其爲一種選擇性中樞活性血淸素（5-羥色胺；5-HT)再攝 取抑制劑，因此具有抗抑鬱活性。 1309163 A7 __B7 ____ 五、發明說明（/ ) 發明領域 本發明係關於化合物艾司西肽普蘭（escitalopram)( INN-名稱）草酸鹽的結晶製劑，艾司西呔普蘭爲知名抗抑 鬱藥西狀普蘭（citalopram)的S-對映異構體，亦即(S)-l-[3-(二甲基胺基)丙基]-1-(4-氟苯基)-l，3-二氫-5-異苯并呋喃 腈。 發明背景 西te普蘭爲已經上市數年的知名抗抑鬱藥，具有下結 構： CH3 西酞普蘭首揭於DE 2,657,013中，其對應於US 4，136，193。此專利公告案敘述經由一種方法製備西駄普蘭 並槪述另一個可用來製備西肽普蘭方法。所製得之西酞普 蘭係分別以草酸鹽、氫溴酸鹽及鹽酸鹽等結晶形式離析。 此外’西肽普蘭鹼係以一種油（B.P. l75°C/0.〇3 mmHg) 獲得。此公告案亦槪述含西酞普蘭鹽之藥片的製造方法。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂〆. ..線i A7 1309163 五、發明說明（i) 西肽普蘭係分別以氫溴酸鹽和鹽酸鹽販售。 艾司西酞普蘭、其醫藥活性及結晶艾司西肽普蘭草酸 鹽係揭示於US專利案號4,943,590中。製備艾司西酞普蘭 醫藥製劑之方法亦有所槪述。 西肽普蘭係以一種經由壓縮粒狀西酞普蘭氫溴酸鹽、 乳糖及其他賦形劑所製得之藥片銷售於許多國家。 廣受認可的是，具有可再製組成之藥片製備方法需要 所有的乾成分都具有良好的流動性質。在一些情況下，當 活性成分具有良好流動性質時，藥片可經由直接壓縮該成 分而製得。然而，在許多情況中，活性物質的粒子大小太 小，活性物質會黏結或具有不良的流動性質。 再者，與具有較大粒子大小之賦形劑混合的具有小粒 子大小之活性物質，在製藥片程序期間，通常會分離或分 散。 小粒子大小與不良流動性的問題，傳統上係藉由增大 活性物質之粒子大小來解決，通常是經由使活性物質單獨 成粒或結合填料及/或其他習用藥片成分一起成粒。 此種成粒作用中有一種方法是”濕式”成粒方法。利用 此方法，將乾燥固體（活性成分、塡料、黏合劑等等）摻 合，用水或其他濕潤劑（例如醇）將其潤濕，然後附聚物 或顆粒便由潤濕固體聚集而成。濕式塊化一直持續到已經 達到所需的均勻粒子大小，然後將粒狀產物乾燥。 替代”濕式”成粒方法的一種方法是，，熔化”成粒作用， 其亦稱爲”熱塑性”成粒方法’其中係使用低熔點固體作爲 —___4 __ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂*: i線. A7 1309163 _ _ B7___ 五、發明說明（j ) / 成粒劑。一開始，將乾燥固體摻合，並加熱直到黏合劑熔 化爲止。當黏合劑被液化且散佈於粒子表面上時，粒子將 彼此黏著而形成顆粒。黏合劑隨冷卻固化而形成乾燥的顆 粒狀產物。 濕式成粒作用以及熔化成粒作用都是需要複雜且昂貴 設備及精密技巧之能量密集單元操作。 然而，如果活性成分具有適當流動性質，則可免除成 粒步驟且藥片可經由直接壓縮製得，其爲較便宜的生產方 法。 用以製備西肽普蘭氫溴酸鹽之方法可得到具有約2-20 微米極小粒子大小的產物，如同其他具有小粒子大小之微 粒產物，其具有非常差的流動性質。因此，爲了達到西酞 普蘭氫溴酸鹽在製藥片期間的適當定量給料，故考慮有必 要製造具有較大粒子大小與改良流動性質的西肽普蘭氫溴 酸鹽顆粒。 上市的西肽普蘭藥片是一種由粒狀西酞普蘭氫溴酸鹽 與各種不同賦形劑製得的藥片。 我們已經發現，艾司西酞普蘭具有與西肽普蘭外消旋 物顯著不同的溶解度和鹽形成性質。舉例來說，目前爲止 唯一知道的醫藥上結晶鹽是草酸鹽，但西酞普蘭還可形成 結晶氫溴酸鹽和鹽酸鹽。 如US專利案號4,943,590所槪述經由自丙酮結晶所製 得之艾司西肽普蘭草酸鹽產物，如同上述之西肽普蘭氫溴 酸鹽產物，具有約2-20微米之極小粒子大小而得到類似的 ____5____ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填.寫本頁) 訂-: 線 A7 1309163 玉_、發明說明（f) 不良流動性質。 鑑於直接壓縮遠比涉及成粒作用之方法更爲簡單和便 宜的事實，故希望有較大的艾司西酞普蘭或其醫藥上可接 受之加成鹽的晶體。 大量實驗工作與全面的硏究已得到一種新穎且進步的 結晶方法，其可製造較大的艾司西酞普蘭草酸鹽晶粒，亦 即，大小可比塡料大小的粒子。該粒子可用於直接壓縮藥 片之製造。在膠囊中精確的給劑亦可以此等大粒子得到。 發明目的 本發明之目的是提供適合用於直接壓縮之艾司西肽普 蘭草酸鹽大晶粒。 本發明之第二個目的是製造艾司西肽普蘭草酸鹽大晶 粒的方法。 本發明之第三個目的是提供含有艾司西酞普蘭草酸鹽 大晶粒之新穎醫藥單位劑型，其中該單位劑型可爲一種藥 片，其較佳可經由直接壓縮製得，或一種膠囊。 發明摘述 除此之外，本發明尙包括下列各項（單獨或組合）： 具有至少40微米中値粒子大小且適合用於固體單位劑 型之艾司西酞普蘭草酸鹽晶粒。 —種製造具有至少4〇微米中値粒子大小且適合用於固 體單位劑型之艾司西酞普蘭草酸鹽晶粒的方法，其中該方 ____6____ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 幻V. --線· A7 1309163 五、發明說明（f ) 法包括：將處於第一溫度之艾司西酞普蘭草酸鹽於適當溶 劑系統中所成之溶液逐漸冷卻到第二溫度，同時維持控制 的冷卻分佈曲線，在冷卻期間經由至少添加一次艾司西缺 普蘭草酸鹽晶體在結晶批料中播入晶種，接著於該第二溫 度一段保留時間，然後藉由習知固/液分離技術離析該晶體 〇 包含艾司西肽普蘭之固體單位劑型係藉由直接壓縮艾 司西肽普蘭鹼或其醫藥上可接受之鹽與醫藥上可接受賦形 劑之混合物而製得，或者藉由將該混合物塡入硬質明膠膠 囊而製得。 將艾司西肽普蘭、塡料及其他醫藥上可接受之賦形劑 直接壓縮成藥片有個很大的優點，就是免除成粒作用與乾 燥步驟。此外，由於免除了成粒步驟，故不再須要添加黏 合劑。 當用於本文時，”艾司西肽普蘭草酸鹽”意謂由艾司西 酞普蘭、草酸及視需要選用之水所組成的任何加成鹽。此 等鹽類的實例爲艾司西酞普蘭草酸氫鹽，亦即，由每分子 草酸一分子艾司西酞普蘭所組成的鹽，以及艾司西酞普蘭 草酸鹽’亦即’由每分子草酸二分子艾司西酞普蘭所組成 的鹽。 當用於本文時，，’晶粒，，意謂單晶、聚集體和附聚物的 任意組合。 當用於本文時，”直接壓縮”意謂固體單位劑型係經由 活性成分與賦形劑之單純混合物壓縮而製得，而無須使活 -----7_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） (請先閱讀背面之ii意事項再填寫本頁) ij.. 線· A7 B7 1309163 五、發明說明（b) 性成分經過中間的成粒程序將其包埋至較大粒子內及改良 其流動性質。 當用於本文時，”黏合劑”意謂一種試劑，其係用於濕 式或熔化成粒方法中且係當作粒狀產物的黏合劑。 當用於本文時，”粒子大小分佈”意謂相等球直徑之累 積體積大小分佈，如在Sympatec Helos設備中藉由雷射繞 射於1巴分散壓力所測得者。相對應地，”中値粒子大小” 意謂該粒子大小分佈之中間値。 當用於本文時，”回流溫度”意謂溶劑或溶劑系統於大 氣壓力下回流或沸騰的溫度。 當用於本文時，”冷卻分佈曲線”意謂結晶批料溫度爲 時間的函數。 當用於本文時，”冷卻速率”意謂每單位時間溫度的下 降量。 因此，在本發明之一個具體實例中，艾司西酞普蘭草 酸鹽晶粒具有至少40微米，較佳在50-200微米範圍內之 中値粒子大小。 對於直接壓縮而言，流動、聚集和分散等性質’及由 此所致之艾司西肽普蘭草酸鹽晶體的適合度，除了取決於 中値粒子大小之外，還取決於粒子大小分佈。 