TW201417825A - Compositions comprising antifungal drug and lactate buffer agent - Google Patents
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Abstract
Description
本發明涉及治療和/或預防真菌感染的醫藥組成物，其包括卡泊芬淨或其可藥用鹽和乳酸鹽緩衝劑。 The present invention relates to a pharmaceutical composition for treating and/or preventing a fungal infection comprising caspofungin or a pharmaceutically acceptable salt thereof and a lactate buffer.
卡泊芬淨具有如下的結構式，
它屬於棘白菌素類的氮雜環六肽的抗真菌藥，其的製備方法在US5378804(ZL94191487.9)，US5552521，US595230，US6136783，CN101305018A，CN101792486A已經被描述和公開。卡泊芬淨能夠抑制β-(1,3)-D-葡聚糖的合成，這是許多絲狀真菌和酵母菌細 胞壁的一種基本成份而哺乳類動物的細胞中則不存在β-(1,3)-D-葡聚糖。卡泊芬淨對許多種致病性曲黴菌屬和念珠菌屬真菌具有抗菌活性，並且對耐兩性黴素B和氟康唑的真菌有效。 It is an antifungal agent of the arachidin-like azahet hexapeptide, which has been described and disclosed in US Pat. No. 5,378, 804 (ZL, issued No. 5, 519, 198 7.9), US Pat. No. 5,552, 521, US 595,230, US Pat. Caspofungin inhibits the synthesis of β-(1,3)-D-glucan, which is fine for many filamentous fungi and yeasts. An essential component of the cell wall and no β-(1,3)-D-glucan in the cells of mammals. Caspofungin has antibacterial activity against a wide variety of pathogenic Aspergillus and Candida fungi and is effective against amphotericin B and fluconazole resistant fungi.
卡泊芬淨化合物本身高度不穩定，可以以各種方式降解，所述方式包括(但不限於)水解、二聚作用和氧化。由於卡泊芬淨的不穩定性，為了保證卡泊芬淨的長期穩定性和用藥穩定性，需要開發一種能夠保證卡泊芬淨穩定的技術方案及其製劑，以儘量的減少不需要的降解物的產生。 The caspofungin compound itself is highly unstable and can be degraded in a variety of ways including, but not limited to, hydrolysis, dimerization, and oxidation. Due to the instability of caspofungin, in order to ensure the long-term stability and drug stability of caspofungin, it is necessary to develop a technical solution and its preparation which can ensure the stability of caspofungin to minimize the unwanted degradation. The production of things.
專利ZL97195514.X或US6136783中披露了卡泊芬淨的含乙酸鹽緩衝劑的藥用組成物，認為因使用了乙酸鹽緩衝劑而使延長了組成物的儲存期，並且凍幹產物比使用其他鹽的緩衝劑更穩定、含有更少的不需要的降解物，但其只披露若干的實施例方案而沒有給出明確的降解產物的資料，經發明人試驗，該含有乙酸鹽緩衝劑的藥用組成物並不夠穩定。 The pharmaceutical composition of caspofungin containing an acetate buffer is disclosed in the patent ZL97195514.X or US Pat. No. 6,136,783, which is believed to extend the shelf life of the composition by the use of an acetate buffer, and to freeze-dried products than to use other The buffer of the salt is more stable and contains less unwanted degradants, but it discloses only a few examples of the scheme without giving clear information on the degradation products. The inventors tested the acetate buffer. The composition is not stable enough.
WO2009002481A1中披露了使用非還原性糖，如海藻糖，製備得到凍幹組成物，認為使用非還原性糖可以提高凍乾粉的玻璃化轉變溫度(Tg)而提高凍乾組成物對熱的穩定性，其依然使用的是乙酸鹽緩衝劑，起到穩定作用的還是乙酸鹽緩衝劑，整個發明並沒有脫離專利ZL97195514.X或US6136783的發明範圍，該醫藥組成物也不夠穩定。 WO2009002481A1 discloses the preparation of a lyophilized composition using a non-reducing sugar such as trehalose, and it is considered that the use of non-reducing sugars can increase the glass transition temperature (Tg) of the lyophilized powder and increase the stability of the lyophilized composition to heat. Sexually, it still uses an acetate buffer, which is a stabilizing effect or an acetate buffer. The entire invention does not deviate from the scope of the invention of the patent ZL97195514.X or US6136783, and the pharmaceutical composition is not stable enough.
