WO2016082714A1 - 具有长期稳定性的不含抗氧化剂的药物注射溶液的制备方法 - Google Patents

具有长期稳定性的不含抗氧化剂的药物注射溶液的制备方法 Download PDF

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WO2016082714A1
WO2016082714A1 PCT/CN2015/094985 CN2015094985W WO2016082714A1 WO 2016082714 A1 WO2016082714 A1 WO 2016082714A1 CN 2015094985 W CN2015094985 W CN 2015094985W WO 2016082714 A1 WO2016082714 A1 WO 2016082714A1
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pressure
torr
injection solution
container
controlled temperature
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French (fr)
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胡宇方
林春绸
李承禹
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台湾东洋药品工业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to a method of preparing an injection solution, especially a drug injection solution containing no antioxidant.
  • aqueous solution such as pemetrexed or a pharmaceutically acceptable salt thereof (for example, a disodium salt)
  • a pharmaceutically acceptable salt thereof for example, a disodium salt
  • the injection medium such as physiological saline, is reconstituted into an injection solution and then administered to the patient.
  • Pemetrexed is an anti-folate antitumor drug with the chemical name: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrole [ 2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid.
  • the currently commercially available product of pemetrexed is a lyophilized powder which is administered to a patient after the lyophilized powder is reconstituted with physiological saline. When lyophilized powder is applied clinically, it must have a recovery step using physiological saline, which causes inconvenience to medical personnel and increases the risk of microbial contamination.
  • a ready-to-use product such as an aqueous solution of pemetrexed
  • pemetrexed is less stable in aqueous solution and is prone to various degradation products.
  • WO 01/56575 A1 discloses a liquid preparation suitable for parenteral administration comprising pemetrexed, an excipient and at least one selected from the group consisting of thioglycerol, L-cysteine and ethanethiol acid. Antioxidants, however, their long-term stability is not ideal.
  • WO 2012/015810 A2 discloses a long-term storage stable liquid pharmaceutical composition containing pemetrexed, which comprises pemetrexed or a salt thereof, an antioxidant such as lipoic acid, dihydrolipoic acid, methylthioamide
  • an antioxidant such as lipoic acid, dihydrolipoic acid, methylthioamide
  • a chelating agent such as lactobionic acid, trisodium citrate or a mixture thereof
  • a pharmaceutically acceptable liquid have a long-term stability of storage at 5 ° C to 25 ° C for at least 18 months.
  • the use of antioxidants contributes to long-term stability, it may cause unclear degradation products or oxidative degradation products derived from the antioxidant itself.
  • WO2012/121523 A2 discloses a pemetrexed injection solution containing no antioxidant and a preparation method thereof, the preparation method comprising: (a) controlling the concentration of dissolved oxygen in an injection solution containing pemetrexed or a salt thereof In a closed system of 1 ppm or less; and (b) in a partial pressure of oxygen of 0.2% v/v or less, the solution obtained in the step (a) is filled with a container for injection.
  • a stable liquid preparation containing pemetrexed can be prepared without using a stabilizer such as an antioxidant.
  • the process uses various known degassing processes, including vacuum degassing, distillation degassing, nitrogen degassing, membrane degassing, and catalysts.
  • degassing of the resin or the like a combination of the foregoing methods may be used to reduce the dissolved oxygen concentration to 1 ppm or less.
  • it may be necessary to perform a combination of different degassing processes, and it may be necessary to perform more than one degassing process.
  • a solution for injection is prepared by using a distillation degassing method and a vacuum degassing method.
  • the inventors of the present invention conducted a number of studies and experiments and found that a stable liquid preparation for injection can be prepared by reducing the amount of dissolved oxygen in the solution to a certain extent (about 2 ppm or less) without using a stabilizer such as an antioxidant. Further, a method of preparing a drug injection solution containing no antioxidant has been developed. Compared with the prior art, the process of the invention is simpler and more suitable for mass production.
  • the present invention provides a method of preparing a drug injection solution containing no antioxidant, the method comprising the steps of:
  • the headspace gas pressure in the vessel is lowered to a pressure slightly higher than the boiling of the injection solution at the controlled temperature.
  • the medium for injection in the above step (a) is water for injection.
  • the controlled temperature in the above step (b) is 60 ° C, the headspace gas pressure in the vessel is reduced to about 360 Torr; or the controlled temperature is 40 ° C, and the headspace gas pressure in the vessel is reduced to about 200 Or control the temperature at 25 ° C, the headspace gas pressure in the container is reduced to about 100 Torr.
  • the controlled temperature in the step (b) may be lower than the freezing point of the injection solution, for example -10 ° C or below to freeze the injection solution to a solid, such that the headspace gas pressure in the container is reduced regardless of the pressure at which the injection solution boils.
  • the headspace gas pressure within the vessel can be reduced to near vacuum, such as between about 80 Torr and about 0.02 Torr, between about 80 Torr and 0.5 Torr, or between about 0.5 Torr and 0.1 Torr.
  • the controlled temperature in step (b) is -10 ° C and the headspace gas pressure in the vessel is reduced to 0.1 Torr.
  • step (i) of filling the inert gas into the headspace of the vessel may be added after step (b) above and prior to step (c), optionally, steps (b) and ( i) Repeatable operation twice or more.
  • the pressure reducing device is a temperature controlled vacuum box.
  • the active ingredient which can be used in the method of the present invention is pemetrexed or a pharmaceutically acceptable salt thereof and the like.
  • the active ingredient is pemetrexed disodium salt.
  • the anti-oxidant-free drug injection solution prepared according to the method of the present invention has good long-term stability.
  • the method of the present invention allows for the processing of larger batches at a time due to the use of equipment such as temperature controlled vacuum chambers. Moreover, compared with the use of nitrogen glove bag production line filling, there is no need to set up a dedicated production line using nitrogen isolation line equipment, and the cost is also low, so it is suitable for mass production.
