TW201311239A - Pharmaceutical composition comprising fexofenadine - Google Patents
Pharmaceutical composition comprising fexofenadine Download PDFInfo
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本發明係有關供口服投與用之非索非那定(fexofenadine)鹽酸鹽(HCl)之穩定醫藥組成物。 The present invention relates to a stable pharmaceutical composition for fexofenadine hydrochloride (HCl) for oral administration.
特別是，本發明乃有關一種包含非索非那定鹽酸鹽及醫藥上可接受之賦形劑，視需要封裝於軟明膠膠囊中之改良調配物。 In particular, the invention relates to an improved formulation comprising fexofenadine hydrochloride and a pharmaceutically acceptable excipient, optionally encapsulated in a soft gelatin capsule.
本發明再者亦有關製備此等醫藥組成物之方法及使用此等醫藥組成物製備用於治療過敏反應之藥物之用途。 The invention further relates to a method of preparing such pharmaceutical compositions and the use of such pharmaceutical compositions for the preparation of a medicament for the treatment of an allergic reaction.
非索非那定於水溶液中之溶解度很低，調配此等化合物供有效投與病患用時造成困難。經良好設計之調配物應該至少能提供呈可吸收形式之治療有效量之該疏水性化合物至所需吸收部位。當疏水性治療劑之遞送需要與例如胃液與腸液等水性生理環境相互作用時，即使此最小功能亦難以達成。再者，不同個體之藥物吸收由於胃腸功能與食物攝取不同而可能有明顯差異；因此劑量之決定及控制相當困難。 The solubility of fexofenadine in aqueous solutions is very low and it is difficult to formulate such compounds for effective administration to patients. A well-designed formulation should provide at least a therapeutically effective amount of the hydrophobic compound in an absorbable form to the desired site of absorption. This minimal function is difficult to achieve when the delivery of a hydrophobic therapeutic agent requires interaction with an aqueous physiological environment such as gastric juice and intestinal fluid. Furthermore, drug absorption in different individuals may vary significantly due to differences in gastrointestinal function and food intake; therefore, dose determination and control are quite difficult.
非索非那定[(+)-4-[1-羥基-4-[4(羥基二苯甲基)-1-哌啶基-丁基]-α,α-二甲苯乙酸]係第二代組織胺H1受體拮抗劑(抗組織胺)特非那定(terfenadine)之活性代謝物，非索非 那定之獨特性在於即使於活體外模式高劑量下，亦似乎全然無鎮靜作用。據報導，外排轉運體P-醣蛋白運送非索非那定，被認為是非索非那定藥物動力學之重要決定因素。由於非索非那定係P-gp與數個有機陰離子轉運多肽(OATP)之基質，食物及多種藥物共投與對其口服生物利用性將具顯著影響。調配口服投與型非索非那定之另一進一步挑戰為非索非那定特別是於胃液條件下之低溶解度(每毫升pH 1.2水性緩衝液溶解度為0.2毫克非索非那定HCl)。 Fexofenadine [(+)-4-[1-hydroxy-4-[4(hydroxybenzhydryl)-1-piperidinyl-butyl]-α,α-dimethylacetic acid] is the second Generation of histamine H1 receptor antagonist (antihistamine), an active metabolite of terfenadine, Fenofia The uniqueness of that is that even at high doses in the in vitro mode, there appears to be no sedation. It has been reported that efflux transporter P-glycoprotein delivery of fexofenadine is considered to be an important determinant of pharmacokinetics of fexofenadine. Due to the matrix of fexofenadine P-gp and several organic anion transport polypeptides (OATP), the co-administration of food and various drugs will have a significant impact on its oral bioavailability. Another further challenge in formulating oral-administered fexofenadine is the low solubility of fexofenadine, especially in gastric fluid conditions (0.2 mg of fexofenadine HCl per ml of pH 1.2).
而，調配非索非那定口服醫藥組成物之另一難題為其令人討厭、強烈的苦味及嚐過後導使對治療不良順從性或甚至不順從，因而對治療功效具有負面影響。 However, another difficulty in formulating the oral medicinal composition of fexofenadine is that it is annoying, intense bitterness, and has been adversely affected by poor therapeutic compliance or even disobedience.
鑑於上述情況，增進口服投與藥物之吸收乃解決難溶藥物低生物利用性問題之關鍵點。 In view of the above, improving the absorption of oral administration drugs is a key point in solving the problem of low bioavailability of poorly soluble drugs.
迄今，已使用增進難溶藥物生物利用性之許多方法，例如將其轉化為可溶鹽類或酯類、減少粒徑及增加表面積以提高藥物溶解性、添加助溶劑等。此外，雖然活性成分可轉化為供藥物投與用之可溶鹽類，惟由於胃腸道之pH變化，該可溶鹽類可能回復為難溶形式，因而導致藥物沉澱。 Heretofore, many methods for improving the bioavailability of poorly soluble drugs have been used, such as converting them into soluble salts or esters, reducing particle size and increasing surface area to improve drug solubility, adding a solubilizing agent, and the like. Further, although the active ingredient can be converted into a soluble salt for administration of the drug, the soluble salt may return to a poorly soluble form due to a change in the pH of the gastrointestinal tract, thereby causing precipitation of the drug.
又，由於涉及P-醣蛋白代謝途徑之首渡代謝(first pass metabolism)，非索非那定鹽酸鹽面臨口服生物利用性減少(高達33%)之問題。 Moreover, fexofenadine hydrochloride faces a problem of reduced oral bioavailability (up to 33%) due to the first pass metabolism involving the P-glycoprotein metabolic pathway.
因此，業界對於防止發生生物利用性減少之上述缺點，並增加吸收率以促進藥劑之最大生物利用性，達到極迅速之藥理作用，同時具有穩定性之組成物存在需求。 Therefore, the industry has a need to prevent the above-mentioned disadvantages of bioavailability reduction and increase the absorption rate to promote the maximum bioavailability of the drug, to achieve extremely rapid pharmacological action, and to have a stable composition.
