Butylphthalide small volume injection, its preparation method and application

Abstract

The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a butylphthalide small volume injection. The injection contains butylphthalide, HS-15 and water. It is characterized in that the mass ratio of butylphthalide, HS-15 and water in the injection is 1:10-40:200-800, and the pH value of the injection is 3.5-5.5. The butylphthalide small volume injection of the present invention has a shorter cloud point recovery time, and is of stable quality, safe and controllable.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a butylphthalide oral solution, a preparation method thereof and an application thereof. Background Art

[0002] Butylphthalide (3-n-butylphthalide, abbreviated as NBP), with the chemical name of 3-butyl-1(H)-isobenzofuranone, also known as apiumetin, can be extracted from celery seeds or synthesized artificially. Butylphthalide is an oily liquid, insoluble in water, sensitive to light, with a strong celery smell, and contains a chiral carbon atom in the molecule. Therefore, it exists in two optical isomers, namely levobutylphthalide and dexbutylphthalide, and its pharmaceutical form is usually levobutylphthalide or racemic butylphthalide. Butylphthalide can reduce the infarct volume after focal cerebral ischemia, increase cerebral blood flow in the ischemic area and improve microcirculation in the cerebral ischemic area, protect mitochondrial function, reduce the degree of neurological function damage, and improve cerebral energy metabolism after global cerebral ischemia, etc., acting on multiple links of the pathological process of cerebral ischemia; the reported indications include mild, moderate and severe stroke, cerebral ischemia, cerebral infarction, dementia, antithrombosis, Parkinson's syndrome, etc.

[0003] The chemical structural formula of butylphthalide is as follows:

[0004] 。

[0005] Combined with clinical practice, butylphthalide is mostly prepared into an injection dosage form; however, due to the water-insolubility of butylphthalide, a large amount of solubilizing agents need to be used for solubilization treatment. Commonly used ones are cyclodextrin-based solubilizing agents, such as hydroxypropyl-β-cyclodextrin and sodium sulfobutyl ether β-cyclodextrin reported in the patent document CN112386571A. But because the injection directly enters the blood for metabolism, it is reported that such cyclodextrin excipients have large adverse reactions such as nephrotoxicity, hemolysis, teratogenicity and carcinogenicity, with great potential safety hazards. In addition, for the convenience of transportation and storage, the current large-volume infusion completely fails to meet the needs. Therefore, there is an urgent clinical need for a mild and non-toxic butylphthalide small-volume injection.

[0006] Patent CN103505409B first confirmed that 15-hydroxystearate polyethylene glycol ester (hereinafter referred to as "HS-15") can solve the solubilization and safety problems of butylphthalide injection. However, there are very few reports on butylphthalide injection using this new cosolvent in the prior art. Currently, the only available example is Example 2 in Patent CN103505409B. However, the amount of HS-15 used in this example is very small. Although the solution is a clear solution, there are still floating objects visible to the naked eye, indicating that the quality of the small water injection does not meet the pharmaceutical grade standard. In addition, it has been found through research that the solubilization effect of HS-15 is limited. In order to improve the solubilization effect, its mass ratio with butylphthalide needs to reach 10:1 or above; however, HS-15 will produce a blistering phenomenon at high temperatures (such as the sterilization temperature of 121°C in the preparation process), that is, the solubility of HS-15 decreases in a high temperature environment, resulting in the loss of some of its solubilization ability, causing the solution to produce precipitates. However, as the temperature decreases, HS-15 begins to slowly dissolve and recover its solubilizing ability, and the precipitate also slowly dissolves until the precipitate completely disappears. This process is called blister recovery. And the more HS-15 is used, the easier it is to produce blistering, and the recovery after blistering will affect the stability of the quality of the preparation product. However, if the content of butylphthalide in the small water injection is high, the amount of HS-15 required is also high, which will inevitably cause the above-mentioned blistering phenomenon. Regarding this phenomenon, there is no related solution reported in the prior art.

[0007] In view of this, how to provide a pharmaceutical-grade butylphthalide small aqueous injection that is easy to transport and store, safe and effective, and has stable and controllable quality is a difficult problem that needs to be solved urgently in clinical practice. Summary of the invention

[0008] In view of the problems existing in the prior art, the purpose of the present invention is to provide a butylphthalide small water injection solution which is small in size, simple in preparation process, and can be used for both intramuscular injection and intravenous injection. The butylphthalide small water injection solution of the present invention is safe and non-nephrotoxic, has a short recovery time from nausea and vomiting, and has stable and controllable quality.

