CN111346061A - Chlorogenic acid composition and preparation method thereof - Google Patents
Chlorogenic acid composition and preparation method thereof Download PDFInfo
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- CN111346061A CN111346061A CN201811572044.6A CN201811572044A CN111346061A CN 111346061 A CN111346061 A CN 111346061A CN 201811572044 A CN201811572044 A CN 201811572044A CN 111346061 A CN111346061 A CN 111346061A
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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Abstract
The invention provides a novel chlorogenic acid composition which has the advantages of good stability at normal temperature, high solubility, small redissolution volume, more tolerable pH value for human bodies and the like, and is suitable for an injection administration system for subcutaneous/intramuscular administration. The preparation can better meet the safety in the production, transportation and use processes, and provides a more effective drug delivery system composition for clinical application of chlorogenic acid.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a chlorogenic acid composition and a preparation method thereof.
Background
Chlorogenic acid (also known as caffeotannic acid or caffeotannic acid) is a depside formed by the condensation of caffeic acid (caffeicid) and quinic acid (quinic acid), which is a product of aerobic respiratory metabolism of plants. The chemical name of chlorogenic acid is 5-O-caffeoylquinic acid (5-O-caffeoylquinic acid), and the molecular formula is as follows: c16H18O9Molecular weight: 354.31, the structural formula is shown below.
Chlorogenic acid is an important bioactive substance, and the prior art discloses that the chlorogenic acid has multiple purposes of resisting oxidation, resisting aging, resisting musculoskeletal aging, resisting tumors and inflammation, treating immune-related diseases, protecting heart and cerebral vessels and the like. Chlorogenic acid has low oral bioavailability, and the best administration mode at present is injection administration, but due to structural characteristics, the chlorogenic acid has the following defects.
Chlorogenic acid has a low solubility in water, which only reaches about 10mg/ml at 25 ℃. When the dosage of clinical dose is more than 100 mg/person/time, the administration route with small volume such as subcutaneous, intramuscular and the like can not be adopted; in addition, chlorogenic acid has strong acidity, and the pH value of a 10mg/ml aqueous solution of chlorogenic acid is about 2.5, so that severe irritation is caused by injection administration, and a large clinical safety risk is brought. In order to increase the solubility of chlorogenic acid and reduce the problem of irritation, the prior art generally increases the solubility of chlorogenic acid and reduces irritation by adjusting the pH of the injectable formulation.
Prepared according to the prior patent CN103446064B, sodium bisulfite is taken as an antioxidant, mannitol is taken as a propping agent, phosphate is taken as a pH regulator, and the obtained preparation has poor stabilizer.
In the prior art, because a strong acid carboxylic acid structure and ester bonds which are easy to hydrolyze and lose biological activity exist in the chlorogenic acid structure, in order to ensure the stability of the chlorogenic acid and reduce the irritation, the currently disclosed injection preparation technology can only increase the pH to about 3.0, and cannot control the pH value to be in a range of 4.0-9.0 which is more tolerable to a human body. And the preparation sample needs to be stored and transported under the conditions of light resistance and low temperature, so that the clinical use of the chlorogenic acid is greatly limited.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a chlorogenic acid composition and a preparation method thereof, and the chlorogenic acid composition provided by the present invention has the advantages of good stability at normal temperature, high solubility, small redissolution volume, more tolerable pH value for human body, and the like, and is suitable for injection administration system of subcutaneous/intramuscular administration. The preparation can better meet the safety in the production, transportation and use processes, and provides a more effective drug delivery system for clinical application of chlorogenic acid.
The invention provides a chlorogenic acid composition which comprises chlorogenic acid and arginine. The surprising discovery that the characteristic that the solubility of chlorogenic acid is different in dissolution at different pH values is utilized, and the auxiliary material arginine capable of improving the pH value of the solution is added in the prescription process, so that the dissociation of the chlorogenic acid can be promoted, and the concentration of the prepared solution can be improved, compared with the prior art, the concentration of the solution is improved by 3-15 times, so that more products can be prepared by freeze-drying equipment with the same size, the production efficiency is improved, the redissolution volume is small, the administration volume of the chlorogenic acid can be reduced, and the stimulation to a human body can be reduced.