  • Fig. 1 is a graph showing a boiling point-pressure relationship obtained in Example 1 according to the present invention.
  • the inventor of the present invention found that as long as the pressure of the head space gas in the container containing the drug solution or the oxygen partial pressure of the head space gas is lowered before the high temperature sterilization step after the filling process, the oxygen content of the drug solution in the container will be It is then lowered, and the elevated temperature can also reduce the oxygen content of the drug solution.
  • Such a low dissolved oxygen drug solution eliminates the need to add an antioxidant to the drug composition, thereby obtaining a stable drug solution, thereby avoiding possible degradation products using antioxidants and any oxidative degradation from the antioxidant itself. product.
  • the gas pressure in the head space in the container containing the drug injection solution is lowered to an appropriate pressure at an appropriate temperature by an appropriate device, or the drug injection solution is frozen first and then the top of the container is lowered.
  • the gas pressure in the space is filled with the inert gas to the head space in the container as needed, and the steps of depressurizing and filling the inert gas are repeated twice or more as needed, preferably three times or more.
  • the oxygen content in the solution can be reduced to a certain level without previously reducing the oxygen content in the drug solution during the preparation of the drug solution and the filling process.
  • the low oxygen content of the drug liquid in the container can be maintained, thereby increasing the long-term stability of the drug.
  • any container made of a material suitable for formulating a pharmaceutical injection solution can be used in the method of the present invention, such as a container made of glass, stainless steel, plastic, or the like.
  • the pressure reducing device which can be used in the present invention includes a pressure reducing device which can be depressurized to a specific pressure, such as a vacuum box. It is preferably provided with a pressure reducing device capable of controlling the temperature, such as a temperature controlled vacuum box. Commercially available freeze dryers are also a convenient choice when refrigeration is required.
  • the control temperature for performing the depressurization step can be selected according to various factors such as the nature of the injection solution medium, the specifications of the decompression device, and the process requirements. For example, when the injectable medium used is less volatile, such as water for injection, or does not contain volatile excipients, the control temperature can be set to a higher temperature, such as 60 ° C, such that the injection solution itself contains The amount of oxygen is low because of the high temperature, and it does not need to be lowered to a too low pressure when the pressure is reduced, and is usually reduced to about 360 Torr, which is not too demanding for the device specifications.
  • the control temperature should be set at a low temperature, such as 25 ° C, or lower, and even the injection solution can be frozen to avoid the volatile excipients in the injection solution. Pressing and escaping, and then performing the depressurization step, the purpose of reducing the oxygen partial pressure in the head space of the container, thereby reducing the oxygen content of the injection solution.
  • the extent to which the headspace reduces pressure is dependent on the controlled temperature at which the depressurization step is performed. Since the purpose of decompression is to reduce the oxygen partial pressure (gas pressure) in the head space of the container but not to affect the concentration of the drug in the injection solution, the injection solution cannot be boiled at the control temperature when the pressure is reduced at the controlled temperature to avoid the injection solution. Volatilized by decompression.
  • a feature of the method of the invention is to reduce the gas pressure in the headspace of the vessel to a pressure slightly above the boiling of the injection solution at the controlled temperature.
  • the controlled temperature can also be referred to as the boiling point of the injectable solution.
  • a boiling point (control temperature)-pressure analysis can be performed prior to performing the preparation process of the present invention. That is, after the injection solution is prepared in a suitable container, the headspace of the container is depressurized at a different controlled temperature by a pressure reducing device until the injection solution boils, and the container is observed and recorded as the container is boiled at the controlled temperature. The pressure in the head space. Based on the obtained boiling point-pressure data, a boiling point-pressure curve can be obtained, such as Figure 1. Thereafter, the target value of the pressure reduction in the method of the present invention can be set based on the obtained boiling point-pressure curve.
  • reducing the gas pressure in the head space of the injection container can achieve the purpose of reducing the oxygen partial pressure.
  • the present invention In order to reduce the oxygen content in the injection solution as much as possible, the pressure target value when the head space is depressurized should be closer to the boiling pressure of the injection solution at the control temperature. Therefore, the target value of the pressure reduction is preferably slightly higher. The pressure at which the injection solution boils at the controlled temperature.
  • the reduced pressure step has a controlled temperature of 25 ° C and the headspace gas pressure is reduced to 100 Torr. In another embodiment of the invention, the reduced pressure step has a controlled temperature of 40 ° C and the headspace gas pressure is reduced to 200 Torr. In another embodiment of the invention, the reduced pressure step has a controlled temperature of 60 ° C and the headspace gas pressure is reduced to 360 Torr.
  • the container After the pressure reduction, the container can be sealed to obtain a hypoxic injection solution.
  • the step of filling the head space of the container with an inert gas may be performed after performing the depressurization step and before sealing, thereby diluting the proportion of oxygen in the head space gas and maintaining the head space pressure.
  • the risk of external gas infiltration or container rupture due to low internal pressure inside the container can be avoided.
  • the pressure-reducing and filling of the inert gas may be repeated twice or more as needed, preferably three or more times. It can also be directly plugged to maintain negative pressure after the last step of depressurization. Maintaining a negative pressure lowers the dissolved oxygen in the solution at the same partial pressure of oxygen.
  • the control temperature of the depressurization step can be set below the freezing point of the injection solution, and the injection solution is frozen and then subjected to a depressurization step, so that the target gas pressure reduction target value of the container head space is independent of the control temperature, without Worried about the problem of low pressure boiling of the injection solution, the headspace gas pressure can be reduced as much as possible, even close to the vacuum.
