TWI546087B - Containing aqueous preparations of acetaminophen and ibuprofen - Google Patents

Description

含有對乙醯氨基酚和布洛芬的水性製劑Aqueous preparation containing acetaminophen and ibuprofen

本發明涉及對乙醯氨基酚和布洛芬混合的穩定水性製劑的製備方法、利用該方法得到的組合物以及其作為藥物特別是靜脈注射劑的用途。本發明對於期望獲得對乙醯氨基酚和布洛芬混合的穩定液體藥物製劑進行注射給藥特別是靜脈注射或輸注的醫院應用是特別有用的。 The present invention relates to a process for the preparation of a stable aqueous preparation of a mixture of acetaminophen and ibuprofen, a composition obtained by the method and its use as a medicament, in particular an intravenous injection. The present invention is particularly useful for hospital applications where it is desirable to obtain a stable liquid pharmaceutical formulation in which a mixture of acetaminophen and ibuprofen is administered by injection, particularly intravenous or infusion.

布洛芬是一種已知的具有解熱鎮痛活性的非甾體類抗炎藥物。其化學名稱為2-(對-異丙苯基)丙酸。被用於治療緩解類風濕性關節炎和骨關節炎的徵兆和症狀，緩解輕中度疼痛和治療原發性痛經。 Ibuprofen is a known non-steroidal anti-inflammatory drug with antipyretic and analgesic activity. Its chemical name is 2-(p-isopropylphenyl)propionic acid. It is used to treat signs and symptoms of rheumatoid arthritis and osteoarthritis, relieve mild to moderate pain and treat primary dysmenorrhea.

布洛芬極難溶於水。因而，曾經難以發展諸如口服或注射液等劑型。後來一種提高水溶解度的方法是使用水溶性配合物和製備布洛芬的鹽，例如鈉鹽或氨基酸鹽。 Ibuprofen is extremely difficult to dissolve in water. Thus, it has been difficult to develop dosage forms such as oral or injectable solutions. A later method for increasing the solubility of water is to use a water-soluble complex and to prepare a salt of ibuprofen, such as a sodium salt or an amino acid salt.

對乙醯氨基酚也稱為撲熱息痛，是一種已知的非阿片類、非水楊酸類的解熱鎮痛藥物。其化學名稱為N-(4-羥苯基)乙醯胺。它能夠暫時緩解輕微疼痛和胃灼熱或胃酸過多導致的疼痛以及緩解伴隨這些症狀的胃部不適。 Acetaminophen, also known as paracetamol, is a known anti-opioid, non-salicylic antipyretic analgesic. Its chemical name is N-(4-hydroxyphenyl)acetamide. It temporarily relieves pain from mild pain and heartburn or hyperacidity and relieves stomach upset with these symptoms.

已知對乙醯氨基酚在水溶液中易於發生水解。對乙醯氨基酚在水解後形成對氨基酚，它本身可降解成醌亞胺，參見例如出版物“J.E. Fairbrother,“Acetaminophen”in Analytical Profiles of Drug Substances,1974,vol.3,pages 1-109”的記載。對乙醯氨基酚的降解速率隨溫度和光照的增加而增加。該速率在pH 6附近區域最小(K.T.Koshy et al.,1961,J.Pharm.Sci.50,pages 116-118)。也已知對乙醯氨基酚易被氧化。其水溶液需要使用抗氧化劑和/或從溶液中除氧來保持穩定。考慮到某些抗氧化劑的毒性以及/或除去易溶於水的氧的複雜性，這對於開發靜脈注射劑產生額外的約束條件。根據所用技術的不同，除氧可能需要相當長的時間。另一個缺點是，氧化產物會導致形成有色化合物，從而使得水溶液不適於治療應用。 It is known that acetaminophen is susceptible to hydrolysis in an aqueous solution. The acetaminophen forms a para-aminophenol after hydrolysis, which itself degrades to quinone imine, see for example the publication "J.E. Fairbrother, "Acetaminophen" in Analytical Profiles of Drug Substances, 1974, vol. 3, pages 1-109". The rate of degradation of acetaminophen increases with increasing temperature and light. The rate is near pH 6. Minimal (KT Koshy et al., 1961, J. Pharm. Sci. 50, pages 116-118). It is also known that acetaminophen is easily oxidized. Its aqueous solution requires the use of antioxidants and/or deoxygenation from solution. To maintain stability. Considering the toxicity of certain antioxidants and/or the complexity of removing water-soluble oxygen, this creates additional constraints for the development of intravenous injections. Depending on the technology used, oxygen removal may take a considerable amount of time. Another disadvantage is that the oxidation product can result in the formation of colored compounds, making the aqueous solution unsuitable for therapeutic applications.

布洛芬單獨使用會存在多種副作用，例如皮疹、耳鳴、頭痛、頭暈、嗜睡、腹痛、噁心、腹瀉、便秘及胃灼熱。這些副作用可導致患者的不適感並且可能導致藥物追蹤較差。一種已知的方法是將與布洛芬互補的其他活性成分與布洛芬進行組合，優選降低布洛芬的劑量。 Ibuprofen alone can have a variety of side effects such as rash, tinnitus, headache, dizziness, lethargy, abdominal pain, nausea, diarrhea, constipation, and heartburn. These side effects can cause discomfort to the patient and can result in poor drug tracking. One known method is to combine the other active ingredients complementary to ibuprofen with ibuprofen, preferably to reduce the dose of ibuprofen.

在該領域裡，存在將布洛芬與對乙醯氨基酚組合製成產品，特別製成適用於靜脈注射劑型產品的需求。 In this field, there is a need to combine ibuprofen with acetaminophen to produce a product, particularly for use in an intravenous dosage form.

布洛芬單劑市場中的現有製劑的pH值為約7，而對乙醯氨基酚市場中的現有製劑的pH值為約5.5至6.0。pH 7能夠避免布洛芬發生沉澱，pH 5.5-6.0對於對乙醯氨基酚是有利的，因為對乙醯氨基酚在該pH值下的水解降解最小。對乙醯氨基酚在pH 7時顯著降解，而布洛芬在pH 5.5-6.0時發生沉澱。 Existing formulations in the ibuprofen single-dose market have a pH of about 7, while existing formulations in the acetaminophen market have a pH of about 5.5 to 6.0. pH 7 prevents precipitation of ibuprofen, and pH 5.5-6.0 is advantageous for acetaminophen because hydrolysis degradation of acetaminophen at this pH is minimal. The acetaminophen was significantly degraded at pH 7, while ibuprofen precipitated at pH 5.5-6.0.

本發明的一個目的是提供一種能夠解決至少一個上述問題的布洛芬和對乙醯氨基酚的組合物產品。具體而言，本發明旨在提供一種適用於靜脈注射的水劑形式的組合物產品。本發明的另一個目的是提供一 種製備布洛芬/對乙醯氨基酚組合物的方法。 It is an object of the present invention to provide a composition product of ibuprofen and p-acetaminophen which is capable of solving at least one of the above problems. In particular, the present invention is directed to a composition product in the form of a liquid suitable for intravenous injection. Another object of the present invention is to provide a A method of preparing an ibuprofen/p-acetaminophenol composition.

本發明通過提供一種相容性改善的布洛芬與對乙醯氨基酚的組合物來提供一種解決至少一個上述問題的技術方案。 The present invention provides a solution to at least one of the above problems by providing a combination of improved ibuprofen and acetaminophen.

在第一方面，本發明提供一種製備包含混合的布洛芬和對乙醯氨基酚的水性組合物的方法，該方法包括以下順序步驟：提供pH 6.3-7.3的水性溶劑，以及將布洛芬和對乙醯氨基酚溶解在所述水性溶劑中以製備組合物，其中在每ml所述組合物中溶解2.8至3.2mg布洛芬和9.8至10.2mg對乙醯氨基酚。 In a first aspect, the present invention provides a process for the preparation of an aqueous composition comprising mixed ibuprofen and p-acetaminophen, the process comprising the following sequential steps: providing an aqueous solvent having a pH of 6.3-7.3, and ibuprofen And the acetaminophen is dissolved in the aqueous solvent to prepare a composition in which 2.8 to 3.2 mg of ibuprofen and 9.8 to 10.2 mg of acetaminophen are dissolved per ml of the composition.

