Traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases and preparation method thereof

Abstract

The invention discloses a traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases and a preparation method thereof, and relates to the technical field of traditional Chinese medicine injections.The injection is an erigeron breviscapus freeze-dried powder injection, takes an erigeron breviscapus extract as a unique active ingredient and contains pharmaceutical auxiliary materials; wherein each unit of the preparation contains 3-5g of erigeron breviscapus total flavonoids, the water content of the freeze-dried powder injection is less than or equal to 3.0%, and the pharmaceutical auxiliary materials comprise a stabilizer and a supporting agent; the stabilizer is one of sodium pyrosulfite or sodium hydrogen sulfite, and the addition amount of the stabilizer is 0.05-0.1% of the total weight of the preparation; the supporting agent is a combination of mannitol and glucose, and the addition amount of the supporting agent is 3-5% of the total weight of the preparation, according to the scheme, through purification-molding-quality control three-in-one innovation, on the premise that no high-end equipment is added, four breakthrough of safety, effectiveness, stability and economical efficiency is achieved, the upgrading requirement of the traditional Chinese medicine injection industry is completely met, and the application prospect is wide. The problem of safety of traditional Chinese medicine injections is effectively solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine injection, more particularly to a traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases and a preparation method thereof. BACKGROUND

[0002] The current traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases is represented by Breviscapine Injection, the production process of which is strictly in accordance with the national drug standard: the medicinal materials are decocted and concentrated, and then subjected to preliminary impurity removal by single ethanol precipitation (alcohol content 70-80%); the final preparation form is a water-soluble injection containing sodium chloride for adjusting osmotic pressure.

[0003] The main technical features of the current production process of Breviscapine Injection are as follows: the prescription medicinal material Breviscapine is decocted twice with water, and the decoction is combined and concentrated; then ethanol is added for alcohol precipitation, and after cold storage, filtration is performed; the filtrate is subjected to ethanol recovery under reduced pressure and then concentrated again, and the extract obtained by extraction with ethyl acetate is the Breviscapine extract. When preparing the injection, an appropriate amount of the extract is dissolved with water, heated and boiled, and then filtered; sodium chloride for injection is added to dissolve and adjust to the specified volume, and after filtration, filling and sealing, sterilization, the finished product is obtained. However, the quality of the injection is easily affected by many factors such as production process, storage conditions and transportation process, and it is difficult to control, which may affect the clinical treatment effect.

[0004] Based on this, the present application provides a traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases and a preparation method thereof. SUMMARY

[0005] In order to solve the problems raised in the background art, the present application provides a traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases and a preparation method thereof.

[0006] The present application provides a traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases, which adopts the following technical solution:

[0007] A traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases, which comprises that the injection is Breviscapine freeze-dried powder, Breviscapine extract is used as the only active ingredient, and pharmaceutical excipients are contained; wherein each unit of preparation contains 3-5 g of Breviscapine total flavonoids, and the water content of the freeze-dried powder is ≤3.0%.

[0008] Preferably, the pharmaceutical excipients comprise a stabilizer and a supporting agent; the stabilizer is one of sodium metabisulfite or sodium bisulfite, and the addition amount is 0.05-0.1% of the total weight of the preparation; the supporting agent is a combination of mannitol and glucose, and the addition amount is 3-5% of the total weight of the preparation.

[0009] A preparation method of a traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases, comprising the following steps:

[0010] S1. Take the medicinal material of Erigeron breviscapus, add 8-10 times the amount of water and boil twice for 2 hours each time. Combine the decoctions, filter through a 100-mesh sieve, and concentrate the filtrate under reduced pressure at 70°C to a relative density of 1.35. Add ethanol to make the alcohol content reach 80±5%, refrigerate at 4°C for 48 hours, collect the supernatant to recover ethanol, and concentrate to a relative density of 1.38 at 70°C. Extract with ethyl acetate three times, combine the extracts, and concentrate under reduced pressure at 60°C until no solvent remains to obtain Erigeron breviscapus extract;

[0011] S2. Take the extract, add water for injection to 1000 mL, adjust the pH to 6.8–7.2 with 5 mol / L NaOH, add 0.08% sodium metabisulfite and 4% mannitol-glucose (1:1) mixed support agent, stir to dissolve, add 0.05% activated carbon, boil for 10 minutes, and filter through a 0.22 μm microporous membrane;

[0012] S3. Dispense the drug solution into vials, pre-freeze to -40°C and keep warm for 2 hours, dry at -20°C and 10Pa for 6 hours, then desorb and dry at 25°C and 10Pa for 4 hours, cap and seal to obtain freeze-dried powder injection with a moisture content of ≤3.0%.