US 4,929,605敘述一種供口服投與用之包含哌啶烷醇化合物與增加哌啶烷醇化合物之吸收及生物利用性之非離子性界面活性劑[例如聚山梨糖醇酯80(Tween 80)]之醫藥組成物。此文件並未敘述或建議包含非索非那定鹽酸鹽與至少一種非離子親水性界面活性劑與至少一種非離子疏水性界面活性劑之液體混合物之醫藥組成物。再者，此文件未能解決增進包含哌啶烷醇化合物之醫藥組成物之貯存穩定性與適用期等技術問題。 No. 4,929,605 describes a nonionic surfactant (for example, polysorbate 80 (Tween 80)) comprising a piperidinol compound for oral administration and for increasing the absorption and bioavailability of a piperidinol compound. Pharmaceutical composition. This document does not describe or suggest a pharmaceutical composition comprising a liquid mixture of fexofenadine hydrochloride and at least one nonionic hydrophilic surfactant and at least one nonionic hydrophobic surfactant. Furthermore, this document fails to solve the technical problems of improving the storage stability and pot life of the pharmaceutical composition containing the piperidinol compound.
WO99/08690揭示利用口服共投與p-醣蛋白抑制劑例如聚乙二醇(PEG 400或PEG 1000)或聚山梨糖醇酯而提高非索非那定鹽酸鹽生物利用性之方法；其中並未提及包含非索非那定鹽酸鹽與至少一種非離子親水性界面活性劑與至少一種非離子疏水性界面活性劑之液體混合物之任何醫藥組成物。再者，該發明人等觀察到，非索非那定鹽酸鹽與單僅非離子親水性界面活性劑之組合物於一段時間後不穩定，非索非那定鹽酸鹽顯現分解，且生物利用性比根據本發明之組成物更小。 WO 99/08690 discloses a method for enhancing the bioavailability of fexofenadine hydrochloride by oral co-administration with a p-glycoprotein inhibitor such as polyethylene glycol (PEG 400 or PEG 1000) or polysorbate; No pharmaceutical composition comprising a liquid mixture of fexofenadine hydrochloride and at least one nonionic hydrophilic surfactant and at least one nonionic hydrophobic surfactant is not mentioned. Furthermore, the inventors observed that the combination of fexofenadine hydrochloride and a single nonionic hydrophilic surfactant is unstable after a while, and that fexofenadine hydrochloride appears to decompose, and Bioavailability is smaller than the composition according to the invention.
因此本發明之目的在於提供增進非索非那定鹽酸鹽之溶解性與生物利用性，且於一段時間內穩定之口服投與之液體醫藥組成物。 It is therefore an object of the present invention to provide a liquid pharmaceutical composition for oral administration which enhances the solubility and bioavailability of fexofenadine hydrochloride and which is stable over a period of time.
申請人等已發現藉由提供包含非索非那定鹽酸鹽與醫藥上可接受之賦形劑之改良液體組成物可達成此目的。 Applicants and the like have found that this can be achieved by providing an improved liquid composition comprising fexofenadine hydrochloride and a pharmaceutically acceptable excipient.
頃令人驚奇地發現，相較於已知液體調配物，根據本發明之非索非那定鹽酸鹽組成物之溶解性與生物利用性大為增加。 Surprisingly, it has been found that the solubility and bioavailability of the fexofenadine hydrochloride composition according to the present invention is greatly increased compared to known liquid formulations.
進一步發現，含此調配物之膠囊形式減少了藥劑之殘留味道。 It has further been found that a capsule form containing this formulation reduces the residual taste of the agent.
本發明係提供可口服投與之包含非索非那定鹽酸鹽之穩定液體醫藥組成物，其利用複合建立提高藥物生物利用性之最適條件，例如藥物與伴隨成分間之關連性、各別成分最適混合比率之選擇與使用特定界面活性劑、水分含量及pH調節劑。 The present invention provides an orally administrable stable liquid pharmaceutical composition comprising fexofenadine hydrochloride, which utilizes a complex to establish optimal conditions for improving the bioavailability of the drug, such as the association between the drug and the concomitant component, and the respective The optimum blending ratio of the ingredients is selected using a specific surfactant, moisture content, and pH adjuster.
本發明調配物包含至少一種親水性界面活性劑與至少一種疏水性界面活性劑及一或多種醫藥上可接受賦形劑之液體混合物，而產生具有快迅治療作用、較佳吸收與生物利用性之美味且穩定之調配物。 The formulation of the present invention comprises a liquid mixture of at least one hydrophilic surfactant and at least one hydrophobic surfactant and one or more pharmaceutically acceptable excipients to produce a rapid therapeutic effect, preferably absorption and bioavailability A delicious and stable blend.
本發明之另一目的在於提供具有增進之崩解度與溶解速率同時生物利用性增加之製劑(例如軟膠囊)。特別是，本發明乃有關製備非索非那定鹽酸鹽之軟膠囊調配物，其最終容許獲得與得自習知非索非那定鹽酸鹽口服固體調配物(舉例而言，例如以Allegra®商標市售可得之錠劑)者具生體相等性之藥物動力學參數。 Another object of the present invention is to provide a preparation (e.g., a soft capsule) having an increased degree of disintegration and dissolution rate while increasing bioavailability. In particular, the present invention relates to a soft capsule formulation for the preparation of fexofenadine hydrochloride which ultimately permits the obtaining of an oral solid formulation derived from the conventional fexofenadine hydrochloride (for example, in Allegra, for example ® Pharmacokinetic parameters for bioequivalence in the market for commercially available tablets.
本發明之又另一目的在於提供具有增進化學穩定性之醫藥調配物，例如，包含本發明調配物之軟膠囊、硬膠囊、兩片式膠囊或錠劑。 Still another object of the present invention is to provide a pharmaceutical formulation having improved chemical stability, for example, a soft capsule, a hard capsule, a two-piece capsule or a lozenge comprising the formulation of the present invention.
本發明之另一目的在於提供製備本發明口服醫藥組成物之方法，該方法包括於至少一種親水性界面活性劑與至少一種疏水性界面活性劑之適量液體混合物中溶解非索非那定鹽酸鹽，使pH值成為可接受之範圍，從而提高該調配物之貯存穩定性及適用期。 Another object of the present invention is to provide a process for the preparation of an oral pharmaceutical composition of the present invention which comprises dissolving fexofenadine hydrochloride in an appropriate amount of a liquid mixture of at least one hydrophilic surfactant and at least one hydrophobic surfactant. The salt is such that the pH is within an acceptable range to enhance the storage stability and pot life of the formulation.