專利申請CN101516397A或WO2008012310A1中披露了使用極少量的乙酸作為pH調節劑可以製備得到穩定性良好的卡泊芬淨醫藥組成物，依然是採用了乙酸鹽緩衝體系，發明仍然在專利ZL97195514.X或US6136783的發明範圍，且該醫藥組成物比專利ZL97195514.X或US6136783中公開的醫藥組成物更為不穩定，實踐中無法採用。 Patent application CN101516397A or WO2008012310A1 discloses that a very stable caspofungin pharmaceutical composition can be prepared using a very small amount of acetic acid as a pH adjuster, and an acetate buffer system is still used, and the invention is still in patent ZL97195514.X or US6136783. The scope of the invention, and the pharmaceutical composition is more unstable than the pharmaceutical composition disclosed in the patents ZL97195514.X or US6136783, and cannot be used in practice.
CN102166186A聲稱製成了一種含有硫酸鹽、枸櫞酸鹽、磷酸鹽、或乳酸鹽的卡泊芬淨組成物，但經考察，該文獻中實驗資料與實際情況相差甚遠，卡泊芬淨極不穩定，凍乾粉需在2至8℃下保存，而複溶接觸水後會迅速產生大量雜質，而根據該申請來看，40℃下放置，市售卡泊芬淨在複溶後還具有不錯的穩定性，與實際情況矛盾，因此本領域的技術人員在閱讀完該申請說明書後，並不會認為該申請真正完成了所述卡泊芬淨組成物的製備。 CN102166186A claims to have a caspofungin composition containing sulfate, citrate, phosphate, or lactate, but after investigation, the experimental data in this literature is far from the actual situation, and caspofene is extremely non-existent. Stable, freeze-dried powder needs to be stored at 2 to 8 ° C, and re-dissolved contact with water will quickly produce a large amount of impurities, and according to the application, placed at 40 ° C, the commercial caspofungin also has after reconstitution Good stability, contradictory to the actual situation, therefore, after reading the application specification, those skilled in the art do not think that the application actually completes the preparation of the caspofungin composition.
可見，極需開發一種穩定的卡泊芬淨的醫藥組成物，使得其能夠容易地保存，方便臨床使用，提高其安全性。 It can be seen that it is highly desirable to develop a stable pharmaceutical composition of caspofungin that allows it to be easily preserved, facilitate clinical use, and improve its safety.
本發明人意外的發現了一種具有比含乙酸鹽緩衝劑的卡泊芬淨醫藥組成物更好的穩定性的醫藥組成物，這完全出於對現有公開文獻和公知技術的預料之外。 The inventors have unexpectedly discovered a pharmaceutical composition having better stability than the caspofungin pharmaceutical composition containing an acetate buffer, which is entirely unexpected from the prior art and known techniques.
本發明的組成物可以提高卡泊芬淨或其藥 學上可接受的鹽的化學穩定性，而穩定性的提高可以保證其作為藥用產品商業化的可能性和延長其作為藥用產品的儲存期。 The composition of the present invention can improve caspofungin or its medicine The chemical stability of a salt that is acceptable for the study, and the improvement in stability, can ensure its commercialization as a pharmaceutical product and prolong its shelf life as a medicinal product.
