Carboprost tromethamine injection and a preparation method thereof

Abstract

The present application relates to a kind of carboprost tromethamine injection and its preparation method.The injection uses meglumine as pH regulator, not only stable to CO2 in environment, and it is beneficial to improve the stability of carboprost tromethamine;At the same time, pre-charged needle injection is also avoided the operation of ampoule sealing, so that the prepared carboprost tromethamine injection can be stored at 2~20 ℃, storage and transportation and clinical use are more convenient.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a carboprost tromethamine injection and its preparation method. Background Technology

[0002] Carboprost tromethamine, molecular formula C 25 H 47 NO8, with a molecular weight of 489.643, is used as a pharmaceutical product and is a 15-methyl analogue of prostaglandin F2α. It can effectively promote regular uterine contractions and significantly reduce postpartum hemorrhage.

[0003] Postpartum hemorrhage is a high-risk condition in obstetrics and gynecology, defined as bleeding exceeding 500 mL within 24 hours postpartum. Postpartum hemorrhage can adversely affect a mother's health and can easily lead to postpartum death. Therefore, providing high-quality and effective treatment to patients with postpartum hemorrhage is crucial to ensuring their safety. Uterine atony-related postpartum hemorrhage is one of the most common types, accounting for 70% of postpartum hemorrhage cases. It is often caused by factors such as excessive maternal stress, prolonged labor, or rapid labor. Providing reliable treatment for patients with uterine atony-related postpartum hemorrhage is essential for their health. Currently, using medication to strengthen uterine contractions is a relatively effective treatment measure. Carboprost tromethamine injection is a drug with good efficacy in increasing uterine contractions, helping to promote coordinated and beneficial uterine contractions, and has high clinical application value.

[0004] Pre-filled injectable solutions are simple and convenient to use, and can be used directly, avoiding potential secondary contamination during clinical use.

[0005] Furthermore, existing carboprost tromethamine injections use tromethamine as an amino buffer. However, tromethamine is an organic amine with strong alkalinity and can combine with hydrogen ions of carbonic acid to form bicarbonate. Therefore, tromethamine solutions easily absorb CO2 from the air, affecting the pH and thus reducing the stability of carboprost tromethamine injections. Simultaneously, during commercial production, the combustion of liquefied petroleum gas and natural gas during ampoule sealing generates locally high concentrations of CO2. During ampoule sealing, the pH decreases by 0.3–0.5, further impacting product stability. Commercially available carboprost tromethamine injections are packaged in ampoules and vials, and stored at 2–8°C.

[0006] CN 112057417 A discloses a carboprost tromethamine injection solution, which, to improve stability, contains a number of excipients, such as stabilizers, antioxidants, chelating agents, and buffer solutions. The stabilizers are trehalose and proline, the antioxidants are disodium EDTA, sodium benzoate, and sodium thiosulfate, the chelating agent is sodium diethyldithiocarbamate, and the buffer solution is disodium hydrogen citrate and trisodium citrate buffer solution. Summary of the Invention

[0007] This invention discloses an injection solution containing carboprost tromethamine, an osmotic pressure regulator, meglumine, and hydrochloric acid; wherein the mass ratio of meglumine to carboprost tromethamine is (0.5:3) to (4:3); and the pH range of the injection solution is 8.0 to 8.5.

[0008] In some embodiments, the concentration of hydrochloric acid is 0.01% to 1.0%.

[0009] In some embodiments, the mass ratio of meglumine to carboprost tromethamine is (1:3) to (3:3), for example, 1:3, (1-2):3, 2:3, 3:3.

[0010] In some embodiments, the concentration of hydrochloric acid is 0.1% to 0.2%.

[0011] In some embodiments, the pH range of the injection solution is 8.2 to 8.4.

[0012] In some embodiments, the pH of the injection solution is 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.

[0013] In some embodiments, the osmotic pressure regulator is sodium chloride or a solution thereof.

[0014] In some embodiments, the formulation of the injection solution is as follows:

[0015] Carboprost Tromethamine 333mg Sodium chloride 900mg meglumine 111-333mg hydrochloric acid Appropriate amount Water for Injection Add to 1L

[0016] The pH range of the injection solution is 8.2 to 8.4.

[0017] This invention discloses a pre-filled syringe injection solution of carboprost tromethamine, wherein the injection solution is the above-mentioned injection solution.

[0018] In some embodiments, the pre-filled needle is a borosilicate glass pre-filled syringe.