[0013] Preferably, in S1, the ethyl acetate extraction is performed three times, and the shaking time for each extraction is ≥15 minutes.

[0014] Preferably, in S2, sterile filtration is performed using a 0.22 μm polyethersulfone filter membrane.

[0015] Preferably, in S3, the pre-freezing adopts programmed cooling: from 25°C to -40°C at a rate of 1°C / min, and maintained at -40°C for 2 hours.

[0016] Preferably, in step S1, the volume of ethyl acetate: the volume of the concentrated solution = 1:1.

[0017] Preferably, in S2, the extract contains 3-5 g of total flavonoids.

[0018] In summary, the present invention has the following beneficial technical effects:

[0019] This solution achieves four breakthroughs in safety, effectiveness, stability, and economy through the three-in-one innovation of "purification-molding-quality control" without adding any high-end equipment. It fully meets the needs of the upgrading of the Chinese medicine injection industry and effectively solves the stubborn safety problem of Chinese medicine injection.

[0020] The above summary is for illustrative purposes only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments and features described above, further aspects, embodiments and features of the present invention will be readily apparent by reference to the accompanying drawings and the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The present invention is a flowchart of a method for preparing a Chinese medicine injection for treating cardiovascular and cerebrovascular diseases according to an embodiment of the present invention. DETAILED DESCRIPTION

[0022] The following is combined with Figure 1 The present invention is described in further detail.

[0023] It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0024] This embodiment provides a traditional Chinese medicine injection for treating cardiovascular and cerebrovascular diseases, including an injection of breviscapus breviscapus freeze-dried powder injection, which contains breviscapus breviscapus extract as the sole active ingredient and contains pharmaceutical excipients; wherein each unit of preparation contains 3-5g of breviscapus breviscapus total flavonoids, and the water content of the freeze-dried powder injection is ≤3.0% (determined by Karl Fischer method).

[0025] Pharmaceutical excipients include stabilizers and supporting agents; the stabilizer is one of sodium metabisulfite or sodium bisulfite, and the added amount is 0.05-0.1% of the total weight of the preparation; the supporting agent is a combination of mannitol and glucose (weight ratio 1:1-1:2), and the added amount is 3-5% of the total weight of the preparation.

[0026] Example 1

[0027] S1. Take the medicinal material of Erigeron breviscapus, add 8-10 times the amount of water and boil twice, each time for 2 hours. Combine the decoctions, filter through a 100-mesh sieve, and concentrate the filtrate under reduced pressure at 70°C to a relative density of 1.35. Add ethanol to make the alcohol content reach 80±5%, refrigerate at 4°C for 48 hours, take the supernatant to recover ethanol, and concentrate to a relative density of 1.38 at 70°C. Extract with ethyl acetate three times, combine the extracts, and concentrate under reduced pressure at 60°C until no solvent remains to obtain Erigeron breviscapus extract. The number of ethyl acetate extractions is 3, and the shaking time for each extraction is ≥15 minutes. The volume of ethyl acetate: volume of concentrate = 1:1;

[0028] S2. Take the extract (containing 3–5 g of total flavonoids), add water for injection to 1000 mL, adjust the pH to 6.8–7.2 with 5 mol / L NaOH, add 0.08% sodium metabisulfite and 4% mannitol-glucose (1:1) mixed support agent, stir to dissolve, add 0.05% activated carbon and boil for 10 minutes, filter through a 0.22 μm microporous membrane, and sterile filter using a 0.22 μm polyethersulfone membrane;

[0029] S3, the medicine liquid is divided into the Westlin bottle, pre-freezing to -40℃ and keeping warm 2 hours, drying 6 hours under the condition of -20℃, 10Pa, then resolving drying 4 hours under the condition of 25℃, 10Pa, pressing the lid and sealing, the water content of the freeze-dried powder is ≤3.0%, the pre-freezing uses the programmed temperature drop: from 25℃ to -40℃ at 1℃ / min, and keeping -40℃ for 2 hours.