本發明亦有關使用本發明之口服醫藥組成物製備用於治療病患中過敏反應之藥物之用途。 The invention also relates to the use of an oral pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of an allergic reaction in a patient.
參照下述說明及申請專利範圍將更加瞭解本發明之彼等及其他觀點、特徵及優點。 These and other aspects, features, and advantages of the present invention will become more apparent from the description and appended claims.
除非本文中另行界定，否則有關本發明所用之科學及技術名詞具有一般熟習此項技藝者通常瞭解之意義。該等名詞之意義及範圍應當很明確；然而，發生任何潛在之意義不明確時，則本文中提供之界定優先於辭典或外來之界定。除非說明書中另有需求，否則單數形名詞應包含複數形及複數形名詞應包含單數形。 Unless otherwise defined herein, the scientific and technical terms used in connection with the present invention have the meaning commonly understood by those skilled in the art. The meaning and scope of such terms should be clear; however, where any potential meaning is unclear, the definitions provided herein take precedence over the definition of the dictionary or foreign. Unless otherwise required in the specification, the singular nouns shall include plural and plural nouns shall include the singular.
根據本發明，穩定調配物意指，特別是，對非索非那定鹽酸鹽之分解展現高抗性之調配物。因此，於40℃及75%濕度貯存3個月後，根據本發明之醫藥組成物通常未展現高度分解之任何跡象(雜質總含量小於非索非那定鹽 酸鹽之1重量%)及含有至少99重量%之初始非索非那定鹽酸鹽量(由HPLC分析證明)。 According to the invention, a stable formulation means, in particular, a formulation which exhibits a high resistance to the decomposition of fexofenadine hydrochloride. Therefore, after storage at 40 ° C and 75% humidity for 3 months, the pharmaceutical composition according to the present invention generally does not exhibit any indication of high decomposition (the total impurity content is less than that of fexofenadine salt). 1% by weight of the acid salt) and at least 99% by weight of the initial amount of fexofenadine hydrochloride (proven by HPLC analysis).
本發明使用一種溶劑系，該溶劑系係複合考慮各種因素(包括提高藥物生物利用性之最適條件，例如藥物與伴隨成分間之關連性、各別成分最適混合比率之選擇與使用特定界面活性劑、水分含量及pH調節劑)而達成。 The present invention employs a solvent system which combines various factors (including an optimum condition for improving the bioavailability of the drug, such as the correlation between the drug and the concomitant component, the selection of the optimum mixing ratio of the respective components, and the use of a specific surfactant. , water content and pH adjuster).
欲投與之活性劑與特定調配物之確切劑量取決於若干因素，例如，欲治療之症狀、該治療所需持續時間及活性劑釋放速率。舉例而言，需要之非索非那定鹽酸鹽量及其釋放速率可測定特定活性劑於血漿中之濃度保持於達到治療效果之可接受含量多久的時間，其根據已知之活體外或活體內技術決定。 The exact dose of active agent to be administered to a particular formulation will depend on a number of factors, such as the condition to be treated, the duration of the treatment, and the rate of active agent release. For example, the amount of fexofenadine hydrochloride required and its rate of release can be determined by determining how long the concentration of a particular active agent in plasma is maintained at an acceptable level for achieving a therapeutic effect, according to known in vitro or live In vivo technical decisions.
因此，本發明之第一觀點係有關一種包含非索非那定鹽酸鹽與醫藥上可接受之賦形劑，且生物利用性大為增加之醫藥組成物。 Accordingly, the first aspect of the present invention relates to a pharmaceutical composition comprising fexofenadine hydrochloride and a pharmaceutically acceptable excipient, and having a greatly increased bioavailability.
於本發明組成物中，非索非那定鹽酸鹽存在之量為組成物之1至35重量%不等。於最佳具體實例中，非索非那定鹽酸鹽存在之量為組成物之10至30重量%不等。 In the compositions of the present invention, fexofenadine hydrochloride is present in an amount ranging from 1 to 35 weight percent of the composition. In a preferred embodiment, fexofenadine hydrochloride is present in an amount ranging from 10 to 30% by weight of the composition.
於本發明組成物中，非索非那定鹽酸鹽具有1.0與4.0平方米/克間範圍之較佳比表面積。於最佳具體實例中，非索非那定鹽酸鹽具有3.2平方米/克之比表面積。 In the composition of the present invention, fexofenadine hydrochloride has a preferred specific surface area in the range of 1.0 to 4.0 m 2 /g. In a preferred embodiment, fexofenadine hydrochloride has a specific surface area of 3.2 square meters per gram.
於本發明組成物中，非索非那定鹽酸鹽之較佳粒徑分佈(根據Malvern)為D(0.1)0.913微米(其中90%之分佈在 其上及10%在其下之直徑)；D(0.5)9.207微米(其中50%之分佈在其上及50%在其下之體積中數直徑)及D(0.9)15.896微米(其中10%之分佈在其上及90%在其下之體積中數直徑)。 In the composition of the present invention, the preferred particle size distribution of fexofenadine hydrochloride (according to Malvern) is D (0.1) 0.913 μm (90% of which is distributed in Above and 10% below the diameter); D (0.5) 9.207 microns (where 50% is distributed over it and 50% of the volume below it) and D (0.9) 15.896 microns (10% of which It is distributed over it and 90% of the volume below it is the diameter).
組成物考量使用至少一種非離子親水性界面活性劑與具油性媒液功能之至少一種非離子疏水性界面活性劑之液體混合物。該界面活性劑混合物存在之量足以促進本發明所考量之有利作用。 The composition is considered to use a liquid mixture of at least one nonionic hydrophilic surfactant and at least one nonionic hydrophobic surfactant having an oily vehicle function. The surfactant mixture is present in an amount sufficient to promote the beneficial effects contemplated by the present invention.
於一具體實例中，醫藥組成物包含至少一種相當於具有10至18，較佳為11至16之親水親脂平衡(HLB)值之界面活性劑之非離子親水性界面活性劑；與至少一種相當於具有4至10，較佳為4至6之HLB值之界面活性劑之疏水性界面活性劑之混合物。HLB系(Fiedler,H.B.,Encylopedia of Excipients,5th ed.,Aulendorf：ECV-Editio-Cantor-Verlag(2002))為界面活性劑之屬性數值，親脂性(或疏水性)物質得到較低之HLB值，親水性得到較高之HLB值。 In one embodiment, the pharmaceutical composition comprises at least one nonionic hydrophilic surfactant corresponding to a surfactant having a hydrophilic lipophilic balance (HLB) value of 10 to 18, preferably 11 to 16,; A mixture of hydrophobic surfactants equivalent to a surfactant having an HLB value of 4 to 10, preferably 4 to 6. The HLB line (Fiedler, HB, Encylopedia of Excipients, 5th ed., Aulendorf: ECV-Editio-Cantor-Verlag (2002)) is the attribute value of the surfactant, and the lipophilic (or hydrophobic) substance gives a lower HLB value. Hydrophilicity gives a higher HLB value.