[0019] This invention discloses a method for preparing the above-mentioned injection solution, comprising:

[0020] (1) Add 50% to 99% water for injection to the solution preparation tank, and control the water temperature at 2 to 20°C; add meglumine, sodium chloride, and carboprost tromethamine to the solution preparation tank and stir until completely dissolved;

[0021] (2) Check whether the pH of the solution is within the corresponding range; if it is not within the range, the pH of the solution can be adjusted to the corresponding range with an appropriate amount of hydrochloric acid solution; the corresponding range is as described above, the pH range is 8.0 to 8.5, and further, the pH range is 8.2 to 8.4; the hydrochloric acid solution is a solubility commonly used to adjust the pH of the solution, such as 0.1% (W / W) hydrochloric acid solution.

[0022] (3) Add water for injection to the prescribed amount and stir well;

[0023] (4) The medicine solution is sterilized by two-stage 0.22μm PES filter cartridges.

[0024] This invention discloses a method for preparing the above-mentioned carboprost tromethamine pre-filled syringe injection solution, comprising:

[0025] (1) Add 50% to 99% water for injection to the solution preparation tank, and control the water temperature at 2 to 20°C; add meglumine, sodium chloride, and carboprost tromethamine to the solution preparation tank and stir until completely dissolved;

[0026] (2) Check whether the pH of the solution is within the range of 8.3±0.1; if it is not within the range, the pH of the solution can be adjusted to the corresponding range with an appropriate amount of 0.1% (W / W) hydrochloric acid. The corresponding range is as described above, with a pH range of 8.0 to 8.5, and further, a pH range of 8.2 to 8.4.

[0027] (3) Add water for injection to the prescribed amount and stir well;

[0028] (4) The medicine solution is sterilized by two-stage 0.22μm PES filter cartridges;

[0029] (5) Fill the injection solution obtained in step (4) into a borosilicate glass pre-filled syringe to obtain carboprost tromethamine pre-filled syringe injection solution.

[0030] The volume of the borosilicate glass pre-filled syringe is 1 ml.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] This invention provides a stable pre-filled syringe injection solution of carboprost tromethamine, which uses fewer excipients and is not only stable against CO2 in the environment, but also beneficial to the biostability of carboprost tromethamine; in particular, the rate of increase of impurity I, impurity II, unknown impurities and total impurities is significantly reduced during long-term storage.

[0033] Wherein, impurity I is C 21 H 36 O5, (E)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E)-(3S)-3-hydroxy-3-methyl-octenyl-1]cyclopentyl]-5-heptenic acid, with the following structural formula:

[0034]

[0035] The impurity II is C 21 H 36 O5, (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E)-(3R)-3-hydroxy-3-methyl-octenyl-1]cyclopentyl]-5-heptenic acid, with the following structural formula:

[0036]

[0037] Using pre-filled syringes also avoids the need for ampoule sealing, allowing the prepared carboprost tromethamine injection to be stored at 2–20°C, such as 5°C, 10°C, 15°C, and 19°C, making storage, transportation, and clinical use more convenient.

[0038] There are currently no reports on the preparation method of carboprost tromethamine pre-filled syringe injection. This invention provides a stable carboprost tromethamine pre-filled syringe injection.

[0039] The technical solution of this invention provides more options for clinical use and increases patient adaptability. Attached Figure Description

[0040] Figure 1 This is a schematic diagram of a pre-filled needle syringe according to an embodiment of the present invention.

[0041] Figure 2 This is a schematic diagram of a pre-filled needle syringe according to an embodiment of the present invention. Detailed Implementation

[0042] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the examples, they should be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0043] Example 1

[0044] This embodiment provides a pre-filled syringe injection of carboprost tromethamine (pH 8.3), with the following formulation:

[0045]

[0046]

[0047] This embodiment also provides a method for preparing carboprost tromethamine pre-filled syringe injection:

[0048] (1) Add 90% of the prescribed amount of water for injection to the mixing tank, and control the water temperature at 15℃. Add the prescribed amounts of meglumine, sodium chloride, and carboprost tromethamine to the mixing tank, and stir until completely dissolved;

[0049] (2) Adjust the pH of the solution to 8.3 with 0.1% (w / w) hydrochloric acid;

[0050] (3) Add water for injection to the prescribed amount and continue stirring until well mixed;

[0051] (4) The medicine solution is sterilized by two-stage 0.22μm PES filter cartridges;

[0052] (5) Fill the drug solution into a 1ml borosilicate glass pre-filled syringe.

