TWI343825B

TWI343825B -

Info

Publication number: TWI343825B
Application number: TW95106991A
Authority: TW
Inventors: Fang Hsiung Hsiao; Ya Ching Changchien
Priority date: 2006-03-02
Filing date: 2006-03-02
Publication date: 2011-06-21
Also published as: TW200733987A

Description

1343825 九、發明說明：【發明所屬之技術領域】本發明係關於一種包含萬拉法辛（venlafaxine)及其、1 s九鹽類，作為活性藥物成份的口服持續性釋放之醫藥組、合物製劑及其製造方法。 '* 【先前技術】 —萬拉法辛（venlafaxme)，卜匕兴二甲基胺基）_卜（4曱氧 _ 本基）乙基]環己醇’為用於治療抗憂#的重要藥物。萬拉法辛及其酸加成鹽係首先揭示於美國專利第4 353 186號中於Μ” 年經美國FDA核准用於憂鬱症治療。萬拉法辛（venlafaxine)作用機轉主要是能選擇性對血/月素及正腎上腺素再吸收產生抑制作用，產生療效時間 , 比其他抗鬱藥快，大約1週即可快速達到抗憂鬱效果，其，機轉可能與本藥快速引發石-受器（沒-receptor)的向下調節（down regulation)有關。一般建議初始劑量為 φ 75mg/day，可分兩或三次和食物一起吞服，視臨床症狀慢慢調整劑量至有效劑量’最大劑量為375mg/day。臨床常、見副作用包括噁心、胃不舒服、嘔吐、性慾降低、睡眠障 ^ 礙等，其產生噁心的副作用比SSRIs(選擇性血清素再吸收、抑制劑 Selective Serotonin Re-uptake Inhibitors 此類藥物勺括 Fluoxetine、Fluvoxamine、Paroxetine、Sertraline) t 此副作用可經由慢慢調整劑量的方式來減少此一副作用一般緩釋型萬拉法辛（venlafaxine)比立刻釋放劑型能維持藥物》農度的平穩，因此發生戒斷症狀的副作用較低。 5 1343825 萬拉法辛鹽醆鹽目前以75毫克至35〇毫克/a劑量範圍之心鍵劑形式，成人給藥量分成_天二次或三次之方式給予。一般服用萬拉法辛鹽酸鹽鍵劑之治療劑量中，駿劑會迅速溶解:造成在給藥後短時間内血㈣之活性成分濃度迅速增加，接者數小時内因活性化合物減少或代謝致使血漿活性成分濃度減少’直到服藥後約12小時’方達到治療所需之血漿濃度， 2需錢高藥物，以延長活性成分於血㈣維持治療所了間因為每日反覆服用高劑量藥物，造成常見的副作用為反胃，、約繼以上的病人以萬拉法辛或其鹽酸鹽治療時會發生前述情況，約17%的病人亦發生嘔吐。既有持續性釋放藥物之劑型’係將活性成分與纖維素（例如甲基纖維素 '乙基纖維素或經丙基甲基纖維素）選擇性與其他賦形劑混合’然後將所得的混合物壓縮成錠劑。當口服鍵劑時，消化系統中纖維素驗類與水份產生水合作用並膨脹’藉此限制活性成份暴露於水份。當纖維素被水：逐漸侵蝕出日夺，水份滲透至凝膠基層中且活性成份 •.農k /合解或擴散通過凝膠，使其可有利用的被身體吸收。在既有藥物工業之錠劑製藥技術，並無法提供持續緩釋！·生貝〜膠囊化藥物配方。因此，持續釋放之膠囊劑型需藉由將活性成分與一種或一種以上之黏合劑混合，以形成均勻此〇物，然後以水或乙醇等類之溶劑濕潤形成可擠壓之團塊，從該團塊擠壓成藥物/基質之小直徑，一般為丄公分切成適當長度之圓柱體，然後使用標準球型化設備變升y成圓粒。圓粒在乾燥之後以薄膜包覆以延遲溶解。明膠 6 1W825 谬囊# A *上士 • =為充填治療之有效量之經薄膜包覆圓粒。以不同釋速率所釋出活性成分之圓粒，可與明膠膠囊組合以得到 2要的釋放速率和血中含量。在擠壓製造過程，發生熱積；；:仏：其使擠出物太乾而不易由擠壓之圓柱轉變成圓粒。在、美國專利第493,993號中將經丙基曱基纖維素22〇8添加至萬拉法辛鹽酸鹽—微晶纖維素混合物擠壓製粒成不規則 ° ;核、，作為含藥之圓粒核心。雖可以得到較佳之圓 φ =，但由於轉移操作多次，既耗時及成本高。對於尋求一 #單易作且具良好均一之製備方法而言，仍屬複雜。美國專利第4, 1 38, 475號揭示一種緩釋藥學組成物，其由充填包括與微晶纖維素摻合之丙醇薄膜包覆之球型體的硬明膠膠囊所組成，其中薄膜包覆層由乙基纖維素，視，需要與羥丙基甲基纖維素及/或可塑劑組成。，我國第861 02797號專利申請案（公告493993號）為「萬拉法辛（venlafaxine)鹽酸鹽之長效型配方劑」，其特徵籲在於該製劑係包含有球狀體，該球狀體包含3〇%至㈣之萬拉法辛鹽酸鹽’ 5跑7嶋晶纖維素，及Q25%至職、丙基甲基纖維素，該球狀體上塗覆有具80%至90¾之乙基 " 纖維素及1 0%至20%羥丙基甲基纖維素之膜塗層。 = 我㈣號專^請案（二S 555568號）揭示；「-種膠囊化持續釋放之配方」，其係包含一有效治療用量之經塗層塗覆之圓粒核心，其中該圓粒核心為實質上不具有經丙基甲基纖維素，而含有3〇%至4〇%之萬拉法辛（venhfaxine)鹽醆鹽及6〇%至7〇%之微晶纖维素（以 7 1343825 該球狀體核心重量計），及該塗層含有80%至90%重量之乙基纖維素’及10%至20%重量之羥丙基甲基纖維素（以該塗層之重量計）。在上述之萬拉法辛（ven i aiax i ne)鹽酸鹽之長效型配方劑之製法中，我國第86102797號專利申請案（公告493993 號）之製法係採傳統之混製核法，將含萬拉法辛 (venlafaxine)鹽酸鹽、微晶纖維素及羥丙基甲基纖維素之混合物擠壓製粒成不規則之圓粒核心，作為含藥之圓粒核心’由於轉移操作多次，既耗時及成本高。而在第 861 02797A01號專利申請案（公告555568號）之製法相同於前述申請案之製法，其差異僅在該圓粒核心為實質上不具有羥丙基甲基纖維素。在此製法中，雖可以得到較佳之圓粒’但由於轉移操作多次，既耗時及成本高。對於尋求一簡單易插作且具良好均一之製備方法而言，仍屬複雜。上述各習知製程所製出之藥劑普遍存在一個問題，即含萬拉法辛（venlafaxine)鹽酸鹽之膠囊，其内容物為含微晶纖維素’而以習知方法所製之含萬拉法辛 (venlafaxine)鹽酸鹽顆粒之核心，具有很大之顆粒大小差異性。由於萬拉法辛鹽酸鹽被證實為極端之水溶性的藥物 ( 5 72 mg/ml水），所以可獲得持續釋放之製劑是完全不可預期的。藉由水凝膠技術製備持續釋放之錠劑的數種嘗試證明是有困難的，因為在溶離試驗研究中經壓縮之錠劑均有溶解太迅速之問題。文獻中提及，呈水凝膠緩釋製劑之 8 ^43825 所製得的錠劑在2小時產生40-45%的溶解’於4小時溶解 60-7 0% ’於8小時溶解達85-1 0 0%。综上所述，既有萬拉法辛醫藥組合物及相關製造方法仍有存多種問題，有待進一步克服及解決。【發明内容】有鑒於既有高度水溶性之醫藥組合物，包含萬拉法辛或其鹽酸鹽類之醫藥組合物，其不足與缺點，本發 :度水溶性之醫藥組合物，提供一種具緩釋效 =樂組合物’包含以萬拉法辛或其鹽酸鹽類作為活性樂物成伤，以供病患使用。為解決上述之問韻，士 & αη 门喊本發明一方面相關於—種令右μ 拉法辛（venlafaxine)^：}主路：is» 有萬 une)的持續釋出型醫藥組合核心圓粒、載藥層及批雜a 具包括把.Μ ^ 其中該載藥層包含有效量萬拉法辛，控釋層包含控釋溶離劑，且載藥^文里萬包覆於核心圓粗上，γ 控釋層均係 &釋層位於載藥層之外屛。較佳的是，控釋層外曰卜口Ρ另依次設有—組 _ 的載藥層及控釋層。、上間Pft設置較佳的是，並中兮技 ”甲垓核心圓粒包含—種戍— 形劑。戎種以上的賦更佳的是，盆Φ ^ '、中忒賦形劑係一種或— 糖、澱粉、甘露醇、# φ β 飞種以上選自由乳化鈉、氣化鉀、Ρ + 甘—％;殿粉鈉、氯巴I、海藻酸鹽、滑石粉、二 S旨酸、硬酯酸鹽、微結 _ —氧化鈦、硬檬酸三乙酯、檸檬醆二 ^ 來乙二醇、檸 —丁^曰、三乙酸丙酷1酸氣朽、峨 i 9 iJ43825 ^ 酸三鈉、硫酸鈣、環糊精澱粉及蓖麻油所組成之族群中。更佳的是，其中該核心圓粒係選自由蔗糖核心圓粒、蔗糖及澱粉核心圓粒及微結晶纖維素核心圓粒所組成之族 ' 群中。 ' 、較佳的是，其中該載藥層進而包含黏合劑、可塑劑或 ' 稀釋劑。更佳的是，其中載藥層所含之黏合劑為一種或—種以 % 上選自由聚乙烯四氫嫠咯酮（pvp)、明膠、羥乙基纖維素 (HEC)、羥丙基纖素（HPC)、羥丙基曱基纖維素（HpMc)、乙烯乙酸鹽（VA)、聚乙烯醇（PVA)、甲基纖維素（MC)、乙基纖維素（EC)、羥丙基曱基纖維苯二曱酸鹽（HpMcp)、乙^ 笨一曱基纖維素（CAP)、三仙膠（xanthan gum)、海藻酸、海藻酸鹽、曱基丙烯酸曱基丙烯酸酯共聚物、共聚之曱美、内烯酸/甲基丙烯酸甲酷或聚乙烯乙酸苯二甲酸酿（ρνΑρ^ 所組成之族群中。 • 更佳的是，其中載藥層所含之稀釋劑為一種或—種以上選自由乳糖、澱粉、甘露醇、羥曱基纖維素鈉、甘二醇；鐵粉鈉、氯化鈉、氣化鉀、色素 '海藻醆鹽、滑石粉、二、氧化鈦 '硬酯酸、硬酯酸鹽、微結晶纖維素、丙三 χ ' 7 _ ^ —•醇、聚 >二醇、棒樣酸三乙酷；檸檬酸三丁酯 '三乙酸丙酯、破醆氫鈣、磷酸三鈉、硫醆鈣、環糊精澱粉及萬麻油所組牛之族群中。、· 更佳的是，其中載藥層所含之可塑劑為一種或—種以上選自由丙三醇、聚乙二醇、檸檬酸三乙酯 '檸檬醆三丁 1343825 酯、三乙酸丙酯、酸二乙酯（diethyl phthalate)及酸二丁酿（dibutyl phthalate)所組成之族群中。更佳的是，其中載藥層所含之抗黏劑為一種或一種以上選自由滑石粉、硬酯酸、硬酯酸鹽、延胡索硬酯酸鈉 (sodium stearyl fumarate)及二十二酸甘油酯（glyceryl behenate)、尚嶺土（kaol in)、膠體二氧化矽（aer〇si 1)所組成之族群中。較佳的是，其中該控釋層進而包含抗黏劑及可塑劑。更佳的是，其中該控釋層所含之溶離控釋劑為一種或一種以上選自由乙基纖維素（EC) '丙基甲基纖維素（HpMC) 及甲基丙烯酸甲基丙烯酸酯共聚物所組成之族群中。更佳的是，其中該控釋層所含之抗黏劑為一種或一種以上選自由滑石粉' 硬酯酸、硬酯酸鹽、延胡索硬酯酸鈉 (sodium stearyi fumarate)及二十二酸甘油酯（giyceryi behenate)、高嶺土（kaolin)、膠體二氧化矽（aer〇sii)所組成之族群中。更佳的是，其中，控釋層所含之可塑劑為一種或一種以上選自由丙三醇、聚乙二醇、檸檬酸三乙酯、檸檬酸三丁酯、三乙酸丙酯、酸二乙酯（diethyl phthalate)及酸二丁酯（dibutyl phthaUte)所組成之族群中。更佳的是，其中該控釋層所含之可塑劑為聚乙二醇或檸檬酸三乙酯。1343825 IX. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical composition and composition for oral sustained release comprising venlafaxine and its 1 s non-salt as active pharmaceutical ingredients Formulations and methods of making the same. '* [Previous technique] - venlafaxme, dioxetamine dimethyl sulfonate is an important drug for the treatment of anti-worry #. Venlafaxine and its acid addition salts are first disclosed in U.S. Patent No. 4,353,186, which is approved by the US FDA for the treatment of depression. The venlafaxine action machine is mainly capable of selecting Sexually inhibits blood/monthly and norepinephrine reuptake, produces therapeutic time, is faster than other anti-depressant drugs, and can quickly reach anti-depression effect in about 1 week, which may be triggered by the drug quickly. It is related to the downward regulation of the device (no-receptor). It is generally recommended that the initial dose be φ 75mg/day, which can be swallowed together with food two or three times. The dose is slowly adjusted to the effective dose according to the clinical symptoms. The dose is 375mg/day. Clinically, side effects include nausea, stomach discomfort, vomiting, decreased libido, sleep disorders, etc., which produce nausea and side effects than SSRIs (selective serotonin reuptake, inhibitor Selective Serotonin Re- Uptake Inhibitors Such drugs include Fluoxetine, Fluvoxamine, Paroxetine, Sertraline) t This side effect can be reduced by slowly adjusting the dose to reduce this side effect. The type of venlafaxine is more stable than the immediate release dosage form, so the side effects of withdrawal symptoms are lower. 5 1343825 The valproic acid salt is currently 75 mg to 35 mg/a. In the dosage range of the heart-binder dosage form, the adult dosage is divided into two or three times. The therapeutic dose of venlafaxine hydrochloride salt is usually dissolved rapidly: after administration In a short period of time, the concentration of active ingredient in blood (4) increases rapidly, and the concentration of plasma active ingredient decreases due to the reduction or metabolism of active compound within a few hours until the plasma concentration required for treatment is reached until about 12 hours after taking the drug. In order to prolong the active ingredient in the blood (four) maintenance treatment, because the daily repeated use of high-dose drugs, the common side effect is nausea, the above-mentioned patients will be treated with venlafaxine or its hydrochloride In the case, about 17% of patients also have vomiting. A dosage form that has a sustained release of the drug' is the active ingredient with cellulose (eg methylcellulose 'ethylcellulose or C- Methylcellulose) is optionally mixed with other excipients' and then the resulting mixture is compressed into a tablet. When the key is applied, the cellulose in the digestive system produces hydration and swells with water. The active ingredient is exposed to moisture. When the cellulose is gradually eroded by the water: the water penetrates into the gel base layer and the active ingredient is hydrated or diffused through the gel to make it available. The body absorbs. In the pharmaceutical industry of the pharmaceutical industry, it does not provide sustained sustained release! · Shengbei ~ capsuled drug formula. Thus, a sustained release capsule dosage form is formed by mixing the active ingredient with one or more binders to form a homogeneous mass which is then wetted with a solvent such as water or ethanol to form an extrudable mass. The agglomerates are extruded into a small diameter of the drug/matrix, typically a chopped centimeter cut into cylinders of appropriate length, and then expanded into round pellets using standard spheroidizing equipment. The pellets are coated with a film after drying to delay dissolution. Gelatin 6 1W825 谬 # # A *Sergeant • = A film-coated round granule that is effective for filling the treatment. The round particles of the active ingredient which are released at different release rates can be combined with gelatin capsules to obtain the desired release rate and blood