Ganciclovir for injection and preparation method thereof

Abstract

The invention discloses ganciclovir for injection and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. According to the preparation, through innovative auxiliary material combination and process optimization, the problems that in the prior art, high pH value irritation is high, a freeze-drying structure is prone to collapse, and redissolution performance is poor are solved. The ganciclovir freeze-drying preparation comprises ganciclovir, trehalose, poloxamer 188 and sodium hydroxide, and through auxiliary material innovation and freeze-drying process improvement, the stability of the drug is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to ganciclovir for injection and its preparation method. Background Art

[0002] Ganciclovir is a nucleoside broad-spectrum antiviral drug, mainly used for preventing and treating cytomegalovirus infections in immunocompromised patients, and is one of the core drugs for clinical antiviral treatment. Ganciclovir sodium is often marketed in the form of a freeze-dried powder injection to improve the stability of the preparation and facilitate transportation. However, there are still the following significant problems in the industrial production and clinical application of the existing freeze-dried ganciclovir for injection:

[0003] 1. Technical defects of the existing freeze-drying process

[0004] In US Patent 4,355,032, the freeze-dried ganciclovir powder injection needs to dissolve the drug and form a salt through a highly alkaline solution (pH 10.5 - 11.5), resulting in too high a pH value of the final preparation. As described in CN102274197A, it is easy to cause serious irritation reactions such as local pain and phlebitis in patients during injection. CN101711746A attempts to reduce the pH to 9.5 through the inclusion technology of hydroxypropyl-β-cyclodextrin (HP-β-CD), but HP-β-CD has potential renal toxicity and hemolysis risk, and the safety of clinical application is in doubt.

[0005] 2. Insufficient freeze-drying efficiency and structural stability

[0006] In the existing process, the solid content of the ganciclovir preparation solution is high and it is in a glassy state during the freeze-drying process, resulting in low heat transfer efficiency. It is necessary to extend the freeze-drying cycle to avoid the melting phenomenon. In addition, as described in CN102274197A, an increase in the shelf temperature is likely to cause the collapse of the skeleton and the freeze-dried microstructure, directly affecting the reconstitution performance, manifested as an increase in insoluble particles, a decrease in clarity, and even not meeting the pharmacopoeia standards. After long-term storage, the collapse problem intensifies, further leading to an increase in related substances and a decrease in stability.

[0007] 3. Limitations of excipients and processes

[0008] In traditional formulations such as CN1125823C, a large amount of excipients such as mannitol and dextran are used as freeze-drying protectants. Although it can improve hygroscopicity, a high concentration of sodium hydroxide is still required to assist in dissolution during the freeze-drying process, exacerbating alkaline irritation. In addition, the activated carbon adsorption process disclosed in CN1403084A causes a loss of ganciclovir content (about 5%) while removing endotoxins, affecting the quality uniformity of the preparation. Some technologies attempt to introduce new excipients, but their industrial application is not yet mature, and the safety of the excipients still needs to be further verified.

[0009] 4. Long-term stability and safety issues

[0010] Existing freeze-dried powder injections are prone to moisture absorption during storage. As shown in the comparative experiment of CN113476413B, the weight of some excipients increased by 1.89% in 6 hours, resulting in appearance changes and an increase in impurity content. In addition, highly alkaline liquid medicines are prone to corrode the inner wall of glass containers during sterilization or long-term storage, releasing insoluble particles, as described in CN107753444A, further increasing the clinical medication risk.

[0011] 5. Deficiencies of existing patented technologies

[0012] Although CN113476413B proposes to use mannitol as a protective agent to improve moisture absorption, it still relies on an alkaline environment to dissolve the drug; CN102627643A adopts a low-grade fatty acid refining process to reduce impurities, but does not solve the problem of freeze-dried structure collapse. Most technologies such as CN102274197A and CN101711746A are difficult to balance between shortening the freeze-drying cycle and maintaining structural stability, and the excipient selection fails to take into account both safety and solubilization efficiency.

[0013] In summary, developing a ganciclovir freeze-dried powder injection for injection with low pH, high purity, short freeze-drying cycle, stable structure, and safe excipients has become a key requirement for improving product quality, reducing production costs, and improving patient medication safety. Summary of the Invention

[0014] As an antiviral drug, the freeze-dried preparation of ganciclovir has technical bottlenecks in poor reconstitution performance and insufficient stability in clinical applications. Traditional formulations rely on strong alkaline conditions (pH > 11) to dissolve the drug, which is prone to cause vascular irritation and has a relatively long reconstitution time. Commonly used excipients (such as mannitol and hydroxypropyl-β-cyclodextrin) are prone to form crystals or cause drug degradation during the freeze-drying process, and the impurity growth is significant in the accelerated test. In view of the above problems, the present invention proposes an innovative ganciclovir formulation for injection and its preparation method, breaking through the limitations of existing technologies through formulation improvement and process optimization.