該方法的優點在於所採用的條件能夠同時克服布洛芬的低溶解性和對乙醯氨基酚的降解敏感性。所得產物具有長期的貯存穩定性。 The advantage of this method is that the conditions employed can simultaneously overcome the low solubility of ibuprofen and the sensitivity to degradation of acetaminophen. The resulting product has long-term storage stability.

在第二方面，本發明提供一種水性組合物，優選通過本發明方法得到的水性組合物。 In a second aspect, the invention provides an aqueous composition, preferably an aqueous composition obtained by the process of the invention.

根據本發明的一個實施方案得到的產品的特徵在於，其提供了在生理學可接受的pH值下的布洛芬和對乙醯氨基酚的穩定組合物。 A product obtained according to one embodiment of the invention is characterized in that it provides a stable composition of ibuprofen and acetaminophen at a physiologically acceptable pH.

在另一方面，本發明提供了根據本發明的組合物的藥物用途。根據本發明的產品可以有利地用於同時進行布洛芬和對乙醯氨基酚的給藥。由此克服了分別管理這兩種藥物的問題。 In another aspect, the invention provides the pharmaceutical use of a composition according to the invention. The product according to the invention can advantageously be used for the simultaneous administration of ibuprofen and acetaminophen. This overcomes the problem of managing the two drugs separately.

在最後一個方面，本發明提供一種包含在雙貯室注射裝置例如注射器中的根據本發明的水性組合物。 In a final aspect, the invention provides an aqueous composition according to the invention contained in a dual chamber injection device such as a syringe.

除非另有定義，本發明使用的所有術語包括技術術語和科學術語具有本領域所屬普通技術人員公知的含義。通過進一步的指導，給出術語定義以更好地理解本發明的教導。 Unless otherwise defined, all terms used in the present invention, including technical and scientific terms, have the meanings that are known to those of ordinary skill in the art. By further guidance, definitions of terms are given to better understand the teachings of the present invention.

本文所使用的以下術語具有以下含義：本文中不使用數量詞限定的物件是指一個或多個的所指物件，除非上下文中有明確的其它說明。例如，“貯室”是指一個或多於一個的貯室。 The following terms as used herein have the following meanings: An article defined herein without the use of a singular term refers to one or more of the indicated items unless the context clearly dictates otherwise. For example, "reservoir" refers to one or more than one reservoir.

本文中使用的“約”是指諸如參數、數量、持續時間等的可測量值具有偏離指定值的+/-20%以下、優選+/-10%以下、更優選+/-5%以下、甚至更優選+/-1%以下、還優選+/-0.1%以下的變化，在此範圍內該變化量適合在本發明中實施。然而，應當理解的是，具有修飾語“約”的值自身被具體公開。 As used herein, "about" means that a measurable value, such as a parameter, quantity, duration, etc., has +/- 20% or less, preferably +/- 10% or less, more preferably +/- 5% or less, from a specified value. An even more preferred variation of +/- 1% or less, still preferably +/- 0.1% or less, within this range is suitable for implementation in the present invention. However, it should be understood that the value with the modifier "about" is itself specifically disclosed.

本文使用的術語“包含”與“包括”或“含有”是同義詞，是包括性或開放型的術語，是指存在該詞之後所跟隨的要素例如組分並且不排除存在本領域已知或本文中公開的除此之外未予記載的組分、特徵、要素、成員、步驟等。 The term "comprising", as used herein, is synonymous with "including" or "comprising," and is an inclusive or open-ended term that refers to the elements that are followed after the word, such as a component, and does not exclude the presence or Components, features, elements, members, steps, etc., which are not described in the above, are disclosed.

具有端點的數值範圍包括該範圍內包括的所有數值和部分以及所記載的端點。所有百分數應該理解為是重量百分數並且簡寫為“%wt”，除非另有限定或者除非本領域技術人員對於其使用以及在其所處的上 下文中具有不同含義是顯而易見的。 Numerical ranges with endpoints include all values and parts included in the range, and the recited endpoints. All percentages are to be understood as being by weight and abbreviated as "%wt" unless otherwise defined or unless the person skilled in the art is using it and The different meanings below are obvious.

在第一方面，本發明涉及一種製備包含布洛芬和對乙醯氨基酚的組合物的方法，該方法包括以下順序步驟：提供pH 6.3~7.3的水性溶劑，以及將布洛芬和對乙醯氨基酚溶解在所述水性溶劑中以製備組合物，其中在每ml所述組合物中溶解2.8至3.2mg布洛芬和9.8至10.2mg對乙醯氨基酚。本發明還涉及一種通過本發明的方法獲得的液體製劑。 In a first aspect, the present invention is directed to a method of preparing a composition comprising ibuprofen and p-acetaminophen, the process comprising the steps of providing an aqueous solvent having a pH of 6.3 to 7.3, and ibuprofen and b. The indole aminophenol is dissolved in the aqueous solvent to prepare a composition in which 2.8 to 3.2 mg of ibuprofen and 9.8 to 10.2 mg of p-acetaminophen are dissolved per ml of the composition. The invention also relates to a liquid preparation obtained by the method of the invention.

術語“水性”是指含有水。優選地，水性溶劑是水。 The term "aqueous" means containing water. Preferably, the aqueous solvent is water.

優選地，在機械攪動例如攪拌下，將布洛芬和對乙醯氨基酚溶解在水性溶劑中。布洛芬優選以布洛芬鈉鹽的形式使用。組合產品中布洛芬的含量為2.8~3.2mg/ml組合物；優選該含量為3.0mg/ml。組合產品中對乙醯氨基酚的含量為9.8~10.2mg/ml組合物；優選為10.0mg/ml。在其中加入活性成分的水性溶劑的特徵在於pH值為6.3~7.3。在一個優選實施方案中，水性溶劑的pH值為6.4~6.9，更優選為6.5~6.8，最優選為約6.6。 Preferably, ibuprofen and p-aminophenol are dissolved in an aqueous solvent under mechanical agitation such as agitation. Ibuprofen is preferably used in the form of a sodium salt of ibuprofen. The content of ibuprofen in the combination product is from 2.8 to 3.2 mg/ml of the composition; preferably, the content is 3.0 mg/ml. The content of the acetaminophen in the combination product is 9.8 to 10.2 mg/ml of the composition; preferably 10.0 mg/ml. The aqueous solvent to which the active ingredient is added is characterized by a pH of 6.3 to 7.3. In a preferred embodiment, the aqueous solvent has a pH of from 6.4 to 6.9, more preferably from 6.5 to 6.8, most preferably about 6.6.

該pH值範圍同時避免了布洛芬的沉澱和對乙醯氨基酚的降解。 This pH range also avoids the precipitation of ibuprofen and the degradation of acetaminophen.

該pH值可以在混合之前利用pH調節劑例如NaOH或HCl調節至所需水準。 This pH can be adjusted to the desired level with a pH adjusting agent such as NaOH or HCl prior to mixing.

溶液的pH值可以進行緩衝。合適的緩衝劑可以包括檸檬酸、檸檬酸鈉、磷酸鈉、檸檬酸鉀等中的一種或多種。優選地，緩衝劑是磷酸氫二鈉。 The pH of the solution can be buffered. Suitable buffering agents can include one or more of citric acid, sodium citrate, sodium phosphate, potassium citrate, and the like. Preferably, the buffer is disodium hydrogen phosphate.

在一個優選實施方案中，水性溶劑的溶解氧含量低於2ppm。 In a preferred embodiment, the aqueous solvent has a dissolved oxygen content of less than 2 ppm.

最高不超過2ppm的氧含量有利於避免在本發明的方法以及由此方法獲得的組合物中，對乙醯氨基酚在布洛芬存在下發生降解。 An oxygen content of up to 2 ppm is advantageous to avoid degradation of the acetaminophen in the presence of ibuprofen in the process of the invention and the composition obtained by this process.