在本發明之另一個具體實例中，具有至少40微米（較 佳在50-200微米範圍內）之中値粒子大小且適合用於固體 單位劑型之艾司西肽普蘭草酸鹽晶粒，係結晶自艾司西肽 普蘭草酸鹽於適當溶劑系統中之溶液。該溶劑系統可包含 __8 ____ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） («-先閲讀背面之注意事項再填寫本頁) •Λ ί線· A7 1309163 五、發明說明（广I) . —或多種醇類及視需要選用的水，較佳該溶劑系統是乙醇 。艾司西肽普蘭草酸鹽較佳係於在50°c與該溶劑系統回流 溫度之間，較佳在60°C與該溶劑系統回流溫度之間且更佳 在70。(：與該溶劑系統回流溫度之間範圍的溫度下溶於溶劑 系統中，適當而言，艾司西肽普蘭草酸鹽係於回流溫度下 溶解。艾司西酞普蘭之醫藥上可接受鹽與所用溶劑的量較 佳係相當於在〇_〇5 : 1至〇·6 : 1，更佳0.1:1至〇5:1且 最佳0.2 : 1至0.4 : 1範圍內之溶劑：溶質重量比。艾司 西酞普蘭草酸鹽溶液係逐漸冷卻到晶體將自母液中離析出 來的溫度，其係在0-20。(：，較佳0-15。(：且更佳7-15。(：之 範圍內，同時維持一種控制的冷卻分佈曲線，如此一來， 在最初冷卻期間的冷卻溫度不超過〇.6°C/分，且較佳該冷 卻速率係保持在0‘2-0_4°C/分的範圍內，而該最初冷卻期間 係延續到結晶批料之溫度低於60°C，較佳低於50°C且更 佳低於40°C爲止，適當而言，該冷卻速率在整個冷卻期間 可保持在此範圍內。結晶批料係藉由在冷卻時間內添加至 少一次艾司西肽普蘭草酸鹽晶體來播入晶種，以免艾司西 缺普蘭草酸鹽過度地過飽和，而造成瞬間結晶成小晶粒。 播入晶種較佳重複進行，以確保結晶艾司西酞普蘭草酸鹽 在冷卻期間一直不變的存在，適當而言，在結晶批料中係 以半連續方式播入晶種’直到開始結晶爲止。結晶批料係 保持在該第二溫度一段保留時間，以供晶體成長至少1小 時，較佳在4至24小時且更佳6至12小時之範圍內。在 該保留時間之後，利用習知分離技術如過濾，將艾司西駄 9 本紙尺度適用中國國家標準（CNS)A4規格（210孓297公釐) " " " ' (請先閲讀背面之注意事項再填寫本頁) 訂： -線. 1309163 a； _____—_B7__ 五、發明說明（(f ) 普蘭晶粒自母液離析出來。 在本發明之一個具體實例中，本發明係關於一種由具 有至少40微米（較佳在50-200微米範圍內）中値粒子大 小之艾司西肽普蘭草酸鹽大晶粒與醫藥上可接受賦形劑的 混合物所製得之藥片。較佳而言，該藥片係由直接壓縮製 成。 在本發明之另一個具體實例中，本發明係關於一種經 由將具有至少40微米（較佳在50-200微米範圍內）中値 粒子大小之艾司西酞普蘭草酸鹽大晶粒與醫藥上可接受賦 形劑的混合物塡入硬質明膠膠囊所製得之膠囊。 較佳而言，根據本發明之固體單位劑型不含黏合劑。 根據本發明之固體單位劑型可含有以艾司西肽普蘭鹼 所計算之l-60%w/w活性成分，較佳以艾司西酞普蘭鹼所 計算之4-40%w/w活性成分，更佳以艾司西肽普蘭鹼所計 算之6-10%w/w活性成分。適當而言，本發明之固體單位 劑型含有以艾司西肽普蘭鹼所計算之8%w/w活性成分。 根據本發明之固體單位劑型可含有選自下列之塡料： 乳糖’或其他糖類，如山梨糖醇、甘露糖醇、右旋糖及蔗 糖，銘磷酸鹽（二價、三價、含水及無水），澱粉，改性 澱粉，微晶纖維素，硫酸鈣及/或碳酸鈣。在一較佳具體實 例中，本發明之固體單位劑型不含乳糖。 適虽而g ’塡料爲一種微晶纖維素，如PenwestIt is a selective central active hemoglobin (5-hydroxytryptamine; 5-HT) recapture inhibitor and thus has antidepressant activity. 1309163 A7 __B7 ____ V. INSTRUCTION DESCRIPTION (/) FIELD OF THE INVENTION The present invention relates to a crystalline preparation of the compound escitalopram (INN-name) oxalate, which is a well-known antidepressant The S-enantiomer of citalopram, ie (S)-l-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-l,3-di Hydrogen-5-isobenzofuranonitrile. BACKGROUND OF THE INVENTION West Tepland is a well-known antidepressant that has been on the market for several years and has the following structure: CH3 Citalopram was first disclosed in DE 2,657,013, which corresponds to US 4,136,193. This patent publication describes the preparation of citalopram by one method and a further description of the process for preparing citalopram. The obtained citalopram is isolated in the form of crystals such as oxalate, hydrobromide and hydrochloride. Further, cisplatin is obtained as an oil (B.P. l75 ° C / 0. 〇 3 mmHg). This announcement also describes the manufacturing method of tablets containing citalopram. This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Ordering. .. Line i A7 1309163 V. Description of invention (i) West peptide Pura is sold separately as hydrobromide and hydrochloride. Escitalopram, its pharmaceutically active and crystalline escitalopramine salt is disclosed in U.S. Patent No. 4,943,590. Methods for preparing escitalopram pharmaceutical preparations are also described. Peptide is sold in many countries as a tablet made via compressed granular citalopram hydrobromide, lactose and other excipients. It is widely accepted that a tablet preparation method having a reconstitutable composition requires that all dry ingredients have good flow properties. In