  • the headspace gas pressure can be reduced to between 80 Torr and 0.02 Torr, preferably between 80 Torr and 0.5 Torr. More preferably, it is between 0.5 Torr and 0.1 Torr to sufficiently reduce the oxygen partial pressure.
  • the depressurization step can be performed using a temperature-controlled vacuum chamber having a freezing function, so that freezing and decompression can be performed simultaneously without an additional freezing device.
  • the freezing temperature of the injection solution is controlled at -10 ° C or below, for example, about -10 ° C, about -15 ° C, and most preferably at about -10 ° C.
  • the method of the invention is suitable for the preparation of any pharmaceutical injection solution, especially where the active ingredient is unstable to oxygen in an injection solution, such as pemetrexed or a pharmaceutically acceptable salt thereof.
  • pemetrexed or a pharmaceutically acceptable salt thereof includes alkali metal salts, alkaline earth metal salts, ammonium salts and substituted ammonium salts such as sodium, potassium, lithium, calcium, magnesium. Salts, aluminum salts, zinc salts, ammonium salts, trimethylammonium salts, triethylammonium salts, monoethanolammonium salts, triethanolammonium salts, pyridinium salts, substituted pyridinium salts, and the like. Preferred is pemetrexed disodium salt.
  • the injectable medium of the present invention includes any aqueous or non-aqueous solvent suitable for the preparation of a medicament, such as for injection.
  • aqueous or non-aqueous solvent suitable for the preparation of a medicament, such as for injection.
  • Water, water for injection and alcohol-containing aqueous alcohols such as ethanol, propylene glycol, glycerin, oils, polysorbates, and the like.
  • Excipients which can be used in the present invention include diluents such as mannitol, lactose, osmotic regulators such as sodium chloride, lactic acid, glucose, and pH control agents such as sodium hydroxide, hydrochloric acid, and other injectable solutions. Excipients used, such as preservatives, ethylenediaminetetraacetic acid, sodium benzoate, and the like.
  • the drug injection solution prepared according to the method of the present invention can be sterilized by a conventional method such as a film sterilization method and/or a high pressure heat sterilization method.
  • the drug solution in the following examples is prepared by dissolving 25 mg/mL of pemetrexed or a pharmaceutically acceptable salt thereof and at least one excipient selected from the group consisting of sodium chloride, mannitol and a pH controlling agent. It is prepared by using water for injection, and the water for injection does not need to go through the oxygen removal step.
  • the membrane electrode method JENCO 9173R was used to measure the dissolved oxygen concentration in the mother liquor, and the instrument was subjected to full-point calibration (the saturated aqueous solution corrected by the full-point calibration was confirmed by iodometry) and the zero point was confirmed before use.
  • the device has a pressure display function at different temperatures, and the headspace of a suitable transparent glass container containing 4 mL of the drug solution is continuously lowered at a controlled temperature of 25 ° C, 40 ° C, and 60 ° C until the boiling of the drug solution, and the time is observed and recorded.
  • the gas pressure in the headspace ie the boiling point pressure
  • Table 1 The measured boiling point pressure results are shown in Table 1:
  • the control temperature is plotted against the boiling point pressure to obtain the boiling point-pressure relationship diagram of Figure 1.
  • the dissolved oxygen amount analysis after the step of depressurizing was carried out in a suitable transparent glass vessel containing 4 mL of the drug solution.
  • the boiling point-pressure relationship diagram obtained in Example 1 sets the target value of the headspace depressurization step: after reducing the pressure to about 100 Torr, about 200 Torr, and about 360 Torr at 25 ° C, 40 ° C, and 60 ° C, respectively.
  • the rubber stopper plugs the container and removes the seal.
  • the autoclave was autoclaved at 121 ° C for 15 minutes in a sterilizer.
  • Example 3 Analysis of dissolved oxygen content of a sample prepared by a freeze-pressure step
  • Example 4 The samples obtained in Example 4 were placed under different storage conditions, and the storage conditions were 5 ° C, 25 ° C and 60 ° C, respectively, and the storage time was 4 weeks or 3 days, respectively, and were stored in the dark.
  • the content of the active ingredient before and after storage and the impurities were analyzed using an HPLC system using the Pemetrexed analysis method described in the European Pharmacopoeia.
  • the results of the content analysis are shown in Table 5, and the results of the impurity analysis are shown in Table 6.
  • the results show that repeated buck-filled nitrogen (to 0.1 Torr) has better stability.
  • Example 4 In the same manner as in Example 4, two steps of depressurization-nitrogenation (to 100 Torr) were applied, and the cap was removed.
  • the autoclave was autoclaved at 121 ° C for 15 minutes in a sterilizer.
  • the products were filled with 4 mL and 20 mL, respectively, and the production batches were 1000 needles each.
  • the stability at 1, 2, 3 and 6 months was observed at 5 ° C and 25 ° C in the dark.
  • the results of the impurity analysis are shown in Tables 7 to 8.
  • a nitrogen filling needle is used for conventional nitrogen filling, plugging, and taking out the cap.
  • the wet heat sterilization was carried out in a sterilizer at 121 ° C for 15 minutes.
  • the products were filled with 4 mL and 20 mL, respectively, and the production batches were 1000 needles each.
  • the stability at 1, 2, 3 and 6 months was observed under light-proof storage conditions at 5 °C.
  • the results of the impurity analysis are shown in Table 9.
  • Example 8 Analysis of dissolved oxygen content of samples produced by different steps of nitrogen reduction and nitrogen reduction
  • Example 8 The sample obtained in Example 8 was placed under different storage conditions, 25 ° C and 60 ° C, and the storage time was 4 weeks, 3 days or 7 days, respectively, and stored in the dark.
  • the active ingredients and impurities before and after storage were analyzed using a HPLC system using the Pemetrexed assay described in the European Pharmacopoeia.