以組成物總重計，非離子性界面活性劑之總量為至少60重量%，較佳為65至90重量%。更佳為，界面活性劑之總量為組成物之65至85重量%。 The total amount of the nonionic surfactant is at least 60% by weight, preferably from 65 to 90% by weight, based on the total weight of the composition. More preferably, the total amount of surfactant is from 65 to 85% by weight of the composition.
可用於本發明情況下之較佳非離子疏水性界面活性劑包括惟不限於月桂酸丙二醇酯(lauroglycol 90)、單癸酸丙二醇酯(capryol-90)及其混合物。包含於醫藥組成物中之最佳疏水性界面活性劑係HLB值為4之單月桂酸丙二醇 酯(lauroglycol 90)。 Preferred nonionic hydrophobic surfactants useful in the context of the present invention include, but are not limited to, lauroglycol 90, propylene glycol monoester (capryol-90), and mixtures thereof. The most preferred hydrophobic surfactant contained in the pharmaceutical composition is propylene glycol monolaurate with an HLB value of 4. Ester (lauroglycol 90).
於本發明組成物中，較佳為疏水性界面活性劑以組成物之至少30重量%之量存在。根據本發明醫藥組成物之有利具體實例，疏水性界面活性劑存在之量為組成物之50至85重量%範圍間。更佳為，疏水性界面活性劑存在之量為組成物之60至85重量%範圍間。於最佳具體實例中，疏水性界面活性劑存在之量為組成物之75至80重量%範圍間。 Preferably, the hydrophobic surfactant is present in the composition of the invention in an amount of at least 30% by weight of the composition. According to an advantageous embodiment of the pharmaceutical composition of the invention, the hydrophobic surfactant is present in an amount ranging from 50 to 85% by weight of the composition. More preferably, the hydrophobic surfactant is present in an amount ranging from 60 to 85% by weight of the composition. In a preferred embodiment, the hydrophobic surfactant is present in an amount ranging from 75 to 80% by weight of the composition.
包含於醫藥組成物中之另一較佳親水性界面活性劑係HLB值為15之聚山梨糖醇酯80(聚氧乙烯山梨醇酐單油酸酯；Tween 80)。 Another preferred hydrophilic surfactant included in the pharmaceutical composition is polysorbate 80 (polyoxyethylene sorbitan monooleate; Tween 80) having an HLB value of 15.
於本發明組成物中，較佳為，親水性界面活性劑存在之量為組成物之1至40重量%範圍間。亦較佳為，親水性界面活性劑存在之量為組成物之1至15重量%範圍間。於最佳具體實例中，親水性界面活性劑存在之量為組成物之1至10重量%範圍間。 In the composition of the present invention, it is preferred that the hydrophilic surfactant is present in an amount ranging from 1 to 40% by weight of the composition. It is also preferred that the hydrophilic surfactant is present in an amount ranging from 1 to 15% by weight of the composition. In a preferred embodiment, the hydrophilic surfactant is present in an amount ranging from 1 to 10% by weight of the composition.
於本發明之另一較佳具體實例中，醫藥組成物至少為月桂酸丙二醇酯(lauroglycol 90)(非離子疏水性界面活性劑)與聚山梨糖醇酯80(非離子親水性界面活性劑)之混合物。 In another preferred embodiment of the invention, the pharmaceutical composition is at least lauroglycol 90 (nonionic hydrophobic surfactant) and polysorbate 80 (nonionic hydrophilic surfactant) a mixture.
於進一步觀點中，本發明係有關包含非索非那定鹽酸鹽及至少一種親水性界面活性劑與至少一種疏水性界面活性劑之液體混合物之口服投與調配物，其中非索非那定 鹽酸鹽對界面活性劑液體混合物之重量比為1：1.5至1：8。於本發明較佳具體實例中，非索非那定鹽酸鹽對界面活性劑液體混合物之重量比為1：2至1：7，此比值最佳為等於1：4。 In a further aspect, the invention relates to an oral administration formulation comprising fexofenadine hydrochloride and a liquid mixture of at least one hydrophilic surfactant and at least one hydrophobic surfactant, wherein fexofenadine The weight ratio of the hydrochloride to the surfactant liquid mixture is from 1:1.5 to 1:8. In a preferred embodiment of the invention, the weight ratio of fexofenadine hydrochloride to the surfactant liquid mixture is from 1:2 to 1:7, and the ratio is preferably equal to 1:4.
本發明之另一觀點為非索非那定鹽酸鹽於適當醫藥媒液中之pH，以確保醫藥調配物之適當貯存穩定性與增進其貯存穩定性及其適用期；介於4與9間及更佳為5至6之pH值可達到最佳結果。 Another aspect of the invention is the pH of fexofenadine hydrochloride in a suitable pharmaceutical vehicle to ensure proper storage stability of the pharmaceutical formulation and to enhance its storage stability and pot life; between 4 and 9 The optimum pH is between 5 and 6 pH.
根據本發明，彼等pH值可利用添加方便之酸化劑與鹼化劑達成。 According to the present invention, their pH values can be achieved by the addition of an acidifying agent and an alkalizing agent.
本發明所用之鹼化劑可選自碳酸鈣、氫氧化鎂、***膠、磷酸二鈣、氫氧化鉀、乙酸鈉、磷酸鉀、碳酸鈉、三乙醇胺等及其組合物。於較佳具體實例中，鹼化劑為三乙醇胺。 The alkalizing agent used in the present invention may be selected from the group consisting of calcium carbonate, magnesium hydroxide, gum arabic, dicalcium phosphate, potassium hydroxide, sodium acetate, potassium phosphate, sodium carbonate, triethanolamine, and the like, and combinations thereof. In a preferred embodiment, the basifying agent is triethanolamine.