In the present invention, the arginine is not particularly limited as long as it is pharmaceutically acceptable, which is well known to those skilled in the art, and L-arginine is preferable in the present invention.
The molar ratio of chlorogenic acid to arginine is preferably 1: (0.05 to 1.1), more preferably 1: (0.1 to 1.1), and preferably 1: (0.3 to 1.1), and preferably 1: (0.5 to 1.1), and preferably 1: (0.5 to 1), most preferably 1: (0.5 to 0.96); in some embodiments provided herein, the molar ratio of chlorogenic acid to arginine is preferably 1: 0.5; in some embodiments provided herein, the molar ratio of chlorogenic acid to arginine is preferably 1: 0.6; in some embodiments provided herein, the molar ratio of chlorogenic acid to arginine is preferably 1: 0.8; in some embodiments provided herein, the molar ratio of chlorogenic acid to arginine is preferably 1: 0.9; in other embodiments provided herein, the molar ratio of chlorogenic acid to arginine is preferably 1: 0.98.
the pH value of the chlorogenic acid composition provided by the invention is preferably 3.5-6, more preferably 3.6-5.8, and still more preferably 3.63-5.73.
The formulation of the chlorogenic acid composition provided by the invention is preferably freeze-dried powder injection; the powder injection belongs to injection, in order to ensure the safety, effectiveness and stability of the injection, besides the main medicine, the injection can be added with proper substances to increase the solubility and stability of the main medicine and reduce the stimulation to the body, and the substances are collectively called as additives.
The additive should be safe and harmless, and does not influence the curative effect and content measurement of the main drug; commonly used additives are: solubilizer, cosolvent, propping agent, surfactant, antioxidant, complexing agent, inert gas, preservative, pH value regulator, isotonic regulator, analgesic and the like. Wherein, the additives for increasing the main chemical stability comprise an antioxidant, a metal complexing agent, inert gas and the like; additives for adding physical stabilizer of injection include flocculant, wetting agent and emulsifier; the additives for increasing the solubility of the main drug comprise solubilizer, cosolvent and the like; the additive for inhibiting the growth of microorganisms comprises bacteriostatic agents; the additives for improving the adaptability of the organism mainly comprise a pH regulator, an isotonic regulator, an analgesic and the like.
The chlorogenic acid composition provided by the invention preferably further comprises pharmaceutically acceptable auxiliary materials such as a propping agent for powder injection and/or an antioxidant and the like besides chlorogenic acid and arginine. The proppant is a proppant well known to those skilled in the art, and is not particularly limited, and in the present invention, one or more of mannitol, lactose and glycine is preferable; the antioxidant is not particularly limited as long as it is known to those skilled in the art, and in the present invention, one or more of ascorbic acid, sodium edetate, sodium bisulfite, and sodium metabisulfite are preferable.
The chlorogenic acid freeze-dried powder injection provided by the invention is preferably suitable for small-volume injections, particularly smaller injections such as subcutaneous or intramuscular injections and the like.
According to the needs of clinical treatment, the administration routes of the injection mainly comprise intradermal injection, subcutaneous injection, intramuscular injection, intravenous injection, arterial injection, spinal injection and the like, and the chlorogenic acid freeze-dried powder needle composition provided by the invention is preferably clinically suitable for subcutaneous/intramuscular injection or intravenous injection.
The invention also provides a preparation method of the chlorogenic acid composition, which comprises the following steps: mixing chlorogenic acid, arginine and water, filtering, sterilizing, and lyophilizing to obtain chlorogenic acid composition.
The present invention is not particularly limited in terms of the source of all raw materials, and may be commercially available.
Wherein, the chlorogenic acid and the arginine are the same as those described above, and are not repeated herein.
Mixing chlorogenic acid, arginine and water; the water is preferably water for injection; mixing to make chlorogenic acid and arginine completely dissolved in water; the concentration of chlorogenic acid in the mixed solution is preferably 1-20 wt%, more preferably 5-20 wt%, even more preferably 8-15 wt%, even more preferably 8-12 wt%, and most preferably 10 wt%.
