Butorinol tartrate injection and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a butorphinol tartrate injection and a preparation method thereof. Every ml of the butorphanol tartrate injection is prepared from 2mg of butorphanol tartrate, 0.18 to 2.2 mg of tartaric acid, 2.9 to 3.32 mg of sodium tartrate, 0.01 to 0.5 mg of antioxidant, 6.4 mg of sodium chloride and water for injection, and the pH (Potential of Hydrogen) of the butorphanol tartrate injection is 3.0 to 5.0. According to the butorphanol tartrate injection prepared by the preparation method disclosed by the invention, through the synergistic effect of the tartaric acid and the specific antioxidant, the influence of illumination on the product quality is solved, the butorphanol tartrate injection has good illumination stability, and meanwhile, the influence of leaching of metal ions in a brown glass bottle on the product quality during long-term storage of the product is avoided; and the stability of the product is obviously improved, so that the effectiveness and the safety of the product are ensured.

Description

Technical Field

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

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

[0003] Butorphanol's chemical name is L-(-)-17-cyclobutylmethyl-3,14-dihydroxymorphinan, which has a typical morphinan structure nucleus. Butorphanol was first approved by the FDA in 1978, with the trade name Stadol, and has two dosage forms: injection and nasal spray. The injection has two specifications of 1mg / 1ml and 4mg / 2ml. The chemical structure of butorphanol tartrate is shown below:

[0004]

[0005] The current commercially available butorphanol tartrate injection contains butorphanol tartrate, citric acid, sodium citrate, sodium chloride and water for injection. CN116818928B discloses that during the storage process, two impurities (IB428 and IB429) of the above prescription were found to have increased significantly, and there is a risk of exceeding the identification limit. The applicant found in the study that butorphanol tartrate is sensitive to metal ions (especially Fe 3+ The product is sensitive to sunlight and / or oxygen, and will undergo significant degradation to produce oxidative impurities P0Z1 and P0Z6, 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 effects of light and oxidative degradation on the quality of finished products during storage, butorphanol tartrate injection on the market is currently mostly packaged in brown bottles. However, the effects of light during clinical use cannot be avoided, and brown bottles are usually made by adding metal oxides such as iron oxide to the materials. This type of packaging material will leach Fe when in contact with the product. 3+ , resulting in Fe 3+ Sensitive drugs degrade, resulting in unstable product quality during long-term storage.

[0008] Patent RU2312662C1 Example 1 discloses that the drug prepared in a steel reactor with a commercial prescription does not meet the requirements in terms of "color and transparency" after being placed for half a year, and impurities show a significant increase. It adds ethylenediaminetetraacetic acid (EDTA) or sodium dithiopropanesulfonate or glycerol or mannitol as a complexing agent in the prescription, and the complexing substance helps to form a stable complex water-soluble compound with a large number of cations, and the corresponding cations cannot be detected, thereby avoiding the destructive effect of trace heavy metals on butorphanol, so that the prepared solution obtained in the steel reactor meets the quality standard. However, EDTA can combine with calcium ions to form a soluble complex to cause a decrease in calcium. In intravenous injection, the presence of EDTA in the preparation will cause the patient's blood calcium to decrease. Other metal complexing agents such as sodium dithiopropanesulfonate will not complex calcium ions and will not cause hypocalcemia, but long-term use can cause a decrease in trace elements. At the same time, the chelating agent is expensive, resulting in an increase in production costs; and it still cannot solve the problem of butorphanol tartrate injection being degraded under light and oxidation to produce impurities exceeding the limit.

[0009] The 2020 edition of the Chinese Pharmacopoeia stipulates that the single impurity in butorphanol tartrate injection should not exceed 0.3%, the total impurity should not exceed 1%, and the butorphanol tartrate content should be 90.0% to 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] In order to overcome the above technical problems, the present invention provides a butorphanol tartrate injection and a preparation method thereof, which can solve the problem of excessive impurities generated by butorphanol tartrate under light, can be stored in colorless glass bottles and reduce the influence of light degradation during clinical use, while avoiding the risk of unstable product quality due to leaching of metal ions in brown bottles during long-term storage; by passivating the stainless steel liquid preparation tank and pipelines during the preparation process, the influence of metal ions in the liquid preparation process is avoided, thereby ultimately ensuring the effectiveness and safety of the product.