本發明所用之酸化劑可選自乙酸、乳酸、抗壞血酸、檸檬酸、磷酸、草酸、氯化鈣、氫氧化銨等及其組合物。 The acidifying agent used in the present invention may be selected from the group consisting of acetic acid, lactic acid, ascorbic acid, citric acid, phosphoric acid, oxalic acid, calcium chloride, ammonium hydroxide, and the like, and combinations thereof.
本發明亦有關用於製備包含1至35%(w/w)之非索非那定鹽酸鹽及至少60%(w/w)之至少一種非離子親水性界面活性劑與至少一種非離子疏水性界面活性劑液體混合物之醫藥製劑之方法。此方法包括下述步驟：攪拌下，使非索非那定鹽酸鹽溶於至少一種非離子親水性界面活性劑與至少一種非離子疏水性界面活性劑之液體混合物中，以獲得均質混合物；然後使用足量酸化劑或鹼化劑將 pH調至介於5-6之間。 The invention also relates to the preparation of 1 to 35% (w/w) of fexofenadine hydrochloride and at least 60% (w/w) of at least one nonionic hydrophilic surfactant and at least one nonionic A method of pharmaceutical formulation of a hydrophobic surfactant liquid mixture. The method comprises the steps of: dissolving fexofenadine hydrochloride in a liquid mixture of at least one nonionic hydrophilic surfactant and at least one nonionic hydrophobic surfactant to obtain a homogeneous mixture; Then use a sufficient amount of acidifier or alkalizing agent The pH is adjusted to between 5-6.
本發明之一觀點係提供軟明膠膠囊，其包含由明膠及/或塑化劑與需要時之進一步輔助物質組成之膠囊殼。 One aspect of the present invention is to provide a soft gelatin capsule comprising a capsule shell composed of gelatin and/or a plasticizer and further auxiliary substances as needed.
於開發根據本發明非索非那定鹽酸鹽組成物之軟明膠膠囊時，必須認定的為，該膠囊係由非索非那定鹽酸鹽組成物及用以封裝非索非那定組成物之明膠殼組成之系統。就其本身而論，不僅所裝填之非索非那定組成物產生所需溶解性及生物利用性很關鍵，該明膠殼調配物由於必須與非索非那定鹽酸鹽組成物相容，亦十分關鍵。熟習此項技藝者將意識到可能導致物理及化學上之膠囊不穩定性之潛在之裝填物-殼相互作用。因此，於本發明中亦優先考慮用以形成非索非那定組成物之膠囊之明膠殼調配物。 In the development of a soft gelatin capsule according to the composition of fexofenadine hydrochloride according to the present invention, it must be determined that the capsule is composed of fexofenadine hydrochloride and is used to encapsulate fexofenadine. The system consisting of gelatin shells. For its part, it is critical that not only the filled fifenofibine composition produces the desired solubility and bioavailability, the gelatin shell formulation must be compatible with the fexofenadine hydrochloride composition, It is also very crucial. Those skilled in the art will be aware of potential filler-shell interactions that may result in physical and chemical capsule instability. Accordingly, gelatin shell formulations for forming capsules of fexofenadine compositions are also preferred in the present invention.
一般而言，軟明膠膠囊之明膠殼膠囊調配物係由未加工明膠及添加以塑化明膠以產生依設計或優先選擇需要適當硬度之膠囊之一或多種成分組成。典型之塑化劑包括甘油與山梨糖醇(例如：得自SPI Pharma之SpecialTM MDF 85)。又，亦可使用山梨醇酐類與甘露糖醇。再者，其他非傳統成分亦可用以塑化明膠。 In general, gelatin shell capsule formulations of soft gelatin capsules are composed of unprocessed gelatin and added to plasticize gelatin to produce one or more ingredients that are designed or preferred to require a suitable hardness. Typical of the plasticizers include glycerin and sorbitol (eg: available from SPI Pharma's Special TM MDF 85). Further, sorbitol and mannitol can also be used. Furthermore, other non-traditional ingredients can also be used to plasticize gelatin.
用於建構與本發明非索非那定組成物一起使用之軟明膠膠囊之較佳明膠調配物包含明膠與塑化劑。為醫藥調配物技藝中悉知之此類塑化劑包括，例如，丙二醇、與山梨糖醇。 Preferred gelatin formulations for constructing soft gelatin capsules for use with the fexofenadine compositions of the present invention comprise gelatin and a plasticizer. Such plasticizers well known in the art of pharmaceutical formulation include, for example, propylene glycol, and sorbitol.
膠囊調配物亦可包含用以穩定膠囊或賦予膠囊例如顏色或外觀等具體特徵之其他適當添加劑，例如防腐劑或著色劑。醫藥上可接受之防腐劑可包括，例如，對羥苯甲酸甲酯與對羥苯甲酸丙酯。使用FD&C或D&C染料可賦予明膠殼顏色。染料之實例包括惟不限於酒石(Tartrazine)黃、蔚然(Azura)紅等。可使用乳白劑(例如二氧化鈦或氧化鐵類)著色或使膠囊不透明。 Capsule formulations may also contain other suitable additives, such as preservatives or colorants, to stabilize the capsule or to impart specific characteristics such as color or appearance to the capsule. Pharmaceutically acceptable preservatives can include, for example, methyl paraben and propyl paraben. Gelatin shell color can be imparted using FD&C or D&C dyes. Examples of the dye include, but are not limited to, Tartrazine Yellow, Azura Red, and the like. Coloring agents such as titanium dioxide or iron oxides may be used or the capsules may be opaque.
本發明考量使用包覆劑，其可包括非功能性或腸衣包覆劑例如纖維素系聚合物、膜衣包覆劑或熟習此項技藝人士已知之其他包覆劑。 The present invention contemplates the use of a coating agent which may include a non-functional or casing coating such as a cellulosic polymer, a film coating or other coating agents known to those skilled in the art.
