Butorphanol Tartrate Injection and Its Preparation Method

Abstract

The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a butorphanol tartrate injection and a preparation method thereof. Each milliliter of the butorphanol tartrate injection comprises: 2 mg of butorphanol tartrate, 0.18 - 2.2 mg of tartaric acid, 2.9 - 3.32 mg of sodium tartrate, 0.01 - 0.5 mg of antioxidant, 6.4 mg of sodium chloride and water for injection, and the pH is 3.0 - 5.0. The butorphanol tartrate injection prepared by the present invention solves the influence of light on the product quality through the synergistic effect of tartaric acid and a specific antioxidant, has good light stability, and at the same time avoids the influence of the leaching of metal ions in the brown glass bottle on the product quality during long-term storage of the product, significantly improves the stability of the product, and thus ensures the effectiveness and safety of the product.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a butorphanol tartrate injection and a preparation method thereof. Background Art

[0002] Butorphanol is a central analgesic drug first developed by Bristol-Myers Squibb Company. It is a mixed opioid receptor agonist-antagonist drug. Clinically, its tartrate salt is used mainly as a preoperative or preanesthetic medication and an adjuvant anesthetic medication for labor analgesia and severe pain that requires opioid analgesia or is ineffective with other treatments.

[0003] Butorphanol has the chemical name of (-)-17-cyclobutylmethyl-3,14-dihydroxymorphinan and has a typical morphinan structural nucleus. Butorphanol was first approved by the FDA for marketing in 1978 under the trade name Stadol and has two dosage forms: injection and nasal spray. The injection has two specifications: 1 mg / 1 ml and 4 mg / 2 ml. The chemical structural formula of butorphanol tartrate is shown as follows:

[0004]

[0005] Currently, the commercially available butorphanol tartrate injection prescription contains butorphanol tartrate, citric acid, sodium citrate, sodium chloride, and water for injection. CN116818928B discloses that two impurities (IB428 and IB429) have a significant increase during the storage process of the above prescription, and there is a risk of exceeding the identification limit. The applicant found in the research that butorphanol tartrate is sensitive to metal ions (especially sensitive to Fe 3+ sensitive), and will significantly degrade to produce oxidation impurities P0Z1 and P0Z6 under light and / or oxygen conditions, resulting in unstable quality of the product during long-term storage and clinical use, and the safety and effectiveness of clinical use cannot be guaranteed.

[0006]

[0007] In order to avoid the influence of light and oxidative degradation on the quality of the finished product during storage, the currently available butorphanol tartrate injections mostly use brown bottle packaging, but still cannot avoid the influence of light during clinical use. Moreover, brown bottles are usually prepared by adding metal oxides such as iron oxide to the material. Such packaging materials will leach out Fe 3+ when contacting with the product, causing degradation of the Fe 3+ sensitive drug, thus making the quality of the product unstable during long-term storage.

[0008] Example 1 of Patent RU2312662C1 discloses that the commercially available prescription drug prepared in a steel reactor does not meet the requirements in terms of "color and transparency" after being stored for half a year, and there is a significant increase in impurities. By adding ethylenediaminetetraacetic acid (EDTA), sodium dimercaptopropanesulfonate, glycerol, or mannitol as complexing agents to the prescription, the complexing substances help form stable complex water-soluble compounds with a large number of cations, making the corresponding cations undetectable, avoiding the destructive effect of trace heavy metals on butorphanol tartrate, and enabling the prepared solution obtained in the steel reactor to meet the quality standards. However, EDTA can combine with calcium ions to form soluble complexes, causing a decrease in calcium. In intravenous injection, the presence of EDTA in the preparation will lead to a decrease in the patient's blood calcium. Other metal complexing agents such as sodium dimercaptopropanesulfonate, although they do not complex with calcium ions and do not cause hypocalcemia, long-term use can cause a decrease in trace elements. At the same time, the chelating agents are expensive, resulting in an increase in production costs; and it still cannot solve the problem that the impurities generated by the degradation of butorphanol tartrate injection under light and oxidation exceed the limit.

[0009] In the 2020 edition of the Chinese Pharmacopoeia, it is stipulated that the single impurity in butorphanol tartrate injection shall not exceed 0.3%, the total impurity shall not exceed 1%, and the content of butorphanol tartrate shall be 90.0% - 110.0% of the labeled amount. Therefore, it is necessary to optimize the prescription of butorphanol tartrate injection to solve the above problems. Summary of the Invention

[0010] To overcome the above technical problems, the present invention provides a butorphanol tartrate injection and its preparation method, which can solve the problem that the related impurities generated by butorphanol tartrate under light exceed the standard, can be stored in colorless glass bottles, and reduce the impact of light degradation during clinical use. At the same time, it avoids the risk of unstable product quality during long-term storage caused by the leaching of metal ions in brown bottles; by passivating and pre-treating the stainless steel liquid preparation tank and pipeline in the preparation process, the influence of metal ions during the liquid preparation process is avoided, and finally the effectiveness and safety of the product are ensured.