[0011] The first aspect of the present invention provides a butorphanol tartrate injection, wherein each ml of the injection comprises: 2 mg butorphanol tartrate, 0.18-2.2 mg tartaric acid, 2.9-3.32 mg sodium tartrate, 0.01-0.5 mg antioxidant, 6.4 mg 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 antioxidant is used in an amount of 0.01-0.1 mg.

[0016] In some preferred embodiments, each ml of butorphanol tartrate injection consists of the following ingredients: 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 content of impurities P0Z1 and P0Z6 in the butorphanol tartrate injection is less than 0.02%; and the total impurities are less than 1.0%.

[0018] Another aspect of the present invention provides a method for preparing butorphanol tartrate injection, the preparation method comprising:

[0019] Step 1), pretreatment: Use 0.001% low concentration EDTA to treat and rinse the stainless steel liquid preparation tank and stainless steel pipeline to remove metal impurities, and use injection water to circulate for 0.5-2 hours to clean to remove residual EDTA and complexes;

[0020] Step 2), liquid preparation: measure about 90% of the prescription amount of water for injection that has been cooled and filled with nitrogen, add the prescription amount of tartaric acid, sodium tartrate, thiourea, and sodium chloride, stir to dissolve, then add the prescription amount of butorphanol tartrate, stir until completely dissolved, and dilute to the prescription amount with water for injection;

[0021] Step 3), filling: the obtained solution is filtered using a 0.22 μm PES (polyethersulfone) filter membrane, and then filled with a borosilicate glass ampoule (colorless) of corresponding specifications, and nitrogen is filled before and after filling;

[0022] Step 4) Sterilization: After filling, sterilize (121° C., 15 min) 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 minutes.

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

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

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

[0027] 2. The types and dosages of acids in the prescription were screened, and it was found that when tartaric acid and thiourea were used together, a synergistic effect could be exerted to increase the antioxidant effect of thiourea and further reduce the dosage of antioxidants in the prescription.

[0028] 3. During the preparation process, EDTA is used to treat the stainless steel liquid preparation tank and stainless steel pipes to remove trace metal impurities remaining on the surface, avoid increasing the metal ion concentration in the liquid, and improve product stability.

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

[0030] The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the protection scope of the present invention.

[0031] Unless otherwise specified, the raw materials and reagents used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0032] When preparing the injection below, unless otherwise stated, the total injection volume for each batch is 1 L, but it can be scaled up or down when describing the prescription and / or preparation process.

[0033] Among the experimental conditions of the influencing factors described in this article, the high temperature test condition is 60±2℃, and the light test condition is 4500lx±500lx.

[0034] Example 1. Preparation of Butorphanol Tartrate Injection of the Present Invention

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

[0036] 1) Pretreatment: Use 0.001% low concentration EDTA to treat the stainless steel liquid preparation tank and stainless steel pipeline to remove metal impurities, and use injection water to circulate for 0.5-2h for cleaning to remove residual EDTA and complexes;

[0037] 2) Liquid preparation: Measure about 90% of the prescribed amount of water for injection that has been cooled and filled with nitrogen, add the prescribed amount of tartaric acid, sodium tartrate, thiourea, and sodium chloride, stir to dissolve, then add the prescribed amount of butorphanol tartrate raw material, stir for not less than 20 minutes, until it is completely dissolved, and make up the volume with water for injection to the prescribed amount.

[0038] 3) Filling: The obtained solution is filtered through a 0.22 μm PES (polyethersulfone) filter membrane, and then filled with a borosilicate glass ampoule (colorless) of corresponding specifications, and nitrogen is filled before and after filling. The time limit for liquid preparation and filling is controlled within 16 hours.

[0039] 4) Sterilization: After filling, sterilize (121°C, 15 min) to obtain butorphanol tartrate injection.

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

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

[0042] Components 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 Add to 100L Add to 100L Add to 100L Add to 100L

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

[0044] Comparative Example 1. Commercially available prescription: Butorphanol tartrate injection (Noyan), which is packaged in brown vials. It can be purchased directly from the market, or prepared with reference to paragraphs

[0064] to

[0073] of the specification of CN111904928A.