[0009] The invention provides a butylphthalide small water injection, comprising butylphthalide, a cosolvent and water, wherein the cosolvent is HS-15, the pH value of the injection is 3.5-5.5, and the mass ratio of butylphthalide, HS-15 and water in the injection is 1:10-40:200-800.

[0010] In certain embodiments, the mass ratio of butylphthalide, HS-15 and water in the above injection is 1:10-40:400-800.

[0011] Preferably, the mass ratio of butylphthalide, HS-15 and water in the above injection is 1:10-40:600-800.

[0012] More preferably, the mass ratio of butylphthalide, HS-15 and water in the above injection is 1:15-30:400-800.

[0013] In some embodiments, the pH value of the above injection is 4.0-5.0.

[0014] Preferably, the pH value of the above injection is 4.5.

[0015] In some embodiments, the pH regulator of the above injection is selected from sodium acetate, acetic acid, glacial acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, sodium benzoate, sodium carbonate, citric acid, sodium citrate, glycine, glycine hydrochloride, hydrochloric acid, hydrobromic acid, lactic acid, sodium lactate, maleic acid, methanesulfonic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfuric acid, tartaric acid or sodium tartrate.

[0016] Preferably, the pH regulator of the above injection is hydrochloric acid, acetic acid or sodium dihydrogen phosphate.

[0017] In some embodiments, the specification of the above injection is 5-20 ml.

[0018] Preferably, the specification of the above injection is 10-15 ml.

[0019] The present invention also provides a preparation method of the above injection, including the following steps:

[0020] (1) Weigh the prescribed amount of butylphthalide and HS-15, heat and stir for 90-120 minutes to completely dissolve butylphthalide;

[0021] (2) Cool the solution in step (1) to room temperature, add purified water, stir and mix, and then make up the volume;

[0022] (3) Adjust the pH value of the solution with a pH regulator;

[0023] (4) Filter with a membrane filter, fill and sterilize;

[0024] The whole process is protected by nitrogen.

[0025] In some embodiments, the heating temperature in step (1) is 50-80 °C; preferably, the heating temperature is 60-70 °C.

[0026] In some embodiments, the room temperature in step (2) is 20-30 °C; preferably, the room temperature is 25-30 °C.

[0027] In some embodiments, the pH regulator in the above step (3) is selected from sodium acetate, acetic acid, glacial acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, sodium benzoate, sodium carbonate, citric acid, sodium citrate, glycine, glycine hydrochloride, hydrochloric acid, hydrobromic acid, lactic acid, sodium lactate, maleic acid, methanesulfonic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfuric acid, tartaric acid or sodium tartrate; preferably, the pH regulator is selected from hydrochloric acid, acetic acid or sodium dihydrogen phosphate.

[0028] In some embodiments, the filter membrane in the above step (4) is a 0.22 μm - 0.80 μm filter membrane; preferably, the filter membrane is a 0.3 μm - 0.6 μm filter membrane; more preferably, the filter membrane is a 0.48 μm filter membrane.

[0029] In some embodiments, the sterilization condition in the above step (4) is sterilization at 121 °C for 5 - 20 minutes; preferably, the sterilization condition is sterilization at 121 °C for 10 - 15 minutes.

[0030] The present invention also provides a method of using the above injection solution, including diluting the above injection solution with 0.9% sodium chloride solution or 5% glucose solution and then injecting it for use.

[0031] The injection solution of the present invention is used for intravenous drip or intramuscular injection.

[0032] The butylphthalide in the above injection solution includes but is not limited to racemic butylphthalide or levobutylphthalide. In a specific prescription, the mass of butylphthalide is calculated based on C 12 H 14 O2.

[0033] The above water includes but is not limited to purified water, ultrapure water, distilled water.

[0034] The small volume injection solution of the present invention is suitable for common borosilicate glass ampoules and borosilicate glass vials.

[0035] "Above" or "below" in the present invention both include the recited number.

