CN110938001A - Chlorogenic acid ethanolamine salt and application thereof - Google Patents

Chlorogenic acid ethanolamine salt and application thereof Download PDF

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CN110938001A
CN110938001A CN201811109914.6A CN201811109914A CN110938001A CN 110938001 A CN110938001 A CN 110938001A CN 201811109914 A CN201811109914 A CN 201811109914A CN 110938001 A CN110938001 A CN 110938001A
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chlorogenic acid
ethanolamine salt
treating
cancer
solution
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邹德超
陈先红
孙志国
谈敦潮
王颢卓
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BEIJING COLLAB PHARMA Co Ltd
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Abstract

The invention provides chlorogenic acid ethanolamine salt as shown in a formula (I), a product prepared by taking the chlorogenic acid ethanolamine salt as an active ingredient, and applications of the chlorogenic acid ethanolamine salt in disease prevention and health care, wherein the product comprises a medicine and a health care product.

Description

Chlorogenic acid ethanolamine salt and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to chlorogenic acid ethanolamine salt and application 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.
Figure BDA0001808818110000011
Chlorogenic acid is an important bioactive substance, and the prior art discloses that chlorogenic acid has multiple purposes:
1. and (3) tumor resistance: such as preventing and treating nasopharyngeal carcinoma (ZL 200610021897.1); preventing and treating small cell lung cancer (ZL 200710140602.7); prevention and treatment of bladder cancer (ZL 201210086313.4); preventing and treating ependymoma (ZL 201410468334.1); preventing and treating oligodendroglioma (ZL 201410468312.5); preventing and treating cervical cancer (CN 200610021591.6); preventing and treating female organ tumor (CN 200610021909.0); preventing and treating pulmonary blastoma (CN 201510078820.7); prevention and treatment of primary cutaneous T-cell lymphoma (CN 201510079639.8); treatment of melanoma (CN 201510079033.4); treating yolk sac tumor (cn201510053341. x); treating choriocarcinoma (CN 201510080133.9); chinese patents such as CN201710719094.1, CN201710714132.4, CN201810206147.4CN201710719622.3 and the like also disclose that the combined drug of chlorogenic acid and other drugs has the effects of resisting tumors and cancers, treating tumor multidrug resistance and the like;
2. treatment of autoimmune diseases: chinese patent CN201510568417.2 discloses that chlorogenic acid can activate immune-related signal pathways of the body; also has the effects of treating lupus erythematosus (CN 201510078874.3); increasing immune function (CN 200510088025.2); treating vitiligo (CN 201410778100.7); treating psoriasis (CN 201410490695.6);
3. antioxidation, anti-aging, anti-musculoskeletal aging: such as anti-hypoxia (ZL 200710128491.8); treatment and/or prevention of ocular inflammation (CN 201710051216.4); muscular dystrophy disease (CN 201510580291.0); treating premature senility (CN201510072776.9), etc.;
4. protecting the cardiovascular system: treatment of cardiomyopathy (CN201510078634.3), etc.;
furthermore, chinese patent zl200680024175.x discloses that chlorogenic acid has the efficacy of increasing bone marrow cells; chinese patent ZL200910246627.4 discloses that chlorogenic acid has the efficacy of treating thrombocytopenia and anemia; chinese patent ZL200910246134.0 discloses that chlorogenic acid has protection and repair effects on spleen hematopoietic stem cell injury; chinese patent ZL200910246630.6 discloses that chlorogenic acid has the efficacy of treating myelofibrosis; chinese patent CN201510078953.4 discloses chlorogenic acid for treating urticaria; chinese patent ZL201510063970.0 discloses that chlorogenic acid has the efficacy of treating osteopetrosis; chinese patent CN201510568285.3 discloses chlorogenic acid can activate WNT signaling pathway of body; chinese patent CN201510123289.0 discloses that chlorogenic acid has the effect of promoting fibroblast proliferation; chinese patents ZL201110386854.4, ZL201310210438.8, CN200510088023.3 and the like disclose that chlorogenic acid has the effect of protecting liver; chinese patent CN200610021590.1 discloses that chlorogenic acid has estrogen-like or estrogenic promoting effect; chinese patent CN201510078629.2 discloses that chlorogenic acid has the function of treating pathological jaundice; chinese patent CN201510079127.1 discloses that chlorogenic acid can be used for treating epilepsy; chinese patent CN200910246133.6 discloses that chlorogenic acid can treat bone marrow infection; chinese patent CN201510078986.9 discloses that chlorogenic acid can treat amyotrophic lateral sclerosis; chinese patent CN201510079049.5 discloses that chlorogenic acid can treat Parkinson's disease; chinese patent CN201610149050.5 discloses that chlorogenic acid can inhibit LAG-3 target, etc.