[0030] Comparative Example One

[0031] S1, the medicine liquid is divided into the Westlin bottle, pre-freezing to -40℃ and keeping warm 2 hours, drying 6 hours under the condition of -20℃, 10Pa, then resolving drying 4 hours under the condition of 25℃, 10Pa, pressing the lid and sealing, the water content of the freeze-dried powder is ≤3.0%, the pre-freezing uses the programmed temperature drop: from 25℃ to -40℃ at 1℃ / min, and keeping -40℃ for 2 hours.

[0032] S2, the medicine liquid is divided into the Westlin bottle, pre-freezing to -40℃ and keeping warm 2 hours, drying 6 hours under the condition of -20℃, 10Pa, then resolving drying 4 hours under the condition of 25℃, 10Pa, pressing the lid and sealing, the water content of the freeze-dried powder is ≤3.0%, the pre-freezing uses the programmed temperature drop: from 25℃ to -40℃ at 1℃ / min, and keeping -40℃ for 2 hours.

[0033] S3, the medicine liquid is divided into the Westlin bottle, pre-freezing to -40℃ and keeping warm 2 hours, drying 6 hours under the condition of -20℃, 10Pa, then resolving drying 4 hours under the condition of 25℃, 10Pa, pressing the lid and sealing, the water content of the freeze-dried powder is ≤3.0%, the pre-freezing uses the programmed temperature drop: from 25℃ to -40℃ at 1℃ / min, and keeping -40℃ for 2 hours.

[0034] Table One

[0035] Detection indicators Comparative Example 1 Example 1 Advantage Rate Freeze-drying time 14.2h 12.0h ↓15.5％ Reconstitution time 48±3s 22±2s ↓54.2％ Freeze-dried cake crack rate 18% (12 / 60 bottles) 0% (0 / 60 bottles) Completely eliminated Total flavonoid transfer rate 80.1％ 90.3％ ↑12.7％

[0036] From Table One, the compound support (mannitol-glucose) cooperates with the programmed pre-freezing, which significantly improves the freeze-drying efficiency and the product appearance quality by forming the uniform microcrystalline structure.

[0037] Comparative Example Two

[0038] S1, the medicine liquid is divided into the Westlin bottle, pre-freezing to -40℃ and keeping warm 2 hours, drying 6 hours under the condition of -20℃, 10Pa, then resolving drying 4 hours under the condition of 25℃, 10Pa, pressing the lid and sealing, the water content of the freeze-dried powder is ≤3.0%, the pre-freezing uses the programmed temperature drop: from 25℃ to -40℃ at 1℃ / min, and keeping -40℃ for 2 hours.

[0039] S2, take the extract (containing total flavonoids 3-5 g), add water for injection to 1000 mL, adjust pH to 6.8-7.2 with 5 mol / L NaOH, add 0.08% sodium metabisulfite and 4% mannitol-glucose (1:1) mixed support, stir to dissolve, add 0.05% activated carbon, boil for 10 minutes, filter through 0.22 μm microporous filter, sterile filter with 0.22 μm polyether sulfone filter;

[0040] S3, the liquid medicine is divided into a Westlin bottle, pre-frozen to -40℃ and incubated for 2 hours, dried at -20℃, 10 Pa for 6 hours, then resolved and dried at 25℃, 10 Pa for 4 hours, and sealed with a cover, to obtain a freeze-dried powder needle with water content ≤3.0%, the pre-freezing uses a programmed temperature reduction: from 25℃ to -40℃ at 1℃ / min, and keep at -40℃ for 2 hours.

[0041] Table II

[0042]

[0043]

[0044] As shown in Table II, the three-step ethyl acetate extraction can efficiently remove heat-sensitive impurities such as tannins and proteins, and combined with the stabilizer system, the safety problem of traditional Chinese medicine injections is completely solved.

