Injection capable of treating various cancer pains and postoperative pains and preparation method thereof

Abstract

The invention provides an injection capable of treating various cancerous pains and postoperative pains and a preparation method of the injection, and relates to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: filling nitrogen into water for injection at the temperature of 30-60 DEG C, sequentially adding sodium chloride, citric acid and sodium citrate according to a preparation amount, stirring to dissolve the sodium chloride, the citric acid and the sodium citrate, then adding butorphanol tartrate according to a preparation amount, and stirring until the butorphanol tartrate is completely dissolved for later use. According to the preparation method of the butorphinol tartrate injection provided by the invention, the technological parameters are accurately controlled, and the reference preparation prescription of the butorphinol tartrate injection does not need to be changed, so that the sterile guarantee level of the butorphinol tartrate injection can be improved, the increase of the impurity content can be effectively controlled, and the good stability of the butorphinol tartrate injection is ensured.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an injection solution that can treat various types of cancer pain and postoperative pain, and its preparation method. Background Technology

[0002] Butorphanol is an opioid μ-receptor partial agonist and κ-receptor full agonist. Its primary therapeutic effect is analgesia. Clinically, it is administered by titration to provide adequate analgesia, although the dosage may be limited by adverse reactions, including respiratory and central nervous system depression.

[0003] Butorphanol Tartrate Injection was originally developed by APOTHECONINC DIV BRISTOL MYERS SQUIBB and launched in the United States in 1978 under the brand name STADOL PRESERVATIVE FREE, with a strength of 1 ml: 1 mg. The FDA's Orange Book lists it as RLD, but it has since been withdrawn from the market. The Orange Book also lists BUTORPHANOL TARTRATE PRESERVATIVE, approved on January 23, 1997, by HOSPIRA INC, as RS, which is currently available.

[0004] As is well known, pain is a sensation caused by the transmission of information about the need for repair or regulation at the site of pain to the central nervous system. It is one of the main causes of suffering in cancer patients or postoperative patients. Among pain patients, 50% to 80% of pain is not effectively controlled for various reasons. Butorphanol tartrate's main function is analgesia. It has a strong ability to bind to opioid receptors, effectively relieving pain caused by various reasons, such as postoperative pain, traumatic pain, and cancer pain. Its analgesic effect is stronger than morphine. Simultaneously, it has sedative and hypnotic effects, allowing patients to rest and sleep while experiencing pain relief.

[0005] Currently, research on this injection is limited. From the perspective of clinical and market demand, there is an urgent need to develop an injection that can treat various cancer pains and postoperative pains, and it is widely administered clinically via injection. Summary of the Invention

[0006] This invention addresses the problems existing in the prior art by providing an injectable solution and its preparation method for treating various types of cancer pain and postoperative pain. The preparation process of this invention, by controlling the dissolved oxygen level, solution temperature, and feeding sequence, produces a formulation with low impurity content, good stability, and high safety.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: On the one hand, the present invention provides a preparation method for treating various cancer pains and postoperative pains, including the following steps: nitrogen gas is introduced into water for injection at 30℃-60℃, sodium chloride, citric acid and sodium citrate are added in sequence, the mixture is stirred to dissolve, butorphanol tartrate is added in the prepared amount, the volume is adjusted, and the mixture is stirred until completely dissolved and ready for use.

[0008] Furthermore, in the preparation step, the method for introducing nitrogen gas is as follows: nitrogen gas is introduced into the preparation tank containing water for injection.

[0009] Furthermore, in the preparation step, the water for injection purged with nitrogen accounts for 50%-95% of the total volume of the water for injection, and the remaining water for injection is used for volume adjustment.

[0010] Furthermore, in the preparation step, the temperature of the water for injection is 30℃-60℃.

[0011] Furthermore, in the preparation step, the pressure of the nitrogen gas introduced is 0.03MPa-0.30MPa, which is the nitrogen pressure in the liquid preparation tank.

[0012] Furthermore, in the preparation step, after the dissolved oxygen in the water for injection is ≤4.0 mg / L, the prepared amounts of sodium chloride, citric acid, and sodium citrate are added sequentially, and stirred until dissolved.