[0036] It should be noted that in order to simplify this prescription as much as possible, the inventors of this application obtained it with great difficulty after a large amount of arduous exploration. First of all, through a large number of experimental explorations, the inventors of this application found that in the small volume injection, when the dosage of HS-15 relative to butylphthalide reaches at least 6:1, it has better dissolution and inclusion stability (the shape is clear, there are no visible foreign matters, and the content is more than 99.8% after 6 months of high-temperature acceleration); but at the same time, it was also found that the phenomenon of clouding of the solution after high-temperature sterilization is obvious, and it is still difficult to recover after standing overnight. Especially when the dosage of HS-15 is larger, the clouding phenomenon is more obvious. Facing this phenomenon, the inventors of this application made a large number of attempts, such as adjusting the pH value (the pH value range includes 2.0-9.0), using different pH regulators (the reagents include common pH regulators in the art such as hydrochloric acid, sodium hydroxide, acetic acid, glycine, disodium hydrogen phosphate, etc.), adjusting the feeding order of materials (mix butylphthalide and HS-15 first and then add water, or dissolve HS-15 in water first and then add butylphthalide), and the preparation temperature (0°C-120°C), adding other excipients such as stabilizers, emulsifiers, antioxidants, etc., but it was found that the problem of clouding recovery cannot be quickly solved (the shortest time still exceeds 3 hours). By accident, the inventors of this application surprisingly found that when the dosage ratio of HS-15 relative to butylphthalide is increased to 10:1 against the convention and the pH value is controlled at 3.0-6.5, the clouding phenomenon can be significantly reduced, and the clouding recovery time is greatly shortened to less than 2.5 hours. Therefore, the inventors of this application continued to explore based on the above clues and finally found that when the dosage ratio (mass ratio) of butylphthalide, HS-15 and water reaches 1:10-40:200-800 and the pH value is controlled at 3.5-5.5, the clouding phenomenon can be significantly reduced, and the clouding recovery time can be shortened to within 2 hours, even within 1.5 hours, and it is not affected by the type of pH regulator. When HS-15 is too low or too high, or the pH is too low or too high, either the clouding recovery time is unstable, or visible foreign matters appear after the solution is subjected to high-temperature influence factor tests, or the impurity content increases, or there are more insoluble particles, or the shape and color of the solution turn yellow, etc. Only when the material ratio and pH value range of the present invention are met, the obtained small volume injection can simultaneously meet the requirements of short clouding recovery time, stable solution and controllable quality.

[0037] Beneficial effects: Compared with the prior art, the butylphthalide small volume injection of the present invention is small in volume, convenient for transportation and storage, has a short clouding recovery time (less than 2.5 hours), and has stable and controllable quality; especially in the 30-day high-temperature influence factor test, the solution property is colorless and clear, the pH value is stable, the maximum single impurity does not exceed 0.3%, the total impurity does not exceed 0.5%, there are no visible foreign matters to the naked eye, the number of insoluble particles above 10μm does not exceed 10, the number of insoluble particles above 25μm does not exceed 40, and the content is stable, all meeting the pharmaceutical grade quality standards. Detailed implementation manners

[0038] The solution of the present invention will be explained below with reference to examples. Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. For specific technologies or conditions not specified in the examples, they shall be carried out according to the technologies or conditions described in the literature in this field or according to the product specifications. Reagents or instruments not indicating the manufacturer are all conventional products obtained through commercial purchase.

[0039] Comparative Example 1: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0040]

[0041] Preparation process: Weigh the prescribed amount of butylphthalide and HS-15, stir at 60-70 °C for 90-120 minutes to completely dissolve butylphthalide; cool down to 25-30 °C, add purified water, stir and mix and then make up the volume to the total volume; adjust the pH value of the solution to the target value with 1 mol / L hydrochloric acid solution; filter with a 0.45 μm filter membrane, fill into 10 equal portions (10 ml / portion), sterilize at 121 °C for 15 minutes; protect with nitrogen throughout the process.

[0042] Comparative Example 2: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0043]

[0044] Preparation process: The same as Comparative Example 1.

[0045] Comparative Example 3: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0046]

[0047] Preparation process: The same as Comparative Example 1.

[0048] Comparative Example 4: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0049]

[0050] Preparation process: The same as Comparative Example 1.

[0051] Example 1: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0052]

[0053] Preparation process: The same as Comparative Example 1.

[0054] Example 2: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0055]

[0056] Preparation process: same as Comparative Example 1.

[0057] Example 3: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0058]

[0059] Preparation process: same as Comparative Example 1.

[0060] Example 4: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0061]

[0062] Preparation process: same as Comparative Example 1.

[0063] Example 5: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0064]

[0065] Preparation process: same as Comparative Example 1.

[0066] Example 6: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0067]

[0068] Preparation process: same as Comparative Example 1.

[0069] Example 7: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0070]

[0071] Preparation process: same as Comparative Example 1.

[0072] Example 8: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0073]

[0074] Preparation process: same as Comparative Example 1.

[0075] Example 9: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0076]

[0077] Preparation process: same as Comparative Example 1.

[0078] Example 10: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0079]

[0080] Preparation process: same as Comparative Example 1.

[0081] Example 11: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0082]

[0083] Preparation process: same as Comparative Example 1.

[0084] Example 12: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0085]

[0086] Preparation process: same as Comparative Example 1.

[0087] Example 13: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0088]

[0089] Preparation process: same as Comparative Example 1.