[0045] Example II

[0046] S1, take the Erigeron brevisca- phus medicinal material, add 8-10 times the amount of water and decoct for 2 hours each time, combine the decoction, filter through a 100 mesh sieve, concentrate the filtrate to a relative density of 1.35 at 70℃ under reduced pressure, add ethanol to make the alcohol content reach 80±5%, and store at 4℃ for 48 hours, recover the ethanol from the supernatant, and concentrate to a relative density of 1.38 at 70℃, then extract with ethyl acetate for 3 times, combine the extract, and concentrate to no solvent residue at 60℃ under reduced pressure, to obtain the Erigeron brevisca- phus extract, the number of ethyl acetate extraction is 3 times, and the shaking time of each extraction is ≥15 minutes, and the volume of ethyl acetate: the volume of concentrated solution = 1:1;

[0047] S2, take the extract (containing total flavonoids 3-5 g), add water for injection to 1000 mL, adjust pH to 6.8-7.2 with 5 mol / L NaOH, add 0.08% sodium metabisulfite and 4% mannitol-glucose (1:1) mixed support, stir to dissolve, add 0.05% activated carbon, boil for 10 minutes, filter through 0.22 μm microporous filter, sterile filter with 0.22 μm polyether sulfone filter;

[0048] S3. Dispense the drug solution into vials, pre-freeze to -40°C and keep warm for 2 hours, dry at -20°C and 10Pa for 6 hours, and then decompose and dry at 25°C and 10Pa for 4 hours. Seal the bottle with a cap to obtain a freeze-dried powder injection with a moisture content of ≤3.0%. Pre-freeze with programmed cooling: from 25°C to -40°C at a rate of 1°C / min, and keep at -40°C for 2 hours.

[0049] The finished product (lyophilized powder injection) was subjected to accelerated testing at 40°C / RH75% for 6 months.

[0050] Specifically, initially, the total flavonoids content was 4.52 (g / stick), the related substances increased by 0.21%, and it was a white loose mass (appearance); after 3 months, the total flavonoids content was 4.48 (g / stick), the related substances increased by 0.35%, and there was no change (appearance); after 6 months, the total flavonoids content was 4.31 (g / stick), the related substances increased by 0.58%, it was slightly yellow, and there was no cracking (appearance). It can be seen that the moisture content ≤3% + the composite stabilizer enables the product to maintain its core quality under accelerated conditions.

[0051] Example 3

[0052] S1. Take the medicinal material of Erigeron breviscapus, add 8-10 times the amount of water and boil twice, each time for 2 hours. Combine the decoctions, filter through a 100-mesh sieve, and concentrate the filtrate under reduced pressure at 70°C to a relative density of 1.35. Add ethanol to make the alcohol content ≥85%, refrigerate at 4°C for 48 hours, take the supernatant to recover ethanol, and concentrate to a relative density of 1.38 at 70°C. Extract with ethyl acetate three times, combine the extracts, and concentrate under reduced pressure at 60°C until no solvent remains to obtain Erigeron breviscapus extract. The number of ethyl acetate extractions is 3, and the shaking time for each extraction is ≥15 minutes. The volume of ethyl acetate: volume of concentrate = 1:1;

[0053] S2. Take the extract (containing 3–5 g of total flavonoids), add water for injection to 1000 mL, adjust the pH to 6.8–7.2 with 5 mol / L NaOH, add 0.08% sodium metabisulfite and 4% lactose-glucose (1:1) mixed support agent, stir to dissolve, add 0.05% activated carbon and boil for 10 minutes, filter through a 0.22 μm microporous membrane, and sterile filter using a 0.22 μm polyethersulfone membrane;

[0054] S3. Dispense the drug solution into vials, pre-freeze to -40°C and keep warm for 2 hours, dry at -20°C and 10Pa for 6 hours, and then decompose and dry at 25°C and 10Pa for 4 hours. Seal the bottle with a cap to obtain a freeze-dried powder injection with a moisture content of ≤3.0%. Pre-freeze with programmed cooling: from 25°C to -40°C at a rate of 1°C / min, and keep at -40°C for 2 hours.

[0055] This solution achieves four breakthroughs in safety, effectiveness, stability, and economy through the three-in-one innovation of "purification-molding-quality control" without adding any high-end equipment. It fully meets the needs of the upgrading of the Chinese medicine injection industry and effectively solves the stubborn safety problem of Chinese medicine injection.

[0056] In the description of the present invention, the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, a feature specified as "first" or "second" may explicitly or implicitly include one or more of such features. "Multiple" means two or more, unless otherwise specifically defined.