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

[0046] Comparative Examples 3-4. According to the prescription described in Example 2 of patent RU2312662C1, the endpoint values ​​of the EDTA numerical range recorded therein were selected, and Comparative Examples 3 and Comparative Examples 4 were prepared with reference to the preparation method described in Example 1, and the packaging material was a brown ampoule.

[0047] Comparative Example 1-4 Preparation formula of butorphanol tartrate injection

[0048]

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

[0050] Test Example 1. Antioxidant Type and Dosage Screening Test

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

[0052]

[0053] The preparation methods of Prescriptions 1-8 are the same as those of Example 1, except that the auxiliary materials and dosages are adjusted accordingly according to the prescriptions in the above table.

[0054] According to the stability test conditions specified in the Chinese Pharmacopoeia, the prepared samples of prescriptions 1-8 were subjected to an influencing factor investigation test. The results are shown in the following table:

[0055]

[0056]

[0057] As shown in the table above, the applicant found in the formulation study that butorphanol tartrate is extremely sensitive to light and degrades and oxidizes under light conditions to produce impurities P0Z1 and P0Z6.

[0058] 1. When no antioxidant was added (prescription 1), the impurities P0Z1 and P0Z6 in the injection solution increased rapidly under light, with P0Z1 increasing to 0.69%, P0Z6 increasing to 1.57%, and total impurities increasing to 12.66%, far exceeding the limit standards specified in the pharmacopoeia. The content of butorphanol tartrate was also significantly reduced.

[0059] 2. When further antioxidants were added to the formula, we unexpectedly found that when thiourea was selected as the antioxidant, the impurities P0Z1 and P0Z6 were reduced more significantly than other sulfite antioxidants and amino acid antioxidants, and the total impurity content was also lower.

[0060] 3. When selecting the dosage of thiourea, it was found that when the dosage was less than 0.01 mg / ml (prescription 8), the content of single impurities P0Z1 and P0Z6 was still greater than 0.3%, which did not meet the quality standards. When the dosage was in the range of 0.01-0.1 mg / ml, as the dosage increased, the total impurities tended to decrease and met the quality standards. When the dosage increased to 0.5 mg / ml, the total impurities remained basically unchanged. Based on the particularity of the injection, while ensuring the quality of the product, the amount of excipients 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 of buffer type and dosage

[0062] The applicant further screened the types and dosages of buffer pairs, and prepared prescriptions 9-16 according to the prescriptions in the following table. The preparation method was basically the same as that in Experimental Example 1, except that the excipients and dosages were adjusted accordingly according to the prescriptions in the following table.

[0063]

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

[0065]

[0066]

[0067] The results of the screening experiment showed that

[0068] 1. Prescription 6, Prescription 9-11 The results showed that, at the same thiourea dosage, the use of tartaric acid-sodium tartrate buffer pairs can significantly reduce the content of single impurities and total impurities under light conditions compared to not using or using citric acid-sodium citrate and acetic acid-sodium acetate buffer pairs.

[0069] 2. The results of prescription 6 and prescriptions 12-14 show that with the increase of tartaric acid dosage, the stability of the product under light conditions is significantly increased. It is speculated that tartaric acid and thiourea have a synergistic effect in the product of the present invention, which further increases the antioxidant effect of thiourea. Therefore, this hypothesis is verified by prescription 6 and prescriptions 15-16. The results show that under the condition of meeting the osmotic pressure requirements of the product, with the increase of tartaric acid dosage in the prescription, the antioxidant effect of thiourea is enhanced, and the stability of the product under light conditions is significantly increased.

[0070] Test Example 3. Product Quality Comparison

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

[0072]

[0073]

[0074]

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

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

[0077] 2) Although the brown bottle used in the commercial prescription can partially avoid the influence of light, in the high temperature, accelerated and long-term tests, due to the influence of metal oxide leaching in the brown glass bottle, the metal ions accelerated oxidation and increased the oxidized impurities P0Z1 and P0Z6. Moreover, the influence of light cannot be completely avoided in clinical use.

