TW202220661A - Improved pharmaceutical formulations comprising pi3k inhibitors - Google Patents
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Abstract
Description
本發明係關於一種具有非pH依賴性經改良溶解度之口服醫藥調配物，其包含作為活性成分之PI3K抑制劑，諸如嘧啶衍生物5-(7-(甲基磺醯基)-2-N-
歐洲專利EP2050749揭示一類新型磷脂醯肌醇3-激酶（PI3K）之強效抑制劑及其等作為抗癌藥物之用途。此類化合物中之一些在諸如4.5及6.8之升高pH下具有低溶解度。特定言之，此類抑制劑中最有前景的化合物之一，嘧啶衍生物5-(7-(甲基磺醯基)-2-N-
本發明解決之問題為提供一種具有改良的特性的呈固體口服劑型之醫藥組成物。本發明之組成物包含嘧啶衍生物PI3K抑制劑作為活性成分。特定言之，本發明提供一種顯示出快速、非pH依賴性溶解輪廓之調配物。The problem addressed by the present invention is to provide a pharmaceutical composition in a solid oral dosage form with improved properties. The composition of the present invention contains a pyrimidine derivative PI3K inhibitor as an active ingredient. In particular, the present invention provides a formulation that exhibits a rapid, pH-independent dissolution profile.
本發明之發明人在初步溶解度試驗中測試30多種溶解度增強賦形劑及其等之組合（包括不同混合比率）在不同pH值下增加PI3K抑制劑（諸如化合物A）之溶解度的能力。然而，僅少數賦形劑之選擇及其等之協同組合被鑑別為此等活性成分在不同pH值下之有效增溶劑，而大多數測試賦形劑僅具有很小的作用或沒有作用。The inventors of the present invention tested the ability of more than 30 solubility enhancing excipients and combinations thereof (including different mixing ratios) to increase the solubility of PI3K inhibitors such as Compound A at different pH values in preliminary solubility experiments. However, only a few choices of excipients and synergistic combinations of the like were identified as effective solubilizers for these active ingredients at different pH values, while most of the excipients tested had little or no effect.
本發明之發明人意外地觀察到，溶解度試驗之有前景的結果無法轉移至溶解試驗中。令人驚訝的是，本發明之發明人證明環糊精與基於多醣之賦形劑的組合能夠在對醫藥組成物進行之溶解試驗中有效地改良PI3K抑制劑（諸如化合物A）之溶解度，儘管此賦形劑組合（環糊精及基於多醣之賦形劑）在溶解度試驗中僅表現出中等效能。此外，儘管與溶解度試驗相比使用較低的賦形劑/活性成分混合比率，但其在溶解試驗中為最有效的組合。The inventors of the present invention have unexpectedly observed that the promising results of the solubility test cannot be transferred to the dissolution test. Surprisingly, the inventors of the present invention demonstrated that the combination of cyclodextrins and polysaccharide-based excipients can effectively improve the solubility of PI3K inhibitors, such as Compound A, in dissolution tests performed on pharmaceutical compositions, despite the fact that This excipient combination (cyclodextrin and polysaccharide-based excipients) showed only moderate efficacy in solubility tests. Furthermore, it was the most effective combination in the dissolution test, despite using a lower excipient/active ingredient mix ratio compared to the solubility test.
如下文實施例中所示，包含化合物A及環糊精與基於多醣之賦形劑之組合的固體口服組成物在pH 1.2、4.5及6.8下產生＞85%之快速、非pH依賴性溶解。As shown in the Examples below, solid oral compositions comprising Compound A and cyclodextrin in combination with polysaccharide-based excipients produced >85% rapid, pH-independent dissolution at pH 1.2, 4.5, and 6.8.
該非pH依賴性溶解輪廓可使得生體可用率對影響胃腸道pH之聯合用藥或食物影響較不敏感，從而使使用PI3K抑制劑的療法可能對患者更安全且更有效。This pH-independent dissolution profile may make bioavailability less sensitive to combination medications or food effects that affect gastrointestinal pH, making therapy with PI3K inhibitors potentially safer and more effective for patients.
本發明之發明人面臨的另一問題為固體分散體之常見製造技術，如噴霧乾燥、熱熔擠出或冷凍乾燥（其等可藉由藥物在載劑基質中之非晶形分散而顯著改良水溶性差之藥物的溶解）由於需要高封閉性要求而在工業規模對腫瘤藥物實施非常具有挑戰性。Another problem faced by the inventors of the present invention is the common manufacturing techniques for solid dispersions, such as spray drying, hot melt extrusion or freeze drying (which can significantly improve water solubility by amorphous dispersion of the drug in the carrier matrix) Oncology drugs are very challenging to implement on an industrial scale due to the need for high containment requirements.
本發明之發明人亦證明，藉由用標準醫藥製造技術（例如但不限於造粒）製造本發明之醫藥組成物亦可實現高效溶解。The inventors of the present invention have also demonstrated that efficient dissolution can also be achieved by manufacturing the pharmaceutical compositions of the present invention using standard pharmaceutical manufacturing techniques such as, but not limited to, granulation.
因此，本發明之經改良口服調配物可亦使用非常適合於工業規模擴大之簡單標準技術以高度的時間及成本效率的方式製造。Accordingly, the improved oral formulations of the present invention can also be manufactured in a highly time- and cost-effective manner using simple standard techniques well suited for industrial scale-up.
因此，在一個態樣中，本發明提供一種呈固體口服劑型之醫藥組成物，其包含： i)作為活性成分之PI3K抑制劑，特別是化合物A或其醫藥學上可接受之鹽 ii)環糊精； iii)基於多醣之賦形劑。 Accordingly, in one aspect, the present invention provides a pharmaceutical composition in a solid oral dosage form, comprising: i) PI3K inhibitors as active ingredients, especially Compound A or a pharmaceutically acceptable salt thereof ii) cyclodextrins; iii) Excipients based on polysaccharides.
在一個態樣中，本發明提供呈固體口服劑型之該醫藥組成物，其用於治療增生性疾病，特別是用於治療癌症。In one aspect, the present invention provides the pharmaceutical composition in a solid oral dosage form for use in the treatment of proliferative diseases, particularly in the treatment of cancer.
在一個態樣中，本發明提供一種製造該醫藥組成物之方法，其中該方法包含混合該PI3K抑制劑、該環糊精及該基於多醣之賦形劑的步驟，較佳不使用液體或使用水或甲醇。In one aspect, the present invention provides a method of making the pharmaceutical composition, wherein the method comprises the step of mixing the PI3K inhibitor, the cyclodextrin and the polysaccharide-based excipient, preferably without the use of a liquid or with water or methanol.