After mixing, filtering and sterilizing; the filtration sterilization is to remove bacteria in the solution by a physical retention method so as to achieve the purpose of sterility; the device used for filtering and sterilizing is a bacteria filter with tiny pore diameter; in the present invention, a commonly used bacterial filter such as a membrane bacterial filter, a ceramic bacterial filter, an asbestos bacterial filter, a sintered glass bacterial filter, or the like can be used, and a membrane bacterial filter is preferably used; the pore diameter of the filter membrane commonly used in the membrane bacterial filter is 0.45 μm and 0.22 μm, and the filter membrane with the pore diameter of 0.22 μm is preferred in the invention.
Filtering for sterilization, preferably filling into penicillin bottles, freeze-drying, and vacuum-pressing to obtain chlorogenic acid lyophilized powder injection composition. In the invention, the filling amount is preferably 0.5-1 ml, and more preferably 0.5ml due to the high concentration of chlorogenic acid in the solution. Therefore, a penicillin bottle with the caliber of 20mm does not need to be used, and the penicillin bottle with the caliber of 13mm is used for freeze-drying; freeze drying, i.e. freeze drying, refers to a method in which a water-containing material is first frozen into a solid at a low temperature, and then directly sublimated and dried by utilizing the sublimation property of water in a low-temperature vacuum state.
The freeze-drying in the invention adopts a method well known by a person skilled in the art, in addition, the time for freeze-drying is reduced because the concentration of chlorogenic acid in the solution is higher, the specific procedure of freeze-drying is pre-freezing for 3h at-40 ℃, vacuumizing, heating to-20 ℃ for sublimation, and entering a secondary drying stage after 8 h. The temperature is 20 ℃; the secondary drying time is 5-7 h.
Generally, the water content of the freeze-dried powder injection is 1-4% in the quality standard, and the stability of the product is not favorable when the water content is too high or too low; the chlorogenic acid freeze-dried powder injection composition obtained by the invention meets the quality standard.
Lyophilizing into loose mass, adding appropriate solvent (usually sterilized water for injection) before use to obtain injection; a0.9% sodium chloride solution or other suitable aqueous solution may also be used.
In order to further illustrate the present invention, the detailed description of a chlorogenic acid composition and its preparation method provided in the present invention is provided below with reference to examples.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The reagents used in the following examples are all commercially available.
Comparative example 1
The reference patent CN103446064B has the following formula and process:
| components | Dosage (1000 pieces) |
| Chlorogenic acid | 7.5g (7.5 mg/piece) |
| Sodium bisulfite | 0.5g |
| Mannitol | 20g |
| Water (W) | Adding to 500ml |
Taking 90% of the prescription amount of water for injection, and cooling to room temperature (25 ℃);
adding the raw and auxiliary materials weighed according to the prescription amount, fully stirring until the raw and auxiliary materials are completely dissolved, adding disodium hydrogen phosphate to adjust the pH value to 3.3, and supplementing water to the full amount.
Filtering and sterilizing through a 0.22 mu m filter membrane; filling 0.5 ml/vial into a 3ml penicillin bottle, freeze-drying in a freeze dryer, pre-freezing for 3 hours at-40 ℃, vacuumizing the system, heating to-20 ℃ and sublimating, wherein the sublimation drying time is about 8 hours; after most of the water is sublimated, the temperature of the board layer is increased, and the board layer is dried for 6 hours at 20 ℃ in a secondary drying stage; after secondary drying, keeping the vacuum state for tamponade; and (5) recovering the system to normal pressure, and discharging the system out of the box.
Comparative example 2
Meglumine was used as pH adjuster:
| components | Dosage (1000 pieces) |
| Chlorogenic acid | 50g |
| Meglumine | 26g |
| Water (W) | Adding to 500ml |
Taking 90% of the prescription amount of water for injection, cooling to room temperature (25 ℃)
Adding the raw and auxiliary materials weighed according to the prescription amount, fully stirring until the raw and auxiliary materials are completely dissolved, and supplementing water to the full amount.