[0015] The ganciclovir for injection comprises components ganciclovir, trehalose, poloxamer 188, sodium hydroxide, and a pH value of 7.5 - 8.5.

[0016] Preferably, the ganciclovir for injection has a pH value of 7.5 - 8.5 and comprises components in a weight ratio of:

[0017]

[0018] More preferably, the ganciclovir for injection has a pH value of 7.5 - 8.5 and comprises components in a weight ratio of:

[0019]

[0020] Preferably, the pH value of ganciclovir for injection is 7.5 - 8.0, and more preferably 7.5 - 7.8.

[0021] In addition, the present invention provides a ganciclovir formulation, comprising components of ganciclovir, trehalose, poloxamer 188, sodium hydroxide, and water for injection, with a pH value of 7.5 - 8.5.

[0022] Preferably, the ganciclovir formulation has a pH value of 7.5 - 8.5 and comprises components in a weight ratio of:

[0023]

[0024] Preferably, the ganciclovir formulation has a pH value of 7.5 - 8.5 and comprises components in a weight ratio of:

[0025]

[0026] On the other hand, the present invention provides a preparation method of the ganciclovir for injection, comprising a formulation step and a freeze - drying step.

[0027] The preparation method of the ganciclovir formulation comprises the steps of: taking about 60% of the total prescription amount of water for injection, heating it to 60 - 70°C, sequentially adding poloxamer 188 and trehalose according to the weight ratio, and carrying out high - speed shear stirring until completely dissolved. Subsequently, slowly add ganciclovir and continuously stir until completely dissolved. During this period, adjust the pH to 7.5 - 8.5 with sodium hydroxide solution, and supplement water for injection to the full volume to obtain the ganciclovir formulation. Further, in the formulation step, it also includes: adding 0.1% (w / v) of activated carbon for injection for adsorption, and then filtering and sterilizing through 0.45μm and 0.22μm polyethersulfone filter membranes in sequence.

[0028] The freeze - drying step includes: a pre - freezing stage, a sublimation drying stage, and an analytical drying stage. The pre - freezing stage includes quickly cooling to - 40°C and maintaining for 2 hours to ensure the formation of a uniform amorphous matrix;

[0029] The sublimation drying includes a first stage: slowly heating to - 20°C, with a vacuum degree ≤ 15 Pa, and maintaining for 10 hours; a second stage: heating to 0°C, with a vacuum degree ≤ 10 Pa, and maintaining for 8 hours; the analytical drying includes heating to 25°C, with a vacuum degree ≤ 3 Pa, and maintaining for 5 hours to ensure that the water content ≤ 2.0%.

[0030] Long - term test data shows that after the ganciclovir freeze - dried preparation prepared by using this freeze - drying process is stored at 25°C / 60% RH for 18 months, the content still remains ≥ 98.6%, the water content ≤ 0.81%, the related substances ≤ 0.27%, and the bacterial endotoxin always meets the regulations, meeting the clinical long - term storage requirements.

[0031] Ganciclovir for injection provided by the present invention and its preparation method can significantly reduce clinical irritation. By optimizing the excipient combination and process, the pH value of the preparation is controlled at 7.5 - 8.5, preferably 7.5 - 7.8, effectively avoiding adverse reactions such as local pain and phlebitis caused by the traditional high - alkaline formula with pH > 11, and greatly improving the drug safety of patients. The freeze - dried structure has excellent stability. By adopting an innovative pre - freezing stage and staged sublimation drying process, combined with the synergistic effect of trehalose and poloxamer 188, the problem of skeleton collapse during the freeze - drying process is successfully solved. Accelerated and long - term stability tests show that the appearance of the preparation has no collapse, the water content ≤ 2.0%, and the related substances increase slowly (all below 0.3%), meeting the pharmacopoeia standards. The optimized formula makes the reconstitution time of the freeze - dried powder injection ≤ 30 seconds, the clarity of the reconstituted solution is always "colorless and clear", and the clarity time > 48 hours, without turbidity or insoluble particles generated, which is convenient for clinical use and has high safety. The introduction of trehalose and poloxamer 188 enhances the solubilization effect, and the synergistic effect of the excipient combination significantly improves the stability of the solution. Through activated carbon adsorption combined with double filtration (0.45μm and 0.22μm PES membranes), endotoxins are effectively removed with a low drug loss rate; the freeze - drying cycle is shortened to 23 hours, improving the efficiency compared with the traditional process and reducing the production cost. In summary, on the premise of ensuring the drug efficacy, the present invention has comprehensive advantages such as low irritation, high stability, rapid reconstitution, and process economy, providing a safer, more efficient, and stable ganciclovir for injection preparation for clinical use. Detailed implementation modes