本發明提供一種呈固體口服劑型之醫藥組成物，其包含： i) PI3K抑制劑； ii)環糊精； iii)基於多醣之賦形劑。 The present invention provides a pharmaceutical composition in a solid oral dosage form, comprising: i) PI3K inhibitors; ii) cyclodextrins; iii) Excipients based on polysaccharides.
在一個實施方式中，PI3K抑制劑係選自EP2050749之請求項15中所列的化合物之一，該文獻之全部內容以引用之方式併入本文中。In one embodiment, the PI3K inhibitor is selected from one of the compounds listed in claim 15 of EP2050749, which is incorporated herein by reference in its entirety.
在一個較佳實施方式中，該PI3K抑制劑為化合物5-(7-(甲基磺醯基)-2-N-
該醫藥組成物包含該PI3K抑制劑，較佳該PI3K抑制劑對於各口服劑量單位而言呈以下自由鹼之具體量：在0.5與96 mg之間，較佳在10與48 mg之間，更佳在16與32 mg之間。特定言之，PI3K抑制劑可以約以下量存在於組成物中：0.5、1、2、3、4、5、6、7、8 ,9 ,10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、55、53、54、55、56、57、58、59、60、61、66、63、64、66、66、67、68、69、70、71、77、73、74、77、77、77、78、79、80、81、88、83、84、88、88、88、88、89、90、91、92、93、94、95、96 mg。The pharmaceutical composition comprises the PI3K inhibitor, preferably the PI3K inhibitor is the following specific amount of free base for each oral dosage unit: between 0.5 and 96 mg, preferably between 10 and 48 mg, more The optimum is between 16 and 32 mg. In particular, the PI3K inhibitor can be present in the composition in an amount of about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 55, 53, 54, 55, 56, 57, 58, 59, 60, 61, 66, 63, 64, 66, 66 , 67, 68, 69, 70, 71, 77, 73, 74, 77, 77, 77, 78, 79, 80, 81, 88, 83, 84, 88, 88, 88, 88, 89, 90, 91 , 92, 93, 94, 95, 96 mg.
本發明之醫藥組成物中基於多醣之賦形劑可為纖維素或纖維素衍生物，諸如微晶纖維素、羧甲基纖維素、乙酸鄰苯二甲酸纖維素、羥丁基甲基纖維素羥乙基纖維素、羥丙基纖維素、鄰苯二甲酸羥丙基甲基纖維素纖維素、羥丙基甲基纖維素、乙酸丁二酸羥丙基甲基纖維素、甲基纖維素。The polysaccharide-based excipient in the pharmaceutical composition of the present invention can be cellulose or cellulose derivatives, such as microcrystalline cellulose, carboxymethyl cellulose, cellulose acetate phthalate, hydroxybutyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, methyl cellulose.
較佳地，基於多醣之賦形劑為羥丙基甲基纖維素（亦稱為羥丙甲纖維素）。適用於本發明之醫藥組成物的羥丙基甲基纖維素（HPMC）為市售羥丙基甲基纖維素E6。Preferably, the polysaccharide-based excipient is hydroxypropyl methylcellulose (also known as hypromellose). Hydroxypropyl methylcellulose (HPMC) suitable for the pharmaceutical composition of the present invention is commercially available hydroxypropyl methylcellulose E6.
在一個實施方式中，各劑量單位形式中基於多醣之賦形劑與PI3K抑制劑之比率在0.1:1與1.6:1之間，例如比率為0.2:1或0.4:1或0.8:1（w/w）。特定言之，基於多醣之賦形劑與PI3K抑制劑之比率可為0.1:1、0.2:1、0.3:1、0.4:1、0.5:1、0.6:1、0.7:1、0.8:1、0.9:1、1.0:1、1.1:1、1.2:1、1.3:1、1.4:1、1.5:1、1.6:1（w/w）。In one embodiment, the ratio of polysaccharide-based excipient to PI3K inhibitor in each dosage unit form is between 0.1:1 and 1.6:1, eg, a ratio of 0.2:1 or 0.4:1 or 0.8:1 (w /w). In particular, the ratio of polysaccharide-based excipient to PI3K inhibitor may be 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1 (w/w).
在本發明之一個實施方式中，組成物可包含替代或補充此類基於多醣之賦形劑的一或多種聚合物。此類聚合物可為例如聚丙烯酸酯、聚甲基丙烯酸酯、聚甲基丙烯醯胺、聚丙烯醯胺、聚乙二醇、聚氧化乙烯、聚乙酸乙烯鄰苯二甲酸酯、聚乙烯醇。本發明之醫藥組成物中之環糊精（CDx）可為例如α-環糊精、β-環糊精、羥丙基-β-環糊精、γ-環糊精、二甲基-α-環糊精、三甲基-α-環糊精、羥丙基-α-環糊精、羧甲基-β-環糊精、二甲基-β-環糊精、三甲基-β-環糊精、羥乙基-β-環糊精、磺基丁基醚-β-環糊精、隨機甲基化-β-環糊精、二甲基-γ-環糊精、三甲基-γ-環糊精、羥丙基-γ-環糊精、磺基丁基醚-γ-環糊精。In one embodiment of the invention, the composition may comprise one or more polymers in place of or in addition to such polysaccharide-based excipients. Such polymers can be, for example, polyacrylates, polymethacrylates, polymethacrylamides, polyacrylamides, polyethylene glycols, polyethylene oxides, polyvinyl acetate phthalates, polyethylene alcohol. The cyclodextrin (CDx) in the pharmaceutical composition of the present invention can be, for example, α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, dimethyl-α - cyclodextrin, trimethyl-alpha-cyclodextrin, hydroxypropyl-alpha-cyclodextrin, carboxymethyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin, trimethyl-beta - cyclodextrin, hydroxyethyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, random methylation-β-cyclodextrin, dimethyl-γ-cyclodextrin, trimethyl base-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-γ-cyclodextrin.
較佳地，CDx為羥丙基β-環糊精，更佳為具有高莫耳取代之羥丙基β-環糊精，亦即具有在約0.80至約0.99範圍內之（羥丙基）莫耳取代。Preferably, CDx is hydroxypropyl β-cyclodextrin, more preferably hydroxypropyl β-cyclodextrin with high molar substitution, i.e. with (hydroxypropyl) in the range of about 0.80 to about 0.99 Moore replaced.