some cases, when the active ingredient has good flow properties, the tablet can be made by directly compressing the ingredient. However, in many cases, the particle size of the active material is too small, and the active material may stick or have poor flow properties. Further, the active material having a small particle size mixed with an excipient having a larger particle size is usually separated or dispersed during the pharmaceutical tableting process. The problem of small particle size and poor flowability has traditionally been addressed by increasing the particle size of the active material, typically by granulating the active material separately or in combination with fillers and/or other conventional tablet ingredients. One such granulation process is the "wet" granulation process. By this method, dry solids (active ingredients, tanning materials, binders, etc.) are blended, wetted with water or other humectants (such as alcohols), and then agglomerates or granules are aggregated from wet solids. . The wet block is continued until the desired uniform particle size has been reached and the granulated product is dried. One method of replacing the "wet" granulation method is to melt the granulation, which is also known as the "thermoplastic" granulation method, in which a low melting solid is used as the -___4 __ This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) (Please read the note on the back and fill out this page) Order*: i line. A7 1309163 _ _ B7___ V. Invention description (j) / granulating agent. The dry solid is blended and heated until the binder melts. When the binder is liquefied and dispersed on the surface of the particles, the particles will adhere to each other to form granules. The binder solidifies with cooling to form a dry granulated product. Both granulation and melt granulation are energy intensive unit operations that require complex and expensive equipment and sophisticated techniques. However, if the active ingredient has suitable flow properties, the granulation step can be dispensed with and the tablets can be made by direct compression, which is A cheaper production process. The process for preparing citrinop hydrobromide can yield products having a very small particle size of about 2-20 microns, as others have small Particle-sized particulate products with very poor flow properties. Therefore, in order to achieve proper dosing of citalopram hydrobromide during pharmaceutical tablets, it is considered necessary to manufacture a west with larger particle size and improved flow properties. Peptide pulonium hydrobromide granules. The marketed citramopram tablets are tablets made from granular citalopram hydrobromide and various excipients. We have found that escitalopram has cisplatin The racemates of pulan have significantly different solubility and salt forming properties. For example, the only pharmaceutically crystalline salt known so far is oxalate, but citalopram can also form crystalline hydrobromide and hydrochloride. The escitalopram oxalate product obtained by crystallization from acetone, as described above for the cisplatin hydrobromide product having a very small particle size of about 2-20 microns, is described in US Patent No. 4,943,590. Similar ____5____ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill in. Write this page) Order -: Line A7 1309 163 jade_, invention description (f) bad flow properties. In view of the fact that direct compression is much simpler and cheaper than the method involving granulation, it is desirable to have larger escitalopram or its pharmaceutically acceptable Addition of salt crystals. A large number of experimental work and comprehensive research have obtained a novel and advanced crystallization method, which can produce larger escitalopram oxalate crystallites, that is, the size of the comparable material Particles. The particles can be used for the manufacture of directly compressed tablets. The precise agent in the capsule can also be obtained with such large particles. OBJECT OF THE INVENTION The object of the present invention is to provide a large amount of escitalopram oxalate suitable for direct compression. Grains. A second object of the invention is a process for the manufacture of large grains of escitalopram oxalate. A third object of the present invention is to provide a novel pharmaceutical unit dosage form comprising large grains of escitalopram oxalate, wherein the unit dosage form can be a tablet, preferably made by direct compression, or a capsule. SUMMARY OF THE INVENTION In addition to the above, the present invention comprises the following (alone or in combination): escitalopram oxalate crystallites having a cerium particle size of at least 40 microns and suitable for use in solid unit dosage forms. - A method for producing escitalopram oxalate grains having a cerium particle size of at least 4 Å and suitable for use in a solid unit dosage form, wherein the ____6____ paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back and fill out this page) Fantasy V. -- Line · A7 1309163 V. Invention Description (f ) Method includes: will be at the first temperature of escitalopram The solution of oxalate in a suitable solvent system is gradually cooled to a second temperature while maintaining a controlled cooling profile, which is broadcast in the crystallization batch via at least one addition of escital oxalate crystals during cooling. Seeding, followed by a second temperature for a retention time, and then isolating the crystal by conventional solid/liquid separation techniques. The solid unit dosage form comprising escitalopram is by direct compression of escitalopram or its Prepared by mixing a pharmaceutically acceptable salt with a pharmaceutically acceptable excipient or by injecting the mixture into a hard gelatin capsule. The direct compression of escitalopram, dips and other pharmaceutically acceptable excipients into tablets has the great advantage of eliminating the granulation and drying steps. In addition, since the granulation step is eliminated, it is no longer necessary to add a binder. As used herein, "esprilate chloroformate" means any addition salt consisting of escitalopram, oxalic acid, and optionally water. An example of such a salt is escitalopram oxalate, that is, a salt consisting of one molecule of oxacillin per molecule of oxalic acid, and escitalopram oxalate 'is also' a salt composed of two molecules of oxalic acid, escitalopram. As used herein, "grain," means any combination of single crystal, aggregate, and agglomerate. As used herein, "direct compression" means that the solid unit dosage form is prepared by compression of a simple mixture