可包含習知用於醫藥組成物之其他添加劑，彼等添加劑為此項技藝中悉知。此類添加劑包括抗氧化劑、防腐劑、螯合劑、錯合劑、黏度調節劑、張力劑(tonicifiers)、調味劑、著色劑、氣味劑、乳白劑、懸浮劑、黏合劑、及其混合物。此類添加劑之量可由熟習此項技藝者根據所需特定性質容易地決定。本發明亦考量使用熟習此項技藝人士已知之其他醫藥賦形劑例如黏合劑、崩解劑、稀釋劑、潤滑劑、塑化劑、滲透促進劑與增溶劑。 Other additives conventionally used in pharmaceutical compositions may be included, and such additives are well known in the art. Such additives include antioxidants, preservatives, chelating agents, complexing agents, viscosity modifiers, tonicifiers, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, and mixtures thereof. The amount of such additives can be readily determined by those skilled in the art in accordance with the particular properties desired. The invention also contemplates the use of other pharmaceutical excipients known to those skilled in the art such as binders, disintegrants, diluents, lubricants, plasticizers, penetration enhancers and solubilizers.
根據本發明典型調配物之核心成分可包含：- 1至35%(w/w)之非索非那定鹽酸鹽；- 至少60%(w/w)之具油性媒液功能之至少一種非離子疏水性界面活性劑之液體混合物。 The core component of a typical formulation according to the invention may comprise: - 1 to 35% (w/w) of fexofenadine hydrochloride; - at least 60% (w/w) of at least one of the oily vehicle functions A liquid mixture of nonionic hydrophobic surfactants.
根據本發明典型調配物之明膠殼成分可包含：- 35%至50%(w/w)，更佳為40-44%明膠； - 15%至30%(w/w)，更佳為15-25%與甘油結合之山梨糖醇；- 0.1%至10%(w/w)著色劑；- 0.1至10%(w/w)酒石酸；- 10至50%(w/w)純水。 The gelatin shell component of a typical formulation according to the present invention may comprise: - 35% to 50% (w/w), more preferably 40-44% gelatin; - 15% to 30% (w/w), more preferably 15-25% sorbitol combined with glycerin; - 0.1% to 10% (w/w) colorant; - 0.1 to 10% (w/w ) tartaric acid; - 10 to 50% (w/w) pure water.
本發明醫藥組成物可利用熟習此項技藝者悉知之習用方法製備。然而，具體製備方法將取決於最終劑量型。組成物可利用簡單混合或攪拌成分形成預濃縮物而製備。疏水性治療劑可依需要以被載劑溶解之第一個量及於溶劑中之第二個量存在。必須強調的是，各種成分之添加順序通常不重要，方便時可改變。其後，使pH值成為較具穩定性之較佳可接受範圍，振盪此混合物至得到透明溶液。 The pharmaceutical compositions of the present invention can be prepared by conventional methods known to those skilled in the art. However, the specific method of preparation will depend on the final dosage form. The composition can be prepared by simply mixing or stirring the ingredients to form a preconcentrate. The hydrophobic therapeutic agent can be present in a first amount dissolved by the carrier and a second amount in the solvent, as desired. It must be emphasized that the order in which the various ingredients are added is usually not important and can be changed at a convenient time. Thereafter, the pH is made to be a more acceptable acceptable range, and the mixture is shaken to obtain a clear solution.
軟明膠膠囊係於習知方法中使用明膠，以旋轉式模具法製造。使乾明膠顆粒與水及適當塑化劑結合，然後於真空下使結合物混合及加熱，形成熔融明膠塊。保持此明膠塊於其熔融階段下，於鑄帶輪或鑄帶滾筒上使其形成或澆鑄成膜片或帶條(ribbons)。將該等膜片或帶條饋入楔形體下及旋轉式封裝模具間。於封裝模具內，膜片或帶條同時形成呈袋狀物之膠囊。使用任何習用方法將含非索非那定之組成物裝填入軟膠囊中；切割及密封膠囊。密封係於裝填及切割膠囊時，經由壓力及熱之組合形成。 Soft gelatin capsules are manufactured by a rotary mold method using gelatin in a conventional method. The dry gelatin granules are combined with water and a suitable plasticizer, and the conjugate is then mixed and heated under vacuum to form a molten gelatin block. The gelatin block is maintained in its melting stage and formed or cast into a film or ribbon on a cast pulley or cast strip roll. The diaphragms or strips are fed between the wedges and the rotary package mold. In the package mold, the film or strip simultaneously forms a capsule in the form of a pouch. The composition containing fexofenadine is loaded into a soft capsule using any conventional method; the capsule is cut and sealed. The seal is formed by a combination of pressure and heat when filling and cutting the capsule.
於另一觀點中，本發明係有關提供增加非索非那定鹽酸鹽之生物利用性之方法，該方法包括下述步驟：a)提供 包含供口服投與之本發明液體組成物之穩定明膠組成物；及b)投與該宿主該組成物供攝入，從而使該組成物與生物體液接觸，增加醫藥活性劑之生物利用性，俾使獲得與得自習知非索非那定鹽酸鹽口服固體調配物(舉例而言，例如以Allegra®商標市售可得之非索非那定鹽酸鹽錠劑)者具生體相等性之藥物動力學參數。 In another aspect, the invention relates to a method for providing increased bioavailability of fexofenadine hydrochloride, the method comprising the steps of: a) providing a stable gelatin composition comprising a liquid composition of the present invention for oral administration; and b) administering the composition to the host for ingestion, thereby bringing the composition into contact with the biological fluid, thereby increasing the bioavailability of the pharmaceutically active agent, Having an oral solid formulation obtained from the conventional fexinadine hydrochloride salt (for example, a fexofenadine hydrochloride tablet commercially available, for example, under the Allegra® trademark) is equal in life. Pharmacokinetic parameters of sex.
較佳地，於500毫升含胰酶(Pancreatin)之FeSSIF-溶解介質(pH 5.8)中，75 RPM及37℃下進行測試時，裝填入明膠殼中及進行溶解之本發明組成物之非索非那定鹽酸鹽釋放率為至少40%(w/w)非索非那定鹽酸鹽於10分鐘內溶解，及50%以上非索非那定鹽酸鹽於15分鐘內溶解。 Preferably, when tested in 500 ml of Pancreatin-containing FeSSIF-dissolving medium (pH 5.8) at 75 RPM and 37 ° C, the composition of the present invention is filled in a gelatin shell and dissolved. The solifenatine hydrochloride release rate was at least 40% (w/w) of fifenofazidine hydrochloride dissolved in 10 minutes, and more than 50% of fexofenadine hydrochloride dissolved within 15 minutes.