在一個實施方式中，各劑量單位形式中環糊精與PI3K抑制劑之比率在6:1與23:1之間，例如比率為8:1或10:1或12:1（w/w）。特定言之，環糊精與PI3K抑制劑之比率可為6:1、7:1、8:1、9:1、10:1、11:1、12:1、13:1、14:1、15:1、16:1、17:1、18:1、19:1、20:1、21:1、22:1、23:1（w/w）。In one embodiment, the ratio of cyclodextrin to PI3K inhibitor in each dosage unit form is between 6:1 and 23:1, eg, a ratio of 8:1 or 10:1 or 12:1 (w/w). In particular, the ratio of cyclodextrin to PI3K inhibitor may be 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 , 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1 (w/w).
醫藥組成物可進一步包含以下賦形劑中之一或多者：聚乙烯基己內醯胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、膠態二氧化矽、共聚維酮、十二烷基硫酸鈉、微晶纖維素、聚乙烯吡咯啶酮、交聯聚乙烯吡咯啶酮、甘露糖醇、交聯羧甲基纖維素鈉、檸檬酸、α-環糊精、β-環糊精、羥丙基-β-環糊精、γ環糊精、白蛋白、乙酸丁二酸羥丙基甲基纖維素、甲基纖維素SM15、甲基纖維素SM4、聚乙烯亞胺、聚乙烯吡咯啶酮K30、十六烷基三甲基溴化銨、牛膽酸鈉、辛烯基丁二酸澱粉、泊洛沙姆124、泊洛沙姆407、聚氧35氫化蓖麻油、聚山梨醇酯20、Sepitrap 4000、D-α-生育酚聚乙二醇丁二酸酯、Triton X-100、羥丙甲纖維素、Kolliphor CSS、十六烷基硬脂醇、交聯羧甲基纖維素鈉或聚乙二醇-15-羥基-硬脂酸酯。The pharmaceutical composition may further comprise one or more of the following excipients: polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, colloidal silica, copovidone, ten Sodium dialkyl sulfate, microcrystalline cellulose, polyvinylpyrrolidone, crospovidone, mannitol, croscarmellose sodium, citric acid, alpha-cyclodextrin, beta-ring Dextrin, hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, albumin, hydroxypropyl methylcellulose acetate succinate, methylcellulose SM15, methylcellulose SM4, polyethyleneimine, Polyvinylpyrrolidone K30, cetyltrimethylammonium bromide, sodium taurocholate, starch octenylsuccinate, poloxamer 124, poloxamer 407, polyoxy 35 hydrogenated castor oil,
本發明之醫藥組成物可呈任何適合經口投予之固體形式，諸如但不限於膠囊、錠劑、***錠、顆粒。The pharmaceutical compositions of the present invention may be in any solid form suitable for oral administration, such as, but not limited to, capsules, lozenges, lozenges, granules.
本發明之醫藥組成物可呈包含化合物A、羥丙基β-環糊精及羥丙基甲基纖維素之膠囊形式。在一較佳實施方式中，對於各劑量單位形式，化合物A、羥丙基β-環糊精及羥丙基甲基纖維素以1:10:0.4或1:12:0.8（w/w）之比率存在。The pharmaceutical composition of the present invention may be in the form of a capsule comprising Compound A, hydroxypropyl β-cyclodextrin and hydroxypropyl methylcellulose. In a preferred embodiment, for each dosage unit form, Compound A, hydroxypropyl β-cyclodextrin and hydroxypropyl methylcellulose are combined at 1:10:0.4 or 1:12:0.8 (w/w) ratio exists.
本發明之醫藥組成物用於治療增生性疾病，較佳癌症。特定言之，該等組成物用於結腸癌、***癌、乳癌、卵巢癌、肺癌之抗癌治療。The pharmaceutical composition of the present invention is used for the treatment of proliferative diseases, preferably cancer. In particular, the compositions are used for the anticancer treatment of colon cancer, prostate cancer, breast cancer, ovarian cancer, lung cancer.
本發明之另一目的為一種製造根據本文所揭示之實施方式中之任一者之醫藥組成物的方法，其中該方法包含較佳不使用液體或使用水或甲醇作為溶劑混合本發明之醫藥組成物之成分的步驟。該方法亦可包含乾燥步驟，視情況隨後可為將乾燥混合物填充至膠囊中之步驟。 實施例 實驗資料 使用化合物A作為活性物質及單一賦形劑之溶解度試驗 Another object of the present invention is a method of making a pharmaceutical composition according to any of the embodiments disclosed herein, wherein the method comprises mixing the pharmaceutical composition of the present invention preferably without using a liquid or using water or methanol as a solvent The steps of the composition of things. The method may also comprise a drying step, optionally followed by a step of filling the dried mixture into capsules. Example Experimental data Solubility Test Using Compound A as Active Substance and Single Excipient
溶解度試驗之結果係用化合物A作為唯一活性物質且用如表1中所示之調配物（顆粒）來進行（該調配物在本文件通篇及相關圖式中定義為「參考調配物」）。結果證實，在水溶液中，化合物A之溶解度隨pH值之增加而強烈降低（表2）。
表1
正如預期的，與唯一活性物質相比，參考調配物在溶液中測定之化合物A的濃度更高，表明在調配物之開發階段所採用之賦形劑在所測試之兩個pH值下增加溶解度的能力。As expected, the reference formulation measured a higher concentration of Compound A in solution compared to the sole active, indicating that the excipients employed during the development phase of the formulation increased solubility at both pH values tested Ability.
然而，當pH值自1.2增加至6.8時，活性物質及參考調配物之化合物A的濃度分別降低97倍及29倍。因此，只有在模擬胃液（無酶）中，化合物A活性物質及參考調配物才能達到沈降條件——定義為溶解介質之體積至少大於形成藥物物質之飽和溶液所需體積的三倍。由於參考調配物之一個膠囊含有16 mg化合物A自由鹼且一般採用900 mL體積之溶解介質，因此當化合物A自由鹼之濃度不低於53.3 µg/mL時，給出沈降條件。However, when the pH was increased from 1.2 to 6.8, the concentrations of Compound A of the active and reference formulations decreased by 97-fold and 29-fold, respectively. Therefore, only in simulated gastric juice (without enzymes), the Compound A active substance and the reference formulation were able to achieve sedimentation conditions - defined as a volume of dissolution medium at least three times greater than that required to form a saturated solution of drug substance. Since one capsule of the reference formulation contains 16 mg of Compound A free base and typically employs a 900 mL volume of dissolution medium, sedimentation conditions are given when the concentration of Compound A free base is not less than 53.3 µg/mL.
