(mg) 呈順丁烯二酸酯形式之式(la)化合物，經微米尺寸化 3.55 甘露糖醇Μ 200 90.70 微晶纖維素 19.50 聚乙烯吡咯啶酮Κ-30 2.60 檸檬酸 2.60 *純水 a.n. 聚乙稀°比洛σ定酮XL 5.20 氫化蓖麻油 5.85 HPMC塗料 6.00 總計= 136.00 *用於在濕式造粒製程中分散酸化劑且在流化床乾燥之後移除。實例5 將實例4之錠劑在如表5所示之各種溫度及各種相對濕度 (RH)下儲存6個月。在儲存開始時及在3個月與6個月之後由 HPLC來測定呈順丁烯二酸酯形式之式la化合物在彼錠劑中的含量，並計算在該錠劑中之式la化合物的降解。結果示於表5中。表5 時期(月） 25°C / 60% RH DP 30°C / 70% RH DP 40°C / 75% RH DP 0 <0.05 <0.05 <0.05 3 <0.05 0.05 0.22 6 <0.05 0.24 0.63 根據表5，呈順丁烯二酸酯形式之式la化合物在6個月之 96608.doc -23- 200529817 後顯然地，且 -在正常環境條件（25°C及60%RH)下實際上不降解 -在30°C及70%RH下僅降解至低於0.3%之小程度， -在40°C及75%RH下仍僅降解至低於0.7%之程度。 96608.doc -24-More than 10 times of "" and more than twice of the 2E of the tablet core. Example 4 96608.doc -22- 200529817 Table 4 Number of components (mg) Compound of formula (la) in the form of maleate, micron-sized 3.55 Mannitol M 200 90.70 Microcrystalline cellulose 19.50 Polyethylene Pyrrolidone K-30 2.60 Citric acid 2.60 * Pure water an polyethylene ° Bilodonone XL 5.20 Hydrogenated castor oil 5.85 HPMC coating 6.00 Total = 136.00 * Used to disperse the acidulant in the wet granulation process and Remove after fluid bed drying. Example 5 The tablets of Example 4 were stored at various temperatures and various relative humidity (RH) as shown in Table 5 for 6 months. At the beginning of storage and after 3 and 6 months, the content of the compound of the formula la in the form of maleate in the other tablets was measured by HPLC, and the amount of the compound of the formula la in the tablet was calculated. degradation. The results are shown in Table 5. Table 5 Period (month) 25 ° C / 60% RH DP 30 ° C / 70% RH DP 40 ° C / 75% RH DP 0 < 0.05 < 0.05 < 0.05 3 < 0.05 0.05 0.22 6 < 0.05 0.24 0.63 According to Table 5, the compounds of the formula la in the form of maleates are apparent after 96608.doc -23- 200529817 for 6 months, and-under normal environmental conditions (25 ° C and 60% RH) Does not actually degrade-only degrades to less than 0.3% at 30 ° C and 70% RH,-only degrades to less than 0.7% at 40 ° C and 75% RH. 96608.doc -24-

Claims

200529817 X. Scope of patent application · Type L: Compounds' which contain effective reduction or prevention of diphenyl, ... Degrees of dibenzo.oxan and acidifying agents.彳 ~ degradation process 2 »As in the composition of claim 丨, iopenhexyl is a compound of formula I,

Wherein alk is a divalent aliphatic group, and R is unsubstituted or monosubstituted or disubstituted by a monovalent aliphatic group and / or an araliphatic group or by a divalent aliphatic group, an araliphatic group, or a heteroaryl aliphatic group. The second group is: an amine group, and R !, R2, R3, and R4 are independently of each other hydrogen, (Cl 4) alkyl, (U alkoxime, halogen, or trifluoromethyl.) As in claim 1 or 2 A composition, wherein the dibenzoxanthine is a compound of the formula N- (dibenzo (b, f) oxanthyl-Lio-methylfluorenylmethyl 2-ylamine:

4. The composition of claim 1 or 2, wherein the dibenzoxanthine is in the form of a salt. 5. The composition according to claim 1 or 2, wherein the dibenzoxanthine is in the form of a salt with maleic acid. 96608.doc 200529817 wherein the acidifying agent is an organic carboxylic acid wherein the acidifying agent is citric acid. It further comprises at least one of the following: • a composition of item 1 or 2 as explicitly requested, 7 • a composition of item 1 or 2 as claimed, 8 • a character of person 1 or 2 of the item, ^ Feizhi, and mouth Wuxuexiongpiba contains at least one pharmaceutical excipient. 9 'The composition of claim 8 wherein the pharmaceutical form 1 is formed. · = Composition of item 丨 or 2 'which is a pharmaceutical compound, and whose second active ingredient is diheptyl as defined in any one of claims 2 to 5. 1 1 · The composition of claim 1 or 2 which is in solid form. 12. = A composition of claim W, which comprises a compound of the formula h / as defined in claim 3, citric acid, mannitol, microcrystalline cellulose, polyvinylidene chloride, and hydrogenated castor oil. 13. The composition of claim _ which is in the form of a lozenge, capsule, pellet or sachet. 14. The pharmaceutical composition according to claim 9, which is used for the manufacture of a neurodegenerative disorder, cerebral ischemia, glaucoma, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic side Cord sclerosis, multiple sclerosis, retinal degeneration of pigmented retinitis, common or diabetic peripheral neuropathy, bipolar and schizophrenic medicines. 96608.doc 200529817 VII. Designated representative map: (1) The designated representative map of this case is: (none) (II) The component symbols of this representative map are briefly explained: 8. If there is a chemical formula in this case, please disclose the one that can best show the characteristics of the invention. Chemical formula:

96608.doc