[0011] The first aspect of the present invention provides a butorphanol tartrate injection, and each ml of the injection includes: 2 mg of butorphanol tartrate, 0.18 - 2.2 mg of tartaric acid, 2.9 - 3.32 mg of sodium tartrate, 0.01 - 0.5 mg of antioxidant, 6.4 mg of sodium chloride, and water for injection.

[0012] In some embodiments, the pH of the butorphanol tartrate injection is 3.0 - 5.0; preferably, the pH is 4.5.

[0013] In some embodiments, the antioxidant is selected from one or more of sodium bisulfite, sodium metabisulfite, cysteine, and thiourea.

[0014] In some preferred embodiments, the antioxidant is selected from thiourea.

[0015] In some preferred embodiments, the dosage of the antioxidant is 0.01 - 0.1 mg.

[0016] In some preferred embodiments, each milliliter of butorphanol tartrate injection is composed of the following components: 2 mg of butorphanol tartrate, 0.66 mg of tartaric acid, 3.32 mg of sodium tartrate, 0.1 mg of thiourea, 6.4 mg of sodium chloride and an appropriate amount of water for injection; the pH of the butorphanol tartrate injection is 4.5.

[0017] In some preferred embodiments, the contents of impurities P0Z1 and P0Z6 in the butorphanol tartrate injection are less than 0.02%; the total impurities are less than 1.0%.

[0018] On the other hand, the present invention provides a preparation method of butorphanol tartrate injection, and the preparation method includes:

[0019] Step 1), pretreatment: treating and rinsing a stainless - steel liquid - dispensing tank and stainless - steel pipelines with 0.001% low - concentration EDTA to remove metal impurities, and using water for injection to circulate for 0.5 - 2 hours for cleaning to remove residual EDTA and complexes;

[0020] Step 2), liquid - dispensing: measuring about 90% of the prescription amount of cooled and nitrogen - filled water for injection, adding the prescription amounts of tartaric acid, sodium tartrate, thiourea, and sodium chloride, stirring to dissolve, then adding the prescription amount of butorphanol tartrate, stirring until completely dissolved, and making up the volume to the prescription amount with water for injection;

[0021] Step 3), filling and sealing: filtering the obtained solution with a 0.22 - μm PES (polyethersulfone) filter membrane, and then filling and sealing with a corresponding - specification neutral - borosilicate glass ampoule (colorless), and filling nitrogen before and after filling;

[0022] Step 4), sterilization: performing sterilization treatment (121 °C, 15 min) after filling and sealing to obtain butorphanol tartrate injection.

[0023] In some preferred embodiments, the stirring time after adding butorphanol tartrate in step 2) is not less than 20 min.

[0024] In some preferred embodiments, the total time limit for liquid - dispensing and filling and sealing in step 2) and step 3) is controlled within 16 h.

[0025] The beneficial technical effects achieved by the present invention are as follows:

[0026] 1. In the existing formulation, the related substances increase rapidly under light. The applicant added an antioxidant to the formulation and determined thiourea as the preferred antioxidant through screening tests, which can significantly reduce the increase of impurities in butorphanol tartrate injection under light.

[0027] 2. The types and dosages of acids in the formulation were screened, and it was found that when tartaric acid and thiourea were used together, they could play a synergistic role to enhance the antioxidant effect of thiourea and further reduce the dosage of the antioxidant in the formulation.

[0028] 3. During the preparation process, EDTA was used to treat the stainless - steel liquid - dispensing tank and stainless - steel pipeline to remove the residues of trace metal impurities on the surface, avoid increasing the metal ion concentration in the liquid medicine, and improve the product stability.

[0029] 4. The butorphanol tartrate injection prepared by the present invention is stable under light, and the single impurity and total impurities meet the limits specified in the pharmacopoeia. Therefore, it can be packaged in colorless ampoules, thus avoiding the influence of metal ions brought by brown bottles, and the product has more stable storage and a longer shelf life. Detailed implementation mode

[0030] The following further describes the present invention in detail with reference to examples, but it is not a limitation of the present invention. Any equivalent substitution in the art made in accordance with the disclosed content of the present invention belongs to the protection scope of the present invention.