在一個優選實施方案中，水性溶劑的氧含量低於2ppm，優選低於1ppm，更優選低於0.8ppm，還優選低於0.5ppm或低於0.4ppm，最優選低於0.2ppm。 In a preferred embodiment, the aqueous solvent has an oxygen content of less than 2 ppm, preferably less than 1 ppm, more preferably less than 0.8 ppm, still more preferably less than 0.5 ppm or less than 0.4 ppm, and most preferably less than 0.2 ppm.

溶解氧含量可以通過本領域技術人員所熟知的技術進行測量。初始或殘餘的溶解氧含量可以根據克拉克原理利用氧氣計操作進行測量得到以mg/l為單位的氧含量值。考慮介質溫度和大氣壓力，將尺規在零點(除氧溶液)和蒸餾水飽和氧含量之間校準。利用作為溫度和壓力函數的圖表計算氧含量。 The dissolved oxygen content can be measured by techniques well known to those skilled in the art. The initial or residual dissolved oxygen content can be measured using an oxygen meter operation according to the Clark principle to obtain an oxygen content value in mg/l. Consider the medium temperature and atmospheric pressure, and calibrate the ruler between zero (oxygen solution) and distilled water saturated oxygen content. The oxygen content was calculated using a chart as a function of temperature and pressure.

在本發明方法的一個優選實施方案中，利用初始溫度為65℃~99℃，優選80℃~98℃的水性溶劑獲得除氧後的溶解氧含量。在一個實施方案中，本發明涉及一種如本文所限定的方法，其中所述水性溶劑的初始溫度為85℃~97℃或90℃~95℃。 In a preferred embodiment of the process of the invention, the dissolved oxygen content after deoxygenation is obtained using an aqueous solvent having an initial temperature of from 65 ° C to 99 ° C, preferably from 80 ° C to 98 ° C. In one embodiment, the invention relates to a method as defined herein, wherein the aqueous solvent has an initial temperature of from 85 °C to 97 °C or from 90 °C to 95 °C.

一種優選的方法包括在具有升高溫度的水性溶劑中混合活性成分。有利的是，該水性溶劑在混合活性成分之前不被冷卻，這不僅由於無需使用熱交換器來冷卻水性溶劑而有利於減少製劑的製備時間，而且還允許得到合適的氧濃度。與對已經含有對乙醯氨基酚和抗氧化劑的溶液進行除氧不同的是，在低氧含量的介質中添加對氧敏感的對乙醯氨基酚和抗氧化劑具有最大程度減少氧的不利影響的優點。抗氧化劑不被過早消耗而保持可用以提供長期儲存穩定性。 A preferred method comprises mixing the active ingredients in an aqueous solvent having an elevated temperature. Advantageously, the aqueous solvent is not cooled prior to mixing the active ingredients, not only because there is no need to use a heat exchanger to cool the aqueous solvent, but also to reduce the preparation time of the formulation, but also to allow for a suitable oxygen concentration. Unlike deoxygenation of solutions already containing acetaminophen and antioxidants, the addition of oxygen-sensitive acetaminophen and antioxidants to the low-oxygen medium has the greatest potential to reduce the adverse effects of oxygen. advantage. Antioxidants are not consumed prematurely and remain available to provide long term storage stability.

在本發明方法的另一個優選實施方案中，通過將惰性氣體鼓泡通過所述溶劑來實現氧含量的減少。鼓入溶液中以驅除氧氣的氣體可以是氮氣、氬氣或氙氣，優選氮氣。最優選具有低氧含量的氮氣。 In another preferred embodiment of the process of the invention, the reduction in oxygen content is achieved by bubbling an inert gas through the solvent. The gas that is bubbled into the solution to drive off the oxygen may be nitrogen, argon or helium, preferably nitrogen. Nitrogen gas having a low oxygen content is most preferred.

在本發明方法的另一個實施方案中，利用真空實現氧含量的減少。可以利用適當的真空泵如葉片泵來獲得真空。 In another embodiment of the process of the invention, the reduction in oxygen content is achieved using a vacuum. A vacuum can be obtained using a suitable vacuum pump such as a vane pump.

減少製劑中氧含量的技術例如上文所述的溫水、鼓泡和/或真空方法也可以組合使用。 Techniques for reducing the oxygen content of the formulation, such as the warm water, bubbling and/or vacuum methods described above, can also be used in combination.

在本發明的方法和組合物的一個優選實施方案中，在水性組合物中添加抗氧化劑。用於本發明的抗氧化劑優選選自亞硫酸鹽或亞硫酸鹽衍生物、硫醇類物質例如半胱氨酸、乙醯半胱氨酸、二硫蘇糖醇或α-硫代甘油、硫代蘋果酸、硫代甘油、甲硫氨酸；羥基化物例如抗壞血酸、異抗壞血酸、甘露醇、山梨糖醇，烯類不飽和物質例如山梨酸、十一酸或富馬酸或羥基多元酸，或還原糖例如海藻糖、麥芽或異麥芽酮糖。在一個優選實施方案中，抗氧化劑選自半胱氨酸和乙醯半胱氨酸。半胱氨酸優選為半胱氨酸鹽酸鹽。乙醯半胱氨酸或半胱氨酸鹽酸鹽優選為一水合物。本文所用的術語“(乙醯)半胱氨酸”是指乙醯半胱氨酸和/或半胱氨酸。乙醯半胱氨酸或半胱氨酸作為抗氧化劑抑制對乙醯氨基酚氧化降解為未知降解產物。儘管它們的使用存在使溶液變黃的風險，但是它們是優選的，因為它們可以降低對乙醯氨基酚的毒性風險。 In a preferred embodiment of the methods and compositions of the present invention, an antioxidant is added to the aqueous composition. The antioxidant used in the present invention is preferably selected from sulfite or sulfite derivatives, thiol substances such as cysteine, acetylcysteine, dithiothreitol or alpha-thioglycerol, sulfur Malic acid, thioglycerol, methionine; hydroxylate such as ascorbic acid, isoascorbic acid, mannitol, sorbitol, ethylenically unsaturated materials such as sorbic acid, undecanoic acid or fumaric acid or hydroxy polyacid, or Reducing sugars such as trehalose, malt or isomaltulose. In a preferred embodiment, the antioxidant is selected from the group consisting of cysteine and acetaminophen cysteine. The cysteine is preferably cysteine hydrochloride. The cysteine or cysteine hydrochloride is preferably a monohydrate. The term "(acetyl) cysteine" as used herein refers to acetaminophen and/or cysteine. Acetylcysteine or cysteine acts as an antioxidant to inhibit the oxidative degradation of acetaminophen to an unknown degradation product. Although their use has the risk of yellowing the solution, they are preferred because they reduce the risk of toxicity to acetaminophen.

在使用溫水技術時，組合物的溫度降低到低於40℃，然後加入半胱氨酸或乙醯半胱氨酸。冷卻可以在機械攪拌例如攪動下進行。抗氧 化劑在至多40℃的溫度下加入，以避免乙醯半胱氨酸或半胱氨酸的高溫分解。將含有布洛芬和對乙醯氨基酚的水溶液冷卻到至多40℃的溫度，優選冷卻至39℃或38℃、37℃、36℃或35℃，然後加入乙醯半胱氨酸或半胱氨酸。優選地，在所述水性溶劑中加入半胱氨酸或乙醯半胱氨酸不使pH值改變至6.3~7.3以外的範圍。在一個優選實施方案中，水性組合物在添加抗氧化劑前後的pH值為6.3~7.3。優選地，最終產品的pH值為約6.6。 When using warm water techniques, the temperature of the composition is lowered to below 40 ° C and then cysteine or acetaminos cysteine is added. Cooling can be carried out under mechanical agitation such as agitation. Antioxidant The agent is added at a temperature of up to 40 ° C to avoid pyrolysis of cysteine or cysteine. Cooling the aqueous solution containing ibuprofen and acetaminophen to a temperature of up to 40 ° C, preferably to 39 ° C or 38 ° C, 37 ° C, 36 ° C or 35 ° C, then adding acetaminophen or cysteine Amino acid. Preferably, the addition of cysteine or acetylcysteine to the aqueous solvent does not change the pH to a range other than 6.3 to 7.3. In a preferred embodiment, the aqueous composition has a pH of from 6.3 to 7.3 before and after the addition of the antioxidant. Preferably, the final product has a pH of about 6.6.