[0053] Example 2

[0054] This embodiment provides a pre-filled syringe injection of carboprost tromethamine (pH 8.2), with the following formulation:

[0055] raw materials Prescription (1000 vials) Carboprost Tromethamine 333mg Sodium chloride 900mg meglumine 111mg hydrochloric acid Appropriate amount Water for Injection Add to 1L

[0056] This embodiment also provides a method for preparing carboprost tromethamine pre-filled syringe injection:

[0057] (1) Add 90% of the prescribed amount of water for injection to the mixing tank, and control the water temperature at 15℃. Add the prescribed amounts of meglumine, sodium chloride, and carboprost tromethamine to the mixing tank, and stir until completely dissolved;

[0058] (2) The pH of the solution was measured to be 8.2;

[0059] (3) Add water for injection to the prescribed amount and continue stirring until well mixed;

[0060] (4) The medicine solution is sterilized by two-stage 0.22μm PES filter cartridges;

[0061] (5) Fill the drug solution into a 1ml borosilicate glass pre-filled syringe.

[0062] Example 3

[0063] This embodiment provides a pre-filled syringe injection of carboprost tromethamine (pH 8.4), with the following formulation:

[0064]

[0065]

[0066] This embodiment also provides a method for preparing carboprost tromethamine pre-filled syringe injection:

[0067] (1) Add 90% of the prescribed amount of water for injection to the mixing tank, and control the water temperature at 15℃. Add the prescribed amounts of meglumine, sodium chloride, and carboprost tromethamine to the mixing tank, and stir until completely dissolved;

[0068] (2) The pH of the solution was measured to be 8.4;

[0069] (3) Add water for injection to the prescribed amount and continue stirring until well mixed;

[0070] (4) The medicine solution is sterilized by two-stage 0.22μm PES filter cartridges;

[0071] (5) Fill the drug solution into a 1ml borosilicate glass pre-filled syringe.

[0072] Comparative Example 1

[0073] Carboprost tromethamine pre-filled syringe injection (pH 8.3), the prescription is as follows:

[0074] raw materials Prescription (1000 vials) Carboprost Tromethamine 333mg Sodium chloride 900mg meglumine 55.5mg hydrochloric acid Appropriate amount Water for Injection Add to 1L

[0075] The preparation method of this comparative example is the same as that in Example 1.

[0076] Comparative Example 2

[0077] Carboprost tromethamine pre-filled syringe injection (pH 8.3), the prescription is as follows:

[0078] raw materials Prescription (1000 vials) Carboprost Tromethamine 333mg Sodium chloride 900mg meglumine 388.5mg hydrochloric acid Appropriate amount Water for Injection Add to 1L

[0079] The preparation method of this comparative example is the same as that in Example 1.

[0080] Comparative Example 3

[0081] The carboprost tromethamine pre-filled syringe injection has the same formulation as in Example 1, except that the pH of the solution is adjusted to 7.9 with an appropriate amount of 0.1% (w / w) hydrochloric acid in the preparation method.

[0082] Comparative Example 4

[0083] The carboprost tromethamine pre-filled syringe injection has the same formulation as in Example 1, except that the pH of the solution is adjusted to 8.6 with an appropriate amount of 0.1% (w / w) hydrochloric acid during the preparation process.

[0084] Comparative Example 5

[0085] Carboprost tromethamine pre-filled syringe injection (pH 8.3), the prescription is as follows:

[0086] raw materials Prescription (1000 vials) Carboprost Tromethamine 333mg Sodium chloride 900mg Tromethamine 222mg hydrochloric acid Appropriate amount Water for Injection Add to 1L

[0087] The preparation method of this comparative example is the same as that in Example 1.

[0088] Experimental Example 1

[0089] Using the same batch of sample (drug solution) from Example 1, the solution was dispensed into 1ml borosilicate ampoules and 1ml borosilicate glass pre-filled syringes, and the pH of the solution was measured.

[0090] Experimental results:

[0091] Table 1. pH Measurement Results of Different Packaging Materials

[0092] Packaging materials pH results Unfilled samples 8.3 Borosilicate ampoules 7.8 Borosilicate glass pre-filled syringe 8.3

[0093] Conclusion: The use of borosilicate ampoules for sealing will affect the pH of the product, causing the pH to decrease.

[0094] Experiment Example 2

[0095] [Test] pH (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0631).

[0096] The relevant substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0097] Take an appropriate amount of this product for the test solution.

[0098] For the reference solution, accurately weigh an appropriate amount of carboprost tromethamine reference standard, dissolve it in water, and quantitatively dilute it to prepare a solution containing approximately 3.3 μg per ml.