[0031] The raw materials and reagents used in the following examples can be obtained from conventional commercial channels or can be obtained by existing known methods without special instructions.

[0032] When preparing the following injection, unless otherwise stated, the total injection volume per batch of feeding is 1L, but the formulation and / or preparation process can be scaled up or down proportionally when described.

[0033] In the stress testing conditions described herein, the high - temperature testing condition is 60 ± 2°C, and the light testing condition is 4500lx ± 500lx.

[0034] Example 1. Preparation of butorphanol tartrate injection of the present invention

[0035] Prepare the sample of Example 1 according to the prescription dosage shown in Table 1 below. The preparation method is as follows:

[0036] 1) Pretreatment: Treat the stainless - steel liquid - dispensing tank and stainless - steel pipeline with 0.001% low - concentration EDTA to remove metal impurities, and use purified water for circulation for 0.5 - 2h for cleaning to remove the residual EDTA and complexes;

[0037] 2) Preparation of the liquid: Measure approximately 90% of the prescribed amount of cooled and nitrogen-filled water for injection, add the prescribed amounts of tartaric acid, sodium tartrate, thiourea, and sodium chloride, stir to dissolve, then add the prescribed amount of butorphanol tartrate raw material, stir for no less than 20 minutes until completely dissolved, and make up the volume to the prescribed amount with water for injection.

[0038] 3) Sealing: Filter the obtained solution through a 0.22 μm PES (polyethersulfone) membrane, and then use a corresponding specification of medium-borosilicate glass ampoules (colorless) for sealing. Nitrogen is filled before and after filling. The time limit for liquid preparation and sealing is controlled within 16 hours.

[0039] 4) Sterilization: After sealing, perform sterilization treatment (121 °C, 15 minutes) to obtain butorphanol tartrate injection.

[0040] Example 2. Prepare Examples 2 - 4 according to the prescription in Table 1 below, and the preparation method is the same as that of Example 1.

[0041] Table 1. Prescription dosages of Examples 1 - 4

[0042] Component Example 1 Example 2 Example 3 Example 4 Butorphanol Tartrate 200g 200g 200g 200g Tartaric Acid 220g 126g 66g 18g Sodium Tartrate 309g 290g 332g 311g Thiourea 10g 10g 10g 10g Sodium Chloride 640g 640g 640g 640g Water for Injection Make up to 100 L Make up to 100 L Make up to 100 L Make up to 100 L

[0043] The butorphanol tartrate injection prepared in Examples 1 - 4 of the present invention meets the requirements of the pharmacopoeia for single impurities and total impurities under high temperature and light conditions, and has good product quality stability.

[0044] Comparative Example 1. Commercial prescription: Butorphanol tartrate injection (Noyan), which is packaged in a brown vial. It can be directly purchased commercially or prepared by referring to paragraphs

[0064] -

[0073] of the specification of CN111904928A.

[0045] Comparative Example 2. The prescription and preparation method are the same as those of Comparative Example 1, but the packaging material is replaced with a colorless ampoule bottle.

[0046] Comparative Examples 3 - 4. According to the prescription described in Example 2 of Patent RU2312662C1, select the endpoint values of the EDTA numerical range described therein, and prepare Comparative Examples 3 and 4 by referring to the preparation method described in Example 1 thereof. The packaging material is a brown ampoule bottle.

[0047] Prescription for the preparation of butorphanol tartrate injection in Comparative Examples 1 - 4

[0048]

[0049] The beneficial effects of the present invention are illustrated below through test examples.

[0050] Test Example 1. Screening test for the type and dosage of antioxidants

[0051] Prepare Prescriptions 1 - 8 according to the following prescription:

[0052]

[0053] The preparation methods of Formulations 1 - 8 are the same as that of Example 1, except that the excipients and dosages are adjusted accordingly according to the above - mentioned formulations.

[0054] According to the stability test conditions specified in the Chinese Pharmacopoeia, the influencing factor investigation tests were carried out on the samples of Formulations 1 - 8 prepared, and the results are shown in the following table:

[0055]

[0056]

[0057] As shown in the above table, the applicant found in the formulation research that butorphanol tartrate is extremely sensitive to light, and impurities P0Z1 and P0Z6 are produced due to degradation and oxidation under light conditions.

[0058] 1. When no antioxidant is added (Formulation 1), the impurities P0Z1 and P0Z6 in the injection increase rapidly under light, P0Z1 increases to 0.69%, P0Z6 increases to 1.57%, and the total impurities increase to 12.66%, far exceeding the limit standards specified in the pharmacopoeia, and the content of butorphanol tartrate also decreases significantly.