[0057] In the present invention, unless otherwise expressly specified or limited, when a first feature is "above" or "below" a second feature, it may mean that the first and second features are in direct contact, or that the first and second features are in indirect contact through an intermediary. Furthermore, when a first feature is "above," "above," or "above" a second feature, it may mean that the first feature is directly above or diagonally above the second feature, or simply means that the first feature is at a higher level than the second feature. When a first feature is "below," "below," or "below" a second feature, it may mean that the first feature is directly below or diagonally below the second feature, or simply means that the first feature is at a lower level than the second feature.

[0058] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0059] In the drawings of the embodiments disclosed in the present invention, only the structures related to the embodiments disclosed in the present invention are involved. Other structures can refer to the general design. In the absence of conflict, the same embodiment and different embodiments of the present invention can be combined with each other.

[0060] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A Chinese medicine injection for treating cardiovascular and cerebrovascular diseases, characterized in that: include: The injection is a freeze-dried powder injection of Erigeron breviscapus, which contains Erigeron breviscapus extract as the only active ingredient and contains pharmaceutical excipients; Each unit of the preparation contains 3-5g of total flavonoids from Erigeron breviscapus, and the water content of the freeze-dried powder injection is ≤3.0%.

2. A Chinese medicine injection for treating cardiovascular and cerebrovascular diseases according to claim 1, characterized in that: The pharmaceutical excipients include stabilizers and support agents; The stabilizer is one of sodium metabisulfite or sodium bisulfite, and the added amount is 0.05-0.1% of the total weight of the preparation; The supporting agent is a combination of mannitol and glucose, and the added amount is 3-5% of the total weight of the preparation.

3. A method for preparing a Chinese medicine injection for treating cardiovascular and cerebrovascular diseases, characterized in that: The following steps are involved: S1. Take the medicinal material of Erigeron breviscapus, add 8-10 times the amount of water and boil twice for 2 hours each time. Combine the decoctions, filter through a 100-mesh sieve, and concentrate the filtrate under reduced pressure at 70°C to a relative density of 1.

35. Add ethanol to make the alcohol content reach 80±5%, refrigerate at 4°C for 48 hours, collect the supernatant to recover ethanol, and concentrate to a relative density of 1.38 at 70°C. Extract with ethyl acetate three times, combine the extracts, and concentrate under reduced pressure at 60°C until no solvent remains to obtain Erigeron breviscapus extract; S2. Take the extract, add water for injection to 1000 mL, adjust the pH to 6.8–7.2 with 5 mol / L NaOH, add 0.08% sodium metabisulfite and 4% mannitol-glucose mixed support agent, stir to dissolve, add 0.05% activated carbon, boil for 10 minutes, and filter through a 0.22 μm microporous membrane; S3. Dispense the drug solution into vials, pre-freeze to -40°C and keep warm for 2 hours, dry at -20°C and 10Pa for 6 hours, then desorb and dry at 25°C and 10Pa for 4 hours, cap and seal to obtain freeze-dried powder injection with a moisture content of ≤3.0%.

4. The method for preparing a Chinese medicine injection for treating cardiovascular and cerebrovascular diseases according to claim 3, wherein: In S1, the ethyl acetate extraction is performed three times, and the shaking time for each extraction is ≥15 minutes.

5. The method for preparing a Chinese medicine injection for treating cardiovascular and cerebrovascular diseases according to claim 3, characterized in that: In S2, sterile filtration was performed using a 0.22 μm polyethersulfone filter membrane.

6. The method for preparing a Chinese medicine injection for treating cardiovascular and cerebrovascular diseases according to claim 3, characterized in that: In S3, the pre-freezing was performed by programmed cooling: from 25°C to -40°C at a rate of 1°C / min, and maintained at -40°C for 2 hours.

7. The method for preparing a Chinese medicine injection for treating cardiovascular and cerebrovascular diseases according to claim 3, characterized in that: In step S1, the volume of ethyl acetate: the volume of the concentrated solution = 1:

1.

8. The method for preparing a Chinese medicine injection for treating cardiovascular and cerebrovascular diseases according to claim 3, characterized in that: In S2, the extract containing 3–5 g of total flavonoids was taken.

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