  • the results of the impurity analysis are shown in Table 11. The results showed that repeated two-step-nitrogen-depressurization (to 50 Torr) had excellent stability.
  • the headspace of a suitable transparent glass container containing 4 mL and 20 mL of the drug solution was respectively reduced to a pressure of about 50 Torr at 20 ° C, and the headspace of the container was backfilled to 760 Torr with nitrogen, and then separately pressure-reduced to 50 Torr, directly plugged, remove the cover.
  • the autoclave was autoclaved at 121 ° C for 15 minutes in a sterilizer.
  • the products were filled with 4 mL and 20 mL, respectively, and the production batches were 3000 and 1000 needles, respectively.
  • the stability of the first, second, and third months was observed under light-proof storage conditions at 5 °C.
  • the results of the impurity analysis are shown in Table 12.
  • the stability of the first, second, and third months was observed under low light storage conditions at 25 °C.
  • the results of the impurity analysis are shown in Table 13.
  • Example 11 Analysis of dissolved oxygen content of samples produced by different steps of nitrogen reduction and nitrogen reduction
  • Example 12 Stability analysis of different dissolved oxygen samples prepared by different step-down nitrogen filling cycles
  • Example 8 The sample obtained in Example 8 was placed under different storage conditions, 25 ° C and 60 ° C, and the storage time was 4 weeks, 3 days or 7 days, respectively, and stored in the dark.
  • the impurities before and after storage were analyzed using an HPLC system using the Pemetrexed analysis method described in the European Pharmacopoeia. The results of the impurity analysis are shown in Table 15.

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Abstract

一种制备不含抗氧化剂的药物注射溶液的方法，该方法包括下列步骤：（a）在一容器中将活性成分和药学上可接受赋形剂溶解于注射用介质以制备注射溶液；（b）将该含有注射溶液的容器置于一减压装置内，于控制温度下进行减压，其中当控制温度高于注射溶液的凝固点，使该容器内顶部空间气体压力降低至低于大气压力并高于注射溶液于该控制温度下沸腾的压力间，或者当控制温度低于注射溶液的凝固点，使该容器内部顶部空间气体压力降低至低于大气压力，以及（c）密封该容器。

Description

具有长期稳定性的不含抗氧化剂的药物注射溶液的制备方法 技术领域
本发明涉及制备注射溶液，尤其是不含抗氧化剂的药物注射溶液的方法。
背景技术
对于在水溶液中不稳定的药物成分，例如培美曲塞(pemetrexed)或其药学上可接受盐(例如二钠盐)，通常可将其制备成冻干粉剂以供长期稳定保存，在使用前才以注射介质如生理盐水复原成注射溶液后，再投给病人。
培美曲塞(pemetrexed)是一种抗叶酸类抗肿瘤药，化学名称为：N-[4-[2-(2-氨基-4，7-二氢-4-氧代-1H-吡咯[2，3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸。目前市售培美曲塞的产品是冻干粉剂，使用方式为将冻干粉剂以生理盐水复原后，再给患者施用。冻干粉剂于临床上施用时，必须有使用生理盐水的复原步骤，造成医护人员不便以及增加微生物污染的风险。另外，制备冻干制剂的工艺较为复杂，又需要特殊设备，制造成本较大，而且耗时较久，污染的风险也随之增加，故最好是无需冻干技术即可制得稳定的制剂。对于用户而言，以即用型产品，例如培美曲塞的注射水溶液，供临床直接使用是较为理想的形式。然而培美曲塞在水溶液中较不稳定，容易产生各种降解产物。