本發明的醫藥組成物，其含有卡泊芬淨或其藥學上可接受的鹽，還含有藥學上可接受量的乳酸鹽緩衝劑。發明人驚喜地發現，添加乳酸鹽緩衝劑後，能極大的減小卡泊芬淨或其藥學上可接受的鹽的降解。 The pharmaceutical composition of the present invention contains caspofungin or a pharmaceutically acceptable salt thereof, and further contains a pharmaceutically acceptable amount of a lactate buffer. The inventors have surprisingly found that the addition of a lactate buffer greatly reduces the degradation of caspofungin or a pharmaceutically acceptable salt thereof.
所述的醫藥組成物可以是可注射的胃腸外用藥物製劑，較佳所述醫藥組成物是凍乾粉形式。 The pharmaceutical composition may be an injectable parenteral pharmaceutical preparation, preferably the pharmaceutical composition is in the form of a lyophilized powder.
為使得所述醫藥組成物適宜注射，較佳本發明的醫藥組成物中乳酸鹽緩衝劑的用量使所述醫藥組成物有效的得到4至8之間的pH值，較佳為5至7，更佳為5.5至6.5的pH值。 In order to make the pharmaceutical composition suitable for injection, it is preferred that the amount of the lactate buffer in the pharmaceutical composition of the present invention is such that the pharmaceutical composition is effective to obtain a pH of between 4 and 8, preferably 5 to 7. More preferably, it is a pH of 5.5 to 6.5.
為增加組成物的穩定性，本發明的醫藥組成物還含有藥學上可接受量的賦形劑，所述賦形劑選自氯化鈉、甘露醇、蔗糖、果糖、木糖醇、右旋糖、海藻糖、甘胺酸中的一種或幾種，較佳甘胺酸和蔗糖的混合物。 To increase the stability of the composition, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable amount of an excipient selected from the group consisting of sodium chloride, mannitol, sucrose, fructose, xylitol, and dextrorotatory One or more of sugar, trehalose, and glycine, preferably a mixture of glycine and sucrose.
在較佳的實施方案中，該蔗糖與卡泊芬淨或其藥學上可接受的鹽的重量比為1.5：1至0.2：1，較佳為1：1至0.5：1。該卡泊芬淨的重量，當使用卡泊芬淨藥學上可接受的鹽時，以其含有的卡泊芬淨鹼計。 In a preferred embodiment, the weight ratio of the sucrose to caspofungin or a pharmaceutically acceptable salt thereof is from 1.5:1 to 0.2:1, preferably from 1:1 to 0.5:1. The weight of the caspofungin, when using caspofungin pharmaceutically acceptable salt, is based on the caspofungin base it contains.
發明人驚訝地發現，蔗糖作為製劑穩定的關鍵因素，其用量並非隨意選定的，更不是越多越好，相反，提高蔗糖的用量至一定量時，製劑的穩定性反而下降， 同時蔗糖的用量提高更不經濟。因此，選定一個合適的用量是非常關鍵的。經反復驗證，發明人發現上述用量範圍內的蔗糖可以發揮最佳的穩定效果。 The inventors have surprisingly found that sucrose is a key factor in the stability of the preparation, and the amount thereof is not arbitrarily selected, and the more it is not, the better. On the contrary, when the amount of sucrose is increased to a certain amount, the stability of the preparation is decreased. At the same time, the increase in the amount of sucrose is less economic Therefore, it is very important to choose a suitable amount. After repeated verification, the inventors found that sucrose in the above dosage range can exert the best stabilizing effect.
在另一個較佳的實施方案中，該甘胺酸與卡泊芬淨或其藥學上可接受的鹽的重量比為1：10至10：1，更佳為1：4至4：1。 In another preferred embodiment, the weight ratio of the glycine to caspofungin or a pharmaceutically acceptable salt thereof is from 1:10 to 10:1, more preferably from 1:4 to 4:1.
在另一個較佳的實施方案中，本發明的醫藥組成物含有以卡泊芬淨鹼計的30至50mg/mL的卡泊芬淨或其藥學上可接受的鹽，10至60mM的乳酸鹽緩衝劑，30至70mg/mL的賦形劑和水。 In another preferred embodiment, the pharmaceutical composition of the present invention contains 30 to 50 mg/mL of caspofungin or a pharmaceutically acceptable salt thereof, based on caspofungin, 10 to 60 mM of lactate. Buffer, 30 to 70 mg/mL of excipient and water.