content. During the extrusion process, heat build-up occurs;;: 仏: it causes the extrudate to be too dry to be easily converted into round pellets from the extruded cylinder. In U.S. Patent No. 493,993, propyl fluorenyl cellulose 22 〇 8 is added to venlafaxine hydrochloride - microcrystalline cellulose mixture by extrusion granulation into irregular °; nucleus, as a drug-containing Round core. Although a better circle φ = can be obtained, it is time consuming and costly due to multiple transfer operations. It is still complicated for the preparation method which is easy to make and has a good uniformity. U.S. Patent No. 4,138,475 discloses a sustained release pharmaceutical composition comprising a hard gelatin capsule filled with a spheroidal body coated with a microalcellulose blended propanol film, wherein the film is coated The layer consists of ethylcellulose, which is required to be composed of hydroxypropylmethylcellulose and/or a plasticizer. The patent application No. 861 02797 (Announcement No. 493993) is a "long-acting formulation of venlafaxine hydrochloride", which is characterized in that the preparation contains a spheroid, the spherical shape The body comprises from 3% to (iv) venlafaxine hydrochloride '5 runs 7 phthalocyanine cellulose, and Q25% to the job, propyl methyl cellulose, the spheroid is coated with 80% to 902⁄4 A film coating of ethyl "cellulose and 10% to 20% hydroxypropyl methylcellulose. = I (4) No. 2 (see No. S 555568); "--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- It is substantially free of propylmethylcellulose, and contains from 3% to 4% of venhfaxine salt strontium salt and from 6% to 7% by weight of microcrystalline cellulose (by 7 1343825 The spheroid core weight), and the coating contains 80% to 90% by weight of ethylcellulose' and 10% to 20% by weight of hydroxypropylmethylcellulose (by weight of the coating) ). In the above-mentioned method for preparing a long-acting formula of venlafaxine hydrochloride, the method of the patent application No. 86102797 (Announcement No. 493993) adopts the traditional mixed nuclear method. Mixing a mixture containing venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose into an irregular round core as a medicated round core core due to transfer operations Many times, it is time consuming and costly. The method of the patent application No. 861 02797 A01 (Announcement No. 555568) is the same as the method of the aforementioned application, except that the core of the pellet is substantially free of hydroxypropyl methylcellulose. In this process, although the preferred pellets can be obtained, the transfer operation is repeated several times, which is time consuming and costly. It is still complicated to find a preparation method that is simple and easy to insert and has a good uniformity. There is a general problem with the preparation of the above-mentioned conventional processes, that is, a capsule containing venlafaxine hydrochloride, the content of which is microcrystalline cellulose-containing 10,000 in a conventional method. The core of venlafaxine hydrochloride granules has a large particle size difference. Since venlafaxine hydrochloride has been shown to be an extremely water-soluble drug (5 72 mg/ml water), it is completely unpredictable to obtain a sustained release formulation. Several attempts to prepare sustained release tablets by hydrogel techniques have proven difficult because the compressed tablets have been so rapidly dissolved in the dissolution test. It is mentioned in the literature that the tablet prepared as a hydrogel sustained-release preparation of 8 ^ 43825 produces 40-45% dissolution in 2 hours 'dissolving 60-7 0% in 4 hours' dissolved in 85 hours at 8 hours. 1 0 0%. In summary, there are still many problems with both venlafaxine pharmaceutical compositions and related manufacturing methods, which need to be further overcome and solved. SUMMARY OF THE INVENTION In view of the disadvantages and disadvantages of a pharmaceutical composition comprising venlafaxine or a hydrochloride thereof, which is a highly water-soluble pharmaceutical composition, the present invention provides a water-soluble pharmaceutical composition. The sustained-release effect = the composition of the music contains the venlafaxine or its hydrochloride as a reactive music for the patient to use. In order to solve the above-mentioned question rhyme, the gentleman & αη gate shouted that the invention is related to the kind of continuous release medicine combination core of the kind of right lylafaxine ^:} main road: is» wan une) The round granules, the drug-loading layer and the batch a include 把.Μ ^ wherein the drug-loading layer comprises an effective amount of venlafaxine, the controlled-release layer comprises a controlled release lysing agent, and the drug-loading agent is coated with the core circle On the coarse, the γ controlled release layer is both the & release layer located outside the drug-loaded layer. Preferably, the controlled release layer is further provided with a drug carrier layer and a controlled release layer of the group _. The upper Pft setting is better, and the middle 兮 ” ” 垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓垓以上以上以上以上 Φ Φ Φ Φ Φ Φ Or - sugar, starch, mannitol, # φ β flying species selected from the group consisting of emulsified sodium, potassium carbonate, hydrazine + gan-%; sodium silicate, chlorobar I, alginate, talc, s-acid, Stearate, micro-knot_TiO2, triethyl citrate, lemon 醆二^ to ethylene glycol, citrate-butyl hydrazine, triacetic acid chlorpyrifos 1 acid rot, 峨i 9 iJ43825 ^ acid three More preferably, the core granules are selected from the group consisting of sucrose core round granules, sucrose and starch core round granules and microcrystalline cellulose core round granules. The composition of the group 'in the group.' Preferably, wherein the drug-loading layer further comprises a binder, a plasticizer or a diluent. More preferably, the binder contained in the drug-loading layer is one or Species selected from the group consisting of polyethylene tetrahydrofuranone (pvp), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl fibrin (HPC), hydroxypropyl Mercapto cellulose (HpMc), ethylene acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl decyl fiber phthalate ( HpMcp), ^ 笨曱纤维素 cellulose (CAP), xanthan gum, alginic acid, alginate, methacrylic acid methacrylate copolymer, copolymerized comparable, endoic acid / A A group of acrylic acid or polyethylene acetate phthalate (ρνΑρ^). More preferably, the drug layer contains one or more diluents selected from the group consisting of lactose, starch, and mannitol. , sodium hydroxymethyl cellulose, glycerol; sodium iron powder, sodium chloride, potassium carbonate, pigment 'sea algae salt, talcum powder, two, titanium oxide 'stearonic acid, stearic acid salt, microcrystalline fiber , propylene triterpenoids ' 7 _ ^ —• alcohol, poly gt; diol, bark acid triethyl sulphate; tributyl citrate propyl triacetate, calcium sulphate, trisodium phosphate, sulphur sulphate, Cyclodextrin starch and the group of cattle in the group of hemp oil. More preferably, the plasticizer contained in the drug-loading layer is one kind or one kind Choose from the group consisting of glycerol, polyethylene glycol, triethyl citrate 'Lemon saponin 1343825 ester, propyl triacetate, diethyl phthalate and dibutyl phthalate More preferably, the anti-adhesive agent contained in the drug-loading layer is one or more selected from the group consisting of talc, stearic acid, stearate, sodium stearyl fumarate and twenty-two A group consisting of glyceryl behenate, kaol in, and colloidal ceria (aer〇si 1). Preferably, the controlled release layer further comprises an anti-adhesive agent and a plasticizer. More preferably, the controlled release layer contains one or more of the controlled release agents selected from the group consisting of ethyl cellulose (EC) 'propyl methyl cellulose (HpMC) and methacrylic acid methacrylate copolymerized. Among the groups of things. More preferably, the controlled release layer contains one or more anti-adhesive agents selected from the group consisting of talc stearic acid, stearic acid ester, sodium stearyi fumarate and behenic acid. A group of glycerides (giyceryi behenate), kaolin (kaolin), and colloidal cerium oxide (aer〇sii). More preferably, wherein the controlled release layer contains one or more plasticizers selected from the group consisting of glycerol, polyethylene glycol, triethyl citrate, tributyl citrate, propyl triacetate, and acid In the group consisting of diethyl phthalate and dibutyl phthaUte. More preferably, the plasticizer contained in the controlled release layer is polyethylene glycol or triethyl citrate.