WO 01/56575 A1公开了一种适合肠胃外给药的液体制剂，其包括培美曲塞、赋形剂和至少一种选自硫代甘油、L-半胱氨酸和乙硫醇酸的抗氧化剂，然而其长期安定性并不理想。WO 2012/015810 A2公开了一种含培美曲塞的可长期贮存稳定的液体医药组合物，其包括培美曲塞或其盐类、抗氧化剂例如硫辛酸、二氢硫辛酸、甲硫胺酸或其混合物，螯合剂例如乳糖酸、柠檬酸三钠或其混合物，以及药学上可接受的液体，具有在5℃到25℃保存至少18个月的长期安定性。虽然抗氧化剂的使用有助于长期安定性，但可能造成不明的降解产物或由抗氧化剂本身衍生出来的氧化降解产物。
WO2012/121523 A2公开了一种不含抗氧化剂的培美曲塞注射溶液及其制备方法，该制备方法包括：(a)将含有培美曲塞或其盐的注射溶液中的溶氧浓度控制在1ppm或更小；以及(b)在氧分压为0.2％v/v或更小的封闭系统中，用步骤(a)得到的溶液填充用于注射的容器。根据其公开内容，将注射溶液中溶氧量实质除去，也就是减少到1ppm或以下时，不需使用抗氧化剂之类的稳定剂即可制备含培美曲塞的稳定液体制剂。该方法使用各种已知的除气工艺，包括真空除气、蒸馏除气、通氮气除气、薄膜除气及催化剂 -树脂除气等，也可使用前述方法的组合，使溶氧浓度降低至1ppm或以下。然而，要达到实质除去注射溶液中的溶氧量，可能需要执行不同除气工艺的组合，而且可能要执行不只一次的除气工艺。例如，实施例中使用蒸馏除气法与真空除气法制备用于注射的溶液，然而此法除了在调液之前须将制备用水在氮气中蒸馏及冷却，或使用真空排气装置减少制备用水中的溶氧量外，在充填过程中还需使用手套袋以人工充填上塞，显然在批量制造时会有所不便。
因此，仍需要适用于大量生产高稳定性注射用液体制剂，尤其是含培美曲塞或其药学上可接受盐的高稳定性注射溶液的方法。
发明内容
本案发明人进行多项研究与试验，发现在不使用稳定剂如抗氧化剂情形下，只要使溶液中溶氧量降低至一定程度时(大约2ppm或以下)就可以制备出稳定的注射用液体制剂，进而开发出一种制备不含抗氧化剂的药物注射溶液的方法。相较于现有技术，本发明方法工序较为单纯，且更适合大量生产。
据此，本发明提供一种制备不含抗氧化剂的药物注射溶液的方法，该方法包括下列步骤：
(a)在一容器中将活性成分和药学上可接受赋形剂溶解于注射用介质以制备注射溶液，
(b)将该含有注射溶液的容器置于一减压装置内，于控制温度下进行减压，其中当控制温度高于注射溶液的凝固点，使该容器内顶部空间气体压力降低至低于大气压力并高于注射溶液于该控制温度下沸腾的压力间，或者当控制温度低于注射溶液的凝固点，使该容器内顶部空间气体压力降低至低于大气压力，以及
(c)密封该容器。
在一个较佳具体实例中，上述步骤(b)中当控制温度高于注射溶液的凝固点，使容器内顶部空间气体压力降低至略高于注射溶液于该控制温度下沸腾的压力。
在一个较佳具体实例中，上述步骤(a)中注射用介质为注射用水。
在一个较佳具体实例中，上述步骤(b)中的控制温度为60℃，容器内顶部空间气体压力降低至约360托；或者控制温度为40℃，容器内顶部空间气体压力降低至约200托；或者控制温度为25℃，容器内顶部空间气体压力降低至约100托。
在一个较佳具体实例中，所述步骤(b)中的控制温度可低于注射溶液的凝固点，例如 -10℃或以下，以使注射溶液冷冻为固体，如此容器内顶部空间气体压力降低与注射溶液沸腾的压力无关。当注射溶液被冷冻时，容器内顶部空间气体压力可降低至接近真空，例如约80托至约0.02托之间，约80托至0.5托之间，或约0.5托至0.1托之间。
在一个较佳具体实例中，所述步骤(b)中的控制温度为-10℃，容器内顶部空间气体压力降低至0.1托。
在一个较佳具体实例中，可在上述步骤(b)之后且在步骤(c)之前增加一个将惰性气体充填至该容器内顶部空间的步骤(i)，视需要，步骤(b)和(i)可重复操作二次或以上。
在一个较佳具体实例中，所述减压装置为控温真空箱。
在一个较佳具体实例中，可用于本发明方法的活性成分为培美曲塞或其药学上可接受盐等。
在一个较佳具体实例中，所述活性成分为培美曲塞二钠盐。
根据本发明方法所制备的不含抗氧化剂的药物注射溶液具有良好的长期稳定性。本发明方法由于使用如控温真空箱此类设备，可以一次处理较大量的批次。而且，与使用氮气手套袋产线充填相较，不需设立一条使用氮气隔离产线设备的专属产线，成本也较低，故而适用于大量生产。
附图说明
图1为根据本发明实施例1所得到的沸点-压力关系图。
具体实施方式
根据亨利定律，要降低某一特定气体在液体中溶解度的方法有三种：(1)降低此气体的分压；(2)降低总体气体压力；及(3)升高液体温度。因此为降低注射用液体制剂的溶氧量，可在工艺中降低氧气分压或容器内气体压力或加热液体。
本案发明人发现，只要在充填工艺后，高温灭菌步骤前，降低含药物溶液的容器内顶部空间气体的压力或是顶部空间气体的氧气分压，该容器中的药物溶液含氧量即会随之降低，另外升高温度也可降低药物溶液的含氧量。而这样低溶氧量的药物溶液就无需再添加抗氧化剂于药物组成中，即可得到稳定的药物溶液，从而能够避免产生使用抗氧化剂带来可能的降解产物和来自抗氧化剂本身的任何氧化降解产物。
因此，在一般充填工艺之后，以适当设备在适当温度下降低含有药物注射溶液的容器内顶部空间的气体压力至适当压力，或者先将药物注射溶液冷冻后再降低容器内顶部 空间的气体压力，视需要再以惰性气体充填容器内顶部空间，并视需要重复操作降压和充填惰气的步骤两次或以上，最佳为三次或以上。如此一来，溶液中的含氧量就可以降至一定含量，而不需要在制备药物溶液及充填过程中预先降低药物溶液中的含氧气量。另外，只要在此环境中将容器密封，即可保持容器中药物液体的低含氧状态，进而增加药物的长期安定性。