在本發明的方法和組合物的一個優選實施方案中，水性溶劑還包含等滲劑。使用等滲劑的優點在於產生在生理鹽水等滲壓範圍內的等滲壓。本文的等滲劑可以是多元醇、糖、選自甘露醇、山梨醇、肌醇、葡萄糖和甘油的具有2~10個碳原子的直鏈或環狀糖醇。優選的等滲劑是甘露醇。 In a preferred embodiment of the methods and compositions of the present invention, the aqueous solvent further comprises an isotonicity agent. The advantage of using an isotonicity agent is that it produces an isotonic pressure within the isotonic pressure range of physiological saline. The isotonizing agent herein may be a polyol, a sugar, a linear or cyclic sugar alcohol having from 2 to 10 carbon atoms selected from the group consisting of mannitol, sorbitol, inositol, glucose, and glycerol. A preferred isotonizing agent is mannitol.

等滲劑與對乙醯氨基酚的品質比(w/w)例如甘露醇：對乙醯氨基酚優選為2~6：1，更優選為3~5：1，最優選為約4：1。優選地，在將等滲劑加入到水性溶液(優選水)中之後，再加入布洛芬和對乙醯氨基酚。 The quality ratio (w/w) of the isotonic agent to the acetaminophen, for example, mannitol: acetaminophen is preferably 2 to 6:1, more preferably 3 to 5:1, and most preferably about 4:1. . Preferably, ibuprofen and p-acetaminophen are added after the isotonic agent is added to the aqueous solution, preferably water.

在一個優選實施方案中，在根據本發明的方法中使用的pH調節劑是氫氧化鈉-磷酸氫二鈉鹽和乙醯半胱氨酸或半胱氨酸。 In a preferred embodiment, the pH adjusting agent used in the method according to the invention is sodium hydroxide-disodium hydrogen phosphate and acetylcysteine or cysteine.

在一個優選實施方案中，製劑的最終pH值為6.3~7.3。優選地，最終pH值是6.4~6.9，更優選為6.5~6.8。在本發明方法的一個優選實施方案中，得到的水性組合物的pH值為約6.6。優選地，在至少六個月的貯存期之後，pH值為6.3~7.3。 In a preferred embodiment, the final pH of the formulation is between 6.3 and 7.3. Preferably, the final pH is from 6.4 to 6.9, more preferably from 6.5 to 6.8. In a preferred embodiment of the process of the invention, the resulting aqueous composition has a pH of about 6.6. Preferably, the pH is between 6.3 and 7.3 after a storage period of at least six months.

在添加完成後，將反應容器封閉，殘留在容器上部的空氣被 從容器上部引入的惰性氣體例如氮氣壓縮。優選地，壓力為1~1.5巴。接著引入惰性氣體，並隨之進行攪拌。 After the addition is completed, the reaction vessel is closed, and the air remaining in the upper portion of the vessel is The inert gas introduced from the upper portion of the vessel, such as nitrogen, is compressed. Preferably, the pressure is from 1 to 1.5 bar. An inert gas is then introduced and stirred therewith.

優選地，半胱氨酸鹽酸鹽與對乙醯氨基酚的品質比(w/w)為0.010~0.040：1，優選為0.020~0.030：1，更優選為0.025：1。 Preferably, the mass ratio (w/w) of cysteine hydrochloride to p-acetaminophen is from 0.010 to 0.040:1, preferably from 0.020 to 0.030:1, more preferably 0.025:1.

優選地，乙醯半胱氨酸或半胱氨酸鹽酸鹽與布洛芬的品質比(w/w)為0.20~0.40：1，優選為0.10~0.20：1，更優選為0.08：1。 Preferably, the quality ratio (w/w) of acetaminophen or cysteine hydrochloride to ibuprofen is from 0.20 to 0.40:1, preferably from 0.10 to 0.20:1, more preferably 0.08:1. .

例如，在本文所限定的製劑和方法中，在最終製劑中的(乙醯)半胱氨酸鹽酸鹽的含量優選為0.015%~0.05%，優選約0.025%(w/v)。 For example, in the formulations and methods defined herein, the level of (acetamidine) cysteine hydrochloride in the final formulation is preferably from 0.015% to 0.05%, preferably about 0.025% (w/v).

所得溶液可進行過濾，例如在過濾單元中過濾。 The resulting solution can be filtered, for example by filtration in a filtration unit.

在配混過程中，優選避免在灌裝/包裝和/或貯存過程中氧氣接觸或氧氣進入水性溶液。 During the compounding process, it is preferred to avoid oxygen contact or oxygen entering the aqueous solution during filling/packaging and/or storage.

優選地，在灌裝之前用溫水洗滌用於存放對乙醯氨基酚-布洛芬的容器，例如小瓶。特別是，可以使用溫度為75℃~100℃的注射用水洗滌容器。這種水具有低的溶解氧含量。這特別適用於從容器中排除氧氣以及減少其氧含量。 Preferably, the container for storing the p-aminophenol-ibuprofen, such as a vial, is washed with warm water prior to filling. In particular, the container can be washed with water for injection at a temperature of 75 ° C to 100 ° C. This water has a low dissolved oxygen content. This is especially useful for removing oxygen from the container and reducing its oxygen content.

在隨後的步驟中，洗滌過的容器可以進行乾燥。優選使用乾燥空氣進行乾燥。乾燥空氣的水分含量低，從而再次最大程度減少由包裝以及隨後由對乙醯氨基酚-布洛芬溶液的氧再攝取。 In a subsequent step, the washed container can be dried. Drying is preferably carried out using dry air. The moisture content of the dry air is low, again minimizing the oxygen uptake by the packaging and subsequent oxygenation of the acetaminophen-ibuprofen solution.

在乾燥之後，可以用氮氣沖洗經洗滌和/或乾燥的容器。優選使用低氧含氧的氮氣。 After drying, the washed and/or dried container can be flushed with nitrogen. It is preferred to use a low oxygen oxygen-containing nitrogen gas.

在對容器進行預處理之後，將所述容器灌裝布洛芬/對乙醯 氨基酚溶液配混過程優選在灌裝/包裝之前提供溶解氧含量低於2.0ppm，更優選低於1.0ppm，甚至更優選低於0.8ppm，最優選低於0.5ppm，通常為約0.4ppm的水性布洛芬/對乙醯氨基酚溶液。 After pretreating the container, the container is filled with ibuprofen/p-acetamidine The aminophenol solution compounding process preferably provides a dissolved oxygen content of less than 2.0 ppm, more preferably less than 1.0 ppm, even more preferably less than 0.8 ppm, most preferably less than 0.5 ppm, typically about 0.4 ppm, prior to filling/packaging. Aqueous ibuprofen / p-acetaminophenol solution.

在一個優選實施方案中，根據本發明方法製備的對乙醯氨基酚-布洛芬溶液在灌裝時具有小於或等於0.8ppm的溶解氧含量。 In a preferred embodiment, the acetaminophen-ibuprofen solution prepared according to the process of the invention has a dissolved oxygen content of less than or equal to 0.8 ppm upon filling.

優選地，容器在真空下密封，優選所述真空為450毫巴~約1巴。 Preferably, the container is sealed under vacuum, preferably the vacuum is from 450 mbar to about 1 bar.

然後將容器密封，例如通過增加一個瓶塞進行真空密封並提供覆蓋瓶塞的壓緊蓋。 The container is then sealed, for example by adding a stopper for vacuum sealing and providing a compression cap covering the stopper.

