TWI459976B - Solidified oil bodies, the producing method, and the use thereof in powder and tablet dosage - Google Patents
Solidified oil bodies, the producing method, and the use thereof in powder and tablet dosage Download PDFInfo
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本發明係關於一種天然及人造油體之固化方法,更特別地,係關於將70%重量/體積以上作為賦形劑之甘露糖醇與油體溶液混合,再進行乾燥程序而製成固化油體之方法。本發明亦關於所製得之固化油體,及其在粉末或錠劑劑型之製備上的應用。 The present invention relates to a method for curing natural and artificial oil bodies, and more particularly to mixing a mannitol as an excipient with 70% by weight or more and an oil body solution, followed by a drying process to prepare a curing oil. The method of body. The invention also relates to cured curative bodies produced and their use in the preparation of powder or lozenge formulations.
植物種子細胞除了表現一些基本所需的蛋白質外,也表現一些特有的蛋白質以提供其生理需求;種子細胞中除了具有基本維持細胞活性的胞器外,亦具備大量的能量儲存胞器,例如蛋白體(protein body)、油體(oil body)以及澱粉粒(starch granule)等,以供種子萌發及萌發後生長所需之能量來源。 In addition to some basic proteins, plant seed cells also express some unique proteins to provide their physiological needs. In addition to the organelles that basically maintain cell activity, seed cells also have a large number of energy storage devices, such as proteins. Protein body, oil body, starch granule, etc., for the energy source needed for seed germination and post-emergence growth.
這些與種子萌發相關的胞器中,包含許多種子特有的蛋白質,例如:蛋白體中的儲存蛋白(storage protein)及油體中的油體膜蛋白(oleosin)等。由於油體膜蛋白本身總電荷和為負電性,因此對油體產生一靜電斥力,防止油體的融合,維持油體在種子細胞內的完整獨立性與穩定性,藉以在種子內長期的儲存。 These organelles associated with seed germination contain many seed-specific proteins, such as storage proteins in protein bodies and oil membrane proteins (oleosin) in oil bodies. Because the oil film protein itself has a total charge and is negatively charged, it generates an electrostatic repulsion to the oil body, prevents oil body fusion, maintains the integrity and stability of the oil body in the seed cells, and thus stores in the seed for a long time. .
油體上除了油體膜蛋白以外,已知還有至少兩個油體微量蛋白質分別可結合鈣離子及類固醇,因此將其命名為油體鈣蛋白(caleosin)及油體固醇蛋白(steroleosin),其中油體鈣蛋白之分子量為27kDa(參見Chen等人,Plant Cell Physiol.40(10):1079-1086,1999)。 In addition to oil body membrane proteins, it is known that at least two oil body microproteins can bind calcium ions and steroids, respectively, so they are named caleosin and steroleosin. Wherein the oil body calpain has a molecular weight of 27 kDa (see Chen et al., Plant Cell Physiol. 40(10): 1079-1086, 1999).
本案發明人已證實將油體的三種基本成份:三酸甘油酯、磷脂質及油體蛋白(油體膜蛋白或油體鈣蛋白),依其各別在油體所占有的相對比例混合,再藉由超音波震盪法提供油體重組所需的能量,可在試管中成功地組成人造油體(Tzen 等人,J Biochem 123:318-323,1998;Chen等人,J Agric Food Chem 52:3982-3987,2004)。人造油體已知可應用於做為厭水性藥物的口服遞送系統,及藉由將特定酵素連接至人造油體表面之油體蛋白上,來固定酵素(Chen等人,Biotechnol.Prog.21:1297-130,2005;Chiang等人,Escherichia coli.Protein Expr.Purif.52:14-18,2007;Chiang等人,J.Agric.Food Chem.58:11695-11702,2010)。 The inventors of the present invention have confirmed that the three basic components of the oil body: triglyceride, phospholipid and oil body protein (oil body membrane protein or oil body calcium protein), according to their respective proportions in the oil body, The artificial oil body can be successfully formed in a test tube by providing the energy required for oil body reorganization by ultrasonic vibration (Tzen et al., J Biochem 123 : 318-323, 1998; Chen et al., J Agric Food Chem 52). :3982-3987, 2004). Artificial oil bodies are known to be useful as oral delivery systems for anaerobic drugs, and to immobilize enzymes by attaching specific enzymes to oil body proteins on the surface of artificial oil bodies (Chen et al., Biotechnol . Prog . 21 : 1297-130, 2005; Chiang et al, Escherichia coli . Protein Expr . Purif . 52 : 14-18, 2007; Chiang et al, J. Agric . Food Chem . 58 : 11695-11702, 2010).