[0099] For system suitability solution, take appropriate amounts of carboprost tromethamine reference standard, impurity I reference standard and impurity II reference standard, dissolve them in water and dilute quantitatively to prepare a mixed solution containing approximately 0.33 mg of carboprost tromethamine, 7.5 μg of impurity I and 7.5 μg of impurity II per ml.

[0100] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; acetonitrile-methanol-0.02 mol / L potassium dihydrogen phosphate buffer (20:30:50), with the pH adjusted to 3.0 by phosphoric acid, was used as the mobile phase; the detection wavelength was 200 nm; the column temperature was 30 ℃; and the injection volume was 50 μL.

[0101] System suitability requirements: In the system suitability solution chromatogram, the resolution between carboprost, impurity I, and impurity II and adjacent peaks should meet the requirements.

[0102] For the assay, accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0103] [Content Determination] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0104] Take an appropriate amount of this product for the test solution.

[0105] For the reference solution, accurately weigh an appropriate amount of carboprost tromethamine reference standard, dissolve it in water, and quantitatively dilute it to prepare a solution containing approximately 0.33 mg per ml.

[0106] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; acetonitrile-methanol-0.02 mol / L potassium dihydrogen phosphate buffer (20:30:50), with the pH adjusted to 3.0 by phosphoric acid, was used as the mobile phase; the detection wavelength was 200 nm; the column temperature was 30 ℃; and the injection volume was 10 μL.

[0107] For the assay, accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results based on peak area using the external standard method (the conversion factor between carboprost and carboprost tromethamine is 0.7526).

[0108] 1) Long-term stability test

[0109] For stability studies, samples from Examples 1-3 and Comparative Examples 1-5 were placed at a temperature of 20℃±2℃. Samples were taken for analysis at 0 months, 3 months, 6 months, 12 months, 18 months, and 24 months after placement. The properties, pH, content, and related substances in the samples after placement were measured and calculated. The results are shown in Table 2.

[0110] 2) Intermediate condition stability test

[0111] For stability studies, samples from Examples 1-3 and Comparative Examples 1-5 were placed at a temperature of 30℃±2℃. Samples were taken for analysis at 0 months, 3 months, 6 months, and 12 months after placement. The properties, pH, content, and related substances in the samples after placement were measured and calculated. The results are shown in Table 3.

[0112] Table 2. Stability results of Examples 1-3 and Comparative Examples 1-5

[0113]

[0114]

[0115]

[0116] Table 3. Stability results of Examples 1-3 and Comparative Examples 1-5

[0117]

[0118]

[0119]

[0120] The above results indicate that the properties, pH, and content of the samples of the present invention did not change significantly over long-term (24 months) and long-term (12 months) periods, although impurities increased slightly, but this was still better than the comparative examples. Comparative examples 1-5 showed no significant change in properties, but a significant increase in impurities and a slight decrease in content. Comparative examples 1, 2, and 5 showed slight pH changes, indicating that an appropriate amount of meglumine and a suitable pH range affect the stability of carboprost tromethamine injection.

[0121] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. An injection solution, characterized in that, The prescription for the injection solution is as follows: The pH range of the injection solution is 8.2 to 8.

4.

2. The injectable solution according to claim 1, characterized in that, The concentration of the hydrochloric acid is 0.01%~1.0%w / w.

3. The injectable solution according to claim 1, wherein The concentration of the hydrochloric acid is 0.1%~0.2% w / w.

4. A carboprost tromethamine pre-filled syringe injection, characterized in that, The injection solution is any one of the injection solutions described in claims 1-3.

5. The pre-filled needle injection of claim 4, wherein, The pre-filled needle is a borosilicate glass pre-filled syringe.

6. A method of preparing the injectable solution of any one of claims 4-5, characterized in that, include: (1) Add 50%~99% water for injection of the prescription amount to the mixing tank, and control the water temperature at 2~20℃; add meglumine, sodium chloride and carboprost tromethamine of the prescription amount to the mixing tank, and stir until completely dissolved; (2) Check whether the pH of the solution is within the required range; if it is not within the range, the pH of the solution can be adjusted to the corresponding value with an appropriate amount of hydrochloric acid solution; (3) Add water for injection to the prescribed amount and stir well; (4) The medicine solution is sterilized by two-stage 0.22μm PES filter cartridges.

7. The method of claim 6, wherein the injectable solution is prepared by, include: The sterilized and filtered drug solution is filled into a borosilicate glass pre-filled syringe.

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