這些容器可以隨後進行熱滅菌，例如在121℃下滅菌15分鐘。 These containers can then be heat sterilized, for example, at 121 ° C for 15 minutes.

在一個優選實施方案中，根據本發明的方法還包括按指定順序的以下步驟：-使用溫度為75℃~100℃的注射用水洗滌所述容器，-利用乾燥空氣乾燥該經洗滌的容器，-將該經氮氣沖洗的容器灌裝布洛芬/對乙醯氨基酚水溶液，-真空密封所述容器，優選壓力為450毫巴~約1巴。 In a preferred embodiment, the method according to the invention further comprises the following steps in the specified order: washing the container with water for injection at a temperature of from 75 ° C to 100 ° C, drying the washed container with dry air, - The nitrogen purged vessel is filled with an aqueous solution of ibuprofen/p-aminophenol, and the vessel is vacuum sealed, preferably at a pressure of from 450 mbar to about 1 bar.

在一個更優選的實施方案中，該真空密封產品容器包括被壓緊蓋覆蓋的彈性材料製成的瓶塞。 In a more preferred embodiment, the vacuum sealed product container includes a stopper of elastomeric material covered by a compression cap.

在一個優選實施方案中，所述瓶蓋的彈性材料是橡膠，優選為丁基橡膠或鹵代丁基橡膠。此類橡膠具有低透氧係數。優選地，所述瓶 蓋由鋁壓緊蓋密封。優選地，所述容器用(鹵代)丁基橡膠優選溴化丁基橡膠瓶塞封閉，並用鋁蓋密封。 In a preferred embodiment, the elastomeric material of the cap is a rubber, preferably a butyl rubber or a halobutyl rubber. Such rubbers have a low oxygen permeability coefficient. Preferably, the bottle The cover is sealed by an aluminum compression cap. Preferably, the container is closed with a (halogenated) butyl rubber, preferably a bromobutyl rubber stopper, and sealed with an aluminum lid.

優選地，用於容納根據本發明的一個實施方案的產品的容器是小瓶(vial)；優選是無色II型玻璃的歐洲藥典3.2.1小瓶。 Preferably, the container for containing the product according to one embodiment of the invention is a vial; preferably a European Pharmacopoeia 3.2.1 vial of a colorless type II glass.

在根據本發明的一個優選實施方案中，封閉有產品的容器內部被減壓。優選地，壓力降低到允許將注射用溶劑通過例如用針頭穿刺透過封閉件的方式添加到該封閉系統內。優選地，所述減壓為450毫巴~約1巴。 In a preferred embodiment according to the invention, the interior of the container enclosing the product is decompressed. Preferably, the pressure is reduced to allow the injection solvent to be added to the closure system by, for example, piercing through the closure with a needle. Preferably, the reduced pressure is from 450 mbar to about 1 bar.

在一個優選實施方案中，容器包括在凸緣內部具有倒流裝置的小瓶。倒流裝置提高了瓶塞的配合並且避免了瓶塞彈出小瓶。小瓶的凸緣和瓶塞的外形尺寸的選擇方式是確保瓶塞在封閉和密封過程中保持良好的配合。優選倒流裝置的外形尺寸能夠在小瓶和瓶塞之間提供充分的密封表面，從而盡可能長時間地保持小瓶內的真空。 In a preferred embodiment, the container includes a vial having a backflow device inside the flange. The backflow device increases the fit of the stopper and prevents the stopper from ejecting the vial. The flange of the vial and the dimensions of the stopper are chosen to ensure a good fit of the closure during closure and sealing. Preferably, the reverse flow device is sized to provide a sufficient sealing surface between the vial and the stopper to maintain the vacuum within the vial for as long as possible.

優選地，容器/封閉系統具有倒流裝置，特別是在施加減壓的情況下。相對於不具有倒流裝置的系統，倒流系統是非常緊密的並且能夠減少空氣流入以及隨之產生氧化的風險。 Preferably, the container/closed system has a backflow device, in particular in the case of applying a reduced pressure. Compared to systems that do not have a backflow device, the backflow system is very tight and can reduce the risk of air inflow and consequent oxidation.

根據本發明的一個實施方案的製劑通常可以如下製備。首先，將精確配方量的等滲劑(甘露醇)、布洛芬鈉和鹽酸以獲得pH值為6.3~7.3的量添加到反應容器中。任選地，可以存在一種或多種其它與水混溶的溶劑和/或表面活性劑。然後，提供溫度介於65℃和98℃之間的作為溶劑的注射用水。將反應容器關閉，利用從容器上部引入的經0.22μm過濾的氮氣來壓縮殘留在容器上部的空氣。接著，將組分攪拌溶解。停止攪拌後，將 反應容器迅速打開並快速加入對乙醯氨基酚。此時該過程不進行混合，以減少空氣的引入。然後將反應容器關閉。空氣在溫度超過60℃時是難溶於水的。 Formulations according to one embodiment of the invention can generally be prepared as follows. First, an accurately formulated amount of an isotonic agent (mannitol), sodium ibuprofen and hydrochloric acid to obtain a pH of 6.3 to 7.3 is added to the reaction vessel. Optionally, one or more other water miscible solvents and/or surfactants may be present. Then, water for injection as a solvent having a temperature between 65 ° C and 98 ° C is provided. The reaction vessel was closed, and the air remaining in the upper portion of the vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel. Next, the components were stirred and dissolved. After stopping the stirring, will The reaction vessel was quickly opened and the p-aminophenol was quickly added. At this point the process is not mixed to reduce the introduction of air. The reaction vessel is then closed. Air is poorly soluble in water at temperatures above 60 °C.

利用從容器上部引入的經0.22μm過濾的氮氣來壓縮殘留在容器上部的空氣，優選壓力為1~1.5巴，然後進行攪拌。將溶液冷卻到至多40℃的溫度。一旦冷卻後，將反應容器迅速打開並快速加入配方中精確量的氫氧化鈉和磷酸氫二鈉，以獲得6.3~7.3的pH值，然後關閉反應容器。利用從容器上部引入的經0.22μm過濾的氮氣來壓縮殘留在容器上部的空氣，優選壓力為1~1.5巴，然後進行攪拌。將反應容器迅速打開並快速加入半胱氨酸或乙醯半胱氨酸，然後再次關閉反應容器。利用從容器上部引入的經0.22μm過濾的氮氣來壓縮殘留在容器上部的空氣，優選壓力為1~1.5巴，然後進行攪拌。所用的氮氣在引入之前利用0.22μm的篩檢程式進行過濾。 The air remaining in the upper portion of the vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel, preferably at a pressure of 1 to 1.5 bar, and then stirred. The solution is cooled to a temperature of up to 40 °C. Once cooled, the reaction vessel was quickly opened and the precise amount of sodium hydroxide and disodium hydrogen phosphate in the formulation was quickly added to obtain a pH of 6.3 to 7.3, and then the reaction vessel was closed. The air remaining in the upper portion of the vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel, preferably at a pressure of 1 to 1.5 bar, and then stirred. The reaction vessel was quickly opened and the cysteine or acetaminophen was added quickly, and then the reaction vessel was closed again. The air remaining in the upper portion of the vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel, preferably at a pressure of 1 to 1.5 bar, and then stirred. The nitrogen used was filtered using a 0.22 μm screening procedure prior to introduction.

在第二方面中，本發明提供一種水性組合物，其包含2.8~3.2mg布洛芬/ml所述組合物、9.8~10.2mg對乙醯氨基酚/ml所述組合物以及半胱氨酸，優選根據前述方法進行製備，其特徵在於，所述組合物的pH值為6.3~7.3。 In a second aspect, the present invention provides an aqueous composition comprising 2.8 to 3.2 mg of ibuprofen/ml of the composition, 9.8 to 10.2 mg of acetaminophen/ml of the composition, and cysteine It is preferably prepared according to the aforementioned method, characterized in that the composition has a pH of 6.3 to 7.3.