基於此等結果，溶解度試驗在pH 6.8之磷酸鹽緩衝介質中進行，此反映在化合物A之溶解度方面最具挑戰性的條件。亦進行溶解度試驗，其目的在於鑑別能夠將化合物A自由鹼濃度增加至≥ 53.3 µg/mL以實現沈降條件之賦形劑。Based on these results, solubility tests were performed in phosphate buffered media at pH 6.8, which reflects the most challenging conditions for the solubility of Compound A. Solubility tests were also performed to identify excipients capable of increasing the Compound A free base concentration to ≥ 53.3 µg/mL to achieve sedimentation conditions.
評估多種賦形劑增加化合物A在磷酸鹽緩衝液pH 6.8中之溶解度的潛力。賦形劑選自以下類別：聚合物（例如HPMC）、載劑分子（例如環糊精）、界面活性劑（例如SDS及Soluplus）及pH調節劑（例如檸檬酸）。Various excipients were evaluated for their potential to increase the solubility of Compound A in phosphate buffer pH 6.8. Excipients are selected from the following classes: polymers (eg HPMC), carrier molecules (eg cyclodextrin), surfactants (eg SDS and Soluplus) and pH adjusters (eg citric acid).
僅在兩小時後測定溶液中化合物A之濃度，因為如表2中關於參考調配物所示，在4小時之延長測試時間後未觀察到化合物A濃度之顯著變化。 使用化合物A活性物質及環糊精（CDx）之溶解度試驗 The concentration of Compound A in solution was determined only after two hours, as no significant change in Compound A concentration was observed after the extended test time of 4 hours, as shown in Table 2 for the reference formulation. Solubility test using compound A active substance and cyclodextrin (CDx)
如表3中所示，與在pH 6.8下測試2小時後達到0.9 µg/mL濃度之單獨的化合物A相比，化合物A及環糊精之物理混合物在2小時後僅實現化合物A濃度之略微增加，達到1.2 µg/mL - 1.8 µg/mL之範圍。As shown in Table 3, the physical mixture of Compound A and cyclodextrin achieved only a slight concentration of Compound A after 2 hours compared to Compound A alone, which reached a concentration of 0.9 µg/mL after 2 hours of testing at pH 6.8 increased to a range of 1.2 µg/mL - 1.8 µg/mL.
為了促進化合物A之複合，藉由在添加甲醇之情況下混合化合物A及羥丙基-β-環糊精（經低取代及高取代為CDx中最有前景的）且隨後乾燥來進行兩種組分之共處理。如表3中所示，與用各自物理混合物獲得之值相比，化合物A與環糊精之共處理僅引起可忽略不計的溶解度增加，大約為10%。
表 3 ：對化合物 A 及環糊精進行之溶解度試驗的結果
在pH值6.8下測試化合物A與各種聚合物，諸如白蛋白以及各種等級之羥丙基甲基纖維素（HPMC）、甲基纖維素（MC）、聚乙烯亞胺及聚乙烯吡咯啶酮之組合的溶解度。如表4中所示，在所有測試聚合物中，僅HPMC及MC實現化合物A之溶解度與單獨活性物質之溶解度相比增加至少10倍（上表2）。Compound A was tested at pH 6.8 with various polymers such as albumin and various grades of hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyethyleneimine and polyvinylpyrrolidone Combined solubility. As shown in Table 4, of all polymers tested, only HPMC and MC achieved at least a 10-fold increase in the solubility of Compound A compared to the solubility of the active alone (Table 2 above).
該兩種測試聚合物均不能使化合物A在pH 6.8下之溶解度增加至與活性物質在pH 1.2下之溶解度相當的水準或超過沈降條件之限值（53.3 µg/mL）
表 4 ：對於化合物 A 活性物質及聚合物進行之溶解度試驗的結果
在所有測試界面活性劑中，僅十二烷基硫酸鈉（SDS）及聚乙烯己內醯胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物（Soluplus®）能夠顯著增加化合物A活性物質在pH 6.8下之溶解度。結果在表5中示出。Among all the tested surfactants, only sodium dodecyl sulfate (SDS) and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) can significantly increase the active substance of compound A Solubility at pH 6.8. The results are shown in Table 5.
由於SDS及Soluplus®均表現出兩性特徵，因此有助於在水中形成微胞。將SDS及Soluplus®之總量增加至≥ 15 g（
HPMC與其他賦形劑（例如，pH調節劑，諸如檸檬酸及HCl；界面活性劑，諸如Solupus及SDS；環糊精）組合進行測試HPMC was tested in combination with other excipients (eg, pH adjusters such as citric acid and HCl; surfactants such as Solupus and SDS; cyclodextrins)
將化合物A分散於含有pH調節劑檸檬酸或鹽酸之HPMC凝膠中。由於2小時後量測之化合物A自由鹼濃度與化合物A分散於不添加任何pH調節劑之HPMC凝膠中的濃度相當，因此無法確定pH調節劑之有益作用（參見表6）。
表 6 ： 對化合物 A 活性物質及 HPMC 與 pH 調節劑之組合進行之溶解度試驗的結果
此外，HPMC E15與SDS或Soluplus®之組合為呈預溶解溶液形式之HPMC與SDS之組合，HMPC及SDS之濃度分別為1 mg/mL及25 mg/mL，對應於API:HPMC:SDS比率為1:1.5:37.5，使得化合物A自由鹼濃度（44.4 µg/mL）接近於沈降條件所定義之限值（53.3 µg/mL）。結果之彙總可見於表7中。
表 7 ： 對化合物 A 活性物質及 HPMC 與界面活性劑之組合進行之溶解度試驗的結果
亦進行HPMC及環糊精（CDx）之測試。選擇HPMC E6，因為其已用於參考調配物中。Testing of HPMC and cyclodextrin (CDx) was also performed. HPMC E6 was chosen as it has been used in the reference formulation.
對於HPMC E6與環糊精（CDx）之組合，效率按以下順序提高：α-CD、γ-CD、β-CD、經低取代（ls）之羥丙基-β-環糊精（HPβCD）、經高取代（hs）之HPβCD。雖然HPMC E6與α-CD（10.7 µg/mL）之組合產生與單獨HPMC E6（11.1 µg/mL）相當的化合物A自由鹼濃度，但與hs-HPβCD之組合使得化合物A自由鹼濃度適度增加（16 µg/mL）。結果之彙總可見於表8中。
表 8 ： 對化合物 A 活性物質及 HPMC E6 與環糊精之組合進行之溶解度試驗的結果
Soluplus ®與其他賦形劑（例如，pH調節劑，諸如檸檬酸；界面活性劑，諸如SDS；聚合物，諸如PVP VA64）組合進行測試。 Soluplus® was tested in combination with other excipients (eg, pH adjusters such as citric acid; surfactants such as SDS; polymers such as PVP VA64).