較佳的疋，其中載藥層包含約20至約35%(W/W)萬拉法辛或其鹽酸鹽D 11 1343825 更佳的是’其中載藥層進而包含約3至約10%(；w/w)乙基纖維素（N F)。更佳的是’其係包含約3〇至約40%(W/W)核心圓粒、約20至約35%(W/W)萬拉法辛或其鹽酸鹽類，和約5至約 20%(W/W)控釋層。更較佳的是，其係包含約35%(W/W)核心圓粒，約 30/D(W/W)萬拉法辛或其鹽酸鹽類，和約丨〇至約丨6%(w/w) 之控釋層。Preferably, the drug-loading layer comprises from about 20 to about 35% (w/w) venlafaxine or its hydrochloride D 11 1343825. More preferably, wherein the drug-loading layer further comprises from about 3 to about 10% (; w/w) ethyl cellulose (NF). More preferably, it comprises from about 3 to about 40% (w/w) core rounds, from about 20 to about 35% (w/w) venlafaxine or its hydrochloride, and from about 5 to about 20% (W/W) controlled release layer. More preferably, it comprises about 35% (w/w) core rounds, about 30/D (W/W) venlafaxine or its hydrochloride, and about 丨 to about 6% ( The controlled release layer of w/w).

較佳的是，該控釋層包含約80至90%(W/W) 素和約 10 至 2〇%(W/W)酸二丁酯（dibutyl phthalate)。本發明另相關於一種含有萬拉法辛的持續釋出型醫藥組合物之製法，其係包含：提供一核心圓粒； a tai t (b )於核心圓粒上包覆一層或多層載藥層，該載藥層含有萬拉法辛作為活性成分；層 )於（b )步驟所得產物上包覆一層或多層控釋，該控釋層含有溶離控釋劑； (d )選擇性重覆操作（b )及（c )步驟。較佳的是’核心圓粒係以濕式造粒方式製造。 ::佳的疋’核心圓粒粒徑為。.5至〇. 85厘米。 ^的疋’❹層係以噴搶噴出霧化方式進行包覆。 =的是’控釋層係以喷搶噴出霧化方式進行包覆。合物：Π目關於—種含有萬拉法辛的持續釋出型醫藥、匕種或多種根據申請專利範圍f 1項之含 12 丄有萬拉法辛的持續釋出型醫藥組合物。 :於本發明所提供具緩釋效果的醫藥層均勻地分佈且包覆於不含活性成分之核心卞物的溶離有較佳的均―性。圓粒上，使樂包人Π#根據本發明提供具有緩釋效果的醫藥組合物，毕植人物法辛或其鹽酸鹽類作為活性成份的緩釋劑型醫二。勿’可提供維持人體在一定的時間Preferably, the controlled release layer comprises from about 80 to 90% (w/w) and from about 10 to about 2% (w/w) dibutyl phthalate. The invention further relates to a method for preparing a sustained release pharmaceutical composition comprising venlafaxine, comprising: providing a core round particle; a tai t (b) coating one or more layers of drug on the core round particle a layer containing venlafaxine as an active ingredient; a layer) coated with one or more layers of controlled release on the product obtained in the step (b), the controlled release layer containing a release controlled release agent; (d) selective repeating Operate steps (b) and (c). Preferably, the core pellets are produced by wet granulation. :: Jia's core particle size is . .5 to 〇. 85 cm. The 疋'❹ layer is coated by spray blasting and atomization. = The 'controlled release layer' is coated by spray blasting atomization. Compound: A sustained-release pharmaceutical composition containing venlafaxine, a medicinal compound containing venlafaxine, or a plurality of sustained-release pharmaceutical compositions containing venlafaxine according to the scope of patent application f1. The drug layer having the sustained release effect provided by the present invention is uniformly distributed and the dissolution of the core material coated with the active ingredient has better uniformity. On the round granules, the medicinal composition having a sustained release effect, the medicinal composition of the physicochemical group or the hydrochloride thereof is used as the active ingredient. Do not provide for maintaining the human body for a certain period of time

續劑量的血中含量。 ’ m 【實施方式】、本發明提供一種包含萬拉法辛鹽酸鹽作為活性藥物成伤的持續釋放之醤藥組合物製劑，係由卜[2-(雙曱氨基）一The blood content of the continuous dose. The present invention provides a sustained release anti-drug composition preparation comprising venlafaxine hydrochloride as an active drug, which is composed of [2-(biguanidino)-

卜（4-曱氧苯基）乙基]環己醇鹽酸鹽與膜衣形成劑所植成。以微粒膠囊化技術形成載藥之含藥圓粒，再加上控釋層包覆以提供所要程度之溶離，一般約5到約20百分比 (W/W)，於約】5到約】8百分比”“）獲得最佳之結果。在本發明之較佳具體實施例中，本發明所提供具以緩釋效果的醫藥組合物，其包括約2〇至35%(w/w)活性成分，較佳係為萬拉法辛或其鹽酸鹽類，約3〇至約4〇%(w/w)核心圓粒1約3至約l〇%(W/W)乙基纖維素（NF)、和約5到約2〇%(w/w) 控釋層。更較佳地，該醫藥組合物包括約3〇%(w/w)活性成分’較佳係為萬拉法辛或其鹽酸鹽類，約35%(w/w)核心圓粒’約5%(W/W)乙基纖維素（Aquacoat®ECD30，其具有30% 固形物含量水溶液之N.M.T. 150 cps之黏度和24 5-29 5% 之乙基纖維素含量），及1〇至16%(W/W)控釋層。 13 1343825 該控釋層係由80至90%(W/W)乙基纖維素（NF)和1〇至 2 0%(W/W)酸二丁 S旨（dibutyl phthalate)所組成。較佳乙基纖維素具有44.0-51%的乙氧基含量和5%水溶液之 5〇cps黏度。在本發明中較佳係使用Aquacoat® ECD30的乙基纖維素。下列名詞對發明所屬技術領域中具有通常知識者而 ° 可以充分理解；下列定義係為避免在本發明的具體實施例中任何意義不明確的解釋。Bu (4-indolylphenyl)ethyl]cyclohexanol hydrochloride is formed with a film forming agent. The microparticle encapsulation technique is used to form a drug-containing granule containing a drug, and a controlled release layer is coated to provide a desired degree of dissolution, generally from about 5 to about 20 percent (W/W), from about 5 to about 8 The percentage "") gets the best results. In a preferred embodiment of the present invention, the present invention provides a pharmaceutical composition having a sustained release effect comprising about 2 to 35% (w/w) of an active ingredient, preferably venlafaxine or Its hydrochloride salt, from about 3 Torr to about 4% by weight (w/w) of core round granules 1 from about 3 to about 10% (w/w) ethylcellulose (NF), and from about 5 to about 2% (w/w) Controlled release layer. More preferably, the pharmaceutical composition comprises about 3% (w/w) active ingredient 'preferably venlafaxine or its hydrochloride salt, about 35% (w/w) core round granules 'about 5 %(W/W) ethylcellulose (Aquacoat® ECD30 with a 30% solids aqueous solution NMT 150 cps viscosity and 24 5-29 5% ethylcellulose content), and 1 to 16% (W/W) controlled release layer. 13 1343825 The controlled release layer consists of 80 to 90% (w/w) ethyl cellulose (NF) and 1 to 20% (w/w) dibutyl phthalate. Preferably, the ethyl cellulose has an ethoxy group content of 44.0 to 51% and a viscosity of 5 〇 cps of a 5% aqueous solution. In the present invention, ethylcellulose of Aquacoat® ECD30 is preferably used. The following terms are generally understood by those of ordinary skill in the art to which the invention pertains; the following definitions are intended to avoid any ambiguous interpretation in the specific embodiments of the invention.

本發明所使用之專有名詞r緩釋效果』意指可以穩定、缓慢且持續之方式釋放活性成分至血液中。較佳係於24 小Θ内血中之活性成分濃度維持穩定。本Ίχ明其他的特徵及優點將可明顯見於下列較佳具體事實及申請專利範圍。貫施例.製造含有活性成分為萬拉法辛或其鹽酸鹽類之醫藥組合物本么明所製作之持續性釋放劑型，不限於用於本發明 =丁之萬拉法辛或其鹽酸鹽類，而可適用於各類具有高义 4 解度之藥物’包含 Fluoxetine、Fluvoxamine、The term "sustained release effect" as used in the present invention means that the active ingredient can be released into the blood in a stable, slow and sustained manner. Preferably, the concentration of the active ingredient in the blood of 24 hours is maintained stable. Other features and advantages of the present invention will be apparent from the following detailed description and claims. The pharmaceutical composition containing the active ingredient is venlafaxine or its hydrochloride is a sustained release dosage form prepared by the present invention, and is not limited to use in the present invention = venlafaxine or its hydrochloride Class, but applicable to all kinds of drugs with high resolution 4's containing Fluoxetine, Fluvoxamine,