人造油體在做為固體劑型載劑之應用時,必須經過乾燥過程,然而,已知得自天然芝麻種子之油體,在一般用於生產食品的乾燥過程中,會發生聚結(coalesced)而形成大的油滴。因此,欲將天然及人造油體應用在固體劑型之製備,必需克服在固化程序時所發生和聚結相關的問題。據此,本發明提出一種天然及人造油體之固化方法,使油體在乾燥前與乾燥後,皆能保持相似的大小及結構完整性,不會發生油體聚結現象,以使其能有效應用於口服固體劑型,例如粉末或錠劑劑型之製備。 The artificial oil body must be subjected to a drying process when it is used as a solid dosage form carrier. However, an oil body derived from natural sesame seeds is known to be coalesced during the drying process generally used for the production of foods. And the formation of large oil droplets. Therefore, in order to apply natural and artificial oil bodies to the preparation of solid dosage forms, it is necessary to overcome the problems associated with coalescence during the curing process. Accordingly, the present invention provides a method for curing natural and artificial oil bodies, so that the oil body can maintain similar size and structural integrity before and after drying, and oil body coalescence does not occur, so that it can It is effective for the preparation of oral solid dosage forms such as powder or lozenge formulations.
於是,本發明之一方面係關於一種製造固化油體粉末之方法,其包含:(1)提供一天然或人造油體溶液;(2)將甘露糖醇添加於該油體溶液中並加以混合,使甘露糖醇之最終濃度為70%重量/體積以上;及(3)將所成之混合物進行乾燥程序,而得到呈固化形式之油體粉末。於本發明之一項具體實施例,該混合物中甘露糖醇之最終濃度為70%重量/體積至90%重量/體積。於本發明之另一項具體實施例,該混合物中甘露糖醇之最終濃度為80%重量/體積。 Accordingly, one aspect of the invention relates to a method of producing a cured oil body powder comprising: (1) providing a natural or artificial oil body solution; (2) adding mannitol to the oil body solution and mixing The final concentration of mannitol is 70% w/v or more; and (3) the resulting mixture is subjected to a drying procedure to obtain an oil body powder in a solidified form. In a particular embodiment of the invention, the final concentration of mannitol in the mixture is from 70% w/v to 90% w/v. In another embodiment of the invention, the final concentration of mannitol in the mixture is 80% w/v.
於本發明之一項具體實施例,該乾燥程序為冷凍乾燥。於本發明之具體實施例,可應用本發明方法進行固化之油體,可為一種分離自天然之油體,或是其中有或無覆載活性物質的人造油體。 In a specific embodiment of the invention, the drying procedure is freeze drying. In a specific embodiment of the present invention, the oil body which can be cured by the method of the present invention may be an oil body separated from natural oil or an artificial oil body with or without an active material.