Soluplus
®與上述賦形劑組合之溶解度試驗的結果彙總於表9中。
表 9 ： 對 Soluplus
® 與其他賦形劑及化合物 A 之組合進行之溶解度試驗的結果
為了模擬具有pH調節劑檸檬酸之pH微環境，將化合物A分散於亦含有檸檬酸之Soluplus ®凝膠中。2小時後量測之化合物A自由鹼濃度與化合物A分散於不含檸檬酸之Soluplus ®凝膠中所測定之濃度相當（參見表5及9）。然而，當將Soluplus ®溶解於5%檸檬酸水溶液中時，觀察到協同效應，化合物A自由鹼濃度為386 µg/mL。 To simulate the pH microenvironment with the pH modifier citric acid, Compound A was dispersed in Soluplus® gel also containing citric acid. The free base concentration of Compound A measured after 2 hours was comparable to the concentration of Compound A dispersed in Soluplus® gel without citric acid (see Tables 5 and 9). However, when Soluplus ® was dissolved in 5% citric acid in water, a synergistic effect was observed with a compound A free base concentration of 386 µg/mL.
Soluplus ®與界面活性劑SDS之組合未提供任何益處，因為與以相同濃度使用之單一賦形劑SDS（35 µg/mL）相比，其產生類似的化合物A自由鹼濃度（32 µg/mL）（參見表5及9）。 The combination of Soluplus® with the surfactant SDS did not provide any benefit as it yielded a similar concentration of Compound A free base (32 µg/mL) compared to the single excipient SDS (35 µg/mL) used at the same concentration (See Tables 5 and 9).
此外，Soluplus ®與PVP VA64之組合鑑別為有希望達到接近於沈降條件所定義之限值的化合物A濃度。 In addition, the combination of Soluplus ® and PVP VA64 was identified as promising to achieve Compound A concentrations close to the limits defined by settling conditions.
Soluplus ®/PVP VA64與甲醇共處理產生81 µg/mL之甚至更高的化合物A自由鹼濃度，但所得產物在乾燥後具有玻璃態及極硬結構，不適合於進一步處理。為了使Soluplus ®及PVP VA64之共處理混合物獲得可接受之粉末特性，將其用膠態二氧化矽（SiO 2）、交聯聚乙烯吡咯啶酮（PVP-CL）、微晶纖維素（MCC）或甘露糖醇進行造粒。 Co-treatment of Soluplus ® /PVP VA64 with methanol yielded an even higher Compound A free base concentration of 81 µg/mL, but the resulting product had a glassy and extremely hard structure after drying and was not suitable for further processing. In order to obtain acceptable powder properties of the co-processed mixture of Soluplus ® and PVP VA64, it was mixed with colloidal silica (SiO 2 ), cross-linked polyvinylpyrrolidone (PVP-CL), microcrystalline cellulose (MCC ) or mannitol for granulation.
在Soluplus:賦形劑添加SiO 2、PVP-CL及MCC共處理之混合物在緩衝液pH 6.8中之可研磨性及崩解時間方面顯示出可接受之粉末特性。 In Soluplus: excipients added SiO2 , PVP-CL and MCC co-treated mixture showed acceptable powder properties in terms of grindability and disintegration time in buffer pH 6.8.
儘管獲得可接受之粉末特性，但Soluplus ®及SiO 2之混合物僅達到4 µg/mL之極低化合物A自由鹼濃度。採用減少量之SiO 2與PVP-CL及PVP VA64組合產生可接受之顆粒，其中化合物A自由鹼濃度接近於沈降條件所定義之限值（30 - 53 µg/mL）。 Although acceptable powder properties were obtained, the mixture of Soluplus ® and SiO 2 only achieved a very low Compound A free base concentration of 4 µg/mL. Using reduced amounts of SiO2 in combination with PVP-CL and PVP VA64 produced acceptable particles with Compound A free base concentrations close to the limit defined by the settling conditions (30 - 53 µg/mL).
總之，Soluplus ®/PVP VA64之組合達到與沈降條件之計算限值相當之化合物A自由鹼濃度，且因此視為最有希望提高溶解度之候選者。 小規模調配試驗 In conclusion, the Soluplus ® /PVP VA64 combination achieves a free base concentration of Compound A that is comparable to the calculated limit for sedimentation conditions and is therefore considered the most promising candidate for improved solubility. Small scale deployment test
為了評估用有前景的賦形劑進行之溶解度試驗中獲得之結果是否可轉化為與參考調配物相比經改良之溶解效能，製造實驗室規模膠囊調配物且進行溶解測試。最終提出之調配物的可接受膠囊尺寸定義為最大尺寸0。To assess whether the results obtained in solubility tests with promising excipients could be translated into improved dissolution potency compared to reference formulations, laboratory scale capsule formulations were manufactured and dissolution tests were performed. The acceptable capsule size for the final proposed formulation was defined as the maximum size of zero.
在所有情況下，溶解輪廓均在pH 6.8下記錄，因為此視為在化合物A溶解度方面最具挑戰性的條件。視情況，亦在pH 4.5及pH 1.2下記錄溶解輪廓。In all cases, dissolution profiles were recorded at pH 6.8, as this was considered the most challenging condition in terms of Compound A solubility. Dissolution profiles were also recorded at pH 4.5 and pH 1.2, as appropriate.