就本发明目的而言，以适用于调配药物注射溶液的材料所制成的任何容器皆可用于本发明方法中，例如玻璃、不锈钢、塑料等制备的容器。
可用于本发明的减压装置包括可减压至特定压力的减压装置，例如真空箱。较佳为具备可控制温度功能的减压装置，例如控温真空箱。在需要冷冻时，市售的冷冻干燥机亦为方便的选择。
进行减压步骤的控制温度可依注射溶液介质性质、减压装置规格、工艺需要等各种因素做选择。举例而言，当使用的注射用介质挥发性较低，例如为注射用水，或不含挥发性赋形剂时，可将控制温度设定在较高温，例如60℃，如此注射溶液本身的含氧量即因为温度较高而较低，而且在进行减压时，也不需降低至太低的压力，通常降低至约360托即可，则对于装置规格无需过于苛求。当注射溶液中含有挥发性赋形剂，例如醇类时，控制温度宜设定在低温，例如25℃，或者更低，甚至可将注射溶液冷冻，避免注射溶液中挥发性赋形剂因为减压而脱逸出，再进行减压步骤，达到降低容器顶部空间氧分压，进而降低注射溶液含氧量的目的。
根据本发明，顶部空间降低压力的程度是取决于进行减压步骤的控制温度。由于减压目的在于降低容器顶部空间的氧分压(气体压力)但不能影响注射溶液中药物的浓度，故而在控制温度下进行减压时，不能让注射溶液于控制温度下沸腾，以免注射溶液因减压而挥发。因此，本发明方法的一个特征在于使容器顶部空间气体压力降低至略高于注射溶液于控制温度下沸腾的压力。换言之，就本发明而言，该控制温度亦可谓为注射溶液的沸点。
为了确保适当的降压，可在执行本发明制备方法之前先进行沸点(控制温度)-压力分析。亦即，在适当的容器中制备好注射溶液之后，以减压装置在不同的控制温度下进行容器顶部空间降压，直到注射溶液沸腾，观察并记录注射溶液于该控制温度下沸腾时，容器顶部空间的压力。根据所得到的沸点-压力数据，可得到沸点-压力曲线，例如图1。之后，即可根据所得沸点-压力曲线设定本发明方法中降压的目标值。
基本上，将注射容器顶部空间气体压力降低即可达到降低氧分压目的。就本发明目 的而言，为使注射溶液中含氧量尽可能减少，顶部空间降压时的压力目标值应愈接近注射溶液于控制温度下沸腾的压力，因此，降压目标值最好是到略高于注射溶液于该控制温度下沸腾的压力。
在本发明的一个具体实例中，减压步骤的控制温度为25℃，顶部空间气体压力降低至100托。在本发明的另一个具体实例中，减压步骤的控制温度为40℃，顶部空间气体压力降低至200托。在本发明的另一个具体实例中，减压步骤的控制温度为60℃，顶部空间气体压力降低至360托。
降压之后即可将容器密封，得到含低氧量的注射溶液。为了达到更好的降低氧分压效果，也可在执行减压步骤之后、密封之前，进行以惰性气体充填容器顶部空间的步骤，藉此稀释顶部空间气体中的氧气比例并维持顶部空间压力，可避免因容器内部低压而有外部气体渗入或容器破裂的风险。视需要，可重复降压和充填惰性气体二次或以上，最佳为重复三次或以上。亦可在最后一次降压后，直接上塞维持负压。维持负压可在相同的氧气分压下将溶液中溶氧降得更低，虽有些许风险，但对产品稳定性效果更佳。基本上，为帮助降低注射溶液内溶氧量及长期稳定性，可重复降压和充填惰性气体多次，但仍应考虑到制造成本及欲达到的目的来决定重复次数。
以大量生产而言，可将减压步骤的控制温度设定至注射溶液凝固点以下，将注射溶液冷冻后再进行减压步骤，如此容器顶部空间气体压力降低目标值便与控制温度无关，而无需担心注射溶液于低压沸腾的问题，便可尽量将顶部空间气体压力降低，甚至接近真空，例如可将顶部空间气体压力降低至80托至0.02托之间，较佳80托至0.5托之间，更佳0.5托至0.1托之间，以使氧分压充分降低。就此实施方式而言，可使用具有冷冻功能的控温真空箱进行减压步骤，如此可同步进行冷冻与减压，而无需另外的冷冻装置。
在本发明的一个具体实例中，注射溶液冷冻温度控制在-10℃或以下，例如约-10℃、约-15℃，最佳是控制在约-10℃。
本发明方法适用于制备任何药物注射溶液，尤其是活性成分在注射溶液中对氧气不稳定者，例如培美曲塞或其药学上可接受盐。
当用于本文，“培美曲塞或其药学上可接受盐”一词包括碱金属盐、碱土金属盐、铵盐及取代铵盐，例如钠盐、钾盐、锂盐、钙盐、镁盐、铝盐、锌盐、铵盐、三甲基铵盐、三乙基铵盐、单乙醇铵盐、三乙醇铵盐、吡锭盐、取代吡锭盐及诸如此类。较佳为培美曲塞二钠盐。
本发明的注射用介质包括任何适用于制备药物的水性或非水性溶剂，例如注射用 水，注射用水与醇类如乙醇、丙二醇、甘油的含醇水溶液，油类，聚山梨醇酯等。
可用于本发明的赋形剂包括稀释剂，例如甘露醇、乳糖，渗透压调节剂，例如氯化钠、乳酸、葡萄糖，以及pH控制剂，例如氢氧化钠、盐酸，以及其它注射溶液中惯常使用的赋形剂，例如保存剂，乙二胺四乙酸、苯甲酸钠等。
根据本发明方法所制备的药物注射溶液可使用传统的方法，例如薄膜器灭菌法及/或高压热灭菌法等，予以灭菌。
为了进一步阐述本发明，下面给出一系列实施例。这些实施例完全是范例性的，它们仅用来对本发明进行更具体描述，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换应视为落入本发明的保护范围内。
实施例
以下实施例中的药物溶液皆为将25mg/mL的培美曲塞或其药学上可接受盐和至少一种选自由氯化钠、甘露醇和pH控制剂所组成群组的赋形剂溶于注射用水配制而成，注射用水无需经过除氧步骤。
在以下的实施例中使用薄膜电极法(JENCO 9173R)来测量用于母液中的溶氧浓度，仪器使用前均经过满点校正(满点校正的饱和水溶液经过碘量法确认)与零点确认。
实施例1沸点-压力分析
在不同温度下以具有压力显示功能的设备，将含有4mL药物溶液的适当透明玻璃容器的顶部空间分别于25℃、40℃、60℃控制温度持续降低压力至药物溶液沸腾，观察并记录此时顶部空间的气体压力(即沸点压力)，重复三次。所测量的沸点压力结果如表1所示：
表1.沸点压力实测值
Figure PCTCN2015094985-appb-000001