使用時，本發明方法及組成物考量若干重要優點，包括：於標的位置強健及增進之遞送：本發明組成物未預期地強健及未預期地藉由使沉澱減至最少而提供治療劑至吸收部位之增進遞送；此增進遞送被認為產生治療劑之較佳生物利用性；多功能性(versatality)：本發明組成物可仔細裁製及縮放治療劑之極性與功能性，而不危及增進之溶解、遞送、及上述其他優點；容易製備：本發明方法提供其中疏水性治療劑易於溶解之組成物，從而節省昂貴之製造及人力資源。 When used, the methods and compositions of the present invention contemplate several important advantages, including: robust and enhanced delivery at the target position: the compositions of the present invention are undesirably robust and unexpectedly provide therapeutic to absorption by minimizing precipitation. Increased delivery of the site; this enhanced delivery is believed to result in better bioavailability of the therapeutic agent; versatality: the compositions of the present invention can carefully tailor and scale the polarity and functionality of the therapeutic agent without compromising the enhancement Dissolution, delivery, and other advantages described above; ease of preparation: The method of the present invention provides a composition in which the hydrophobic therapeutic agent is readily soluble, thereby saving costly manufacturing and human resources.
於下述實施例中進一步界定本發明。應瞭解的是，彼等實施例，於指示本發明較佳具體實例之同時，僅供說明用途。從上述討論及彼等實施例，熟習此項技藝者可確定本發明之主要特徵，及於不偏離其精神與範圍下，可進行本發明之各種變化與修飾，使其適應各種用途與狀況。 The invention is further defined in the following examples. It is to be understood that the examples are intended to be illustrative only, and are intended to be illustrative only. From the above discussion and the examples, those skilled in the art will be able to devise various modifications and modifications of the present invention to adapt to various uses and conditions without departing from the spirit and scope thereof.
分散所有賦形劑；於單月桂酸丙二醇酯(lauroglycol)中(持續攪拌下)，使非索非那定鹽酸鹽與聚山梨糖醇酯80一起分散。攪拌此混合物45分鐘。若需要，則以三乙醇胺將所得混合物之pH調至pH 5至6。根據熟習此項技藝 者本質上已知之一方法，於900毫克裝填重量，180毫克強度下，將此調配物封裝於軟明膠膠囊中。 All excipients were dispersed; fexofenadine hydrochloride was dispersed with polysorbate 80 in lauroglycol (with continuous stirring). This mixture was stirred for 45 minutes. If necessary, the pH of the resulting mixture is adjusted to pH 5 to 6 with triethanolamine. Based on familiarity with this skill One of the methods is known per se, and the formulation is encapsulated in a soft gelatin capsule at a filling weight of 900 mg and an intensity of 180 mg.
分散所有賦形劑；持續攪拌下，使非索非那定鹽酸鹽與單癸酸丙二醇酯(capryol-90)一起分散。加熱至125℃-165℃至形成清澈溶液。冷卻所得混合物至室溫。根據熟習此項技藝者本質上已知之一方法將此調配物封裝於軟明膠膠囊中。 All excipients were dispersed; fexofenadine hydrochloride was dispersed with propylene glycol monocaprate (capryol-90) with constant agitation. Heat to 125 ° C - 165 ° C until a clear solution is formed. The resulting mixture was cooled to room temperature. The formulation is encapsulated in a soft gelatin capsule according to one of the methods known to those skilled in the art.
供口服投與測試用之醫藥組成物係根據下述配方(裝填組成物A)：
1.於不鏽鋼容器中，使非索非那定、Lauroglycol 90、Tween 80混合15分鐘；2.使用足量三乙醇胺將pH調至5-6之間；3.使用熟習此項技藝者本質上已知之一方法，以步驟2所得混合物裝填軟凝膠膠囊；4.於鋁箔泡罩(Alu/Alu blisters)或PVC/PVdC包裝中包裝最終醫藥型。 1. In a stainless steel container, fexofenadine, Lauroglycol 90, Tween 80 are mixed for 15 minutes; 2. using a sufficient amount of triethanolamine to adjust the pH to between 5-6; 3. Using this skill in nature is essentially One method is known, in which the soft gel capsule is filled with the mixture obtained in step 2; 4. The final medical form is packaged in an aluminum foil blister (Alu/Alu blisters) or PVC/PVdC package.
上述表中，雜質量係以非索非那定鹽酸鹽重量計之，相當於藥物含量之分析係以最初非索非那定鹽酸鹽含量計之。 In the above table, the amount of impurities is based on the weight of fexofenadine hydrochloride, and the analysis corresponding to the drug content is based on the initial fexofenadine hydrochloride content.
於40℃及75%濕度貯存3個月後，根據本發明之醫藥組成物未展現任何分解跡象(雜質量低，亦即小於或等於1%)及含有至少99%之最初非索非那定鹽酸鹽含量(由HPLC分析證明)。 After storage at 40 ° C and 75% humidity for 3 months, the pharmaceutical composition according to the invention does not exhibit any signs of decomposition (low mass, ie less than or equal to 1%) and contains at least 99% of the original fexofenadine Hydrochloride content (proven by HPLC analysis).
從上述觀察，由40℃及75% RH條件下3個月後之雜質總量(包裝於透明三重鋁箔泡罩包裝中之軟膠囊於3個月後之0.123% w/w總雜質相較於包裝於相同泡罩包裝中之非索非那定HCL錠劑之0.2% w/w總雜質)證明，軟膠囊調配物比30毫克上市錠劑更穩定。 From the above observation, the total amount of impurities after 3 months from 40 ° C and 75% RH (the soft capsules packaged in the transparent triple aluminum foil blister package was 0.123% w/w total impurities after 3 months compared with The 0.2% w/w total impurities of the fexofenadine HCL tablet packaged in the same blister pack demonstrated that the soft capsule formulation was more stable than the 30 mg listed tablet.
製備根據本發明之不同試樣供溶解研究用，並與Allegra®上市錠劑之藥物釋放量變曲線進行比較。 Different samples according to the present invention were prepared for dissolution studies and compared to the drug release profile curve for Allegra® on-line tablets.
1.於不鏽鋼容器中，使非索非那定、親水性界面活性劑及其他成分混合15分鐘；2.使用足量三乙醇胺將pH調至5-6之間；3.使用熟習此項技藝者本質上已知之一方法，以步驟2所得混合物裝填於不同明膠組成物之軟凝膠膠囊中。 1. In a stainless steel container, fexofenadine, a hydrophilic surfactant and other ingredients are mixed for 15 minutes; 2. using a sufficient amount of triethanolamine to adjust the pH to between 5-6; 3. Use this skill One method is known per se, and the mixture obtained in step 2 is filled in soft gel capsules of different gelatin compositions.