[0013] Furthermore, in the preparation step, after the sodium chloride, citric acid, and sodium citrate have completely dissolved, the prepared amount of butorphanol tartrate is added, the volume is adjusted, and the mixture is stirred until completely dissolved.

[0014] Furthermore, a filling step is set after the preparation step: nitrogen gas is filled in at a pressure of 0.03MPa-0.30MPa, which is the pressure shown on the pressure gauge.

[0015] The present invention introduces nitrogen gas during the filling and sealing process, which can significantly reduce the residual oxygen in the glass vial, prevent the oxidation of butorphanol tartrate and the generation of impurities, and further control the generation of impurities.

[0016] Furthermore, in the filling step, a 2ml borosilicate glass vial is used for injection.

[0017] Furthermore, a sterilization step is set after the filling and sealing step: the sterilization temperature is 121℃, and the sterilization time is 8-15 minutes.

[0018] On the other hand, the present invention provides an injection solution prepared by the above preparation method that can treat various cancer pains and postoperative pains.

[0019] Preferably, the concentration of butorphanol tartrate in the injection solution is 0.5 mg to 1 mg: 1 mL; more preferably, the concentration of butorphanol tartrate in the injection solution is 1 mg: 1 mL.

[0020] Preferably, the injection solution comprises, by weight, the following components: 8-20 parts butorphanol tartrate, 20-80 parts citric acid, 40-160 parts sodium citrate, 40-160 parts sodium chloride, and the remainder being water for injection.

[0021] More preferably, the injection solution, by weight, comprises: 8-15 parts butorphanol tartrate, 25-60 parts citric acid, 50-120 parts sodium citrate, 50-120 parts sodium chloride, and the remainder being water for injection.

[0022] More preferably, the injection solution comprises, by weight, the following components: 10 parts butorphanol tartrate, 50 parts citric acid, 100 parts sodium citrate, 100 parts sodium chloride, and the remainder being water for injection.

[0023] The preparation method of butorphanol tartrate injection provided by this invention has the following beneficial effects: 1. The preparation method of butorphanol tartrate injection provided by the present invention further avoids the generation of impurities by controlling the dissolved oxygen level in the preparation step, thereby preparing an injection with low impurity content and stable drug solution.

[0024] 2. The preparation method of butorphanol tartrate injection provided by the present invention avoids the growth of impurities in the injection caused by instantaneous pH changes by controlling the order of addition of butorphanol tartrate and other excipients, and also makes the product composition more uniform and more stable.

[0025] 3. The preparation method of butorphanol tartrate injection provided by the present invention controls the temperature of the water for injection in the preparation step to avoid degradation of butorphanol tartrate due to excessive temperature, thus ensuring the qualification of related substances in the drug solution. Detailed Implementation

[0026] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0027] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0028] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention are obtained through conventional commercial means. Example

[0029] An injectable solution for treating various types of cancer pain and postoperative pain, in the form of 2.5 mg difluprednisolone: ​​10 parts butorphanol tartrate, 50 parts citric acid, 100 parts sodium citrate, 90 parts sodium chloride, with the remainder of water for injection to be added to the required volume.

[0030] The preparation method of the injection solution used includes the following steps: ① Preparation: Introduce nitrogen gas into a mixing vessel containing 50%-95% water for injection at a pressure of 0.03 MPa-0.30 MPa, while maintaining the temperature of the water for injection at 30℃-60℃. Once the dissolved oxygen in the water for injection is ≤4.0 mg / L, add the prepared amounts of sodium chloride, citric acid, and sodium citrate sequentially, stirring until dissolved. Add the prepared amounts of butorphanol tartrate, and bring the volume up with the remaining water for injection, stirring until completely dissolved.

[0031] ③ Filling: Fill with nitrogen gas and fill into 2ml borosilicate glass vials for injection, controlling the volume to be 1.1-1.2ml, and the nitrogen pressure to be 0.03MPa-0.30MPa.

[0032] ④ Sterilization: Transfer the filled and sealed borosilicate glass vials to the sterilizer. The sterilization conditions are: 121℃, 8-15min.