作為參考點，在生理pH範圍內記錄參考調配物之溶解輪廓。相應的輪廓描繪於圖1中。在pH 1.2下，64%及100%化合物A自由鹼分別在20分鐘及60分鐘後溶解。在pH值增加至4.5及6.8時，觀察到顯著滯後時間，其中未觀察到化合物A在溶解介質中之釋放。因此，在測試60分鐘後，僅11%及˂1%之化合物A自由鹼分別在pH 4.5及6.8下溶解。 包含Soluplus®及PVP VA64之調配物 As a reference point, the dissolution profile of the reference formulation was recorded in the physiological pH range. The corresponding contours are depicted in Figure 1 . At pH 1.2, 64% and 100% of Compound A free base dissolved after 20 and 60 minutes, respectively. Significant lag times were observed when the pH was increased to 4.5 and 6.8, where no release of Compound A in the dissolution medium was observed. Therefore, after 60 minutes of testing, only 11% and ˂1% of Compound A free base was dissolved at pH 4.5 and 6.8, respectively. Formulations containing Soluplus® and PVP VA64
由於Soluplus®與PVP VA64之組合在溶解度實驗中得到有前景的結果，因此以物理或共處理混合物之形式製備含有此等賦形劑之組合的各種小規模膠囊批次。視情況，調配物中包括其他賦形劑（例如PVP-CL），以便共處理混合物在溶解介質中獲得可接受之崩解。用增加量之Soluplus®及PVP VA64製備化合物A、Soluplus®及PVP VA64（及PVP-CL）之物理混合物。相應批次A及B之組成在表10中示出。
表 10 ：批次 A 及 B 及 C 之組成
批次A及批次B在60分鐘後在pH 6.8之溶液中分別產生14%及47%化合物A自由鹼之溶解輪廓（參見圖2），證明增加此等賦形劑之量會使得溶液中化合物A之濃度增加。然而，由於所使用之0號膠囊的填充體積有限，因此進一步增加此等賦形劑之量為不可行的。Batch A and Batch B yielded dissolution profiles of 14% and 47% Compound A free base, respectively, in solution at pH 6.8 after 60 minutes (see Figure 2), demonstrating that increasing the amount of these excipients resulted in a The concentration of Compound A increased. However, further increasing the amount of these excipients is not feasible due to the limited fill volume of the
為了研究與物理混合物（批次B）相比，化合物A、Soluplus®及PVP VA64之甲醇共處理是否會使溶液中之化合物A濃度進一步增加，製造批次C（組成參見表10）。如圖2中所示，甲醇共處理對Soluplus®/PVP VA64調配物之溶解效能產生負面影響，因為觀察到與物理混合物相比，60分鐘後溶液中化合物A之百分比自47%降低至32%。To investigate whether methanol co-treatment of Compound A, Soluplus® and PVP VA64 would further increase the concentration of Compound A in solution compared to the physical mixture (Batch B), Batch C (see Table 10 for composition) was produced. As shown in Figure 2, methanol co-treatment negatively affected the dissolution performance of the Soluplus®/PVP VA64 formulation as it was observed that the percentage of Compound A in solution decreased from 47% to 32% after 60 minutes compared to the physical mixture .
總之anyhow ，, 含有contain Soluplus®/PVP VA64Soluplus®/PVP VA64 之Of 調配物在The formulation is in 6060 分鐘測試後僅實現不完全溶解Only incomplete dissolution achieved after minute test ，, 溶液中之化合物compounds in solution AA 最大為up to 47%47% 。此. this 相當於equivalent to 溶解介質中化合物Compounds in Dissolution Medium AA 之濃度僅為The concentration is only 8 µg/mL8 µg/mL 。.
相反on the contrary ，, 在溶解度試驗期間During the solubility test ，, Soluplus®/PVP VA64Soluplus®/PVP VA64 之Of 組合實現Combination implementation 高達Gundam 81 µg/mL81 µg/mL 之化合物compound AA 濃度。concentration.
因此，在溶解度試驗內觀察到的有前景的結果無法在溶解試驗內得到證實。 包含HPMC及SDS之調配物 Therefore, the promising results observed in the solubility test could not be confirmed in the dissolution test. Formulations containing HPMC and SDS
由於HPMC與SDS之組合在溶解度試驗內鑑別為有前景的，其中化合物A之濃度接近於沈降條件之限值，因此在調配試驗內進一步研究此類組合。由於經修改口服調配物之最大膠囊尺寸定義為0，因此調配試驗中必須減少溶解度試驗中所用之HPMC及SDS的總量，以使得調配物適合此類型之膠囊。Since the combination of HPMC and SDS was identified as promising in solubility experiments, where the concentration of Compound A was close to the limit of settling conditions, such combinations were further investigated in formulation experiments. Since the maximum capsule size of the modified oral formulation is defined as 0, the total amount of HPMC and SDS used in the solubility test must be reduced in the formulation test to make the formulation suitable for this type of capsule.
製備化合物A、HPMC及SDS之物理混合物（批次D）。此外，藉由甲醇共處理製造SDS含量增加之批次（批次E）。相應的組成在表11中示出。
表 11 ： 批次 D 及批次 E 之組成
在pH 6.8下進行溶解測試20分鐘及60分鐘後，批次D之溶解測試分別在溶液中產生僅8%及13%化合物A自由鹼。當SDS之量進一步增加且混合物與甲醇共處理（批次E）時，在pH 6.8下進行溶解測試20分鐘及60分鐘後，分別獲得溶液中具有49%及54%化合物A自由鹼之經改良溶解輪廓。相應的溶解輪廓描繪於圖3中。Dissolution testing of Batch D yielded only 8% and 13% Compound A free base in solution after 20 minutes and 60 minutes of dissolution testing at pH 6.8, respectively. When the amount of SDS was further increased and the mixture was co-treated with methanol (batch E), after dissolution testing at pH 6.8 for 20 minutes and 60 minutes, an improved solution with 49% and 54% Compound A free base was obtained, respectively Dissolve contours. The corresponding dissolution profiles are depicted in FIG. 3 .
由於 60 分鐘之溶解測試後 ， 溶液中 54% 之化合物 A 自由鹼 相當於 僅 10 µg/mL 之 化合物 A 濃度，因此 溶解度試驗之結果 ， 其中獲得的溶液中化合物 A 之最大濃度為 44.4 µg/mL ，無法 在調配試驗內再現。此可能歸因於以下事實：在溶解介質中未達到SDS之臨界微胞濃度。 包含HPMC及HPβCD之調配物 Since 54% of the free base of Compound A in the solution was equivalent to a concentration of only 10 µg/mL of Compound A after the 60 -minute dissolution test , the result of the solubility test showed that the maximum concentration of Compound A in the solution obtained was 44.4 µg/mL , which cannot be reproduced within the blending test. This may be due to the fact that the critical micelle concentration of SDS was not reached in the lysis medium. Formulations containing HPMC and HPβCD
在調配試驗內進一步研究在溶解度試驗中具有中等效能的HPMC與HPβCD之組合。The combination of HPMC and HP[beta]CD with moderate potency in solubility tests was further investigated in formulation experiments.