of the active ingredient and excipients without the need to make the live----7_ paper scale applicable to the Chinese National Standard (CNS). ) A4 size (210 X 297 public) (Please read the back of the ii and then fill out this page) ij.. Line · A7 B7 1309163 V. Invention description (b) Sex components are packaged by intermediate granulation procedures Buried into larger particles and improved its flow properties. As used herein, "adhesive" means an agent which is used in a wet or melt granulation process and which acts as a binder for the granulated product. As used herein, "particle size distribution" means the cumulative volume size distribution of equal sphere diameters as measured by laser diffraction at 1 bar dispersion pressure in a Sympatec Helos apparatus. Correspondingly, "the median particle size" means the middle of the particle size distribution. As used herein, "reflow temperature" means the temperature at which a solvent or solvent system is refluxed or boiled under atmospheric pressure. As used herein, "cooling profile" means that the crystallization batch temperature is a function of time. As used herein, "cooling rate" means the amount of temperature drop per unit time. Thus, in one embodiment of the invention, the escitalopram oxalate grain has a median particle size of at least 40 microns, preferably in the range of 50-200 microns. For direct compression, the properties of flow, aggregation and dispersion, and the suitability of the escitalopram oxalate crystals resulting therefrom, depend on the particle size distribution, in addition to the size of the median particles. In another embodiment of the invention, the escitalopram oxalate crystallites having a ruthenium particle size of at least 40 microns (preferably in the range of 50-200 microns) and suitable for use in solid unit dosage forms are A solution of escitalillium oxalate in a suitable solvent system. The solvent system can contain __8 ____. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) («-Read the back note first and then fill out this page) • Λ ί line · A7 1309163 V. Description of the Invention (Wholesale I) - or a plurality of alcohols and optionally water, preferably the solvent system is ethanol. Preferably, the escitalopram oxalate is between 50 ° C and the reflux temperature of the solvent system, preferably between 60 ° C and the reflux temperature of the solvent system and more preferably 70. (: is dissolved in the solvent system at a temperature ranging between the reflux temperature of the solvent system, and suitably, escitalopram oxalate is dissolved at reflux temperature. The pharmaceutically acceptable salt of escitalopram The amount of the solvent to be used is preferably equivalent to a solvent in the range of 〇_〇5:1 to 〇6:1, more preferably 0.1:1 to 〇5:1 and most preferably 0.2:1 to 0.4:1: solute The weight ratio of escitalopram oxalate solution is gradually cooled to a temperature at which crystals will be separated from the mother liquor, which is 0-20. (:, preferably 0-15. (: and better 7-15) Within the range of (:: while maintaining a controlled cooling profile, such that the cooling temperature during the initial cooling does not exceed 〇6 °C / min, and preferably the cooling rate is maintained at 0'2- 0_4 ° C / min, and the initial cooling period continues until the temperature of