本發明之一方面係關於一種經由本發明之油體固化方法製得之固化油體粉末。於本發明之一項具體實施例,本發明製得之固化油體粉末可用於製備固體劑型,例如粉末或錠劑。於本發明之另一項具體實施例,本發明製得之固化油體粉末可用於載體組合物,供做為製備醫藥或食品組成物之賦形劑。 One aspect of the invention relates to a cured oil body powder produced by the oil body solidification method of the present invention. In one embodiment of the invention, the cured oil body powders produced by the present invention are useful in the preparation of solid dosage forms such as powders or lozenges. In another embodiment of the invention, the cured oil body powders prepared in accordance with the invention are useful in carrier compositions for use as excipients for the preparation of pharmaceutical or food compositions.
根據本發明所呈現的各種實施例,下述各種儀器、裝置、方法和其相關結果者,實施例中為了方便讀者閱讀所使用的標題或副標題,並不被限制在本發明的範圍之內。 In view of the various embodiments of the present invention, the various instruments, devices, methods, and related results described below are not intended to be limited to the scope of the present invention.
本發明之其他特色及優點將於下列實施範例中被進一步舉例與說明,而該實施範例僅作為輔助說明,並非用於限制本發明之範圍。 The other features and advantages of the present invention are further exemplified and illustrated in the following examples, which are intended to be illustrative only and not to limit the scope of the invention.
天然芝麻種子油體,係根據Tzen等人所揭示之方法純化得(J.Biochem.121:762-768,1997)。包含得自芝麻種子之油體鈣蛋白(caleosin),則係根據Liu等人之方法進行製備(J.Agric.Food Chem.57:2308-2313,2009)。 Natural sesame seed oil bodies were purified according to the method disclosed by Tzen et al. ( J. Biochem . 121 :762-768, 1997). Caleosin, which is derived from sesame seeds, is prepared according to the method of Liu et al. ( J. Agric . Food Chem . 57 : 2308-2313, 2009).
將100、300、500、700或900mg之甘露糖醇,添加入1mL經純化的芝麻油體溶液中,使最終濃度分別為10%、30%、50%、70%或90%(重量/體積),並將二者充分混合。將所得之混合物進行冷凍乾燥程序。經過乾燥24小時後,得到呈白色粉末之固化油體(圖1)。 Add 100, 300, 500, 700 or 900 mg of mannitol to 1 mL of purified sesame oil solution to a final concentration of 10%, 30%, 50%, 70% or 90% (weight/volume) And mix the two together. The resulting mixture was subjected to a freeze-drying procedure. After drying for 24 hours, a solid oil body was obtained as a white powder (Fig. 1).
將固化前及經固化後之油體分別懸浮於10mM磷酸鈉緩衝液(pH 7.5)中,並置於Nikon type-104光學顯微鏡下,以400倍之放大倍數觀察油體外觀之變化情形。由圖1右列之光學顯微鏡照片顯示,有添加終濃度達70%重量/體積以上之甘 露糖醇的油體,在乾燥程序中可有效防止聚結現象發生,亦即,經固化之油體粉末,沒有大的油滴出現。 The oil bodies before and after curing were suspended in 10 mM sodium phosphate buffer (pH 7.5), and placed under a Nikon type-104 optical microscope to observe changes in the appearance of the oil body at a magnification of 400 times. An optical micrograph from the right column of Figure 1 shows that the final concentration is increased by 70% w/v or more. The oil body of the sugar alcohol can effectively prevent the coalescence phenomenon from occurring in the drying process, that is, the solidified oil body powder does not have large oil droplets.
如上述,將芝麻種子油體溶液於80%重量/體積甘露糖醇存在下,進行乾燥程序,得到粉末狀固化油體。取100mg經固化之油體粉末,與等量的甘露糖醇(100mg)充分混合,將混合物置於Rimek-I旋轉式製錠機上,使用扁圓模具於500lb壓力下加10壓秒,而製成200mg錠劑。以光學顯微鏡觀察,固化油體粉末在製成錠劑前、後之外觀變化情形。 As described above, the sesame seed oil body solution was dried in the presence of 80% by weight/volume of mannitol to obtain a powdery solidified oil body. Take 100 mg of the solidified oil body powder, mix well with an equal amount of mannitol (100 mg), place the mixture on a Rimek-I rotary tableting machine, and add 10 pressure seconds at 500 lbs using an oblate die. A 200 mg tablet was prepared. The appearance of the cured oil body powder before and after the preparation of the tablet was observed by an optical microscope.