将控制温度对沸点压力作图，得到图1的沸点-压力关系图。
实施例2在不同温度下降压步骤制备的样品溶氧量分析
以含有4mL药物溶液的适当透明玻璃容器进行降压步骤后的溶氧量分析。根据实 施例1所得到的沸点-压力关系图，设定顶部空间降压步骤的目标值：在25℃、40℃及60℃分别降低压力至约100托、约200托及约360托后，用橡皮塞塞住容器，取出密封。以121℃、15分钟条件以灭菌釜进行高温蒸气灭菌。灭菌后在室温下以欧洲药典记载的培美曲塞分析方法使用HPLC系统分析贮存前后药物溶液的不纯物，并以电极测量各样品药物溶液的溶氧量。结果如表2所示。
表2.不同降压步骤所对应药物溶液的不纯物与溶氧量
Figure PCTCN2015094985-appb-000002
实施例3以冷冻降压步骤制备的样品溶氧量分析
在-10℃冷冻状态下，将含有4mL药物溶液的适当透明玻璃容器顶部空间分别降低压力至约0.1托、0.5托及80托后，用橡皮塞塞住容器，取出封盖，回复室温。以121℃、15分钟条件以灭菌釜进行高温蒸气灭菌。灭菌后在室温下以欧洲药典记载的培美曲塞分析方法使用HPLC系统分析贮存前后药物溶液的不纯物，并以电极测各样品药物溶液的溶氧量。测量的结果如表3所示。
表3、不同降压步骤所对应的药物溶液不纯物与溶氧量
Figure PCTCN2015094985-appb-000003
实施例4以不同降压-充氮循环步骤制备不同溶氧量的样品
在25℃下，将含有4mL药物溶液的适当透明玻璃容器顶部空间分别降低压力至约380托、100托，再以氮气回填容器顶部空间至760托后，用橡皮塞塞住容器，取出封盖。另外制备一样品为降压至100托，回填氮气至760托，再重复操作一次，共两次降压-充氮循环，上塞，取出封盖。以121℃、15分钟条件以灭菌釜进行高温蒸气灭菌。 灭菌后在室温下以电极测各样品药物溶液的溶氧量。结果如表4所示。
表4.不同降压充氮步骤所对应药物溶液的溶氧量
Figure PCTCN2015094985-appb-000004
实施例5以不同降压充氮循环步骤所制备的不同溶氧量样品安定性分析
以实施例4所得的样品放置在不同贮存条件下，贮存条件分别是5℃、25℃与60℃，贮存时间分别为4周或3天，均为避光贮存。以欧洲药典记载的培美曲塞分析方法使用HPLC系统分析贮存前后活性成分的含量与不纯物。含量分析结果如表5所示，不纯物分析结果如表6所示。结果显示，重复两次降压-充氮(至0.1托)有较佳的安定性。
表5.不同降压充氮步骤所制备注射溶液中的培美曲塞含量变化
Figure PCTCN2015094985-appb-000005
表6.不同降压充氮步骤所制备的样品安定性(不纯物)
Figure PCTCN2015094985-appb-000006
实施例6以此降压充氮步骤所生产的量产批次样品安定性分析
以实施例4的方法，两次降压-充氮循环(至100托)，上塞，取出封盖。以121℃、15分钟条件以灭菌釜进行高温蒸气灭菌。分别制造充填4mL与20mL的产品，生产批量各1000针。在5℃与25℃避光贮存条件下观察第1、2、3及6个月的安定性。不纯物分析结果如表7至表8。
表7. 5℃避光贮存条件下量产批次样品安定性(不纯物)
Figure PCTCN2015094985-appb-000007
Figure PCTCN2015094985-appb-000008
表8. 25℃避光贮存条件下量产批次样品安定性(不纯物)
Figure PCTCN2015094985-appb-000009
实施例7以常规充氮步骤所生产的量产批次样品安定性分析(对照)
以充填机在药物溶液充填过程中，使用氮气充填针进行常规充氮，上塞，取出封盖。以121℃、15分钟条件以灭菌釜进行湿热灭菌。分别制造充填4mL与20mL的产品，生产批量各1000针。在5℃避光贮存条件下观察第1、2、3及6个月的安定性。不纯物分析结果如表9。
表9.(对照组)5℃避光贮存条件下常规充氮量产批次样品安定性(不纯物)
Figure PCTCN2015094985-appb-000010
实施例8以不同降压充氮步骤所生产的样品溶氧量分析
在20℃下，将含有4mL药物溶液的适当透明玻璃容器顶部空间分别降低压力至约50托，以氮气回填容器顶部空间至760托后，再分别降压至50托，直接上塞，取出封盖。以121℃、15分钟条件以灭菌釜进行高温蒸气灭菌。灭菌后在室温下以电极测各样品药物溶液的溶氧量。结果如表10所示。
表10.不同降压充氮步骤所对应药物溶液的溶氧量
Figure PCTCN2015094985-appb-000011
实施例9以不同降压充氮循环步骤所制备的不同溶氧量样品安定性分析
以实施例8所得的样品放置在不同贮存条件下，25℃与60℃，贮存时间分别为4周、3天或7天，均为避光贮存。以欧洲药典记载的培美曲塞分析方法使用HPLC系统分析贮存前后活性成分与不纯物。不纯物分析结果如表11所示。结果显示，重复两次降压-充氮-降压(至50托)有优良的安定性。
表11.不同降压充氮步骤所制备的样品安定性(不纯物)
Figure PCTCN2015094985-appb-000012
实施例10以此降压充氮步骤所生产的量产批次样品安定性分析
以实施例8的方法，在20℃下，将含有4mL与20mL药物溶液的适当透明玻璃容器顶部空间分别降低压力至约50托，以氮气回填容器顶部空间至760托后，再分别降压至50托，直接上塞，取出封盖。以121℃、15分钟条件以灭菌釜进行高温蒸气灭菌。分别制造充填4mL与20mL的产品，生产批量分别为3000与1000针。在5℃避光贮存条件下观察第1、2、3月的安定性。不纯物分析结果如表12。在25℃避光贮存条件下观察第1、2、3月的安定性。不纯物分析结果如表13。
表12. 5℃避光贮存条件下量产批次样品安定性(不纯物)
Figure PCTCN2015094985-appb-000013