[0090] Example 14: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0091]

[0092] Preparation process: same as Comparative Example 1.

[0093] Example 15: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0094]

[0095] Preparation process: same as Comparative Example 1.

[0096] Example 16: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0097]

[0098] Preparation process: same as Comparative Example 1.

[0099] Example 17: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0100]

[0101] Preparation process: same as Comparative Example 1.

[0102] Example 18: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0103]

[0104] Preparation process: Weigh the prescribed amounts of butylphthalide and HS-15, stir at 50 - 60°C for 100 - 120 minutes until butylphthalide is completely dissolved; cool down to 20 - 25°C, add purified water, stir and mix, then make up the volume to the total capacity; adjust the pH of the solution to the target value with 1mol / L acetic acid solution; filter through a 0.22μm filter membrane, fill into 10 equal portions (13ml per portion), and sterilize at 121°C for 5 minutes; protect with nitrogen throughout the process.

[0105] Example 19: Butylphthalide small volume injection, the prescription and preparation process are as follows:

[0106]

[0107] Preparation process: Weigh the prescribed amounts of butylphthalide and HS-15, stir at 70 - 80°C for 90 - 100 minutes until butylphthalide is completely dissolved; cool down to 25 - 30°C, add purified water, stir and mix, then make up the volume to the total capacity; adjust the pH of the solution to the target value with 1mol / L sodium dihydrogen phosphate solution; filter through a 0.80μm filter membrane, fill into 10 equal portions (17.5ml per portion), and sterilize at 121°C for 20 minutes; protect with nitrogen throughout the process.

[0108] Test Example 1: Investigation of the clouding recovery time

[0109] After the above samples were sterilized at high temperature, clouding phenomena of varying degrees occurred in each sample; during the natural cooling process of the samples, the clouding phenomena in each sample began to disappear, but the recovery times varied greatly. Starting from the end of sterilization, the entire time was recorded until the solution became completely clear (clouding phenomenon disappeared / clouding recovery), and this time was called the clouding recovery time. The clouding recovery times of each sample are summarized as follows:

[0110]

[0111] Note: (1) Clouding: Gel-like lumps appear at the bottom of the bottle;

[0112] (2) Clouding recovery standard: The solution property is colorless and clear.

[0113] As can be seen from the above table, when the pH value of the small volume injection is either higher than 5.5 (Comparative Example 2) or lower than 3.5 (Comparative Example 1), or the mass ratio of butylphthalide to HS-15 in the small volume injection is lower than 1:10 (Comparative Example 3) or higher than 1:40 (Comparative Example 40), the cloud point recovery time is more than 6 hours. Moreover, the larger the dosage of HS-15, the longer the cloud point recovery time, with a significant difference. When the pH value of the small volume injection is between 3.5 and 5.5, and the mass ratio of butylphthalide, HS-15 and water is between 1:10 and 40:200 and 800, the cloud point recovery time does not exceed 2.5 h (Examples 1 to 19); especially when the pH value of the small volume injection is 4.0 to 5.0, and the mass ratio of butylphthalide, HS-15 and water is between 1:12 and 30:400 and 800, the cloud point recovery time does not exceed 2 hours.

[0114] Thus, it can be seen that the cloud point recovery time of the butylphthalide small volume injection of the present invention is relatively short, greatly reducing the product instability risk and the safety of transportation and storage.

[0115] Test Example 2: Investigation of high temperature stability

[0116] Take the samples of the above comparative examples and examples, place them at 60 °C for 30 days, and take samples at 0 day and 30 days respectively for stability investigation.

[0117] Detection method for related substances: The method of Example 2 of Patent CN201910466351.4 is adopted.

[0118] Detection method for content: (1) Chromatographic conditions: Octadecylsilane chemically bonded silica gel is used as the filler; 10 mmol / L potassium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid)-acetonitrile (40:60) is used as the mobile phase; the detection wavelength is 230 nm; the injection volume is 5 μl. (2) Determination method: Calculate the labeled amount of butylphthalide (C 12 H 14 O2) by the external standard method based on the peak area.

[0119] Visible foreign matters: Determined according to the visible foreign matter inspection method of General Chapter 0904 of the Chinese Pharmacopoeia (2020 Edition), the first method (lamp inspection method). 0 visible foreign matters is grade A, and 1 to 5 visible foreign matters is grade B, both meeting the standards.

[0120] Insoluble particles: Determined according to the second method (microscopic counting method) of the insoluble particle inspection method of General Chapter 0903 of the Chinese Pharmacopoeia (2020 Edition).