本發明人已經發現，指定的pH值範圍出乎意料地允許布洛芬和對乙醯氨基酚在水溶液中進行混配，從而同時減少了布洛芬的沉澱和對乙醯氨基酚的降解。 The inventors have found that the specified pH range unexpectedly allows ibuprofen and acetaminophen to be compounded in aqueous solution, thereby simultaneously reducing ibuprofen precipitation and degradation of acetaminophen.

優選地，水性溶劑包括水和等滲劑。在一個更優選的實施方案中，所述等滲劑是甘露醇。 Preferably, the aqueous solvent comprises water and an isotonicity agent. In a more preferred embodiment, the isotonic agent is mannitol.

可以存在多種藥學上可接受的賦形劑。然而，在一個優選實施方案中，不存在額外的賦形劑。 A variety of pharmaceutically acceptable excipients can be present. However, in a preferred embodiment, no additional excipients are present.

優選地，所述水溶液具有285~320mOsmol/l的滲透壓，通過根據USP788的冰點降低方法確定。 Preferably, the aqueous solution has an osmotic pressure of 285 to 320 mOsmol/l, as determined by a freezing point reduction method according to USP788.

在一個優選實施方案中，所述組合物的貯存穩定性為至少6個月，優選至少9個月，更優選至少12個月，最優選24個月，以根據歐洲藥典2.2.29和USP621通過HPLC測量的對乙醯氨基酚/布洛芬的含量為基礎。 In a preferred embodiment, the composition has a storage stability of at least 6 months, preferably at least 9 months, more preferably at least 12 months, most preferably 24 months, to pass according to the European Pharmacopoeia 2.2.29 and USP621. The content of acetaminophen/ibuprofen measured by HPLC was based.

在一個優選實施方案中，製備完成時的組合物中(乙醯)半胱氨酸的含量為其初始加入量的至少80%，優選至少85%，最優選至少90%。 In a preferred embodiment, the content of cysteine in the composition upon completion of preparation is at least 80%, preferably at least 85%, and most preferably at least 90% of the initial amount added.

在一個優選實施方案中，在布洛芬/對乙醯氨基酚溶液的貯存期內，(乙醯)半胱氨酸鹽酸鹽的含量為初始加入量的至少40%，優選至少50%，優選至少75%。(乙醯)半胱氨酸的低消耗表示在貯存期間與氧氣的接觸量低。 In a preferred embodiment, the cysteine hydrochloride salt is present in an amount of at least 40%, preferably at least 50%, of the initial addition during the storage period of the ibuprofen/p-aminophenol solution. Preferably at least 75%. The low consumption of cysteine indicates that the amount of contact with oxygen during storage is low.

在另一實施方案中，所述組合物用作藥物。對於其在藥物和醫療領域的適用性尤為重要的是該組合物的pH值。 In another embodiment, the composition is for use as a medicament. Of particular importance for its suitability in the pharmaceutical and medical fields is the pH of the composition.

在一個更優選的實施方案中，所述組合物用於疼痛和/或炎症的治療用途。 In a more preferred embodiment, the composition is for the therapeutic use of pain and/or inflammation.

該組合物的pH值使得該組合物特別適合通過靜脈內注射給藥。在一個最優選的實施方案中，所述組合物通過靜脈內注射給藥。 The pH of the composition makes the composition particularly suitable for administration by intravenous injection. In a most preferred embodiment, the composition is administered by intravenous injection.

由此得到的溶液可以分配到隨時可用的密封袋或瓶中。 The solution thus obtained can be dispensed into a sealed bag or bottle that is ready for use.

在本發明的再一個方面中，該組合物提供在雙貯室注射裝置 中。 In still another aspect of the invention, the composition is provided in a dual chamber injection device in.

在一個優選實施方案中，所述注射裝置具有包含根據本發明一個實施方案的組合物的第一和第二貯室，其中在一個貯室中含有2.8~3.2mg布洛芬/ml所述組合物，在另一個貯室中含有9.8~10.2mg對乙醯氨基酚/ml所述組合物，其特徵在於，當兩個貯室中的內容物混合時，所述組合物的pH值為6.3~7.3。 In a preferred embodiment, the injection device has first and second reservoirs comprising a composition according to one embodiment of the invention, wherein the combination contains 2.8 to 3.2 mg of ibuprofen/ml in one reservoir. The composition contains 9.8 to 10.2 mg of acetaminophen/ml of the composition in another reservoir, wherein the composition has a pH of 6.3 when the contents of the two reservoirs are mixed. ~7.3.

在一個優選實施方案中，所述注射裝置包括第一和第二貯室，該第一容器具有第一開口端，第二貯室可通過該第一開口端滑動安裝在第一貯室中，該第一貯室具有與第一開口端相對位置的第二開口端，注射針頭可以設置在該第二開口端上，該第二貯室包括與出口配合的底表面，其中在所述出口處設置有突起部，在注射裝置處於安裝狀態時，該突起部從所述底表面向第二開口端的方向延伸，該突起部以可折斷的方式安裝在第二貯室的底表面上，使得當該突起部到達第二開口端時，該突起部自身折斷以打開第二貯室的出口。 In a preferred embodiment, the injection device includes first and second reservoirs, the first container having a first open end, and the second reservoir is slidably mounted in the first reservoir through the first open end, The first reservoir has a second open end opposite the first open end, the injection needle being positionable on the second open end, the second reservoir including a bottom surface mating with the outlet, wherein the outlet Provided with a protrusion extending from the bottom surface toward the second open end when the injection device is in the mounted state, the protrusion being detachably mounted on the bottom surface of the second reservoir, such that When the projection reaches the second open end, the projection itself is broken to open the outlet of the second reservoir.

這樣的注射裝置的特徵在於，在出口處安裝有突出部，並且在注射裝置處於安裝狀態時，該突出部從底表面向所述第二開口端延伸，該突起部以可折斷的方式安裝在第二貯室的底表面上，使得當該突起部到達第二開口端時，其自身折斷以打開第二貯室的出口。因為該突起部設置在第二貯室的底表面上並且在到達第二開口端時折斷，所以它不構成藥物從第一貯室流出的障礙。因此，第一貯室的排空是最優的。因為所述突起部設置在第二貯室的底表面上的出口處，所以該突起部可以在注射裝置生 產過程中同時形成，而無需對第二貯室的注射成型進行額外的步驟。該注射裝置可以廉價生產。 Such an injection device is characterized in that a projection is mounted at the outlet, and when the injection device is in the mounted state, the projection extends from the bottom surface to the second open end, the projection being mounted in a frangible manner The bottom surface of the second reservoir is such that when the projection reaches the second open end, it breaks itself to open the outlet of the second reservoir. Since the projection is disposed on the bottom surface of the second reservoir and is broken when reaching the second open end, it does not constitute an obstacle for the drug to flow out of the first reservoir. Therefore, the emptying of the first reservoir is optimal. Since the protrusion is provided at the outlet on the bottom surface of the second reservoir, the protrusion can be produced at the injection device Simultaneous formation during production without the need for additional steps in injection molding of the second reservoir. The injection device can be produced inexpensively.

適合用於本發明的裝置特別是注射器例如描述在BE1020614中。 Devices suitable for use in the present invention, particularly syringes, are described, for example, in BE 1020614.

在以下實施例中更詳細地描述了本發明，這些實施例作為非限定性的說明給出。在這些實施例中，溫度為室溫或用攝氏度表示，壓力為大氣壓。水和使用的所有試劑均為可注射級的。 The invention is described in more detail in the following examples, which are given as non-limiting illustrations. In these embodiments, the temperature is room temperature or expressed in degrees Celsius and the pressure is atmospheric. Water and all reagents used are injectable grade.

此外，所有實施例形成本發明的組成部分，本說明書的任何特徵均包括實施例，這體現了相對於任何現有技術的新穎性，這只是針對一般特徵而言，並非是指實施例的特定的特徵。 In addition, all of the embodiments form an integral part of the present invention, and any feature of the present specification includes the embodiment, which embodies the novelty with respect to any prior art, which is only for the general features, and does not refer to the specific embodiment. feature.