表13. 25℃避光贮存条件下量产批次样品安定性(不纯物)
Figure PCTCN2015094985-appb-000014
实施例11以不同降压充氮步骤所生产的样品溶氧量分析
在25℃下，将含有4mL药物溶液的适当透明玻璃容器顶部空间分别降低压力至约100托，以氮气回填容器顶部空间至760托后，再分别降压至100托，直接上塞，取出封盖。以121℃、15分钟条件以灭菌釜进行高温蒸气灭菌。灭菌后在室温下以电极测各样品药物溶液的溶氧量。结果如表14所示。
表14.不同降压充氮步骤所对应药物溶液的溶氧量
Figure PCTCN2015094985-appb-000015
实施例12以不同降压充氮循环步骤所制备的不同溶氧量样品安定性分析
以实施例8所得的样品放置在不同贮存条件下，25℃与60℃，贮存时间分别为4周、3天或7天，均为避光贮存。以欧洲药典记载的培美曲塞分析方法使用HPLC系统分析贮存前后之不纯物。不纯物分析结果如表15所示。
表15.不同降压充氮步骤所制备的样品安定性(不纯物)
Figure PCTCN2015094985-appb-000016
结果显示，重复降压-充氮-降压(至100托)有相同优良的安定性。

Claims (16)

  1. 一种制备不含抗氧化剂的药物注射溶液的方法，该方法包括下列步骤：
    (a)在一容器中将活性成分和药学上可接受赋形剂溶解于注射用介质以制备注射溶液，
    (b)将该含有注射溶液的容器置于一减压装置内，于控制温度下进行减压，其中当控制温度高于注射溶液的凝固点，使该容器内顶部空间气体压力降低至低于大气压力并高于注射溶液于该控制温度下沸腾的压力间，或者当控制温度低于注射溶液的凝固点，使该容器内顶部空间气体压力降低至低于大气压力，以及
    (c)密封该容器。
  2. 根据权利要求1所述的方法，其中步骤(b)中当控制温度高于注射溶液的凝固点，使容器内顶部空间气体压力降低至略高于注射溶液于该控制温度下沸腾的压力。
  3. 根据权利要求1所述的方法，其中步骤(a)中注射用介质为注射用水。
  4. 根据权利要求3所述的方法，其中步骤(b)中的控制温度为60℃，容器内顶部空间气体压力降低至约360托。
  5. 根据权利要求3所述的方法，其中步骤(b)中的控制温度为40℃，容器内顶部空间气体压力降低至约200托。
  6. 根据权利要求3所述的方法，其中步骤(b)中的控制温度为25℃，容器内顶部空间气体压力降低至约100托。
  7. 根据权利要求1所述的方法，其中步骤(b)中的控制温度低于注射溶液的凝固点。
  8. 根据权利要求7所述的方法，其中步骤(b)中使该容器内顶部空间气体压力降低至80托至0.02托之间。
  9. 根据权利要求7所述的方法，其中步骤(b)中使该容器内顶部空间气体压力降低至80托至0.5托之间。
  10. 根据权利要求7所述的方法，其中步骤(b)中使该容器内顶部空间气体压力降低至0.5托至0.1托之间。
  11. 根据权利要求7所述的方法，其中步骤(b)中的控制温度为-10℃，容器内顶部空间气体压力降低至0.1托。
  12. 根据权利要求1所述的方法，其中在步骤(b)之后且在步骤(c)之前增加一个将惰性气体充填至该容器内顶部空间的步骤(i)。
  13. 根据权利要求12所述的方法，其中步骤(b)和(i)重复操作二次或以上。
  14. 根据权利要求1所述的方法，其中所述减压装置为控温真空箱。
  15. 根据权利要求1所述的方法，其中所述活性成分为培美曲塞或其药学上可接受盐。
  16. 根据权利要求15所述的方法，其中所述活性成分为培美曲塞二钠盐。
PCT/CN2015/094985 2014-11-26 2015-11-19 具有长期稳定性的不含抗氧化剂的药物注射溶液的制备方法 WO2016082714A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103476397A (zh) * 2011-03-10 2013-12-25 健一制药株式会社 一种制备用于注射的含培美曲塞或其盐的无抗氧化剂溶液形式的药物制剂的方法
WO2014122460A2 (en) * 2013-02-06 2014-08-14 Cipla House Pemetrexed complexes and pharmaceutical compositions containing pemetrexed complexes
WO2014182093A1 (ko) * 2013-05-08 2014-11-13 씨제이헬스케어 주식회사 안정화된 페메트렉시드 제제
WO2015050230A1 (ja) * 2013-10-03 2015-04-09 富士フイルム株式会社 注射液製剤及びその製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103476397A (zh) * 2011-03-10 2013-12-25 健一制药株式会社 一种制备用于注射的含培美曲塞或其盐的无抗氧化剂溶液形式的药物制剂的方法
WO2014122460A2 (en) * 2013-02-06 2014-08-14 Cipla House Pemetrexed complexes and pharmaceutical compositions containing pemetrexed complexes
WO2014182093A1 (ko) * 2013-05-08 2014-11-13 씨제이헬스케어 주식회사 안정화된 페메트렉시드 제제
WO2015050230A1 (ja) * 2013-10-03 2015-04-09 富士フイルム株式会社 注射液製剤及びその製造方法

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