Filtering and sterilizing through a 0.22 mu m filter membrane, filling 0.5 ml/vial into 2-3 ml penicillin bottles, and adding a freeze-drying plug.
Freeze-drying in a freeze-drying machine at-40 deg.C for 3 hr, vacuumizing, heating to-20 deg.C for sublimation, and sublimation-drying for about 8 hr; after most of the water is sublimated, the temperature of the board layer is increased, and the board layer is dried for 6 hours at 20 ℃ in a secondary drying stage; after secondary drying, keeping the vacuum state for tamponade; and (5) recovering the system to normal pressure, and discharging the system out of the box.
Comparative example 3
Ethanolamine was used as a pH adjuster:
90% of the prescribed amount of water for injection was taken and cooled to room temperature (25 ℃).
Adding the raw and auxiliary materials weighed according to the prescription amount, fully stirring until the raw and auxiliary materials are completely dissolved, and supplementing water to the full amount.
Filtering and sterilizing through a 0.22 mu m filter membrane, filling 0.5 ml/vial into 2-3 ml penicillin bottles, and adding a freeze-drying plug.
Freeze-drying in a freeze-drying machine at-40 deg.C for 3 hr, vacuumizing, heating to-20 deg.C for sublimation, and sublimation-drying for about 8 hr; after most of the water is sublimated, the temperature of the board layer is increased, and the board layer is dried for 6 hours at 20 ℃ in a secondary drying stage; after secondary drying, keeping the vacuum state for tamponade; and (5) recovering the system to normal pressure, and discharging the system out of the box.
Examples
The freeze-dried powder injection composition comprises chlorogenic acid and arginine, and the specific components are as follows:
taking 90% of the prescription amount of water for injection, and cooling to room temperature (25 ℃);
adding the raw and auxiliary materials weighed according to the prescription amount, fully stirring until the raw and auxiliary materials are completely dissolved, and supplementing water to the full amount.
Filtering and sterilizing through a 0.22 mu m filter membrane, filling 0.5 ml/vial into 2-3 ml penicillin bottles, and adding a freeze-drying plug.
Freeze-drying in a freeze-drying machine at-40 deg.C for 3 hr, vacuumizing, heating to-20 deg.C for sublimation, and sublimation-drying for about 8 hr; after most of the water is sublimated, the temperature of the board layer is increased, and the board layer is dried for 6 hours at 20 ℃ in a secondary drying stage; after secondary drying, keeping the vacuum state for tamponade; and (5) recovering the system to normal pressure, and discharging the system out of the box.
Detecting the freeze-dried powder injection products obtained in the examples 1-5 and the comparative examples 1-3; product evaluation indexes are as follows: purity, pH, appearance, reconstitution speed. The purity determination method comprises the following steps:
the pH value measuring method comprises the following steps: directly measuring the solution before freeze drying
Redissolution speed:
sample 1, add 1ml of water for injection and record the time to complete dissolution.
The detection results of the purity, pH value, appearance and redissolution speed of the freeze-dried powder injection obtained in the examples 1-5 and the comparative examples 1-3 are shown in the following table.
And (3) performing stability test on the freeze-dried powder injection products obtained in the examples 1-5 and the comparative examples 1-3: and (3) performing an influencing factor test on each sample, and detecting the purity of the sample after the samples are respectively placed under the conditions of 60 ℃, 40 ℃ and illumination for 10 days, wherein the results are as follows:
the table shows that the stability of the freeze-dried preparation is obviously superior to that of a comparative example after arginine is added to adjust the pH value, particularly the stability is obvious under the conditions of high pH value and high temperature, and the chlorogenic acid freeze-dried powder injection composition provided by the invention can completely solve the related problems in the prior art. Under the same pH condition, the stability of the sample added with arginine is far better than that of other organic alkaline compounds.
The chlorogenic acid freeze-dried powder injection composition provided by the invention has good stability at normal temperature, and does not need refrigeration; high solubility, small reconstitution volume, smaller injection volume can be used clinically; the pH value is closer to the tolerance range of the human body, and the irritation is small. The chlorogenic acid freeze-dried powder injection composition is suitable for an injection administration system for subcutaneous/intramuscular administration, can better meet the safety in the production, transportation and use processes, and provides a more effective administration system composition for clinical application of chlorogenic acid.