[0121] The high temperature stability results of each sample at 0 day and 30 days are statistically presented as follows:

[0122]

[0123] Note: The test data of the above samples at day 0 were tested after the samples were sterilized and naturally cooled to room temperature and the cloud point recovery occurred.

[0124] According to the above table, in the 30-day high-temperature investigation test, when the pH value of the butylphthalide small volume injection is greater than 5.5 (Comparative Example 1) or lower than 3.5 (Comparative Example 2), or the mass ratio of butylphthalide to HS-15 is lower than 1:10 (Comparative Example 3) or higher than 1:40 (Comparative Example 4), either the pH is unstable or the impurity content is relatively high. The maximum single impurity at day 0 exceeds 0.4%, and the total impurity exceeds 0.9%; the maximum single impurity at 30 days exceeds 0.9%, and the total impurity exceeds 1.13%; there are visible foreign matters and there are about 10 particles with a size above 10 μm, and the number of particles with a size above 25 μm exceeds 40. While when the pH value of the butylphthalide small volume injection is between 3.5 and 5.5, and the mass ratio of butylphthalide, HS-15 and water is 1:10-40:200-800 (Examples 1-17), not only the pH is stable during the 30-day high-temperature test, but also the impurities and content are stable and the values are relatively low. Among them, the maximum single impurity at day 0 and 30 days is lower than 0.3%, and the total impurity is lower than 0.5%; there are no visible foreign matters to the naked eye, the number of particles with a size above 10 μm does not exceed 10, and the number of particles with a size above 25 μm does not exceed 40, all meeting the pharmaceutical quality control standards.

[0125] Thus, it can be seen that the butylphthalide small volume injection of the present invention has stable quality, has stability in transportation and storage, has stable quality, and is safe and controllable.

Claims

1. A butylphthalide small volume injection, comprising butylphthalide, a cosolvent and water, wherein the cosolvent is HS-15, characterized in that The pH value of the injection is 4.0 - 4.8, and the mass ratio of butylphthalide, HS-15 and water is 1:12 - 30:500 - 720.

2. The injection according to claim 1, characterized in that, The mass ratio of butylphthalide, HS-15 and water is 1:16 - 30:600 - 720.

3. The injection according to claim 1, characterized in that, The pH value of the injection is 4.

5.

4. The injection according to claim 1, wherein, The pH regulator of the injection is selected from sodium acetate, acetic acid, glacial acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, sodium benzoate, sodium carbonate, citric acid, sodium citrate, glycine, glycine hydrochloride, hydrochloric acid, hydrobromic acid, lactic acid, sodium lactate, maleic acid, methanesulfonic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfuric acid, tartaric acid or sodium tartrate.

5. The injection according to claim 1, characterized in that, The specification of the injection is 5 - 20 ml.

6. The injection according to claim 5, characterized in that, The specification of the injection is 10 - 15 ml.

7. The injection according to claim 5, wherein The specification of the injection is 13 - 18 ml.

8. The preparation method of the injection according to any one of claims 1 - 7, comprising the following steps: (1) Weigh the prescribed amounts of butylphthalide and HS-15, heat and stir for 90 - 120 minutes to completely dissolve butylphthalide; (2) Cool the solution in step (1) to room temperature, add purified water, stir and mix and then make up the volume; (3) Adjust the pH value of the solution with a pH regulator; (4) Filter with a filter membrane, fill and sterilize; The whole process is protected by nitrogen filling.

9. The preparation method according to claim 8, wherein, The heating temperature in step (1) is 50 - 80°C; and / or the room temperature in step (2) is 20 - 30°C; and / or the pH regulator in step (3) is selected from sodium acetate, acetic acid, glacial acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, sodium benzoate, sodium carbonate, citric acid, sodium citrate, glycine, glycine hydrochloride, hydrochloric acid, hydrobromic acid, lactic acid, sodium lactate, maleic acid, methanesulfonic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfuric acid, tartaric acid or sodium tartrate; and / or the filter membrane in step (4) is a 0.22μm - 0.80μm filter membrane; and / or the sterilization condition in step (4) is sterilization at 121°C for 5 - 20 minutes.

10. The preparation method according to claim 8, wherein The heating temperature in step (1) is 60 - 70°C.

11. The preparation method according to claim 8, wherein The room temperature in step (2) is 25 - 30°C.

12. The preparation method according to claim 8, characterized in that, The sterilization condition in step (4) is sterilization at 121°C for 10 - 15 minutes.

13. The application of the injection according to any one of claims 1 - 7 for preparing an intravenous drip or intramuscular injection drug.

14. The application according to claim 13, characterized in that, The injection is diluted with 0.9% sodium chloride solution or 5% glucose solution and then used for injection.

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