[0033] Accelerated Conditioning Test The samples were placed under accelerated testing conditions of 40℃±2℃ and 75%RH±5%RH for 6 months, and the results were recorded at the end of 0, 3, and 6 months. The sampling and investigation results are shown in Table 1 below.

[0034] Table 1

[0035] The injection solution and preparation method described in Example 1 were used for preparation, but nitrogen gas was not introduced into the mixing tank, and all other steps were performed.

[0036] For Comparative Example 1 and Example 1, the relevant substances were detected at 0 time, 60℃ for 10 days and 60℃ for 30 days, respectively. The detection results are shown in Table 2.

[0037] Table 2

[0038] The experimental results above show that the increase of related substances is more significant in the unfilled sample than in the nitrogen-filled sample.

[0039] Comparative Example 2: Water for Injection Temperature Adjustment The injection solution and preparation method described in Example 1 were used for preparation. Compared to the preparation method of the injection solution in Example 2, the temperature of the water for injection was changed. The specific differences are as follows: Compared with Example 2.1, nitrogen gas was introduced into a preparation tank containing 50%-95% water for injection at a pressure of 0.03MPa-0.30MPa, while the temperature of the water for injection was maintained at 70°C. All other steps and parameters were the same as in Example 1.

[0040] Comparative Example 2.2: Nitrogen gas was introduced into a preparation tank containing 50%-95% water for injection at a pressure of 0.03MPa-0.30MPa, while the temperature of the water for injection was maintained at 80°C. All other steps and parameters were the same as in Example 1.

[0041] For the formulations of Comparative Example 2.1 and Comparative Example 2.2, the related substances were detected at 0 time, 60℃ for 10 days, and 60℃ for 30 days, respectively. The test results are shown in Table 3.

[0042] Table 3

[0043] The results above show that when the temperature of water for injection is 70℃ and 80℃, the impurity content increases, affecting the quality and stability of the product.

[0044] Comparative Example 3 Ingredient Order The injection solution and preparation method described in Example 1 were followed, except for the order of addition of citric acid and sodium citrate. Specifically, nitrogen gas was introduced into a mixing tank containing 50%-95% water for injection at a pressure of 0.03 MPa-0.30 MPa, while maintaining the temperature of the water for injection at 30℃-60℃. Once the dissolved oxygen in the water for injection was ≤4.0 mg / L, the prepared amounts of sodium chloride and butorphanol tartrate were added sequentially, and the mixture was stirred until dissolved. Then, the prepared amounts of citric acid and sodium citrate were added, and the mixture was brought to a final volume with the remaining water for injection, stirred until completely dissolved. The remaining steps and parameters were the same as in Example 1.

[0045] The related substances in Comparative Example 3 were detected at time 0, and the results compared with those in Example 1 are shown in Table 4. Table 4

[0046] As can be seen from Table 4, the order of feeding also has a certain impact on the relevant substances.

[0047] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing an injectable solution capable of treating various types of cancer pain and postoperative pain, characterized in that, It is composed of butorphanol tartrate, sodium chloride, citric acid, sodium citrate and water for injection. By weight, it includes the following components: 8-20 parts butorphanol tartrate, 20-80 parts citric acid, 40-160 parts sodium citrate, 40-160 parts sodium chloride, and the balance being water for injection. The preparation steps include: purging nitrogen gas into water for injection at 30℃-60℃ at a pressure of 0.03Mpa-0.30Mpa, ensuring the dissolved oxygen content of the added water for injection is ≤4.0mg / L; sequentially adding the prepared amounts of sodium chloride, citric acid, and sodium citrate, stirring until dissolved; then adding the prepared amounts of butorphanol tartrate; and finally adding water for injection to the final volume, stirring until completely dissolved. After filling and sealing, sterilization is performed, purging with nitrogen gas at a pressure of 0.03Mpa-0.30Mpa, and setting the sterilization parameters as follows: sterilization temperature of 121℃ and sterilization time of 8-15min, to obtain the injection solution.

2. The butorphanol tartrate injection prepared by the preparation method according to claim 1.

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