Par〇xetine、GauL aiantamine。本發明之持續釋放劑型，主要包括： A、提供一核心 if] J.A.,. 1 t 圓拉该核心圓粒可為利用不具藥物 >舌性之賦形劑制借，#丄，、八中賦形劑種類可為乳糖、澱粉、甘露醇、羧曱基纖維 _ ’、’、甘一醇截粉鈉、氣化納、氣化鉀、色素、海藻酸鹽、滑杨—氧化鈦、硬酯酸、硬酯酸鹽、 14 1343825 微結晶纖維素、丙三醇、聚乙二醇'檸檬酸三乙酯、檸樣酸二丁酯、二乙酸丙酯、峨酸氫妈、罐酸三納 '硫酸弼、環糊精澱粉或蓖麻油。同時，核心圓粒亦可為直接自供應商靖得’一般可商業購得之核心圓粒種類包含（丨）萬糖核心圓粒、（2)蔗糖及澱粉之核心圓粒、（3)微結晶纖維素之核心圓粒。 B、將含有活性成分之載藥層包覆於前述核心圓粒上，其中載藥層可為包含活性物質、抗黏劑、必要時可添加黏合劑' 可塑劑或其他稀釋劑。其中，黏合劑可為聚乙稀四氫嫠咯酮（PVP)、明膠、羥乙基纖維素（HEC)、羥丙基纖素 (HPC)、羥丙基曱基纖維素（HPMC) '乙烯乙酸鹽（VA)、聚乙烯醇（PVA)、曱基纖維素（MC)、乙基纖維素（EC)、羥丙基甲基纖維苯二甲酸鹽（HPMCP)、乙酸苯二甲基纖維素 (CAP)、三仙膠（xanthan gum)、海藻酸、海藻酸鹽、曱基丙稀酸曱基丙稀酸酯共聚物（Eudragi t，商品名）、共聚之曱基丙烯酸/曱基丙烯酸曱酯或聚乙烯乙酸苯二曱酸酯 (PVAP)。其中’稀釋劑可為乳糖、澱粉、甘露醇、羥曱基纖維素鈉、甘二醇澱粉鈉、氣化鈉、氯化鉀、色素、海藻酸鹽、滑石粉、二氧化鈦、硬酯酸、硬酯酸鹽、微結晶纖維素、丙三醇 '聚乙二醇、檸檬酸三乙酯；檸檬酸三丁酯、三乙酸丙酯、磷酸氫鈣、磷酸三鈉、硫酸鈣 '環糊精澱粉及蓖麻油。其中’可塑劑可為丙三醇、聚乙二醇、檸檬酸三乙醋、檸檬酸三丁酯、三乙酸丙酯' 酸二乙酯（diethy 1 phthalate)及酸二丁酷（dibutyl phthalate)。其中’ 15 1343825 =黏劑可為滑石粉、硬㈣、硬酿酸鹽、延胡索硬醋酸納 s〇dlum stearyi f鳴他）及：十二酸甘㈣⑷乂。㈣ behenate) 、 π x c i i , \ 呵領土（kaolln)、膠體二氧化矽（aer〇sil)。將具有緩釋效果的控釋層係包覆於載藥層外側，控釋^可為既有任一型態可達延緩釋放目的之化合物。 D、視需要地，依次再將載藥層及控釋層間隔包覆。、萬拉法辛為一種具有高度溶解型之藥物，為使其 I於服用後在▲液中持續且緩慢釋出，本發明人在此提出種包含萬拉法辛或其鹽酸鹽作為活性成份的口服持續性釋放之醫藥組合物製劑’其主要使活性成份包覆於一核心上形成載藥層’並於載藥層上再覆蓋-層控釋層，以達到緩釋之目的。。月參考第一圖’本發明之含有萬拉法辛(venlafaxine) 口服持續性釋放之醫藥組合物製劑，其結構將配合製作方法所製之含有萬拉法辛（venlafaxine)鹽酸鹽口之圓粒製劑加以說明，雖該製劑係以萬拉法辛 (venlafaxine)鹽酸鹽進行說明，但本發明實不限於萬拉法辛（Venlafaxine)鹽酸鹽，一般高水溶性之藥物皆可應 :發月所提供之製作方法以形成緩釋劑型；而圓粒製劑之橫斷面為一圓形，但本發明製劑之形狀可為任何合適之形狀’如旋劑、微鍵劑（miniiablet)而不限於劑。包覆該口服用圓粒製劑包括：一核心圓粒（z ) 16 !343825 在核心1U“ 1 )之外的載藥^ 乙）及一包覆在載樂層 (2)之外的控釋層（3)。 ,, 赞明之口服用製劑，所製成之含有萬拉法辛（venlafaY;n 、日人甘 e)鹽酸鹽口服用製劑可再此&其他賦形劑或單獨做成藥 „s . 削里早位之樂品，例如做成顆粒劑、充填在膠囊或打成錠。為了解本發明之含有葸知，土 Α ^ 择…3有萬拉去辛(venlafaxine) 口服持，性釋放之醫樂組合物之成份法如下· μ及m細說明其製作方 (a )首先，將藥劑上可斗，戋又之賦形劑，製成核心圓拉（1 )，其製造之方式可為,丑4,、Λ ~r ^ 為屋式k粒。所使用之造粒機可為biL動床造粒機。在本步驟冬/驟中’核心圓粒（1 )較佳具 .至〇.85關之粒徑。若為錠劑或微錠劑時，則尚以直打方式造粒，如使用扣機’此時鍵劑較佳亦且有3 ~ 5 m m之片徑。 ' )”人將萬拉法辛（venlafaxine)鹽酸鹽成复㈣及抗點劑’溶於或懸浮於上述溶液或懸浮液中，必要 :加點合劑、可塑劑或其他稀釋㈣，形成載藥物溶液于液。在步驟（b)中’係利用噴搶噴出霧化之載華溶液或懸浮液至核心圓粒…，包覆後並乾燥之。經；燥後的栽藥層（2 )内，較佳的β ^ ^ ^ , 粒侄的疋，萬拉法辛（venlafaxine) 酸鹽的比例為約20至35%(W/W)，黏合劑的比㈣約5至20%(W/W)，可塑劑比例為約〇至i〇%(w/w)，抗點劑比例為約〇. 5至3 〇% (w/W)。 (c )取i ’將溶離控釋劑、可塑劑、抗黏劑與溶劑配製成控釋層膜衣溶液，圓私,0 立嘴後到步驟（b )所得之載藥。二（2 )，乾燥後升多成於釋禺r 0、用哈m y玖控釋層（3 )。在本步驟中亦使驟：麗佈且。液。其中’溶離控釋劑可相同或不同於步所用1 m使用者；可塑劑係可相同或不同於步驟（a ) ,t 其中’控釋層的抗黏劑可為滑石S、硬酯酸、硬 =鹽 '延胡索硬醋酸納（sodlum⑽叫fumarate)及 m ^ (glyceryl behenate) ^ ^ % i (kaolin) ' 二Γ—氧化♦(AerGSl1)。纟中，調製控釋層所使用之溶。為水乙醇、丙酮、異丙醇、二氣甲烷或其混合物。車又佳的疋，在本發明中的載藥層係利用約^蚁含有队4%自由驗）（w/w)之萬拉法辛或其鹽酸鹽，動基纖維 # 〇,80/^宁椽酸二乙酯（triethyl citrate)之混合物與39. 0%水混合，使該混合物均勻包覆於中性糖蕊而形成所述之載藥層。使已包覆載藥層的圓粒過篩以篩選獲取直牷介於 0·85μιη(20 mesh)至 1· ΐ8μιη(16 mesh)間的圓粒，該粒徑大小係提供包覆控釋層膜衣之用。而在本發明較佳具體實施例中，控釋層係利用攪拌 70. 8%乙基纖維素 NF(Aquacoat® ECD30)，和 14. 2% 酸二丁酷（dibutyl phthalate)與水形成 24. 0%(w/v)之混合物，，喷覆於前述已包覆載藥層之圓粗。在本發明中’另利用未包覆之載藥層圓粒，使其直接包覆控釋層膜衣溶液供應以獲得1 9%包覆含量之持續釋放、控釋層膜衣包覆之圓粒以作為對照。或後’將已包覆控釋層之圓粒’即具有三層結構之圓 18 1343825 粒’過篩以篩選直徑介於1 · 1 8μιη( 1 6 mesh)至1. 40μπι( 1 4 mesh)間的圓粒，並將該圓粒依照既有方法填充於硬明膠膠囊中。實施例二：配方組成（一）配方組成：Par〇xetine, GauL aiantamine. The sustained release dosage form of the present invention mainly comprises: A. providing a core if] JA,. 1 t round pulling the core round particles can be borrowed from an excipient without a drug > tongue, #丄, ,八中The types of excipients may be lactose, starch, mannitol, carboxymethyl group fibers _ ', ', glycerol powder sodium, gasified sodium, potassium carbonate, pigment, alginate, slippery-titanium oxide, hard Ester acid, stearate, 14 1343825 microcrystalline cellulose, glycerol, polyethylene glycol 'triethyl citrate, dibutyl citrate, propyl diacetate, hydrogen citrate, can acid three Na's barium sulfate, cyclodextrin starch or castor oil. At the same time, the core round pellets can also be directly from the supplier Jingde's generally commercially available core round pellets containing (丨) million sugar core round pellets, (2) core pellets of sucrose and starch, (3) micro The core round of crystalline cellulose. B. The drug-loading layer containing the active ingredient is coated on the core round particle, wherein the drug-loading layer may be an active substance, an anti-adhesive agent, and if necessary, a binder 'plasticizer or other diluent. Among them, the binder may be polyethylene tetrahydrofuranone (PVP), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl fibrin (HPC), hydroxypropyl fluorenyl cellulose (HPMC) 'ethylene Acetate (VA), polyvinyl alcohol (PVA), mercapto cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl fiber phthalate (HPMCP), benzyl acetate fiber (CAP), xanthan gum, alginic acid, alginate, mercaptopropyl acrylate copolymer (Eudragi t, trade name), copolymerized methacrylic acid/mercaptoacrylic acid An oxime ester or a polyvinyl acetate phthalate (PVAP). Among them, 'diluent can be lactose, starch, mannitol, sodium hydroxymethyl cellulose, sodium glycerol starch, sodium gasification, potassium chloride, pigment, alginate, talc, titanium dioxide, stearic acid, hard Ester, microcrystalline cellulose, glycerol 'polyethylene glycol, triethyl citrate; tributyl citrate, propyl triacetate, calcium hydrogen phosphate, trisodium phosphate, calcium sulfate 'cyclodextrin starch And castor oil. Among them, the plasticizer can be glycerin, polyethylene glycol, triethyl citrate, tributyl citrate, propyl triacetate, and dibutyl phthalate. . Among them, ' 15 1343825 = adhesive can be talcum powder, hard (four), hard-gum, sodium sulphate, s〇dlum stearyi f) and: lauric acid (four) (4) 乂. (4) behenate), π x c i i , \ territory (kaolln), colloidal cerium oxide (aer〇sil). The controlled release layer