由圖2之光學顯微鏡觀察結果顯示,於80%重量/體積甘露糖醇存在下,芝麻種子油體在固化前及之後的外觀仍保持一致,表示沒有發生油滴聚結,此與前述之結果相符。又,固化油體粉末在製成錠劑後,仍舊保持其油體之大小及結構完整性,表示油體溶液經由本發明之方法固化後,不僅可防止油滴聚結發生,也能具有其穩定的結構,使其在壓製成錠劑的過程中仍保持結構完整性。 The observation by the optical microscope of Fig. 2 shows that the appearance of the sesame seed oil body before and after curing is consistent in the presence of 80% w/v mannitol, indicating that no oil droplet coalescence occurs, and the above results Match. Moreover, the solidified oil body powder retains the size and structural integrity of the oil body after being formed into a tablet, indicating that the oil body solution is cured by the method of the present invention, thereby preventing not only the occurrence of oil droplet coalescence but also its The stable structure allows it to maintain structural integrity during compression into tablets.
由50mg芝麻油(含有20% PEG 400與薑黃素)、150μg二油醯磷脂醯膽鹼與250μg重組油體鈣蛋白,於1mL之10mM磷酸鈉緩衝液(pH 7.5)中製得人造油體,製法如下述。首先將溶於氯仿之二油醯磷脂醯膽鹼放入微量離心管的底部,並置於化學抽風櫥中過夜使溶劑揮發。經過揮發後,將芝麻油(含有20% PEG 400與薑黃素)及懸浮於於1mL 10mM磷酸鈉緩衝液(pH 7.5)之重組油體鈣蛋白加入該微量離心管中,隨後以超音波樣品處理器Sonics & Materials VCX750,使用3-mm-diaeter探針(條件為施以30%放大率(amplification)20秒)進行超音波震盪,之後將樣本置於冰上冷卻5分鐘,再以上述條件重複震盪兩次,而得其中包覆有 薑黃素(Curcumin)之人造油體。添加20% PEG 400之目的在於,使薑黃素能穩定溶於芝麻油中,以提供做為後續產生人造油體的脂質介質(lipid matrix)。 Artificial oil body was prepared from 50 mg of sesame oil (containing 20% PEG 400 and curcumin), 150 μg of diolein phospholipid choline and 250 μg of recombinant oil body troponin in 1 mL of 10 mM sodium phosphate buffer (pH 7.5). As described below. First, the chlorinated phospholipid choline dissolved in chloroform was placed in the bottom of the microcentrifuge tube and placed in a chemical extraction cabinet overnight to evaporate the solvent. After volatilization, sesame oil (containing 20% PEG 400 and curcumin) and recombinant oil body sialoprotein suspended in 1 mL of 10 mM sodium phosphate buffer (pH 7.5) were added to the microcentrifuge tube, followed by an ultrasonic sample processor. Sonics & Materials VCX750, using a 3-mm-diaeter probe (provided with 30% amplification for 20 seconds) for ultrasonic oscillation, then the sample was placed on ice for 5 minutes, and the shock was repeated under the above conditions. Twice, and it has to be wrapped Artificial oil body of curcumin. The purpose of adding 20% PEG 400 is to stabilize the curcumin in sesame oil to provide a lipid matrix as a subsequent artificial oil body.