含有化合物A、HPβCD及HPMC且採用甲醇共處理製造之調配物（批次F）在20分鐘及60分鐘後使得溶液中化合物A自由鹼濃度分別為66%及77%。當調配物中HPMC之量加倍（批次G）時，溶解效能受到負面影響，在pH 6.8下測試20分鐘及60分鐘後，溶液中之化合物A自由鹼僅為49%及63%。相應的組成彙總於表12中。溶解輪廓描繪於圖4中。
表 12 ：批次 F 及 G 之組成
此被認為是出人意料的，因為用甘露糖醇而非HPβCD進行之試驗表明，HPMC含量增加改良溶解效能（參見表13及圖5）。
表 13 ：批次 H 及 I 之組成
另外，與甲醇共處理（批次G）相比，具有hs-HPβCD及增加之HPMC含量的調配物與水（批次L）或含有檸檬酸之水（批次M）共處理進一步增加溶解效能。雖然與含有檸檬酸之水共處理使得60分鐘後溶液中之化合物A自由鹼為76%，但僅與水共處理具有最明顯的效果，在pH 6.8下測試60分鐘後溶液中性化合物A自由鹼為86%。當調配物以物理混合物形式製造（批次N）時，60分鐘後溶液中化合物A之溶解為71%，高於與甲醇共處理之調配物，但低於與水共處理之調配物（參見圖6）。
表 14 ：批次 L 、 M 及 N 之組成
當溶解介質之pH降低至pH 4.5時，與pH 6.8相比，藉由與水共處理製備之經修改調配物的溶解進一步改良，在20分鐘及60分鐘後溶液中之化合物A自由鹼分別為86%及91%。在pH 6.8及pH 4.5下獲得之結果亦用具有相同組成及製造程序之另一批次（批次O）證實。
表 15 ：批次 L 及 O 及參考調配物之組成
另外，在pH 1.2下測試批次O，其中在20分鐘後獲得溶液中具有98%化合物A自由鹼之快速溶解（圖9）。In addition, batch O was tested at pH 1.2, with a rapid dissolution of 98% Compound A free base in solution obtained after 20 minutes (Figure 9).
確認批次O之溶解效能與先前批次L相當，且顯示出對溶解介質之pH的敏感性低，其中兩個批次在pH 6.8下60分鐘後溶液中具有86%化合物A自由鹼（圖7），且批次L及O在pH 4.5下60分鐘後溶液中分別具有91%及86%化合物A自由鹼（參見圖8）。在pH 1.2下，觀察到在20分鐘後溶液中具有98%化合物A自由鹼之快速溶解。The dissolution potency of Batch O was confirmed to be comparable to the previous batch L and showed low sensitivity to the pH of the dissolution medium, with two batches having 86% Compound A free base in solution after 60 minutes at pH 6.8 (Fig. 7), and batches L and O had 91% and 86% Compound A free base in solution after 60 minutes at pH 4.5, respectively (see Figure 8). At pH 1.2, rapid dissolution with 98% Compound A free base in solution was observed after 20 minutes.
總之，在特定賦形劑/賦形劑組合之溶解度試驗中獲得之有前景的結果令人驚訝地無法在調配試驗內再現，其中測定的溶解介質中化合物A自由鹼之濃度顯著低於溶解度試驗。In conclusion, the promising results obtained in the solubility test of a specific excipient/excipient combination were surprisingly not reproducible in the formulation test, where the concentration of Compound A free base in the dissolution medium was determined to be significantly lower than the solubility test .
更特定言之，Soluplus ®/PVP VA64及HPMC/SDS之組合在溶解度試驗中達到的濃度接近於或甚至高於沈降條件之定義限值53.3 µg/mL，導致調配物在pH 6.8之溶解介質中溶液中化合物A自由鹼的最大濃度≤ 10µg/mL。 More specifically, the combination of Soluplus ® /PVP VA64 and HPMC/SDS achieved concentrations in solubility tests close to or even above the defined limit of 53.3 µg/mL for sedimentation conditions, resulting in formulations in dissolution media at pH 6.8 The maximum concentration of compound A free base in solution is ≤ 10µg/mL.
HPMC及HPβCD之組合在溶解度試驗中僅顯示出中等效能，但在調配試驗中亦證明為有效的。 材料及方法 起始材料 The combination of HPMC and HPβCD showed only moderate efficacy in solubility tests, but also proved effective in formulation tests. Materials and Methods starting material
賦形劑：所有測試賦形劑為市售的。 API Excipients: All tested excipients were commercially available. API
在所述可行性研究中使用來自製造商SAFC公司之化合物A活性物質。 化合物 A 及賦形劑之物理混合物的樣品溶液 Compound A active substance from the manufacturer SAFC was used in the feasibility study. Sample solution of physical mixture of compound A and excipients
將100 mg化合物A及相應賦形劑轉移至錐形瓶中且用刮勺混合，隨後添加150 mL相應介質。 具有化合物 A 及預溶解賦形劑之樣品溶液 100 mg of Compound A and the corresponding excipients were transferred to an Erlenmeyer flask and mixed with a spatula, followed by the addition of 150 mL of the corresponding medium. Sample solution with Compound A and pre-dissolved excipients
將所討論之賦形劑預溶解於相應介質中進行溶解度試驗以避免結塊。隨後，將100 mg化合物A添加至150 mL預溶解賦形劑溶液中。 具有共處理化合物 A 及賦形劑之樣品溶液 Solubility tests were performed predissolving the excipients in question in the respective media to avoid clumping. Subsequently, 100 mg of Compound A was added to 150 mL of the pre-dissolved excipient solution. Sample solution with co-treated compound A and excipients
在添加甲醇或水之情況下，用刮勺將化合物A及相應賦形劑在瓷盤中混合，直至獲得糊狀稠度。隨後，在甲醇之情況下，樣品在室溫下乾燥，在水之情況下，樣品在乾燥烘箱中在高溫（40℃至60℃）下乾燥。必要時，在乾燥後且在添加150 mL介質前研磨共處理混合物。 化合物 A 分散於水性賦形劑凝膠中之樣品溶液 Compound A and the corresponding excipients were mixed with a spatula in a porcelain dish with the addition of methanol or water until a paste-like consistency was obtained. Subsequently, in the case of methanol, the samples were dried at room temperature, and in the case of water, the samples were dried in a drying oven at high temperature (40°C to 60°C). If necessary, the co-treatment mixture was milled after drying and before adding 150 mL of media. Sample solution of Compound A dispersed in an aqueous vehicle gel
在磷酸鹽緩衝液pH 6.8中製備賦形劑濃度為20%（w/w）（HPMC或Soluplus®）之水性凝膠，且將化合物A活性物質分散於凝膠內。在HPMC之情況下，賦形劑在≥90℃下添加至緩衝介質中，隨後冷卻分散液，接著形成凝膠。Aqueous gels at 20% (w/w) excipient concentration (HPMC or Soluplus®) were prepared in phosphate buffer pH 6.8 and Compound A active was dispersed within the gel. In the case of HPMC, the excipients are added to the buffer medium at > 90°C, followed by cooling of the dispersion followed by gel formation.