[0032] To better understand the technical solution of the present invention, the following further illustrates the technical solution of the present invention with specific examples. The examples are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention.

[0033] Example 1. Preparation of the solution of ganciclovir for injection

[0034]

[0035] Take about 60% of the total prescription amount of injection water, heat it to 60 - 70°C, sequentially add poloxamer 188 and trehalose according to the weight ratio, stir at high speed with shear until completely dissolved, then slowly add ganciclovir, and continue to stir until completely dissolved. During this period, adjust the pH to 7.5 - 8.5 with sodium hydroxide solution, make up the injection water to the full volume, and detect the pH and clarity after mixing evenly.

[0036] Example 2. Influence of pH value on the clarity of the solution

[0037] Table 1

[0038] Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8 Prescription 9 pH value 6.5 7.0 7.2 7.5 7.8 8.0 8.5 9.0 9.5 Clarification time ＜12h ＜20h ＞24h ＞48h ＞48h ＞48h ＞48h ＞48h ＞48h

[0039] According to the formulation of Example 1, the effect on the clarity of the prepared solution at different pH values was tested. It can be seen from the experiments in Table 1 that at pH 7.5, ganciclovir can dissolve better. Considering the irritation of high pH values, pH 7.5 was selected for subsequent experiments.

[0040] Example 3. Effect of Excipients on the Clarity of Ganciclovir Sodium for Injection Prepared Solution

[0041] Table 2

[0042] Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Mannitol √ Sorbitol √ Glucose √ Lactose √ Glycine √ Trehalose √ Poloxamer 188 √ √ √ √ √ √ √ Clarity Turbid Slightly turbid Slightly turbid ＜4h ＜8h Turbid ＞48h

[0043] According to the formulation of Example 1, trehalose was successively replaced with mannitol, sorbitol, glucose, lactose, and glycine, and the effect of different excipients on the clarity of the prepared solution at pH 7.5 was tested. It can be seen from the experimental results that when poloxamer 188 was used alone (Formulation 1), the prepared solution became turbid, indicating that its solubilizing ability requires the synergistic effect of specific excipients. When poloxamer 188 was combined with glucose (Formulation 4) or lactose (Formulation 5), the clarification time was shortened to < 4 hours and < 8 hours respectively, but there was still slight turbidity. The combinations of mannitol (Formulation 1) and sorbitol (Formulation 2) with poloxamer 188 did not significantly improve the clarity, suggesting insufficient compatibility with poloxamer 188. While the excipient trehalose has high compatibility with poloxamer 188, which can avoid turbidity caused by crystallization.

[0044] Example 4. Filtration, Sterilization, and Filling

[0045] According to the formulation of Example 1, 0.1% (w / v) activated carbon for injection was added, stirred for 20 minutes, and then filtered to remove carbon. It was successively passed through 0.45 μm and 0.22 μm polyethersulfone (PES) membranes to ensure sterility. The medicinal solution was dispensed into sterile vials, with a filling volume of 2.5 mL per vial, and a half rubber stopper was added.

[0046] Example 5. Freeze-drying Process

[0047] Pre-freezing stage:

[0048] Rapidly cool to -40 °C and maintain for 2 hours to ensure the formation of a uniform amorphous matrix.

[0049] Sublimation drying:

[0050] First stage: Slowly heat up to -20 °C, the vacuum degree ≤ 15 Pa, and maintain for 10 hours.

[0051] Second stage: Heat up to 0 °C, the vacuum degree ≤ 10 Pa, and maintain for 8 hours.

[0052] Desorption drying:

[0053] Heat up to 25 °C, the vacuum degree ≤ 3 Pa, and maintain for 5 hours to ensure the moisture content ≤ 2.0%.