[0059] 2. When further adding antioxidants to the formulation, we unexpectedly found that when thiourea is selected as the antioxidant, compared with other sulfite antioxidants and amino - acid - type antioxidants, it is more obvious in reducing impurities P0Z1 and P0Z6, and the total impurity content is also lower.

[0060] 3. When selecting the dosage of thiourea, it was found that when the dosage is less than 0.01 mg / ml (Formulation 8), the contents of single impurities P0Z1 and P0Z6 are still > 0.3%, not meeting the quality standards. When the dosage is within the range of 0.01 - 0.1 mg / ml, with the increase of the dosage, the total impurities show a decreasing trend and all meet the quality standards. When the dosage increases to 0.5 mg / ml, the total impurities basically remain unchanged. Based on the particularity of the injection, on the premise of ensuring product quality, the excipient dosage should be as small as possible. Therefore, the preferred dosage of thiourea is 0.01 - 0.1 mg / ml.

[0061] Test Example 2. Screening Test for Types and Dosages of Buffer Pairs

[0062] The applicant further screened the types and dosages of buffer pairs, and prepared Formulations 9 - 16 according to the following formulations. The preparation methods are basically the same as those in Experimental Example 1, except that the excipients and dosages are adjusted accordingly according to the following formulations.

[0063]

[0064] Under the stability test conditions specified in the Chinese Pharmacopoeia, the samples of Prescription 6 and Prescriptions 9 - 16 prepared were subjected to stability investigation under light, and the results are as shown in the following table:

[0065]

[0066]

[0067] The results of the screening experiment showed that

[0068] 1. The results of Prescription 6 and Prescriptions 9 - 11 indicated that, at the same thiourea dosage, when using the tartaric acid - sodium tartrate buffer pair, compared with not using or using the citric acid - sodium citrate and acetic acid - sodium acetate buffer pairs, the contents of single impurity and total impurity under light conditions could be significantly reduced.

[0069] 2. The results of Prescription 6 and Prescriptions 12 - 14 showed that as the dosage of tartaric acid increased, the stability of the product under light conditions increased significantly. It was speculated that tartaric acid and thiourea had a synergistic effect in the product of the present invention, further enhancing the antioxidant effect of thiourea. Therefore, Prescriptions 6 and Prescriptions 15 - 16 were used to verify this conjecture. The results showed that, under the condition of meeting the osmotic pressure requirements of the product, as the dosage of tartaric acid in the prescription increased, the antioxidant effect of thiourea was enhanced, and the stability of the product under light conditions increased significantly.

[0070] Test Example 3. Comparison of product quality

[0071] The product qualities of Examples 1 - 4 of the present invention and Comparative Examples 1 - 4 were determined under high temperature, light, accelerated conditions (40°C, RH75%), and long - term conditions (30°C, RH 65%), and the results are shown in the following table:

[0072]

[0073]

[0074]

[0075] Comparing the injection of the present invention with the commercial prescription and the prescription of RU2312662C1, it can be seen that:

[0076] 1) By using the pH buffer pair and antioxidant obtained through screening and optimization of the present invention, and selecting within the specified dosage ratio range, the butorphanol tartrate injection obtained had substantially no detectable impurity P0Z1 and P0Z6 under high temperature, light, accelerated, and long - term conditions, had a low total impurity content, stable properties, good high - temperature stability and light stability, and could be directly stored in colorless ampoules, reducing the influence of metal ions on the effectiveness and safety of the product during storage.

[0077] 2) Although commercially available prescriptions can avoid the influence of partial light by using brown bottles, in high-temperature, accelerated, and long-term tests, due to the influence of the leaching of metal oxides in brown glass bottles, the accelerated oxidation of metal ions causes the growth of oxidation impurities P0Z1 and P0Z6. Moreover, the influence of light cannot be completely avoided during clinical use.

[0078] 3) Packing the commercially available prescription in colorless ampoules can avoid the influence of metal ions during storage, but under light conditions, impurities P0Z1 and P0Z6 grow rapidly and exceed the limits specified in the pharmacopoeia.

[0079] 4) RU2312662C1 adds complexing agents such as EDTA to the prescription, which can effectively reduce the influence of metal ions on the stability of butorphanol tartrate. However, it still cannot solve the problem of its degradation and oxidation under light.

[0080] 5) Adding complexing agents (such as EDTA) to the prescription in RU2312662C1 is equivalent to the product stability of Comparative Example 1. Considering the particularity of the injection, the fewer excipients, the better, and the high safety requirements. Therefore, we preferably use a complexing agent solution to rinse the components and pipelines instead of adding complexing agents to the prescription.