在本發明特別較佳的實施方案中，本發明的醫藥組成物，含有以卡泊芬淨鹼計的42mg/mL的卡泊芬淨或其藥學上可接受的鹽，25mM至50mM的乳酸鹽緩衝劑，30mg/mL的蔗糖，20mg/mL的甘胺酸和水。更佳本發明的醫藥組成物由上述組分組成。 In a particularly preferred embodiment of the invention, the pharmaceutical composition of the invention comprises 42 mg/mL of caspofungin or a pharmaceutically acceptable salt thereof, based on caspofungin, 25 mM to 50 mM lactate Buffer, 30 mg/mL sucrose, 20 mg/mL glycine and water. More preferably, the pharmaceutical composition of the present invention consists of the above components.
發明人驚奇地發現，該乳酸鹽緩衝劑的用量對組成物的穩定性也產生了較為明顯的影響，乳酸鹽緩衝劑的用量過大或過小，對穩定性均產生負面作用，而選擇合適的用量範圍，則能極大地提高穩定性，減少有關物質的產生。在本發明較佳的實施方案中，該乳酸鹽緩衝劑的用量為10至60mM，較佳為25至60mM，更佳為25至50mM。通常，發揮穩定作用的物質用量越高，組成物應越穩定，但是發明人發現，當在60mM以上還繼續增大用量時，組成物的穩定性非但不繼續提高，反而變低。 The inventors have surprisingly found that the amount of the lactate buffer has a significant effect on the stability of the composition. The amount of the lactate buffer is too large or too small, which has a negative effect on the stability, and the appropriate amount is selected. The range can greatly improve the stability and reduce the production of related substances. In a preferred embodiment of the invention, the lactate buffer is used in an amount of 10 to 60 mM, preferably 25 to 60 mM, more preferably 25 to 50 mM. In general, the higher the amount of the substance which exerts a stabilizing effect, the more stable the composition should be, but the inventors have found that when the amount is further increased above 60 mM, the stability of the composition does not continue to increase, but becomes lower.
在較佳的實施方案中，本發明的醫藥組成物中卡泊芬淨的藥學上可接受的鹽為二乙酸卡泊芬淨(或稱醋酸卡泊芬淨)。 In a preferred embodiment, the pharmaceutically acceptable salt of caspofungin in the pharmaceutical composition of the present invention is caspofungin diacetate (or caspofungin acetate).
本發明另一方面提供了上述的醫藥組成物在製備用於治療或預防哺乳動物真菌感染的藥物中的用途。 Another aspect of the invention provides the use of a pharmaceutical composition as described above for the manufacture of a medicament for the treatment or prevention of a fungal infection in a mammal.
本發明還提供了上述的醫藥組成物的製備方法方法，該方法包括下列步驟，a)將賦形劑和乳酸溶於水中；b)加入並溶解卡泊芬淨或其藥學上可接受的鹽，並用鹼調節至所需pH值；在一個較佳的實施方案中，還包括將所述醫藥組成物冷凍乾燥的步驟。 The present invention also provides a method for preparing the above pharmaceutical composition, which comprises the steps of: a) dissolving an excipient and lactic acid in water; b) adding and dissolving caspofungin or a pharmaceutically acceptable salt thereof And adjusting to the desired pH with a base; in a preferred embodiment, further comprising the step of freeze drying the pharmaceutical composition.