[0054] Plug pressing seal:

[0055] After fully pressing the plug and crimping the aluminum cap, perform appearance inspection (white loose lumps, no collapse), redissolution time (≤30 seconds), and sterility testing.

[0056] Example 6. Stability study

[0057] According to the technical specifications of Appendix 9001, "Guidelines for Stability Testing of Raw Drugs and Preparations" in the Chinese Pharmacopoeia (2020 Edition), conduct a stability study on 3 batches of freeze-dried ganciclovir for injection prepared in Example 5. The specific implementation plan is as follows:

[0058] (1) Accelerated stability test

[0059] Continuously examine for 6 months under the enhanced conditions of 40°C ± 2°C and 75% ± 5% relative humidity. Sampling and testing are carried out on the starting day of the test (0 month), and at the end of the 1st, 2nd, 3rd, and 6th months. Parallel samples are set for each batch to ensure data reliability. The test results are shown in Table 3.

[0060] Table 3

[0061]

[0062] Result discussion and analysis

[0063] In the accelerated stability test (40°C ± 2°C, 75% ± 5% RH), the test results of 3 batches of samples (PL001 - PL003) show that: all batches maintained "white loose lumps, no collapse" within 6 months, the pH value fluctuated in the range of 7.5 - 7.9, with no obvious deviation from the initial value (7.5 - 7.6), indicating that the physical form and acid-base stability of the preparation were good under high temperature and high humidity conditions. As the storage time extended, the moisture content gradually increased, but the highest value at the end of 6 months was only 1.0% (PL001), far lower than the pharmacopoeia requirement of ≤3.0%, indicating that the freeze-drying process effectively inhibited hygroscopicity. The related substances increased from the initial 0.09% - 0.15% to 0.17% - 0.20%, with a slow increase rate and all lower than the critical value of 0.3%, meeting the pharmacopoeia requirements for impurity limits. The content decreased from the initial 98.7% - 101.1% to 98.6% - 99.0%, with a decrease rate of ≤2.5%, meeting the standard that the content of the active ingredient of the drug should be ≥95.0%. All batches always met the regulations and did not pose a risk of microbial contamination due to high temperature and high humidity conditions.

[0064] Conclusion: Under accelerated conditions, the physical and chemical properties of the preparation are stable, and the key quality indicators of content, impurities, and moisture all meet the pharmacopoeia standards, proving its good short-term anti-deterioration ability.

[0065] (2) Long-term stability test

[0066] Under the simulated storage conditions of 25°C ± 2°C and 60% ± 5% relative humidity, continuous monitoring was carried out for 18 months. Regular sampling and analysis were carried out at the end of 0, 3, 6, 9, 12, and 18 months as planned. The test results are shown in Table 4.

[0067] Table 4

[0068]

[0069]

[0070] Result discussion and analysis

[0071] In the long-term stability test (25°C ± 2°C, 60% ± 5% RH), the 18-month monitoring data of 3 batches of samples (PL004 - PL006) showed that: for all batches, there was no collapse in appearance within 18 months, the pH value slightly increased from 7.5 - 7.6 to 7.8 - 7.9, but still remained within the process control range of 7.5 - 8.5, indicating that long-term storage did not cause significant acid-base deviation. The moisture content slowly increased from the initial 0.58% - 0.71% to 0.66% - 0.81%, always ≤ 2.0%, meeting the low moisture requirements for freeze-dried preparations. The related substances accumulated from the initial 0.08% - 0.15% to 0.19% - 0.27%. Although there was a slight increase, it was far lower than the impurity limit of 0.5% in the pharmacopoeia, suggesting that the drug degradation rate was controllable. The content decreased from the initial 99.91% - 101.26% to 98.64% - 99.89%, with a decrease of ≤ 2.6%, still higher than the effective limit of 95.0%, indicating excellent stability of the active ingredient. It complied with the regulations throughout the process, proving that the packaging sealability and production process could effectively ensure sterility.

[0072] Conclusion: Under long-term storage conditions, the quality of the preparation is stable, and the key indicators meet the requirements of the pharmacopoeia, supporting the long-term effectiveness and safety of its clinical application.

[0073] Example 7. Reconstitution performance investigation

[0074] The ganciclovir freeze-dried powder injection prepared according to Example 5 was reconstituted with water for injection at 25°C ± 2°C. The test results are shown in Table 5.