having a sustained release effect is coated on the outer side of the drug-loading layer, and the controlled release can be a compound having any type of delayed release. D. Optionally, the drug-loaded layer and the controlled release layer are sequentially coated. Venlafaxine is a highly soluble drug, and the present inventors have proposed to contain venlafaxine or its hydrochloride as active in order to make it sustained and slowly released in ▲ liquid after administration. The pharmaceutical composition preparation for oral sustained release of the ingredient 'which mainly coats the active ingredient on a core to form a drug-loading layer' and overlies the layer on the drug-loaded layer to achieve sustained release. . Referring to the first figure, the pharmaceutical composition preparation containing venlafaxine oral sustained release of the present invention has a structure which is combined with a venlafaxine hydrochloride salt prepared by the production method. The granule preparation is described. Although the preparation is described by venlafaxine hydrochloride, the present invention is not limited to venlafaxine hydrochloride, and generally high water-soluble drugs can be used: The preparation method provided by the hair to form a sustained release dosage form; and the round pellet preparation has a circular cross section, but the shape of the preparation of the invention may be any suitable shape such as a spinner or a miniiablet. Not limited to agents. The coated round granule preparation comprises: a core round granule (z) 16 ! 343825 loaded with a drug outside the core 1U " 1 ) and a controlled release coated outside the layer ( 2 ) Layer (3), ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Pharmacy „s. Cut the early music, for example, into granules, filling in capsules or ingots. In order to understand the 葸 , , , , , , , ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven fa ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven ven The core can be made into a core round pull (1), and the manufacturing method can be ugly 4, Λ ~r ^ is a house type k grain. The granulator used can be a biL moving bed granulator. In this step winter/success, the core pellet (1) preferably has a particle size of .85. In the case of a lozenge or a micro-tablet, it is granulated by a straight-through method, such as the use of a button. The key agent is preferably also a sheet diameter of 3 to 5 m. ')" venlafaxine hydrochloride complex (four) and anti-dot agent 'dissolved or suspended in the above solution or suspension, necessary: add a mixture, plasticizer or other dilution (four), the formation of drugs The solution is in the liquid. In the step (b), the atomized Chinese solution or suspension is sprayed to the core round particles by spraying, and then coated and dried. After drying, the drug layer (2) is dried. Preferably, β ^ ^ ^ , 侄侄 , venlafaxine acid salt ratio is about 20 to 35% (W / W), binder ratio (four) about 5 to 20% (W / W), the ratio of plasticizer is about 〇 to i〇% (w/w), and the ratio of anti-dosing agent is about 〇. 5 to 3 〇% (w/W). (c) taking i 'will release controlled release agent, The plasticizer, the anti-adhesive agent and the solvent are formulated into a controlled release layer film coating solution, and the drug is obtained from the step (b) after the mouth is closed. The second (2) is dried and then increased to a release. Controlled release layer (3) is used in this step. In this step, the solution is also: Libu and liquid. The 'dissolved controlled release agent can be the same or different from the 1 m user used in the step; the plasticizer can be the same or Different from step (a), t where 'controlled release layer The adhesive can be talc S, stearic acid, hard = salt 'fusedil sodium acetate (sodlum (10) called fumarate) and m ^ (glyceryl behenate) ^ ^ % i (kaolin) 'dioxin-oxidized ♦ (AerGSl1). , modulating the dissolution of the controlled release layer, which is water ethanol, acetone, isopropanol, di-halogen methane or a mixture thereof, and the car-loading layer in the present invention utilizes about 4% of the ants. Free test) (w/w) of venlafaxine or its hydrochloride, actinic fiber # 〇, 80 / ^ triethyl citrate mixture with 39.0% water, so that The mixture is uniformly coated on the neutral sugar to form the drug-loading layer. The round particles coated with the drug-loading layer are sieved to obtain a straight 牷 between 0·85 μm (20 mesh) and 1·ΐ8 μιη (16 And 8% of ethyl cellulose NF (in the preferred embodiment of the present invention, the controlled release layer is agitated with 70. 8% ethyl cellulose NF ( Aquacoat® ECD30), and 14.2% dibutyl phthalate and water form a mixture of 24. 0% (w/v), sprayed onto the rounded coating of the previously coated drug layer. In the present invention, the uncoated coated drug layer is used to directly coat the controlled release layer film coating solution to obtain a sustained release, controlled release layer coating coated round pellet of 1 9% coating content. Or as a control. Or after the 'rounded particles of the controlled release layer', that is, a circle having a three-layer structure of 18 1343825 particles is screened to have a diameter ranging from 1 · 1 8 μm (1 6 mesh) to 1. 40 μπι ( The round particles between 1 4 mesh) are filled in hard gelatin capsules according to the existing method. Example 2: Formulation composition (1) Formula composition:

(1 )核心： 270克 (2 )載藥層：萬拉法辛（venlafaxine)鹽酸鹽 280克乙基纖維素（Aquacoat®ECD30) 111.87 克檸檬酸三乙酷（triethyl citrate ) 6.53 克二氧化鈦（Ti02) 9·9克滑石粉（talc ) 66克純水 210毫升 (3 )控釋層：乙基纖維素（Aquacoat®ECD30) 155.8 克酸二丁 S旨（dibutyl phthalate) 9.35 克二氧化鈦（Ti02) 1.65 克滑石粉（talc ) 8_25 克純水 100毫升製造過程 (1 )先將乙基纖維素111. 8 7克’檸檬酸三乙酯6. 5 3 克配與21 0毫升的純水配製成水溶液； (2 )將萬拉法辛（veniafaxine)鹽酸鹽280克，溶解或懸浮於前述（1 )項溶液中； (3 )其次，將二氧化鈦9 · 9克及滑石粉6 6克加入 19 月ίι述（2 )項溶液中配製成懸机動床造粒機内之核心，加以之圓粗核心；浮液，再將此載藥溶液嗔到包覆並乾燥之’即可得載藥 (4 )最後將乙基纖維素1 55, 8克，兄 a义—丁酯9· 35 克 '二氧化鈦1, 65克、滑石粉8, 25克盥1 〇〇奎& , 凡” 1 υ u毫升純水配製成懸浮液，將控釋層膜衣溶液噴到前述步驟（3 )之載藥圓粒核心作為控釋處理。實施例二：配方組成（二）(1) Core: 270 g (2) drug carrier: venlafaxine hydrochloride 280 g ethylcellulose (Aquacoat® ECD30) 111.87 g Triethyl citrate 6.53 g titanium dioxide ( Ti02) 9·9 g of talc (talc) 66 g of pure water 210 ml (3) Controlled release layer: Ethylcellulose (Aquacoat® ECD30) 155.8 g Dibutyl phthalate 9.35 g Titanium dioxide (Ti02) 1.65 g talc powder (talc) 8_25 g pure water 100 ml manufacturing process (1) firstly prepare ethyl cellulose 111. 8 7 g 'triethyl citrate 6. 5 3 g with 21 0 ml of pure water (2) 280 g of venlafaxine hydrochloride dissolved or suspended in the above solution (1); (3) secondly, 9 9 g of titanium dioxide and 6 g of talc In the ίι (2) solution, it was formulated into the core of the suspension motorized bed granulator, and the core was rounded; the liquid was floated, and the drug-loaded solution was then coated and dried to obtain the drug. (4) Finally, ethyl cellulose 1 55, 8 g, brother a-butyl ester 9 · 35 g 'titanium dioxide 1, 65 g Talc powder 8, 25 g 盥 1 〇〇 &&, where "1 υ u ml of pure water is formulated into a suspension, and the controlled release layer coating solution is sprayed to the core of the drug-loaded pellet of the aforementioned step (3) as a control Release treatment. Example 2: Formulation composition (2)

配方組成： (1)核心： (2 )載藥層：萬拉法辛（venlafaxine)鹽酸鹽乙基纖維素（Aquacoat®ECD30) 檸檬酸三乙 g| (triethyl citrate) 二氧化鈦（Ti02) 滑石粉（talc )Formulation composition: (1) Core: (2) Drug carrier: venlafaxine hydrochloride ethyl cellulose (Aquacoat® ECD30) triethyl citrate (triethyl citrate) titanium dioxide (Ti02) talcum powder (talc)