實施例，在下文中，實施例旨在進一步闡明本發明，絕非意圖限制本發明的範圍。 The examples, in the following, are intended to further clarify the invention and are not intended to limit the scope of the invention.

1.製備根據本發明的液體藥物製劑1. Preparation of a liquid pharmaceutical preparation according to the present invention

通過以下方式製備製劑：將等滲劑(甘露醇)、布洛芬、鹽酸、注射用水、對乙醯氨基酚和乙醯半胱氨酸或半胱氨酸混合，並且利用鹽酸、氫氧化鈉和磷酸氫二鈉將pH值調節為6.3~7.3。隨後將該組合物的製備物進行過濾並灌裝到玻璃小瓶或大瓶中。該溶液的過濾在低於40℃的溫度下進行。這些容器在121℃下滅菌15分鐘。 The preparation is prepared by mixing an isotonic agent (mannitol), ibuprofen, hydrochloric acid, water for injection, acetaminophen and acetaminophen or cysteine, and using hydrochloric acid, sodium hydroxide The pH was adjusted to 6.3 to 7.3 with disodium hydrogen phosphate. The preparation of the composition is then filtered and filled into a glass vial or large vial. Filtration of the solution is carried out at a temperature below 40 °C. These containers were sterilized at 121 ° C for 15 minutes.

在加入乙醯半胱氨酸或半胱氨酸之前，相關製備步驟快速進行並避免不必要的中斷，這是為了避免空氣進入混配容器並且保持溶液在所需溫度下即在65℃~98℃下進行混合步驟；乙醯半胱氨酸或半胱氨酸的添 加步驟在低於40℃的溫度下進行。 Prior to the addition of acetaminophen or cysteine, the relevant preparation steps are carried out quickly and avoid unnecessary interruptions, in order to avoid air entering the compounding vessel and keeping the solution at the desired temperature, ie at 65 ° C to 98 ° Mixing step at °C; addition of cysteine or cysteine The addition step is carried out at a temperature below 40 °C.

利用從容器上部引入的經0.22μm過濾的氮氣來壓縮反應容器內的空氣。施加在混配容器內的溶液上的氮氣壓力推動溶液通過篩檢程式。 The air in the reaction vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel. The pressure of nitrogen applied to the solution in the mixing vessel pushes the solution through the screening program.

最終，灌裝好的小瓶在121℃下滅菌15分鐘。 Finally, the filled vials were sterilized at 121 ° C for 15 minutes.

2.製備根據本發明的另一液體藥物製劑2. Preparation of another liquid pharmaceutical preparation according to the present invention

根據實施例中描述的方法製備另一製劑。 Another formulation was prepared according to the method described in the examples.

3.貯存穩定性資料3. Storage stability data

布洛芬/對乙醯氨基酚組合產物製備如下：在混合容器中加入甘露醇、布洛芬、用以獲得pH值6.3~7.3的鹽酸0.1N以及溫度高於75℃的注射用水(WFI)。添加的鹽酸量提前計算，使得所需的pH值保持在6.3~7.3。關閉該混合容器，並利用從容器上部引入的經0.22μm過濾的氮氣來壓縮殘留在容器上部的空氣，壓力為1~1.5巴，然後進行攪拌。 The ibuprofen/p-acetaminophenol combination product was prepared as follows: mannitol, ibuprofen was added to a mixing vessel to obtain 0.1 N hydrochloric acid having a pH of 6.3 to 7.3, and water for injection (WFI) at a temperature higher than 75 ° C. . The amount of hydrochloric acid added is calculated in advance so that the desired pH is maintained at 6.3 to 7.3. The mixing vessel was closed, and the air remaining in the upper portion of the vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel at a pressure of 1 to 1.5 bar, followed by stirring.

快速打開混合容器，並且在不攪拌的情況下迅速加入對乙醯氨基酚。關閉該混合容器，並利用從容器上部引入的經0.22μm過濾的氮氣來壓縮殘留在容器上部的空氣，壓力為1~1.5巴，然後進行攪拌。 The mixing vessel was quickly opened and the p-aminophenol was quickly added without stirring. The mixing vessel was closed, and the air remaining in the upper portion of the vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel at a pressure of 1 to 1.5 bar, followed by stirring.

將溶液冷卻至低於40℃的溫度。達到該溫度之後，快速打開該混合容器，並在不攪拌的情況下迅速加入0.1N氫氧化鈉和磷酸氫二鈉。關閉該混合容器，並利用從容器上部引入的經0.22μm過濾的氮氣來壓縮殘留在容器上部的空氣，壓力為1~1.5巴，然後進行攪拌。 The solution was cooled to a temperature below 40 °C. After reaching this temperature, the mixing vessel was quickly opened and 0.1 N sodium hydroxide and disodium hydrogen phosphate were quickly added without stirring. The mixing vessel was closed, and the air remaining in the upper portion of the vessel was compressed with 0.22 μm of filtered nitrogen gas introduced from the upper portion of the vessel at a pressure of 1 to 1.5 bar, followed by stirring.

氫氧化鈉和磷酸氫二鈉的加入量預先進行計算，使得在加入半胱胺酸後所需的pH值保持在6.3~7.3。從而得到最終pH值為6.3~7.3的穩定的布洛芬/對乙醯氨基酚組合產品。 The amount of sodium hydroxide and disodium hydrogen phosphate added was calculated in advance so that the pH required after the addition of the cysteine was maintained at 6.3 to 7.3. Thus, a stable ibuprofen/p-acetaminophenol combination product having a final pH of 6.3 to 7.3 is obtained.

快速打開該混合容器，在不攪拌的情況下迅速加入乙醯半胱氨酸或半胱氨酸。關閉該混合容器，並利用從容器上部引入的經0.22μm 過濾的氮氣來壓縮殘留在容器上部的空氣，壓力為1~1.5巴，然後進行攪拌。 The mixing vessel was quickly opened and acetaminophen or cysteine was quickly added without stirring. Closing the mixing vessel and using 0.22 μm introduced from the upper part of the vessel The filtered nitrogen gas is used to compress the air remaining in the upper portion of the vessel at a pressure of 1 to 1.5 bar and then stirred.

貯存樣品並且在預定時間間隔後進行分析。在25±2℃的溫度和40±5%的相對濕度下貯存的pH6.6溶液的結果匯總在表3中。在25±2℃的溫度和40±5%的相對濕度下貯存的pH 7.0溶液的結果匯總在表4中。 Samples were stored and analyzed after a predetermined time interval. The results of the pH 6.6 solution stored at a temperature of 25 ± 2 ° C and a relative humidity of 40 ± 5% are summarized in Table 3. The results of the pH 7.0 solution stored at a temperature of 25 ± 2 ° C and a relative humidity of 40 ± 5% are summarized in Table 4.

從上述兩個表中的資料可以看出，提供的是澄清液體溶液。即使貯存12個月後，仍能得到該物理外觀。隨時間推移，半胱氨酸含量仍然很高並且基本穩定。對乙醯氨基酚和布洛芬的雜質含量極低，儘管pH值被認為對於單獨存在的上述活性成分是不利的。 As can be seen from the data in the above two tables, a clear liquid solution is provided. This physical appearance is obtained even after 12 months of storage. Over time, the cysteine content is still high and substantially stable. The impurity content of acetaminophen and ibuprofen is extremely low, although the pH value is considered to be disadvantageous for the above-mentioned active ingredient alone.

如上製備的樣品進行加速貯藏穩定性試驗的結果示於表5中。這些樣品保存在40±2℃的溫度和25±5%的相對濕度下。 The results of the accelerated storage stability test of the samples prepared as above are shown in Table 5. These samples were stored at a temperature of 40 ± 2 ° C and a relative humidity of 25 ± 5%.

加速貯藏穩定性試驗的結果表明兩年的產品保質期是可行的。 The results of the accelerated storage stability test indicate that the shelf life of the product for two years is feasible.