[0081] Test Example 5. Investigation of the stirring time of raw materials

[0082] The 2020 edition of the Chinese Pharmacopoeia shows that butorphanol tartrate is slightly soluble in water. In the research of the liquid preparation process, we investigated the dissolution rate of the butorphanol tartrate raw material. According to the prescription of Example 3, excipients were added, and after complete dissolution, the volume was fixed to the prescription volume. After adding the prescribed amount of butorphanol tartrate raw material, a magnetic stirrer was used to keep it stirring in a weak vortex state, and samples were taken for content detection at 10 min, 20 min, and 30 min respectively. The investigation results are shown in the following table.

[0083] Investigation results of the dissolution rate of raw materials

[0084]

[0085] The investigation results show that only part of the raw materials are dissolved at 10 min, and they are basically completely dissolved when stirred for 20 min. There is basically no difference between stirring for 30 min and 20 min. Therefore, it is proposed that the stirring time during the dissolution process of raw materials during production should not be less than 20 min.

[0086] Test Example 6. Investigation of the time limit for liquid preparation and sealing

[0087] Since butorphanol tartrate is sensitive to light and oxygen, we investigated the total time limit for solution preparation and sealing during large-scale production according to the prescription in Example 3. The total time limits to be investigated were set at 16 h and 24 h. Sealing was stopped when there was a small amount of liquid medicine remaining in the buffer tank, and the nitrogen protection state was maintained. The samples for time limit investigation were prepared by resealing and sterilizing 16 h or 24 h after starting the timing with the injection water added. The results were compared with those of the normal production samples, and are shown in the following table.

[0088] Investigation Results of Solution Preparation and Sealing Time Limits for Large-Scale Samples in Example 3

[0089]

[0090] The investigation results showed that when the total time limit for solution preparation and sealing was controlled within 16 h, there were no significant differences in the single impurities and total impurities before and after sterilization compared with the normal samples, and the product quality could be ensured to be stable. When it exceeded 16 h and the total time limit for solution preparation and sealing was controlled at 24 h, the impurity level increased slightly, and there was a risk of exceeding the identification limit. Therefore, the total time limit for solution preparation and sealing was controlled within 16 h.

[0091] The above-described embodiments are merely descriptions of the preferred embodiments of the present invention, and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the claims of the present invention.

Claims

1. A butorphanol tartrate injection, characterized in that: Each ml of injection comprises: 2 mg of butorphanol tartrate, 0.18-2.2 mg of tartaric acid, 2.9-3.32 mg of sodium tartrate, 0.01-0.5 mg of antioxidant, 6.4 mg of sodium chloride and water for injection. The pH of the butorphanol tartrate injection is 3.0-5.0; the antioxidant is selected from thiourea.

2. The injection according to claim 1, characterized in that The dosage of the antioxidant is 0.01-0.1 mg.

3. The injection according to claim 1, characterized in that Each ml of injection solution consists of the following ingredients: Butorphanol tartrate 2mg Tartaric acid 0.66 mg Sodium tartrate 3.32mg Thiourea 0.1 mg Sodium chloride 6.4mg An appropriate amount of water for injection.

4. The injection according to any one of claims 1 to 3, characterized in that The contents of impurities P0Z1 and P0Z6 in the injection are less than 0.02%.

5. The method for preparing the injection according to claim 1, characterized in that: The steps include: Step 1) Pretreatment: Use 0.001% low concentration EDTA to treat and rinse the stainless steel liquid preparation tank and stainless steel pipe to remove metal impurities, and use injection water to circulate for 0.5-2 hours to clean to remove residual EDTA and complexes; Step 2) Liquid preparation: Measure about 90% of the prescribed amount of cooled and nitrogen-filled water for injection, add the prescribed amount of tartaric acid, sodium tartrate, thiourea, and sodium chloride, stir to dissolve, then add the prescribed amount of butorphanol tartrate, stir until completely dissolved, and dilute to the prescribed amount with water for injection; Step 3) Filling: Filter the obtained solution using a 0.22 μm PES polyethersulfone filter membrane, and then fill it with a colorless borosilicate glass ampoule of corresponding specifications, and fill it with nitrogen before and after filling; Step 4) Sterilization: After filling, sterilize at 121° C. for 15 min to obtain butorphanol tartrate injection.

6. The preparation method according to claim 5, characterized in that The stirring time after adding butorphanol tartrate in step 2) is not less than 20 minutes.

7. The preparation method according to claim 5, characterized in that The total time limit for the liquid preparation and potting of step 2) and step 3) is controlled within 16 hours.

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