However, chlorogenic acid, which is depside generated from caffeic acid and quinic acid, has a hydrophobic structure such as ester bond and benzene ring in its molecular structure, and thus has a low solubility in water at 25 ℃ of only about 10 mg/ml. The low solubility of the chlorogenic acid leads to low bioavailability of the oral preparation, and the injection preparation can only be prepared into a large-volume or small-specification preparation, thereby seriously limiting the clinical application of the chlorogenic acid. 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 oral administration and parenteral administration have serious contact part irritation, and great clinical safety risk is brought.
In order to improve the specification of the chlorogenic acid injection preparation, the prior art generally increases the solubility of the chlorogenic acid by adjusting the pH value of the injection preparation, but ester bonds which are easy to hydrolyze and lose biological activity exist in the structure of the chlorogenic acid, so that in order to ensure the stability of the chlorogenic acid, the pH value of the injection preparation needs to be strictly controlled to be about 3.0, and the chlorogenic acid injection preparation needs to be stored and transported under the conditions of light shielding and low temperature, thereby greatly limiting the further development and application of the chlorogenic acid.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a chlorogenic acid ethanolamine salt and an application thereof, and the chlorogenic acid ethanolamine salt provided by the present invention has characteristics of good stability, high solubility, small irritation, and greatly expanded clinical applications of chlorogenic acid.
The invention provides chlorogenic acid ethanolamine salt. We have surprisingly found that the ethanolamine salt has many advantages over chlorogenic acid, such as significantly higher water solubility than chlorogenic acid (10 mg/ml); the pH value is 5-6, so that the irritation of chlorogenic acid to a human body is obviously reduced, and the oral administration bioavailability of the chlorogenic acid medicine is expected to be greatly improved; the stability of the chlorogenic acid derivative is also obviously higher than that of chlorogenic acid and other derivatives of chlorogenic acid, such as stability under high temperature, illumination and high humidity conditions is obviously improved; the difficulty in normal-temperature production, transportation and use of the injection preparation is reduced, the production, transportation and storage costs of production enterprises and application manufacturers are reduced, the industrial production and scale production are facilitated, the application field of the chlorogenic acid medicine is further widened, and the long-term development and research of the chlorogenic acid medicine are facilitated.
The chlorogenic acid ethanolamine unit structure provided by the invention is shown as a formula (I):
Figure BDA0001808818110000031
in general, the compound of formula (I) can be prepared by dissolving chlorogenic acid in a suitable solvent, filtering to remove impurities, adding the solution to a solvent containing 1-3 equivalents of ethanolamine, and lyophilizing, evaporating to dryness, or crystallizing to obtain the compound of formula (I).
The compounds of formula (I) disclosed herein include pharmaceutically acceptable isotopic variations. Isotopic variations are those compounds in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Useful isotopes include isotopes of hydrogen, carbon, nitrogen and oxygen. Exemplary isotopes thereof include, but are not limited to2H、3H、13C、14C、15N、17O and18O。
the invention discloses isotopes of the compounds of formula (I), such as deuterium, i.e.2The H substitution may result in certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, which may be the case in some casesIs useful. In addition, certain isotopic variants, for example those incorporating a radioisotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotope tritium being thus3H and carbon-14 i.e.14C are particularly useful because they are easily incorporated and are convenient to detect.
Isotopic variations of the compounds disclosed herein can generally be prepared by conventional methods known to those skilled in the art.
The compounds disclosed herein may be administered in the form of crystalline or amorphous products. They can be obtained, for example, in the form of solid plugs, powders or films by processes such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or radio frequency drying may be used to achieve the above objectives.
The invention also provides a pharmaceutical preparation which comprises chlorogenic acid ethanolamine salt shown in the formula (I) and pharmaceutically acceptable auxiliary materials. The pharmaceutical preparation of the present invention may contain chlorogenic acid ethanolamine salt alone or in combination with other drugs.
The term "pharmaceutically acceptable excipient" is meant to include any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, e.w. maetin (Mack Publishing co., Easton, Pa.,1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., any other component that produces no biological effect or interacts in a deleterious manner with a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.
Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; buffer substances, for example: a phosphate salt; glycine; sorbic acid or potassium sorbate; a mixture of partial glyceride esters of saturated vegetable fatty acids; water; salts or electrolytes, for example: disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salt; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; pyrogen-free water; isotonic saline; ethanol; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.
The chlorogenic acid ethanolamine salt shown in the formula (I) provided by the invention can be prepared into a conventional pharmaceutical preparation according to a conventional preparation method; the dosage forms of the pharmaceutical preparation comprise capsules, tablets, pills, granules, emulsions, floating agents, injections, drops, freeze-dried powder injections and the like.
The chlorogenic acid ethanolamine salt shown in the formula (I) is combined with a common carrier or diluent, and the administration route of the chlorogenic acid ethanolamine salt can be oral administration, parenteral administration or local administration.
Oral administration should include swallowing, so that the compound is able to enter the gastrointestinal tract, or buccal or sublingual administration, so that the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid and liquid formulations, solid formulations such as tablets; capsules containing particles, liquids or powders; lozenges (including liquid-filled lozenges); chewable tablets; composite particles and nanoparticles; gelling; a solid solution; a liposome; films (including mucoadhesives); an egg agent; a spray; liquid preparations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers for soft or hard gelatin capsules and typically comprise a carrier such as water, EtOH, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, together with one or more emulsifying and/or suspending agents. Liquid formulations may also be prepared by formulating a solid from, for example, a sachet.
The compounds disclosed herein are also useful in fast dissolving, fast disintegrating dosage forms.
For tablet dosage forms, a disintegrant is typically included in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, polyvinyl polypyrrolidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.
Binders are commonly used to impart cohesive properties to the tablet. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.
The tablets also optionally contain surfactants such as sodium lauryl sulfate and polysorbate vinegar 80, and glidants such as silicon dioxide and talc.
Tablets also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Other ingredients may include preservatives, antioxidants, fragrances and colorants.
In the present invention, the term parenteral administration includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration. Formulations for parenteral administration are typically aqueous solutions containing excipients such as salts, carbohydrates and buffers (preferably at a pH of 3-9), but for some applications are more suitably formulated as sterile, anhydrous solutions or in dry form for use in conjunction with a suitable vehicle such as sterile, pyrogen-free water. Preparation of a parenteral formulation may be conveniently accomplished by lyophilization under sterile conditions using conventional pharmaceutical techniques well known to those skilled in the art.
The chlorogenic acid ethanolamine salt shown in the formula (I) can also be locally administered, can be locally administered to skin or mucous membrane, and can be administered through skin or transdermal delivery. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, emulsions, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, tampons, fibers, bandages and microemulsions, and liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, and propylene glycol. Typical formulations may also contain penetration enhancers.
In the present invention, the administration form of the ethanolamine chlorogenic acid salt represented by the formula (I) is preferably injection administration or oral administration.
The preparation type of the injection administration is preferably injection or freeze-dried powder injection; the solvent of the injection and the double solvent used for the freeze-dried powder injection are aqueous soluble and non-aqueous solvents which are well known by the technical personnel in the field. The aqueous solvent is most commonly water for injection, and can also be 0.9% sodium chloride solution or other suitable aqueous solution; the non-aqueous solvent is usually vegetable oil, mainly soybean oil for injection and other non-aqueous solvents such as ethanol, propylene glycol, polyethylene glycol and glycerol.
The invention also provides application of chlorogenic acid ethanolamine salt, and the effects of chlorogenic acid in the aspects of resisting tumors, treating autoimmune diseases, resisting oxidation, resisting aging, resisting muscular and skeletal aging, protecting cardiovascular system, increasing bone marrow cells, treating thrombocytopenia, anemia, treating spleen hematopoietic stem cell injury, treating myelofibrosis, treating urticaria, treating psoriasis, treating osteopetrosis, promoting fibroblast proliferation, protecting liver, treating epilepsy, treating bone marrow infection, treating amyotrophic lateral sclerosis, treating Parkinson's disease, resisting viruses, resisting bacteria and the like as a medicine and a health-care product are proved.
Therefore, the invention also provides the application of the chlorogenic acid ethanolamine salt in preparing the medicines or health-care products for resisting oxidation, eliminating free radicals, improving central excitation, expanding blood vessels, protecting liver and gallbladder, resisting HIV (acquired immune deficiency syndrome) or resisting bacteria and diminishing inflammation.