the crystallization batch is below 60 ° C, preferably below 50 ° C and more preferably below 40 ° C, suitably The cooling rate can be maintained within this range throughout the cooling period. The crystallization batch is added by at least one escitalopram in the cooling time. Salt crystals are seeded to prevent excessive oversaturation of Essie oxalic acid oxalate, resulting in instant crystallization into small grains. The seeded seed crystals are preferably repeated to ensure crystallization of escitalopram oxalate The presence of constant crystallisation during cooling, suitably in a semi-continuous manner in the crystallization batch, until the crystallization begins. The crystallization batch is maintained at the second temperature for a retention time for the crystal Growing for at least 1 hour, preferably in the range of 4 to 24 hours and more preferably 6 to 12 hours. After this retention time, the standard size of escital is applied to Chinese national standards using conventional separation techniques such as filtration. CNS)A4 specification (210孓297 mm) """ ' (Please read the note on the back and fill out this page) Order: -Line. 1309163 a; _______B7__ V. Invention description ((f) The Plane grains are isolated from the mother liquor. In one embodiment of the invention, the invention relates to an escitalopram oxalic acid having a ruthenium particle size of at least 40 microns, preferably in the range of 50-200 microns. Large grain size and A tablet made from a mixture of pharmaceutically acceptable excipients. Preferably, the tablet is made by direct compression. In another embodiment of the invention, the invention relates to a via having at least 40 microns Preferably, in the range of 50-200 micrometers, a mixture of large crystal grains of escitalopram oxalate having a cerium particle size and a pharmaceutically acceptable excipient is incorporated into a capsule obtained by hard gelatin capsules. In general, the solid unit dosage form according to the invention contains no binder. The solid unit dosage form according to the invention may contain from 1 to 60% w/w of the active ingredient calculated by escitalopramine, preferably Essi 4-40% w/w active ingredient calculated by eucalyptin base, more preferably 6-10% w/w active ingredient calculated by escitalopram. Suitably, the solid unit dosage form of the invention contains 8% w/w of the active ingredient calculated as escitalopram. The solid unit dosage form according to the present invention may contain a pigment selected from the group consisting of: lactose or other sugars such as sorbitol, mannitol, dextrose and sucrose, and phosphates (divalent, trivalent, aqueous and anhydrous). ), starch, modified starch, microcrystalline cellulose, calcium sulfate and/or calcium carbonate. In a preferred embodiment, the solid unit dosage form of the invention is lactose free. Appropriately, g 塡 is a kind of microcrystalline cellulose, such as Penwest