270克 280克 111.87 克 6.53 克 9.9克 66克 210毫升 220克 13.2 克 19.8 克 120毫升純水 (3)控釋層：曱基丙烯酸甲基丙烯酸酯共聚物 (Budragit® NE30D) 酸二乙酯（diethyl phthalate) 滑石粉（talc ) 純水製造過程 (1 )先將乙基纖維素111.87克，檸檬酸三乙龍6 53 20 U43825 克配與21 0毫升的純水配製成水溶液； (2 )將萬拉法辛（veniafaxine)鹽酸鹽28〇克，溶解或懸浮於前述（1 )項溶液中； (4 )最後將甲基丙烯酸曱基丙烯酸酯共聚物1 5〇克，酸二乙酷1 3. 2克、滑石粉1 9. 8克與1 20毫升純水配製成懸浮液，將控釋層膜衣溶液噴到前述步驟（3 )之載藥圓粒核心作為控釋處理。實施例四：配方組成（三）配方組成： (1 )核心： 300克 (2 )載藥層：萬拉法辛（venlafaxine)鹽酸鹽 254克曱基丙烯醆甲基丙烯酸酯共聚物 180.8 ^ (Eudragit® NE30D) 檸檬酸三乙S旨（triethyl citrate ) 10-8 克二氧化鈦（Ti02) 9.0克滑石粉（talc ) 66克纯水 240毫升 (3 )控釋層：乙基纖維素（Aquacoat®ECD30) 155.8 X 酸二丁酯（dibutyl phthalate) 9.35 克二氧化鈦（Ti02) 1.65 克滑石粉（talc ) 8.25 克纯水 100毫升製造過程 21 1343825 (l )先將甲基丙烯酸曱基丙烯酸酯共聚物丨80.8克，挣核酸三乙龍1 〇. 8克配與24〇毫升的純水配製成水溶液； (2 )將萬拉法辛（veniafaxine)鹽酸鹽3〇〇克，溶解或懸浮於前述（1 )項溶液中； (3 )其次’將二氧化鈦9 〇克及滑石粉66克加入則迷（2 )項溶液中配製成懸浮液，再將此載藥溶液喷到 μ動床造粒機内之核心，加以包覆並乾燥之，即可得載藥之圓粒核心；270 g 280 g 111.87 g 6.53 g 9.9 g 66 g 210 ml 220 g 13.2 g 19.8 g 120 ml pure water (3) Controlled release layer: methacrylic acid methacrylate copolymer (Budragit® NE30D) Diethyl acid ( Diethyl phthalate) talc powder (talc) pure water production process (1) first ethyl cellulose 111.87 grams, triethyl citrate 6 53 20 U43825 grams with 21 0 ml of pure water into an aqueous solution; (2) 28 gram of venlafaxine hydrochloride, dissolved or suspended in the above solution (1); (4) finally methacrylic acid methacrylate copolymer 1 5 grams, acid and cool 1 3. 2 g, talcum powder 1 9. 8 g and 1 20 ml of pure water are formulated into a suspension, and the controlled release layer coating solution is sprayed to the drug-loaded round core of the above step (3) as a controlled release treatment. Example 4: Formulation composition (3) Formulation composition: (1) Core: 300 g (2) Drug-loading layer: venlafaxine hydrochloride 254 g hydrazino propylene methacrylate copolymer 180.8 ^ (Eudragit® NE30D) Triethyl citrate 10-8 g Titanium dioxide (Ti02) 9.0 g talc (talc) 66 g pure water 240 ml (3) Controlled release layer: Ethylcellulose (Aquacoat® ECD30) 155.8 Dibutyl phthalate 9.35 g Titanium dioxide (Ti02) 1.65 g Talc powder (talc) 8.25 g Pure water 100 ml Manufacturing process 21 1343825 (l) First methacrylate methacrylate copolymer 丨80.8 g, earning nucleic acid triethylon 1 〇. 8 g with 24 ml of pure water to prepare an aqueous solution; (2) venlafaxine hydrochloride 3 g, dissolved or suspended in the foregoing (1) in the solution; (3) secondly, adding titanium dioxide 9 gram and 66 g of talc powder into the suspension (2) solution to prepare a suspension, and then spraying the drug-loading solution onto the μ-moving bed granulation The core of the machine, coated and dried, can be loaded with drugs. Tablets core;

(4 )最後將乙基纖维素1 5 5 8克，酸二丁酯9 35 克、二氧化鈦1.65克、滑石粉8 25克與1〇〇毫升純水配製成懸浮液，將控釋層膜衣溶液噴到前述步驟（3 )之載藥圓粒核心作為控釋處理。實施例五：本發明所獲製之萬拉法辛醫藥組合物與既有產品（對照組）之比較(4) Finally, 1.55 g of ethyl cellulose, 9 35 g of dibutyl acid ester, 1.65 g of titanium dioxide, 8 25 g of talc and 1 ml of pure water were prepared into a suspension, and the controlled release layer was prepared. The film coating solution is sprayed onto the core of the drug-loaded pellet of the aforementioned step (3) as a controlled release treatment. Example 5: Comparison of venlafaxine pharmaceutical composition obtained by the present invention with existing product (control group)

市售萬拉法辛（venlafaxine)鹽酸鹽膠囊製品分別與本發明的實施例二、三、四作比較。經由分析在膠囊化最後經溶離控釋層包覆圓粒之溶解速率決定包覆層含量的可接接受量性。使用usp裝置 l(Basket)於l〇〇rpm，於〇.1N鹽酸溶液中，3rc進行溶離試驗。而一已知批次之經包覆圓粒按照所需之溶解速率研究釋出藥物太t曼’一部分未包覆之圓粒或具有低包覆膜含量之圓粒可加至該批次中，以徹底混合之後提供—種迅速增加血中藥物含量之負荷劑量。冑出藥物太迅速之經包覆圓粒批次可接受額外之薄膜塗料以產生所要之溶解分佈 22 圖試驗方法係將提佴乂 π m ,山，、斤要早位劑量含量之所需量，且由不同貫知例中所獲製的筮 a 4古亡E 萬拉法辛鹽酸鹽之經包覆圓粒的批 -人填充至硬明勝膠愈φ 15…… 別等於37·5毫克，75毫克和 Ι5ϋ宅克4拉法辛之筮 ^ + 萬拉法辛鹽酸鹽的量。依據美國藥i 所述之方法，於〗η η ’八 ^ ' rpm ’於0· 9升〇. IN HC1水溶液中，測定萬拉法辛鹽酸鹽緩釋膠囊之溶離。Commercially available venlafaxine hydrochloride capsule products are compared to Examples 2, 3, and 4 of the present invention, respectively. The acceptability of the coating content is determined by analyzing the rate of dissolution of the round coated particles by the dissolution-release layer at the end of the encapsulation. The dissolution test was carried out at 3 rc in a 1.1N hydrochloric acid solution using a usp apparatus l (Basket) at l rpm. And a known batch of coated round granules is released according to the desired dissolution rate. The drug is too t-man's part of the uncoated round granules or round granules with a low coating film content can be added to the batch. To provide a loading dose that rapidly increases the amount of drug in the blood after thorough mixing. If the drug is too fast, the coated round batch can accept additional film coating to produce the desired dissolution profile. The test method will increase the amount of π m , mountain, and kilograms required for the early dose. And the batch-man filled with round-grained granules of 筮a 4 ancient E Ehrafacine hydrochloride obtained in different known examples is filled to hard sheng jia φ 15... Not equal to 37· 5 mg, 75 mg and Ι 5 ϋ 克 4 Rafaxine 筮 ^ + venlafaxine hydrochloride amount. The dissolution of venlafaxine hydrochloride sustained-release capsules was determined in accordance with the method described in U.S. Patent 1, i. η η '8 ^ ' rpm ' in 0.99 liter. IN HC1 aqueous solution.