The invention also provides the application of the chlorogenic acid ethanolamine salt in preparing the medicines for treating and/or preventing tumors, inflammatory diseases or autoimmune diseases.
The tumor of the invention comprises solid tumor and non-solid tumor; tumors described in the present invention include, but are not limited to, melanoma, pancreatic cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, multiple myeloma, lymphoma, leukemia, bladder cancer, prostate cancer, bile duct cancer, cervical cancer, ovarian cancer, breast cancer, endometrial cancer, skin cancer, and the like.
The autoimmune diseases described in the present invention include, but are not limited to, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, scleroderma, and the like.
In the above pharmaceutical dosage unit, the compound of formula (I) of the present invention is an effective and nontoxic dosage, preferably 0.1-100 mg/kg, more preferably 0.1-10 mg/kg.
In order to further illustrate the present invention, the following describes the chlorogenic acid ethanolamine salt and the use thereof in detail with reference to the 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
Adding chlorogenic acid (2.0g, 5.64mmol) into a reaction bottle, adding absolute ethyl alcohol (20.0ml) for dissolving, slowly dropwise adding an anhydrous sodium acetate (0.49g, 5.97 mmol)/absolute methanol (5.0ml) solution at room temperature, stirring and reacting for 2 hours at room temperature, filtering, washing a filter cake with a proper amount of absolute ethyl alcohol, and drying at 35 ℃ in vacuum to obtain chlorogenic acid sodium salt, wherein the white powder is 1.63g, and the yield is as follows: 76.74 percent.
Comparative example 2
Adding chlorogenic acid (2.0g, 5.64mmol) into a reaction bottle, adding absolute ethyl alcohol (40.0ml) for dissolving, slowly dropwise adding an absolute potassium acetate (0.58g, 5.91 mmol)/absolute ethyl alcohol (6.0ml) solution at room temperature, stirring and reacting for 2 hours at room temperature, filtering, washing a filter cake with an appropriate amount of absolute ethyl alcohol, and drying in vacuum at 35 ℃ to obtain chlorogenic acid potassium salt, wherein the white powder is 1.81g, and the yield is as follows: 81.72 percent.
Comparative example 3
Lyophilized powder for injection containing chlorogenic acid was prepared according to the following table
Chlorogenic acid 5.0g
Disodium hydrogen phosphate Proper amount of
Mannitol 5.0g
In total 100 pieces
Dissolving chlorogenic acid and mannitol in 100ml water for injection, adjusting pH to 5.4 with disodium hydrogen phosphate, filtering with 0.22 μm filter membrane, packaging into 5ml vials, each 1ml, lyophilizing according to conventional procedure, and vacuum-pressing.
Example 1
Adding chlorogenic acid (5.0g, 14.11mmol) into a reaction bottle, adding absolute ethyl alcohol (50.0ml) for dissolving, slowly dropwise adding an ethanolamine (0.86g, 14.08 mmol)/absolute methanol (2.0ml) solution at room temperature, stirring and reacting for 2 hours at room temperature, filtering, washing a filter cake with a proper amount of absolute ethyl alcohol, and drying in vacuum at 40 ℃ to obtain chlorogenic acid ethanolamine salt, wherein the white powder is 4.98g, and the yield is as follows: 84.95%, mp: 141.0 to 143.5 ℃.
The chlorogenic acid ethanolamine salt obtained in example 1 was detected by nuclear magnetic resonance, and the result was obtained1HNMR:(400MHz,DMSO-d6):δ:11.2(1H,s)；δ9.60(1H,s)；δ9.19(1H,s)；δ7.40(1H,d,J＝16Hz)；δ7.17(1H,s)；δ6.93(1H,d,J＝8)；δ6.79(1H,d,J＝8Hz)；δ6.31(1H,d,J＝16Hz)；δ5.11(2H,s)；δ4.91(2H,s)；δ4.81(1H,s)；δ3.99(1H,m)；δ3.84(1H,t)；δ3.62(3H,m)；δ3.25(1H,m)；δ3.01(2H,m)；δ2.05(2H,m)；δ1.95(2H,m)。
Example 2 relative solubility and pH
The chlorogenic acid, the salt obtained in the comparative example 1, the comparative example 2 and the example 1 are respectively taken and ground, a certain amount of fine powder is accurately weighed, and the solubility and the pH value of the fine powder are measured in water. The results are shown in Table 1.