在Soluplus®之情況下，賦形劑在室溫下添加至緩衝介質中，接著形成凝膠。在某些情況下，將pH調節劑（例如檸檬酸）分散於凝膠中，隨後添加化合物A。藉由用刮勺混合30分鐘，將化合物A分散於750 mg相應凝膠中。隨後，將150 mL相應介質添加至凝膠中。 溶解度試驗 In the case of Soluplus®, the excipients are added to the buffer medium at room temperature, followed by the formation of a gel. In some cases, a pH adjuster (eg, citric acid) was dispersed in the gel, followed by the addition of Compound A. Compound A was dispersed in 750 mg of the corresponding gel by mixing with a spatula for 30 minutes. Subsequently, 150 mL of the corresponding medium was added to the gel. Solubility test
溶解度試驗係在室溫下在用磁性攪拌器連續攪拌下進行。在2小時後且視情況在4小時後，抽出樣品且使其通過適合之膜濾器。製備兩種測試溶液，且根據Ph. Eur. 2.2.29, USP ＜621＞藉由HPLC測定化合物A自由鹼濃度。作為溶解度試驗之結果，報告兩種測試溶液中化合物A自由鹼濃度之平均值。 溶解測試 Solubility tests were carried out at room temperature under continuous stirring with a magnetic stirrer. After 2 hours and optionally after 4 hours, samples were withdrawn and passed through a suitable membrane filter. Two test solutions were prepared and Compound A free base concentration was determined by HPLC according to Ph. Eur. 2.2.29, USP <621>. As a result of the solubility test, the average value of the free base concentration of Compound A in the two test solutions is reported. Dissolution test
根據Ph. Eur. 2.9.3, USP ＜711＞進行小規模調配物批次之溶解測試。在溶解介質（列於表A中）中進行之溶解方法係基於在QC介質中進行之參考調配物的溶解方法。
在溶解測試期間化合物A自由鹼之含量係根據Ph. Eur. 2.2.29, USP ＜621＞用HPLC方法測定。HPLC方法係基於用於參考調配物之溶解測試的HPLC方法。The content of Compound A free base during the dissolution test was determined by the HPLC method according to Ph. Eur. 2.2.29, USP <621>. The HPLC method is based on the HPLC method used for dissolution testing of the reference formulations.
無none
[ 圖 1]：參考調配物在900 mL無酶模擬胃液（pH 1.2）、磷酸鹽緩衝液pH 4.5及磷酸鹽緩衝液pH 6.8中採用75 rpm之槳式設備所記錄之溶解輪廓。 [ 圖 2]：Soluplus®/PVP VA64調配物在900 mL磷酸鹽緩衝液pH 6.8中採用75 rpm之槳式設備的溶解輪廓。 [ 圖 3]：HPMC/SDS調配物在900 mL磷酸鹽緩衝液pH 6.8中採用75 rpm之槳式設備的溶解輪廓。 [ 圖 4]：用不同量之HPMC經由甲醇共處理製造之HPMC/HPβCD調配物在900 mL磷酸鹽緩衝液pH 6.8中採用75 rpm之槳式設備的溶解輪廓。 [ 圖 5]：用不同量之HPMC經由甲醇共處理製造之HPMC/甘露糖醇調配物在900 mL磷酸鹽緩衝液pH 6.8中採用75 rpm之槳式設備的溶解輪廓。 [ 圖 6]：用不同加工液體製造及作為物理混合物之HPMC/HPβCD調配物在900 mL磷酸鹽緩衝液pH 6.8中採用75 rpm之槳式設備所記錄之溶解輪廓。 [ 圖 7]：HPMC/HPβCD調配物及「參考調配物」在900 mL磷酸鹽緩衝液pH 6.8中採用75 rpm之槳式設備的溶解輪廓。 [ 圖 8]：HPMC/HPβCD調配物及「參考調配物」在900 mL磷酸鹽緩衝液pH 4.5中採用75 rpm之槳式設備的溶解輪廓。 [ 圖 9]：HPMC/HPβCD調配物及「參考調配物」在900 mL無酶模擬胃液pH 1.2中採用75 rpm之槳式設備的溶解輪廓。 [ Figure 1 ]: Dissolution profiles of the reference formulations recorded in 900 mL of enzyme-free simulated gastric fluid (pH 1.2), phosphate buffer pH 4.5 and phosphate buffer pH 6.8 using a paddle apparatus at 75 rpm. [ Figure 2 ]: Dissolution profile of Soluplus®/PVP VA64 formulation in 900 mL of phosphate buffer pH 6.8 using a paddle apparatus at 75 rpm. [ Figure 3 ]: Dissolution profile of HPMC/SDS formulation in 900 mL of phosphate buffer pH 6.8 using a paddle apparatus at 75 rpm. [ Figure 4 ]: Dissolution profiles of HPMC/HPβCD formulations made via methanol co-treatment with different amounts of HPMC in 900 mL of phosphate buffer pH 6.8 using a paddle apparatus at 75 rpm. [ Figure 5 ]: Dissolution profiles of HPMC/Mannitol formulations made via methanol co-treatment with varying amounts of HPMC in 900 mL of phosphate buffer pH 6.8 using a paddle apparatus at 75 rpm. [ Figure 6 ]: Dissolution profiles recorded with a paddle apparatus at 75 rpm for HPMC/HPβCD formulations made with different process liquids and as physical mixtures in 900 mL of phosphate buffer pH 6.8. [ Figure 7 ]: Dissolution profiles of HPMC/HPβCD formulations and "reference formulation" in 900 mL of phosphate buffer pH 6.8 using a paddle apparatus at 75 rpm. [ Figure 8 ]: Dissolution profiles of HPMC/HPβCD formulations and "reference formulation" in 900 mL of phosphate buffer pH 4.5 using a paddle apparatus at 75 rpm. [ Figure 9 ]: Dissolution profiles of HPMC/HPβCD formulations and the "reference formulation" in 900 mL of enzyme-free simulated gastric juice pH 1.2 using a paddle apparatus at 75 rpm.
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