以下實施例是為了闡述發明，並不以任何方式限制本發明的範圍。 The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
按下表處方製備卡泊芬淨組成物1，方法如下：
將2g的甘露醇和3g的蔗糖加入到100ml的容量瓶中，加入約60ml水，溶解後加入22.50mg/mL的乳酸溶液10mL混合均勻，之後加入4.66g的醋酸卡泊芬淨(相當於4.2g卡泊芬淨)，輕輕振搖使之溶解，避免產生泡沫。然後使用1mol/mL的氫氧化鈉調節溶液的pH到6.0。然後加水至終體積為100mL。使用0.22um微孔濾膜過濾後，按照1.3mL/vial分裝入10mL西林瓶，進行冷凍乾燥，製備得到醋酸卡泊芬淨的凍幹餅狀物。 Add 2g of mannitol and 3g of sucrose to a 100ml volumetric flask, add about 60ml of water, dissolve and add 10mL of 22.50mg/mL lactic acid solution to mix well, then add 4.66g of caspofungin acetate (equivalent to 4.2g) Caspofungin), gently shake to dissolve, to avoid foam. The pH of the solution was then adjusted to 6.0 using 1 mol/mL sodium hydroxide. Then add water to a final volume of 100 mL. After filtration through a 0.22 um microporous membrane, a 10 mL vial was placed in a volume of 1.3 mL/vial, and lyophilized to prepare a lyophilized cake of caspofungin acetate.
不同pH值的醋酸卡泊芬淨凍乾粉製備及30℃和25℃條件下進行考察對比 Preparation of caspofungin lyophilized powder with different pH values and comparison at 30 °C and 25 °C
按實施例1相同的方法，分別製備pH為5.0、7.0、8.0組成物2、3、4。 Compositions 2, 3, and 4 having a pH of 5.0, 7.0, and 8.0 were prepared in the same manner as in Example 1.
將製得的凍乾粉，在30℃條件下留樣進行考察，分別在5天，10天取樣，在25℃條件下留樣進行考察，在6個月取樣，用HPLC對樣品進行分析測定，對比
雜質L-747969和總雜質的變化，其中雜質L-747969為醋酸卡泊芬淨的主要水解和熱降解雜質。結果見下表：
由不同pH值的醋酸卡泊芬淨凍乾粉穩定性對比結果可知，在pH5.0至8.0的範圍內，組成物的穩定性基本相當，相差不大。 From the results of the stability comparison of caspofungin lyophilized powder with different pH values, it is found that the stability of the composition is basically equivalent in the range of pH 5.0 to 8.0, and the difference is not large.
按實施例1的方法製備組成物5、6、7、8、9、10，各組成物的成分及用量見下表，其中組成物的pH值使用NaOH調節，各組分用量單位均為mg/ml。 The compositions 5, 6, 7, 8, 9, and 10 were prepared according to the method of Example 1. The components and amounts of the compositions are shown in the following table, wherein the pH of the composition was adjusted using NaOH, and the units of each component were mg. /ml.
將實施例3製得的組成物5、6、7、8、9，分別在30℃條件下留樣進行考察，分別在5天、10天取樣，在25℃條件下留樣進行考察，在6M取樣，用HPLC對樣品進行分析測定，對比雜質L-747969和總雜質的變化，其中雜質L-747969為醋酸卡泊芬淨的主要水解和熱降解雜質。 The compositions 5, 6, 7, 8, and 9 prepared in Example 3 were each sampled at 30 ° C, and samples were taken at 5 days and 10 days, respectively, and samples were taken at 25 ° C for investigation. The sample was sampled by 6M, and the sample was analyzed by HPLC to compare the change of impurity L-747969 and total impurities. The impurity L-747969 was the main hydrolysis and thermal degradation impurity of caspofungin acetate.
從實驗結果可以看出，蔗糖的用量與製劑的穩定性有較為密切的關係，其用量並非越多越好，當其與卡泊芬淨重量比大於2：1時，穩定性反而下降，其與卡泊芬淨的重量比在1.5：1至0.2：1更為穩定，尤其在1：1至0.5：1之間最為穩定。 It can be seen from the experimental results that the amount of sucrose is closely related to the stability of the preparation, and the amount thereof is not as high as possible. When the weight ratio to caspofungin is more than 2:1, the stability is decreased. The weight ratio to caspofungin is more stable from 1.5:1 to 0.2:1, especially between 1:1 and 0.5:1.