Claims (10)
1. A chlorogenic acid composition is characterized by comprising chlorogenic acid and arginine.
2. The chlorogenic acid composition according to claim 1, wherein the arginine is L-arginine.
3. The chlorogenic acid composition according to claim 1, wherein the molar ratio of chlorogenic acid to arginine is 1: (0.05-1.1).
4. The chlorogenic acid composition according to claim 1, wherein the molar ratio of chlorogenic acid to arginine is 1: (0.5 to 1).
5. The chlorogenic acid composition according to claim 1, further comprising a proppant and/or an antioxidant.
6. The chlorogenic acid composition according to claim 5, wherein the proppant is selected from one or more of mannitol, lactose and glycine.
7. The chlorogenic acid composition according to claim 5, wherein the antioxidant is selected from one or more of ascorbic acid, sodium edetate, sodium bisulfite and sodium metabisulfite.
8. The chlorogenic acid composition of claim 1, in the form of a lyophilized powder for injection.
9. A method for preparing a chlorogenic acid composition, which is characterized by comprising the following steps:
mixing chlorogenic acid, arginine and other adjuvants with water, filtering, sterilizing, and lyophilizing to obtain chlorogenic acid composition.
10. Use of the chlorogenic acid composition of any one of claims 1 to 8 or the chlorogenic acid composition prepared by claim 9 in the preparation of medicaments for treating and/or preventing tumors, inflammatory diseases or autoimmune diseases, and medicaments and/or health products for resisting oxidation, aging, musculoskeletal aging or protecting cardiovascular system.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022074798A1 (en) * | 2020-10-08 | 2022-04-14 | 花王株式会社 | Solid composition |
| WO2023130205A1 (en) * | 2022-01-04 | 2023-07-13 | 成都夸常奥普医疗科技有限公司 | Stabilizing solution, preparation method, application, pharmaceutical composition, and kit |
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| US20120294954A1 (en) * | 2009-12-29 | 2012-11-22 | Hill's Pet Nutrition, Inc | Compositions including ginger for the amelioration or prevention of inflammatory conditions |
| CN103446064A (en) * | 2013-08-21 | 2013-12-18 | 四川九章生物化工科技发展有限公司 | Chlorogenic acid powder-injection and preparation method thereof |
| CN105434369A (en) * | 2014-09-22 | 2016-03-30 | 四川九章生物科技有限公司 | High-solubility and high-stability chlorogenic acid freeze-dried powder injection |
| CN105920081A (en) * | 2016-04-27 | 2016-09-07 | 于爱华 | Compound preparation for treating cecal granuloma and preparation method thereof |
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2018
- 2018-12-21 CN CN201811572044.6A patent/CN111346061B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120294954A1 (en) * | 2009-12-29 | 2012-11-22 | Hill's Pet Nutrition, Inc | Compositions including ginger for the amelioration or prevention of inflammatory conditions |
| CN103446064A (en) * | 2013-08-21 | 2013-12-18 | 四川九章生物化工科技发展有限公司 | Chlorogenic acid powder-injection and preparation method thereof |
| CN105434369A (en) * | 2014-09-22 | 2016-03-30 | 四川九章生物科技有限公司 | High-solubility and high-stability chlorogenic acid freeze-dried powder injection |
| CN105920081A (en) * | 2016-04-27 | 2016-09-07 | 于爱华 | Compound preparation for treating cecal granuloma and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 黄青萍: "抗感I号的制备及临床应用", 《中国药业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022074798A1 (en) * | 2020-10-08 | 2022-04-14 | 花王株式会社 | Solid composition |
| WO2023130205A1 (en) * | 2022-01-04 | 2023-07-13 | 成都夸常奥普医疗科技有限公司 | Stabilizing solution, preparation method, application, pharmaceutical composition, and kit |
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| CN111346061B (en) | 2022-02-18 |
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