[0078] 3) The commercially available prescription was packaged in colorless ampoules. Although this avoided the influence of metal ions during storage, the impurities P0Z1 and P0Z6 increased rapidly under light conditions, exceeding the limits specified in the pharmacopoeia.

[0079] 4) RU2312662C1 adds a chelating agent such as EDTA to the formulation, which can effectively reduce the effect of metal ions on the stability of butorphanol tartrate, but it still cannot solve the problem of its degradation and oxidation under light.

[0080] 5) Adding a chelating agent (such as EDTA) to the formulation of RU2312662C1 has comparable product stability to that of Comparative Example 1. Considering the particularity of the injection, the fewer excipients the better, and the high safety requirements, we prefer to flush the components and pipelines with a chelating agent solution instead of adding a chelating agent to the formulation.

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

[0082] The 2020 edition of the Chinese Pharmacopoeia shows that butorphanol tartrate is slightly soluble in water. In the preparation process study, we investigated the dissolution rate of butorphanol tartrate raw materials. According to the prescription of Example 3, the excipients were added, and the volume was adjusted to the prescription volume after complete dissolution. After adding the prescription amount of butorphanol tartrate raw materials, a magnetic stirrer was used to maintain a weak vortex state of stirring, and samples were taken at 10min, 20min, and 30min to detect the content. The results of the investigation are detailed in the table below.

[0083] Results of investigation on raw material dissolution rate

[0084]

[0085] The investigation results showed that the raw material was only partially dissolved after 10 minutes, and was basically completely dissolved after stirring for 20 minutes. There was basically no difference between stirring for 30 minutes and 20 minutes. Therefore, it is planned that the stirring time during the raw material dissolution process in production should not be less than 20 minutes.

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

[0087] Since butorphanol tartrate is sensitive to light and oxygen, we investigated the total time limit for liquid preparation and filling during the scale-up production according to the prescription in Example 3. The total time limit for investigation was proposed to be 16 hours and 24 hours. When a small amount of liquid medicine remained in the buffer tank, filling was stopped, and the nitrogen protection state was maintained. The time limit inspection samples were used as time limit inspection samples for 16 hours or 24 hours after the injection of water for injection and then filling and sterilization. The results were compared with the normal production samples. The results are shown in the table below.

[0088] Example 3: Results of the investigation on the time limit of sample preparation and encapsulation

[0089]

[0090] The results of the investigation show that when the total time limit for liquid preparation and filling is controlled within 16 hours, there is no significant difference in single impurities and total impurities before and after sterilization compared with normal samples, which can ensure stable product quality. When it exceeds 16 hours and the total time limit for liquid preparation and filling is controlled within 24 hours, the impurity level increases slightly, and there is a risk of exceeding the identification limit. Therefore, the total time limit for liquid preparation and filling is controlled within 16 hours.

[0091] The embodiments described above are merely descriptions of preferred implementation modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all 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.

2. The injection according to claim 1, characterized in that: The antioxidant is selected from one or more of sodium bisulfite, sodium pyrosulfite, cysteine ​​and thiourea.

3. The injection according to claim 2, characterized in that: The antioxidant is selected from thiourea.

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

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

6. The injection according to any one of claims 1 to 5, characterized in that The contents of impurities P0Z1 and P0Z6 in the injection are less than 0.02%.

7. 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 pipeline 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 prescription amount of water for injection that has been cooled and filled with nitrogen, add the prescription amount of tartaric acid, sodium tartrate, thiourea, and sodium chloride, stir to dissolve, then add the prescription amount of butorphanol tartrate, stir until completely dissolved, and dilute to the prescription amount with water for injection; Step 3), filling: the obtained solution is filtered using a 0.22 μm PES (polyethersulfone) filter membrane, and then filled with a borosilicate glass ampoule (colorless) of corresponding specifications, and nitrogen is filled before and after filling; Step 4) Sterilization: After filling, sterilize (121° C., 15 min) to obtain butorphanol tartrate injection.

8. The preparation method according to claim 7, characterized in that: The stirring time after adding butorphanol tartrate in step 2) is not less than 20 minutes.

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

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