按實施例1的方法製備組成物11、12、13、14，各組成物的成分及用量見下表，其中組成物的pH值使用NaOH調節，各組分用量單位均為mg/ml。 The compositions 11, 12, 13, and 14 were prepared in the same manner as in Example 1. The components and amounts of the respective compositions are shown in the following table, wherein the pH of the composition was adjusted using NaOH, and the components were each in mg/ml.
將實施例3製得的組成物11、12、13、14，分別在30℃條件下留樣進行考察，分別在5天、10天取樣，在25℃條件下留樣進行考察，在6M取樣，用HPLC對樣品進行分析測定，對比雜質L-747969和總雜質的變化，其中雜質L-747969為醋酸卡泊芬淨的主要水解和熱降解雜質。 The compositions 11, 12, 13, and 14 prepared in Example 3 were each sampled at 30 ° C for sampling, and samples were taken at 5 days and 10 days, respectively, and samples were taken at 25 ° C for sampling at 6 M. The sample was analyzed by HPLC to compare the change of impurity L-747969 and total impurities, wherein the impurity L-747969 was the main hydrolysis and thermal degradation impurity of caspofungin acetate.
從上面的實驗結果可知，甘胺酸的用量對製劑的穩定性影響不大，其與卡泊芬淨的重量比為10：1至1：10之間時，製劑都較為穩定。 It can be seen from the above experimental results that the amount of glycine has little effect on the stability of the preparation, and the preparation is relatively stable when the weight ratio to caspofungin is between 10:1 and 1:10.
按實施例1的方法製備組成物15、16、17、18、19，這些組成物除乳酸鹽緩衝劑的用量不同外，其餘 成分及含量均相同，其中組成物的pH值使用NaOH調節，各成分用量單位為mg/ml，經換算，各組成物中乳酸鹽緩衝劑的用量分別為5mM、20mM、50mM、60mM、70mM。 Compositions 15, 16, 17, 18, 19 were prepared as in Example 1, except that the amounts of the lactate buffer were different. The components and contents were the same, wherein the pH of the composition was adjusted with NaOH, and the amount of each component was mg/ml. The conversion amount of the lactate buffer in each composition was 5 mM, 20 mM, 50 mM, 60 mM, 70 mM, respectively.
將實施例3製得的組成物15、16、17、18、19，分別在30℃條件下留樣進行考察，分別在5天、10天取樣，在25℃條件下留樣進行考察，在6M取樣，用HPLC對樣品進行分析測定，對比雜質L-747969和總雜質的變化，其中雜質L-747969為醋酸卡泊芬淨的主要水解和熱降解雜質。 The compositions 15, 16, 17, 18, and 19 prepared in Example 3 were each sampled at 30 ° C, and samples were taken at 5 days and 10 days, respectively, and samples were taken at 25 ° C for investigation. The sample was sampled by 6M, and the sample was analyzed by HPLC to compare the change of impurity L-747969 and total impurities. The impurity L-747969 was the main hydrolysis and thermal degradation impurity of caspofungin acetate.
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| CN106860856B (en) * | 2015-12-14 | 2019-05-31 | 山东新时代药业有限公司 | A kind of freeze-dried powder and preparation method containing anidulafungin |
| CN107158359A (en) * | 2017-05-26 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | A kind of Caspofungin freeze-dried composition of stabilization and preparation method thereof |
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| RU2013114993A (en) * | 2010-09-20 | 2014-10-27 | Кселлия Фармасьютикалз Апс | COMPOSITION OF CASPOFUNGIN |
| CN102166186A (en) * | 2011-04-18 | 2011-08-31 | 深圳市健元医药科技有限公司 | More stable nitrogen heterocyclic peptide preparation |
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| CN103212059A (en) * | 2012-01-18 | 2013-07-24 | 江苏恒瑞医药股份有限公司 | Composition containing antifungal drug and lactate buffering liquid |
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