由水浴(精準地維持設定溫度)、一組溶解碗(固定於水浴中平板上)、碗中液體內容物之攪拌裝置與自動取樣配件(抽取及補充液體介質至容器中)組成之自動溶解系統。 Automatic dissolution system consisting of a water bath (precisely maintaining the set temperature), a set of dissolving bowls (fixed on a flat plate in a water bath), a stirring device for liquid contents in the bowl, and an automatic sampling fitting (extracting and replenishing the liquid medium into the container) .
(廠商：LabIndia instruments Ltd.,Model：Disso 2000)由泵(連接於管柱恒溫器，能精準地遞送溶劑混合物)與紫外線-可見光檢測器組成之HPLC系統；產生之數據必須被能從上述硬體處理數據之軟體獲取。 (Manufacturer: LabIndia instruments Ltd., Model: Disso 2000) An HPLC system consisting of a pump (connected to a column thermostat that accurately delivers a solvent mixture) and an ultraviolet-visible detector; the data generated must be hard from the above Software processing of data processing.
廠商：Agilent Technologies Ltd.,Model：1200 series with OpenLABTM Disso 2000) Manufacturer: Agilent Technologies Ltd., Model: 1200 series with OpenLAB TM Disso 2000)
設備：8-容器組合與攪拌器(paddles) Equipment: 8-container combination with paddles
介質：如下述 Medium: as follows
容積：500毫升 Volume: 500 ml
攪拌速率：75 RPM Stirring rate: 75 RPM
溫度：37℃ Temperature: 37 ° C
溫度保持於37℃下，在含有所需介質容積之各容器中放置一已稱重之膠囊，立即操作裝置60分鐘。於不同時間間隔及溶解週期末了，抽取固定容積之試樣。通過0.45微米濾膜過濾各試樣。以貯存於37℃之等量介質替換。 The temperature was maintained at 37 ° C, a weighed capsule was placed in each container containing the desired volume of media, and the device was immediately operated for 60 minutes. A sample of a fixed volume is taken at different time intervals and at the end of the dissolution cycle. Each sample was filtered through a 0.45 micron filter. Replace with an equal amount of medium stored at 37 °C.
製備對等濃度之標準溶液，使用HPLC分析試樣。 A standard solution of the equivalent concentration was prepared and the sample was analyzed using HPLC.
管柱：內徑4.6毫米，長150毫米之管柱(填塞連接著辛基鏈之混合矽石顆粒)；例如Waters C-8 150毫米X 4.6毫米。 Column: Pipe column with an inner diameter of 4.6 mm and a length of 150 mm (filled with mixed osmium particles of octyl chain); for example, Waters C-8 150 mm X 4.6 mm.
管柱溫度：常溫 Column temperature: normal temperature
移動相：磷酸鹽緩衝液(pH 3.0)：乙腈之比率為60：40 V/V Mobile phase: phosphate buffer (pH 3.0): acetonitrile ratio 60:40 V/V
流速：1.5毫升/分鐘 Flow rate: 1.5 ml / min
檢測器：220nm(為紫外線時，調至精確波長) Detector: 220nm (for ultraviolet light, adjust to precise wavelength)
注入量：10微升 Injection volume: 10 microliters
將上述調配裝填物B、C及D裝填入空的硬明膠殼中，進行溶解研究。 The above formulated fillings B, C and D were loaded into an empty hard gelatin shell for dissolution studies.
調配非索非那定HCL軟凝膠膠囊之最終目標在於使其與Allegra錠劑具生體相等性。於此前提下，相當重要的為，首先使軟膠囊Vs.Allegra錠劑之溶解量變曲線(尤其是於pH 5.8 FeSSIF介質中)相符合。 The ultimate goal of formulating fexofenadine HCL soft gel capsules is to make them bioequivalent to Allegra tablets. Under this premise, it is quite important to first match the dissolution profile of the soft capsule Vs. Allegra tablet (especially in pH 5.8 FeSSIF media).
使用非離子親水性界面活性劑與有或無非離子疏水性界面活性劑之不同組合物調配，並於生物相關介質中進行溶解研究之上述實驗裝填物顯示，由相較於裝填組成物D(不含疏水性界面活性劑)於10分鐘後溶解16%(w/w)非索非那定鹽酸鹽之藥物釋放，裝填組成物B或C於10分鐘後分別釋放溶解之63%或48%(w/w)明顯看出，若裝填物包含組合非離子疏水性界面活性劑之非離子親水性界面活性劑，則該裝填物之非索非那定鹽酸鹽釋放增加。 The above experimental fillings using nonionic hydrophilic surfactants formulated with different compositions with or without nonionic hydrophobic surfactants and subjected to dissolution studies in biologically relevant media are shown as compared to the loading composition D (not Containing a hydrophobic surfactant) Dissolved 16% (w/w) of the drug release of fexofenadine hydrochloride after 10 minutes, and loaded the composition B or C to release 63% or 48% of the dissolution after 10 minutes, respectively. It is apparent from (w/w) that if the filler comprises a nonionic hydrophilic surfactant in combination with a nonionic hydrophobic surfactant, the release of fexofenadine hydrochloride of the filler is increased.
因此，相較於不含非離子疏水性界面活性劑之組成物(裝填組成物D)，使用含有至少60%(w/w)之至少一種非離子親水性界面活性劑與至少一種非離子疏水性界面活性 劑液體混合物之根據本發明之裝填組成物(裝填組成物B與C)更快開始作用。 Therefore, at least 60% (w/w) of at least one nonionic hydrophilic surfactant and at least one nonionic hydrophobic are used as compared to a composition containing no nonionic hydrophobic surfactant (filling composition D). Sexual interface activity The loading composition according to the invention (filling compositions B and C) of the liquid mixture of the agents starts to function more quickly.
前述討論及說明為本發明若干具體實例之例證，惟不擬對其實施構成侷限。 The foregoing discussion and illustrations are illustrative of several specific embodiments of the invention and are not intended to be limiting.
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| US201161499856P | 2011-06-22 | 2011-06-22 | |
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