4.相容性4. Compatibility

為了測試布洛芬和對乙醯氨基酚的組合相容性，進行以下實驗。 In order to test the combined compatibility of ibuprofen and acetaminophen, the following experiment was conducted.

將相當於3mg/ml布洛芬的3.85mg/ml布洛芬鈉．2H₂O的pH 8.80水溶液逐漸降低pH值，觀察沉澱是否產生作為溶解性/相容性的指標。結果記錄並匯總於表6。觀察到pH值為5.75時布洛芬出現沉澱。將該布洛芬溶液在25℃下貯存1個月。再次觀察沉澱的跡象。結果匯總於表7中。布洛芬溶液在pH 6時出現沉澱，而布洛芬溶液在pH 6.2時不存在沉澱。 Will be equivalent to 3mg / ml ibuprofen 3.85mg / ml of ibuprofen sodium. The pH of the 2H ₂ O 8.80 aqueous solution gradually lowered the pH value, and it was observed whether the precipitation produced an index as solubility/compatibility. The results are recorded and summarized in Table 6. Ibuprofen precipitated when a pH of 5.75 was observed. The ibuprofen solution was stored at 25 ° C for 1 month. Observe the signs of precipitation again. The results are summarized in Table 7. The ibuprofen solution precipitated at pH 6, while the ibuprofen solution did not precipitate at pH 6.2.

在另一實驗中，研究了布洛芬鈉．2H₂O與10mg對乙醯氨基酚/1濃度的對乙醯氨基酚混合的溶解性。不同pH值的結果匯總於表8。25℃下貯存1個月後的結果示於表9。25℃下貯存6個月後的結果示於表10。 In another experiment, ibuprofen sodium was studied. The solubility of 2H ₂ O with 10 mg of acetaminophen / 1 concentration of acetaminophen. The results for the different pH values are summarized in Table 8. The results after storage at 25 ° C for one month are shown in Table 9. The results after storage at 25 ° C for 6 months are shown in Table 10.

對乙醯氨基酚的量在不同的時間點和pH值下進行研究。資料顯示對乙醯氨基酚在pH 6.3~7.3範圍內降解最小。 The amount of acetaminophen was studied at different time points and pH values. The data showed that the degradation of acetaminophen was minimal in the range of pH 6.3-7.3.

綜上所述，布洛芬和對乙醯氨基酚的組合物在pH 6.3~7.3範圍內是穩定的。 In summary, the composition of ibuprofen and acetaminophen is stable in the range of pH 6.3-7.3.

Claims (18)

一種水性組合物，包括2.8~3.2mg布洛芬/ml組合物和9.8~10.2mg對乙醯氨基酚/ml組合物，其特徵在於，所述組合物的pH值為6.3~7.3。 An aqueous composition comprising 2.8 to 3.2 mg of ibuprofen/ml of composition and 9.8 to 10.2 mg of acetaminophen/ml of a composition, wherein the composition has a pH of from 6.3 to 7.3. 根據申請專利範圍第1項所述的組合物，包括3mg布洛芬/ml組合物和10mg對乙醯氨基酚/ml組合物。 The composition of claim 1 comprising 3 mg of ibuprofen/ml of composition and 10 mg of acetaminophen/ml of composition. 根據申請專利範圍第1項或第2項所述的組合物，進一步包括等滲劑。 The composition according to claim 1 or 2, further comprising an isotonic agent. 根據申請專利範圍第3項所述的組合物，其中所述等滲劑為甘露醇。 The composition of claim 3, wherein the isotonic agent is mannitol. 根據申請專利範圍第1~4項中任一項所述的組合物，其中所述組合物具有低於2ppm的溶解氧含量。 The composition of any one of claims 1 to 4, wherein the composition has a dissolved oxygen content of less than 2 ppm. 根據申請專利範圍第1~5項中任一項所述的組合物，其配方適合用作藥物的用途。 The composition according to any one of claims 1 to 5, which is suitable for use as a medicament. 根據申請專利範圍第1~6項中任一項所述的組合物，其配方適合用於治療疼痛和/或炎症的用途。 The composition according to any one of the preceding claims, wherein the composition is suitable for use in the treatment of pain and/or inflammation. 根據申請專利範圍第1~6項中任一項所述的組合物，其配方適合通過靜脈內注射給藥用於治療疼痛和/或炎症。 The composition according to any one of the preceding claims, wherein the composition is suitable for administration by intravenous injection for the treatment of pain and/or inflammation. 一種製備根據申請專利範圍第1項所述的水性組合物的方法，該水性組合物包含混配的布洛芬和對乙醯氨基酚，所述方法包括以下步驟：- 提供pH 6.3~7.3的水性溶劑，- 在所述溶劑中溶解2.8~3.2mg布洛芬/ml組合物和9.8~10.2mg對乙醯氨基酚/ml組合物。 A method of preparing an aqueous composition according to claim 1, wherein the aqueous composition comprises compounded ibuprofen and p-acetaminophen, the method comprising the steps of: - providing a pH of 6.3 to 7.3 Aqueous solvent, - 2.8 to 3.2 mg of ibuprofen/ml of the composition and 9.8 to 10.2 mg of acetaminophen/ml of the composition are dissolved in the solvent. 根據申請專利範圍第9項所述的方法，其中所述水性溶劑具有低於2ppm的溶解氧含量。 The method of claim 9, wherein the aqueous solvent has a dissolved oxygen content of less than 2 ppm. 根據申請專利範圍第10項所述的方法，其中所述具有低於2ppm的溶解氧含量的水性溶劑是通過使用溫度為85℃~99℃的水性溶劑和/或通過將惰性氣體鼓泡通過所述水性溶劑而得到。 The method of claim 10, wherein the aqueous solvent having a dissolved oxygen content of less than 2 ppm is obtained by using an aqueous solvent having a temperature of from 85 ° C to 99 ° C and/or by bubbling an inert gas. It is obtained by describing an aqueous solvent. 根據申請專利範圍第9~11項中任一項所述的方法，其中所述組合物進一步包含抗氧化劑。 The method of any one of clauses 9 to 11, wherein the composition further comprises an antioxidant. 根據申請專利範圍第12項所述的方法，其中在加入對乙醯氨基酚之後加入所述抗氧化劑，並且在加入所述抗氧化劑之前將溫度降到低於40℃。 The method of claim 12, wherein the antioxidant is added after the addition of p-aminophenol and the temperature is lowered below 40 °C prior to the addition of the antioxidant. 根據申請專利範圍第12~13項中任一項所述的方法，其中所述抗氧 化劑為半胱氨酸或乙醯半胱氨酸。 The method according to any one of claims 12 to 13, wherein the antioxidant The agent is cysteine or acetylcysteine. 根據申請專利範圍第12~14項中任一項所述的方法，其中在加入所述抗氧化劑之前或之後，所述水性組合物的pH值為6.3~7.3。 The method according to any one of claims 12 to 14, wherein the aqueous composition has a pH of 6.3 to 7.3 before or after the addition of the antioxidant. 根據申請專利範圍第9~15項中任一項所述的方法，其中所述水性溶劑進一步包括等滲劑。 The method of any one of claims 9 to 15, wherein the aqueous solvent further comprises an isotonicity agent. 根據申請專利範圍第16項所述的方法，其中所述等滲劑為甘露醇。 The method of claim 16, wherein the isotonic agent is mannitol. 一種具有申請專利範圍第1~8項中任一項所述的組合物的注射裝置，包括第一和第二貯室，其中在一個貯室中含有2.8~3.2mg布洛芬/ml所述組合物，在另一個貯室中含有9.8~10.2mg對乙醯氨基酚/ml所述組合物，其特徵在於，當兩個貯室中的內容物混合時，所述組合物的pH值為6.3~7.3。 An injection device having the composition of any one of claims 1 to 8, comprising first and second reservoirs, wherein said reservoir contains 2.8 to 3.2 mg of ibuprofen/ml The composition contains 9.8 to 10.2 mg of acetaminophen/ml of the composition in another reservoir, characterized in that the pH of the composition is when the contents of the two reservoirs are mixed 6.3~7.3.