由使用本發明之經控釋層膜衣包覆之圓粒組成物已達成K凝膠技術不可能達成之所要的萬拉法辛鹽酸鹽之持縯性釋放劑型的溶解速率。請參閱第二至四圖所示萬拉法辛鹽酸鹽醫藥組合物釋放之效果。不同實施例中所獲製的含有均可使藥物的溶離達到零次The round particle composition coated with the controlled release film coat of the present invention has reached the dissolution rate of the sustained release dosage form of venlafaxine hydrochloride which is not possible with K gel technology. See the effects of venlafaxine hydrochloride pharmaceutical composition release as shown in Figures 2 to 4. The content obtained in different examples can make the dissolution of the drug reach zero times

根據本發明可作之不同修正及變化對於熟悉該項技術者而言均顯然不會偏離本發明的範圍與精神。耗本發明已敘述特疋的較佳具體事實，必須瞭解的是本發明不應被不當地限制於料特定具體事實上。事實i，在實施本發明之已述模式方面，對於熟習該項技術者而言顯而易知之不同修正亦被涵蓋於下列申請專利範圍之内。【圖式簡單說明】第—圖係本發明之含有萬拉法辛（venlafaxine) 口服持、’Λ性釋放之醫藥組合物之橫斷面示意圖。第圖係本發明之含有萬拉法辛（venlafaxine) 口服持續性釋放之醫藥組合物之實施例：與對照組的溶離率曲 23 線圖。秦第二圖係本發明之合亡t , 有萬拉法辛（venlafaxine) 口服持續性釋放之醫荸组a物樂、物之實施例三與對照組的溶離率曲 ·· 線圖。 . 第四圖係本發明之含有萬拉法辛（venlafaxine) 口服持續性釋放之醫藥組合物之實施例四與對照組的溶離率曲綉圖。、叉 • 【主要元件符號說明】 (1 )核心圓粒 (2 )載藥層 (3 )控釋層 24It is apparent to those skilled in the art that various modifications and variations can be made without departing from the scope and spirit of the invention. The present invention has been described in terms of preferred specific facts, and it must be understood that the present invention should not be unduly limited to the specific details. In fact, the various modifications that are apparent to those skilled in the art are also covered by the following claims. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic cross-sectional view of a pharmaceutical composition containing venlafaxine orally administered in accordance with the present invention. The figure is an example of the pharmaceutical composition of the present invention containing venlafaxine oral sustained release: a plot of the dissolution rate with the control group. The second picture is the combination of the present invention, the venlafaxine oral sustained release of the medical group, the third embodiment of the music, the dissolution rate of the control group and the control group · · line graph. The fourth panel is a plot of the dissolution rate of the fourth embodiment of the pharmaceutical composition containing venlafaxine orally sustained release of the present invention and the control group. , fork • [Main component symbol description] (1) core round particle (2) drug carrier layer (3) controlled release layer 24

Claims

1343825 Correction and replacement page for May, 100, 100. Patent application scope:

What is claimed is: 1. A sustained release pharmaceutical composition comprising venlafaxine comprising a core pellet, a drug-loaded layer and a controlled release layer, wherein the drug-loading layer comprises an effective amount of venlafaxine, a controlled release layer The controlled release lysing agent is included, and the drug-loading layer and the controlled-release layer are coated on the core granule, and the controlled-release layer is located outside the drug-loading layer, and the medium-controlled release layer further comprises a group of drug carriers arranged at intervals Layer and controlled release layer.

2. The sustained release pharmaceutical composition according to the scope of the patent application of the invention wherein the core pellet comprises _ or more than one excipient. 3. The sustained release pharmaceutical composition according to claim 2, wherein the excipient is one or more selected from the group consisting of lactose, mannitol, sodium ketamine, and glycol diol. Powder, gasified sodium, potassium carbonate, pigment, alginate, talc, titanium dioxide 'hard acid, hard acetate' microcrystalline cellulose, glycerol, polyethylene glycol, bar acid triglyceride , rod-like acid three-butyl, triacetate, cool, dish

:= Dance, carbonated sodium, sulfuric acid, cyclodextrin powder and sesame oil. 4. The patented composition, wherein the core granules and the starch core are in the round and microcrystalline groups. The continuous release medicine group of item 2 is selected from the group consisting of sucrose core round particles and sucrose cellulose core round particles. • If you apply for a patent, the drug-loaded layer is included in the continuous release pharmaceutical group of item 1, and contains a binder, a plasticizer or a dilution of 25 Γ 343825 η 6 . The continuous release pharmaceutical combination as claimed in item 5 of the patent application The adhesive contained in the drug-loading layer is one or more selected from the group consisting of polyethylene tetrahydropyrene (PVP), gelatin, hydroxyethyl cellulose (HEC), propyl propyl fibrin (HPC), Propylmethylcellulose (HpMc), ethylene acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (mc), ethyl cellulose (EC), hydroxypropyl methyl cellulose Salt (HPMCP), phenyldimethylcellulose acetate (CAp), Sanxian gum (xanthan)

A group consisting of gunO, alginic acid, alginate, methacrylic acid methacrylate copolymer, copolymerized methacrylic acid/methyl methacrylate or polyethylene phthalate (pVAP).

7. The sustained release pharmaceutical composition according to claim 5, wherein the drug-loading layer contains one or more diluents selected from the group consisting of lactose, starch, mannitol, sodium hydroxymethyl cellulose, and ganolic Alcohol sodium starch, sodium gasification, potassium hydride, pigment, alginate, talc, titanium dioxide, stearic acid, stearic acid ester, microcrystalline cellulose, glycerol, polyethylene glycol 'citric acid triethyl An ester; a group consisting of tributyl citrate, triethyl propyl propyl ester, calcium hydrogen phosphate, trisodium phosphate, calcium sulfate, cyclodextrin starch, and castor oil. 8. The sigma of the sustained-release pharmaceutical group according to item 5 of the patent scope, wherein the drug-loading layer contains one or more plasticizers selected from the group consisting of propylene glycol, polyethylene glycol, triethyl citrate, A group consisting of tributyl citrate, propyl triacetate, diethyl phthalate & dibutyl phthalate. 9. The continuous release medicine group of claim 5 of the patent scope 26 1343825 May 2014> 曰Revision replacement page & thing' wherein the carrier layer contains one or more anti-adhesive agents selected from talc Powder, hard acetic acid, stearic acid ester, sodium stearyl fumarate, glyceryl behenate, kaolin, colloidal silica dioxide (aer〇si 1) Among the ethnic groups. 1 0 The sustained release pharmaceutical composition of claim 1 wherein the controlled release layer further comprises an anti-adhesive agent and a plasticizer. 1 1 . The sustained release pharmaceutical composition according to claim 9 , wherein the controlled release layer contains one or more selected from the group consisting of propyl decyl cellulose glass vinegar ( Hpmcas), carboxypropyl methylcellulose phthalate (HPMCP), bismuth citrate cellulose (CAP), polyethylene acetate phthalate (pVpA), mercapto acrylate acrylic acid In the group consisting of ester copolymers and shellac (shel lac). 1 2 . The sustained release dosage form pharmaceutical composition according to claim 00, wherein the controlled release layer comprises one or more anti-adhesive agents selected from the group consisting of talc, stearic acid, stearate, and corydalis Sodium stearyl fumarate and glyceryl behenate, kaolin, and aceros i 1 are composed of a group of alkaloids. The sustained release pharmaceutical composition according to the invention of claim 3, wherein the controlled release layer contains one or more plasticizers selected from the group consisting of glycerol, polyethylene glycol, and lime acid Ethyl dibutyl citrate, diacetate, diethyl phthalate 27 1343825 May 2014 > day modified replacement page Phthalate) and dibutyl pMhalate group. The pharmaceutical composition of the sustained release medicine according to the first aspect of the patent application, wherein the plasticizer contained in the controlled release layer is polyethylene glycol or triethyl citrate. The pharmaceutical composition of the present invention as claimed in claim 5, wherein the drug-loading layer comprises from about 20 to about 35% (w/w) venlafaxine or its hydrochloride. 1 6 - A sustained release pharmaceutical composition according to claim 15 wherein the drug-loading layer further comprises from about 3 to about 1% (w/ tyrosine ethylcellulose (NF). ^ 1 7 . The sustained release pharmaceutical composition of claim 1 which comprises from about 30 to about 40% (w/w) core rounds, from about 20 to about 35% (w/w) venlafaxine or a hydrochloride, and a controlled release layer of from about 5 to about 20% (w/w). #1 8 · A sustained release pharmaceutical composition according to claim 17 of the patent application, which comprises about 35% (w) /w) core round granules, about 3 〇%^) > venlafaxine or its hydrochloride, and a controlled release layer of about 1 〇 to about 16% (w/w). η 1 9 . The pharmaceutical composition of claim 18, wherein the controlled release layer comprises about 80 to 9 % (w/w) ethyl cellulose and about 10 to 20% (W/W) 酞Dibutyl phthaUte. 20 . A method for preparing a sustained release pharmaceutical composition containing venlafaxine, comprising: 28 Γ 343825, May of the year] revised date replacement page ~~1 - _ (a) providing a core round particle; b) coating one or more drug-loading layers on the core round particles, the drug-loading layer containing venlafaxine as an active ingredient; (c) coating one or more layers of the controlled release layer on the product obtained in the step (b), The controlled release layer contains a dissolution controlled release agent; (d) a selective repeat operation (乜) and (c). 21. The method of claim 2, wherein the core pellet is produced by wet granulation. 2 2 . The method of claim 20, wherein the core particle size is 〇 5 to 〇 8 5 cm. A method of claim 2, wherein the drug-loading layer is coated by spray blasting and atomization. 2 4 · The method of the second paragraph of the patent scope is as follows, wherein the controlled release layer is coated by spray blasting and atomization. , 29