[0075] Table 5

[0076] Batch PL007 PL008 PL009 pH after reconstitution 7.6 7.8 7.6 Reconstitution time (s) 12 10 14 Clarity Colorless and clear Colorless and clear Colorless and clear Clarification time (h) ＞48 ＞48 ＞48 Related substances (%) 0.07 0.11 0.08 Content (%) 100.33 99.61 98.96

[0077] Result discussion and analysis

[0078] The reconstitution performance tests on 3 batches of samples (PL007 - PL009) showed that the reconstitution time ≤ 14 seconds, significantly better than ≥ 30 seconds of the traditional process, indicating that the optimized formulation and lyophilization process significantly improved the reconstitution efficiency. The reconstituted solutions were all "colorless and clear", with a clarification time > 48 hours, and no turbidity or insoluble particles were generated, meeting the strict requirements of the pharmacopoeia for the clarity of injections. The pH value after reconstitution was stable at 7.6 - 7.8, and the related substance content was 0.07% - 0.11%, with no significant difference from that before lyophilization, indicating that the reconstitution process did not cause drug degradation or impurity increase. The content after reconstitution was 98.96% - 100.33%, basically consistent with the initial content, verifying the reliability of the reconstitution operation.

[0079] Conclusion: The preparation has excellent reconstitution performance, convenient clinical use, and high solution stability, meeting the requirements of rapid drug administration and safety for injections.

[0080] It should be noted that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art can still modify the technical solutions described in the above embodiments or perform equivalent replacements for some of the technical features, and all should be included in the protection scope of the present invention.

Claims

1. Ganciclovir for injection, characterized in that, It comprises components in the following weight ratios: 100 parts of ganciclovir, 80 - 150 parts of trehalose, 20 - 50 parts of poloxamer 188, and an appropriate amount of sodium hydroxide, and the pH value of the preparation is 7.5 - 8.

5.

2. The ganciclovir for injection according to claim 1, wherein The weight ratio of the components is: 100 parts of ganciclovir, 100 parts of trehalose, 30 parts of poloxamer 188, and an appropriate amount of sodium hydroxide.

3. The ganciclovir for injection according to claim 1 or 2, characterized in that, The pH value is 7.5 - 8.

0.

4. The ganciclovir for injection according to claim 3, wherein, The pH value is 7.5 - 7.

8.

5. The preparation method of ganciclovir for injection according to any one of claims 1-4, characterized in that, It comprises the following steps: (1) Solution preparation: Take 60% of the total prescription amount of water for injection, heat it to 60 - 70 °C, sequentially add poloxamer 188 and trehalose, stir to dissolve, then add ganciclovir, adjust the pH to 7.5 - 8.5, and make up the volume with water for injection to the full amount. (2) Freeze-drying: It includes a pre-freezing stage, a sublimation drying stage, and an analytical drying stage. The pre-freezing stage is to rapidly cool down to -40 °C and hold for 2 hours. The sublimation drying includes: in the first stage, raise the temperature to -20 °C, the vacuum degree ≤ 15 Pa, and maintain for 10 hours. In the second stage, raise the temperature to 0 °C, the vacuum degree ≤ 10 Pa, and maintain for 8 hours. The analytical drying is to raise the temperature to 25 °C, the vacuum degree ≤ 3 Pa, and maintain for 5 hours to make the water content ≤ 2.0%.

6. The preparation method according to claim 5, characterized in that, The solution preparation step further includes: adding 0.1% (w / v) of activated carbon for injection for adsorption, and then sequentially filtering and sterilizing through 0.45 μm and 0.22 μm polyethersulfone filter membranes.

7. The preparation method according to claim 5 or 6, characterized in that, The reconstitution time of the freeze-dried preparation ≤ 30 seconds, the clarity of the reconstituted solution remains colorless and clear for > 48 hours, and the content of related substances ≤ 0.3%.

8. Use of ganciclovir for injection in the preparation of an antiviral drug, characterized in that, The drug is used for preventing or treating cytomegalovirus infection in immunocompromised patients.

9. The application according to claim 8, characterized in that, After the ganciclovir for injection is stored at 25 °C / 60% RH for 18 months, the content ≥ 98.6%, the water content ≤ 0.81%, and the related substances ≤ 0.27%.

10. A ganciclovir solution, characterized in that, It comprises components in the following weight ratios: 100 parts of ganciclovir, 80 - 150 parts of trehalose, 20 - 50 parts of poloxamer 188, and an appropriate amount of sodium hydroxide, and the volume is made up to the full amount with water for injection, and the pH value of the solution preparation is 7.5 - 8.5.

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