Pharmaceuticals 所製造之 ProSolv SMCC90，或 FMC 公司 所製造之Avicel PH 200。 ___10____ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ' (請先閱讀背面之注意事項再填.寫本頁) - 訂· -線_ B7 1309163 五、發明說明（^/ ) 除了活性成分和塡料之外’固體醫藥單位劑型可包含 各種不同的其他習知賦形劑，例如崩解劑及視需要選用的 少量潤滑劑、著色劑和增甜劑。 根據本發明所使用之潤滑劑可適當地爲選自包含金屬 硬脂酸鹽（鎂、鈣、鈉）、硬脂酸、蠟、氫化蔬菜油、滑 石和膠體二氧化矽之集合的一或多者。 較佳而言，潤滑劑爲選自包含滑石、硬脂酸鎂或硬脂 酸鈣之集合的一或多者。適當而言，潤滑劑爲滑石與硬脂 酸鎂的組合。硬脂酸鎂在固體單位劑型中的重量百分比較 佳係在0.4%至2%之範圍內，且更佳係在0.7%至1.4%之 範圍內。 崩解劑包括羥基乙酸澱粉鈉、聚羧甲基纖維素、聚乙 烯聚吡咯烷酮、低取代羥丙基纖維素、改性玉米澱粉、預 凝膠化澱粉及天然澱粉。適當而言，崩解劑爲聚羧甲基纖 維素，如FMC所製造之Ac-Di-Sol。 視情況而定，本發明之固體醫藥單位劑型可經塗覆。 適當而言，塗料爲一種以習知塗料混合物爲主之薄膜塗料 ，例如由Colorcon所製造之Opadry〇Y-S-28849，白色。 本發明之固體醫藥單位劑型可藉由利用具有強制進料 容量之壓片機的習知方法製得。 本發明之塡充硬質明膠膠囊可藉由利用適合粉末塡充 之膠囊塡充器的習知方法製得。 在下文中，本發明係經由實施例來說明。然而，這些 實施例僅意欲說明本發明而不應解釋爲限制。 __11 本紙張尺度適用"中國國家標準（CNS)A4~規格（2κΓχ 297公釐厂 (請先閱讀背面之注意事項再填寫本頁) *SJ· -線· A7 1309163 五、發明說明（iD ) 實施例1 將分別經由混合艾司西酞普蘭與草酸之乙醇溶液來沈 澱粗製艾司西酞普蘭草酸鹽所獲得且含有大約35公斤艾司 西肽普蘭草酸鹽之濕濾餅懸浮於322升乙醇中。藉由加熱 至回流使此物質溶解，並藉蒸餾除去150升乙醇。施加冷 卻，使混合物在80至40°C的溫度間隔內，以0.2至 〇.5°C/分之間的冷卻速率從回流冷卻到15°C。在冷卻期間 ，於75、65及60°C時以艾司西酞普蘭草酸鹽對混合物播 入晶種（每次10克）。在離析出結晶艾司西酞普蘭草酸鹽 之前，使結晶混合物保持在15°c下10小時。將結晶混合 物過濾，用乙醇洗滌並乾燥濾餅，得到純化的艾司西肽普 蘭草酸鹽（27.7公斤，理論値之58_2%)。所得艾司西缺 普蘭草酸鹽之粒子大小分佈係列示於表1 (請先閲讀背面之注意事項再填寫本頁) 訂: 表1 :艾司西肽普蘭草酸鹽與ProSolv SCMC90之粒子大小 分佈 (Sympatec Helos )_^_ 分位數（％) 實施例1(微米） ProSolv SCMC90 (微米） 90 455 291 50 163 130 10 13 37 實施例2 藉由直接壓縮艾司西肽普蘭草酸鹽大晶粒所製得之藥 片 _______12.____ t氏張尺度適用中國國家標準（CNS)A4規^格（210 x 297公β •線· 1309163 A7 B7 (10.2% w/w ) (5.6% w/w) (19.6% w/w ) (3.6% w/w) (1.0%w/w) 五、發明說明（ 藥片成分： 藥片核芯 艾司西肽普蘭草酸鹽 迟4克 滑石 1400克ProSolv SMCC90 manufactured by Pharmaceuticals, or Avicel PH 200 manufactured by FMC. ___10____ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ' (Please read the notes on the back and fill in. Write this page) - Order · Line _ B7 1309163 V. Invention description (^ /) In addition to the active ingredients and tanning materials, the 'solid pharmaceutical unit dosage form can contain a variety of other conventional excipients, such as disintegrating agents and, if desired, small amounts of lubricants, colorants, and sweeteners. The lubricant used in accordance with the present invention may suitably be one or more selected from the group consisting of metal stearates (magnesium, calcium, sodium), stearic acid, waxes, hydrogenated vegetable oils, talc, and colloidal cerium oxide. By. Preferably, the lubricant is one or more selected from the group consisting of talc, magnesium stearate or calcium stearate. Suitably, the lubricant is a combination of talc and magnesium stearate. The weight percentage of magnesium stearate in the solid unit dosage form is preferably in the range of from 0.4% to 2%, and more preferably in the range of from 0.7% to 1.4%. Disintegrators include sodium starch glycolate, polycarboxymethylcellulose, polyvinylpolypyrrolidone, low substituted hydroxypropylcellulose, modified corn starch, pregelatinized starch, and natural starch. Suitably, the disintegrant is polycarboxymethyl cellulose, such as Ac-Di-Sol manufactured by FMC. The solid pharmaceutical unit dosage form of the invention may be coated, as the case may be. Suitably, the coating is a film coating based on a conventional coating mixture, such as Opadry(R) Y-S-28849, manufactured by Colorcon, white. The solid pharmaceutical unit dosage form of the present invention can be prepared by conventional methods using a tablet press having a forced feed capacity. The sputum-filled hard gelatin capsule of the present invention can be obtained by a conventional method using a capsule damper suitable for powder filling. Hereinafter, the invention is illustrated by way of examples. However, these examples are intended to illustrate the invention and are not to be construed as limiting. __11 This paper size applies to "China National Standard (CNS) A4~Specifications (2κΓχ 297 mm factory (please read the notes on the back and fill out this page) *SJ·-Line·A7 1309163 V. Invention Description (iD) Example 1 A wet cake obtained by precipitating crude escitalopram oxalate with a solution of escitalopram and oxalic acid in ethanol and containing about 35 kg of escitalopram oxalate was suspended in 322. In ethanol, the material is dissolved by heating to reflux, and 150 liters of ethanol is removed by distillation. Cooling is applied to make the mixture at a temperature interval of 80 to 40 ° C, between 0.2 and 0.5 ° C / min. The cooling rate was cooled from reflux to 15 ° C. During cooling, the mixture was seeded with escitalopram oxalate at 75, 65 and 60 ° C (10 g each). Prior to escitalopram oxalate, the crystallization mixture was maintained at 15 ° C for 10 hours. The crystallization mixture was filtered, washed with ethanol and the filter cake was dried to give purified escitalopram oxalate (27.7 kg, The theoretical theory is 58_2%). The particle size distribution series of salt is shown in Table 1. (Please read the note on the back and fill out this page) Order: Table 1: Particle size distribution of escitalopram and ProSolv SCMC90 (Sympatec Helos )_^_ Quantile (%) Example 1 (micron) ProSolv SCMC90 (micron) 90 455 291 50 163 130 10 13 37 Example 2 Tablets prepared by directly compressing large grains of escitalopram oxalate _ ______12.____ The t-scale is applicable to the Chinese National Standard (CNS) A4 regulation (210 x 297 gong β • line · 1309163 A7 B7 (10.2% w/w ) (5.6% w/w) (19.6% w/w (3.6% w/w) (1.0% w/w) V. Description of the invention (Tablet composition: Pill core escitalopram oxalate 4 g of talc delayed 1400 g
ProSolv SMCC90 1_9896 克ProSolv SMCC90 1_9896 g
Ac-Di-Sol 900 克 硬脂酸鎂 250克 薄膜塗料Ac-Di-Sol 900 g Magnesium stearate 250 g Film coating
Opadry OY-S-28849 -白 625 克 (核芯重量之 2_5 % 色 w/w) 使實施例1所得之艾司西肽普蘭草酸鹽晶粒與滑石一 同經過710微米篩網篩分，並在100升Bohle PTM 200混 合機中以6 rpm摻合15分鐘。添加ProSolv SMCC90和 Ac-Di-Sol，繼續摻合15分鐘。使硬脂酸鎂經過Ή0微米 篩網篩分，將其加入並繼續摻合3分鐘。 在裝備長方形之具浮雕刻痕之5.5 X 8毫米打孔器的 Korsch PH 230壓片機上，將25公斤所得混合物壓成藥片 (125,000個藥片/小時）。將藥片核芯重量設定爲125毫 克。公稱產量爲200,000個藥片。使壓片機運行直到混合 物液面恰位於強制進料器上方，亦即，壓製藥片係儘可能 長久地持續，以確認在混合物最後量中可能的聚集傾向。 所製得之藥片具有令人滿意的技術性質。 13 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂--- .線.Opadry OY-S-28849 - white 625 g (2_5 % color w/w of core weight) The escitalopram oxalate crystal grains obtained in Example 1 were sieved together with talc through a 710 micron sieve, and Blend at 6 rpm for 15 minutes in a 100 liter Bohle PTM 200 mixer. ProSolv SMCC90 and Ac-Di-Sol were added and blending was continued for 15 minutes. Magnesium stearate was sieved through a Ή0 micron sieve, added and blended for 3 minutes. On a Korsch PH 230 tablet press equipped with a rectangular 5.5 X 8 mm punch with a floating engraving, 25 kg of the resulting mixture was compressed into tablets (125,000 tablets per hour). The tablet core weight was set to 125 mg. The nominal production is 200,000 tablets. The tablet press was run until the level of the mixture was just above the forced feeder, i.e., the compressed tablets continued for as long as possible to confirm the likely tendency to aggregate in the final amount of the mixture. The tablets produced have satisfactory technical properties. 13 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Order --- .