已成功產生呈一種黃色乳化溶液之穩定人造油體,而所得之人造油體,較前述實施例一所分離得之天然芝麻種子油體小(比較圖2與3中油體固化前之照片)。將人造油體溶液依照前述實施例一所述之油體固化方法進行固化,並將經固化之油體粉末依實施例所述相同的方法壓製成錠劑。 A stabilized artificial oil body in the form of a yellow emulsified solution has been successfully produced, and the resulting artificial oil body is smaller than the natural sesame seed oil body isolated in the foregoing Example 1 (compare the photographs before the oil body solidification in Figs. 2 and 3). The artificial oil body solution was cured according to the oil body solidification method described in the foregoing Example 1, and the solidified oil body powder was pressed into a tablet in the same manner as described in the examples.
由圖3顯示,包覆有薑黃素之人造油體,在經固化之乾燥程序後得到黃色粉末。經由顯微鏡觀察油體外觀之變化情形,證明包覆有薑黃素之人造油體在經固化及製成錠劑後,仍舊保持其油體之結構完整性。故本發明之油體固化方法可應用於天然油體,及有或無包覆活性物質的人造油體。 As shown in Fig. 3, the artificial oil body coated with curcumin obtained a yellow powder after the curing drying process. The change in the appearance of the oil body was observed by a microscope, and it was confirmed that the artificial oil body coated with curcumin maintained the structural integrity of the oil body after being cured and formed into a tablet. Therefore, the oil body solidification method of the present invention can be applied to natural oil bodies, and artificial oil bodies with or without active materials.
為進一步評估經固化油體於劑型製造方面之可應用性,遂利用加速應力測試(accelerated stress test)(參見,Larry,L.Augsburger and Stephen W.Hoag.Pharmaceutical Dosage Forms:Tablets third edition Volume 1:Unit Operation and Mechanical Properties.2008,499)來分析固化油體在長期儲存下之安定性。 To further evaluate the applicability of cured oil bodies in the manufacture of dosage forms, an accelerated stress test is used (see, Larry, L. Augsburger and Stephen W. Hoag. Pharmaceutical Dosage Forms: Tablets third edition Volume 1: Unit Operation and Mechanical Properties . 2008 , 499) to analyze the stability of solidified oil bodies under long-term storage.
將由前述實施例製得之經固化人造油體粉末及錠劑,放置於濕度設定於75%之40℃烘箱中達四個月。之後,依照前述實施例一之方法,以光學顯微鏡觀察固化油體粉末及錠劑,在經過四個月儲放期前、後之油體外觀變化情形。如圖3所示,經過加速應力測試後,溶自經固化油體粉末或錠劑之油體顆粒,仍舊穩定地保持其油體結構之完整性,而且無明顯的潮解或溶解現象發生。表示,經本發明固化方法製得之固化油體,具有極佳潛力應用於固體劑型,包括粉末或錠劑等之製備,作為一種安定的醫藥或食品組成物用賦形劑。 The cured artificial oil body powder and lozenge prepared by the foregoing examples were placed in an oven set to a humidity of 75% at 40 ° C for four months. Thereafter, according to the method of the foregoing Example 1, the appearance of the oil body before and after the four-month storage period was observed by observing the solidified oil body powder and the tablet by an optical microscope. As shown in Fig. 3, after the accelerated stress test, the oil body particles dissolved in the solidified oil body powder or tablet still maintain the integrity of the oil body structure stably, and no obvious deliquescence or dissolution occurs. It is indicated that the solidified oil body obtained by the curing method of the present invention has an excellent potential for use in the preparation of solid dosage forms, including powders or tablets, as a stable pharmaceutical or food composition excipient.
本說明書中所揭示之全部特徵可以任何組合方式組合。於是,本說明書中所揭示之各別特徵可由依相同、相等或類似目的之替代特徵取代。因此,除非另行清楚地指示,所揭示之各特徵僅為一系列同等物或類似特徵之實例。 All of the features disclosed in this specification can be combined in any combination. Thus, the individual features disclosed in this specification can be replaced by alternative features that are the same, equivalent, or similar. Therefore, the various features disclosed are merely examples of a series of equivalents or similar features, unless otherwise clearly indicated.
從前述之說明,習於該項技藝人士可容易地確定本發明之基本特徵,且在未偏離其範圍下,可進行本發明之各種改變與修飾,以使其適於各種不同用途與狀況。因此,於申請專利範圍內亦包含其他具體態樣。 From the foregoing description, those skilled in the art can readily determine the essential features of the invention, and various changes and modifications of the invention can be made to adapt to various different uses and conditions without departing from the scope thereof. Therefore, other specific aspects are included in the scope of patent application.
圖1為於不同濃度(10%重量/體積、30%重量/體積、50%重量/體積、70%重量/體積及90%重量/體積)之甘露糖醇存在下,所得經固化芝麻油體的粉末外觀照片(左列圖);及以光學顯微鏡觀察經懸浮於10mM磷酸鈉緩衝液(pH 7.5)中30分鐘後之油體樣本的顯微照片(右列圖)。圖中尺規線段代表10μm。 Figure 1 shows the obtained cured sesame oil in the presence of different concentrations (10% w/v, 30% w/v, 50% w/v, 70% w/v and 90% w/v) of mannitol A photograph of the appearance of the powder (left panel); and a photomicrograph of the oil body sample (right panel) after 30 minutes of suspension in 10 mM sodium phosphate buffer (pH 7.5) was observed under an optical microscope. The ruler line segment in the figure represents 10 μm.
圖2為呈粉末之經固化天然芝麻油體,及其經過壓製成錠劑形式的外觀照片(上列圖)與顯微照片(下列圖)。圖中的經固化芝麻油體粉末,係藉由將油體溶液與80%重量/體積甘露糖醇混合及進行乾燥程序而得。光學顯微照片係將經固化前及後之油體粉末或錠劑中的油體,懸浮於10mM磷酸鈉緩衝液(pH 7.5)中30分鐘後取樣進行觀察而得。圖中尺規線段代表10μm。 Figure 2 is a photograph of the appearance of a cured natural sesame oil in powder and its compacted tablet form (top panel) and photomicrograph (below). The cured sesame oil powder in the figure was obtained by mixing an oil body solution with 80% by weight/volume mannitol and drying. The optical micrographs were obtained by observing the oil bodies in the oil body powder or tablets before and after curing in a 10 mM sodium phosphate buffer (pH 7.5) for 30 minutes and then taking samples. The ruler line segment in the figure represents 10 μm.
圖3為為呈粉末之經固化人造油體(其中覆載有薑黃素),及其經過壓製成錠劑形式的外觀照片(上列圖)與顯微照片(下列圖)。圖中的經固化人造油體粉末,係藉由將油體溶液與80%重量/體積甘露糖醇混合及進行乾燥程序而得。光學顯微照片係將經固化前、後,以及經過4-個月儲放前、後之 油體粉末或錠劑中的油體,懸浮於10mM磷酸鈉緩衝液(pH 7.5)中30分鐘後取樣進行觀察而得。圖中尺規線段代表10μm。 Figure 3 is a photograph (top panel) and a photomicrograph (pictured below) of a cured artificial oil body in powder form (containing curcumin) and its compressed tablet form. The cured artificial oil body powder in the figure is obtained by mixing an oil body solution with 80% by weight/volume mannitol and performing a drying process. Optical micrographs will be before, after, and after 4-month storage. The oil body in the oil powder or tablet was suspended in 10 mM sodium phosphate buffer (pH 7.5) for 30 minutes, and then sampled and observed. The ruler line segment in the figure represents 10 μm.
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全文 劉廷航,CHEMISTRY (The Chinese Chemical Society, Taipei) March 2007, Vol. 65, No. 1, pp.55-62全文 * |
吳建民,以油體為包覆薑黃素之材料並評估其適用性,國立勤益科技大學化工與材料工程系碩士論文,2007年7月 * |
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