TABLE 1 solubility and PH test results
Chlorogenic acid Example 1 Comparative example 1 Comparative example 2
Solubility 25 deg.C (mg/ml) 10 70 90 80
pH value (10mg/ml) 2.58 5.35 6.91 4.5
As a result: the chlorogenic acid becomes ethanolamine salt, so that the solubility of the chlorogenic acid in water can be obviously improved to 70mg/ml, and the requirements of developing small-volume and large-specification injections can be met; and the pH value of the chlorogenic acid ethanolamine salt solution is 5.35, so that the stimulation effect of the chlorogenic acid on human bodies is obviously reduced.
Example 3 stability study
The stability of the samples was preliminarily determined by performing the experiments on the influence factors of the conditions of 60 ℃, RH 92.5% and the light test on the salts provided in example 1 and comparative examples 1 and 2, respectively, according to the guidelines on drug stability (9001, the fourth pharmacopoeia of china, 2015). The results are shown in tables 2 to 5.
TABLE 2 chlorogenic acid stability influencing factor test 10 days results
Figure BDA0001808818110000091
TABLE 3 stability influencing factor test results for comparative example 1 over 10 days
Figure BDA0001808818110000092
TABLE 4 stability influencing factor test results for comparative example 2 over 10 days
Figure BDA0001808818110000101
Table 5 example 1 stability influencing factor test 10 days results
Figure BDA0001808818110000102
As can be seen from tables 2 to 5, the potassium chlorogenic acid salt and the sodium chlorogenic acid salt have poor stability under various conditions and certain hygroscopicity; chlorogenic acid is degraded under the conditions of high temperature and illumination, and the stability is poor; the chlorogenic acid ethanolamine salt is not degraded under all conditions, has better stability than chlorogenic acid, and can meet the requirements of further developing pharmaceutical preparations as raw material medicaments.
EXAMPLE 4 Freeze-dried powder injection
Lyophilized powder containing chlorogenic acid ethanolamine salt was prepared according to the following table.
Example 1 Compounds 1.41g
Water (W) 20ml
In total 1.41g
Adding 1.41g of the compound obtained in example 1 into 20ml of water, filtering with a 0.22 mu m membrane, subpackaging into 5ml of penicillin bottles with 1ml of each, and preparing 20 lyophilized powder injections with 60mg (calculated as chlorogenic acid) per injection according to the conventional operation of the lyophilized powder injection.
EXAMPLE 5 resolubility and pH determination of lyophilized powder for injection
Taking the freeze-dried preparation in the embodiment 4, adding 1ml of sodium chloride injection, and obtaining a clear solution after 10s, wherein the concentration of the solution reaches 70mg/ml, and the pH value is 5.43; the chlorogenic acid ethanolamine salt freeze-dried powder injection has good re-solubility and a pH value with better human tolerance.
Example 6 lyophilized powder stability study
Referring to the guiding principle of drug stability (9001 of the fourth pharmacopoeia of China, 2015 edition), the lyophilized powder for injection obtained in comparative example 3 and example 4 were subjected to the influence factor experiments of 60 ℃, RH 92.5% and illumination experimental conditions, and the stability of the preparation was preliminarily determined. The results are shown in Table 6.
Table 6 example 4 and comparative example 3 stability influencing factor test results for 10 days
Figure BDA0001808818110000111
Figure BDA0001808818110000121
As can be seen from Table 6, the lyophilized powder for injection prepared in comparative example 3, which contains chlorogenic acid, has degradation of different degrees under various conditions, poor stability, and need to be stored at low temperature; whereas the freeze-dried powder injection prepared by chlorogenic acid ethanolamine salt in the embodiment 4 is not degraded under all conditions and can be stored at normal temperature.
EXAMPLE 7 tablets
The compound of example 1, mannitol, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl starch, magnesium stearate were combined and compressed into tablets in the following proportions.
Components mg
Example 1 Compounds 500
Mannitol 150
Microcrystalline cellulose 200
Hydroxypropyl cellulose 50
Sodium carboxymethyl starch 100
Stearic acid magnesium salt 10
In addition to the raw materials, the tablet formula generally comprises pharmaceutically acceptable auxiliary materials, and the auxiliary materials generally comprise a filler, a disintegrant, a colorant, a wetting agent, a lubricant, a glidant and the like. The quality of the tablet depends on the prescription composition, the selection of auxiliary materials and the preparation process. Generally, the preparation method of tablets is divided into two types: direct compression and granulation compression. The granulation method can be divided into wet granulation and dry granulation. No matter the method is adopted for tabletting, the raw materials are firstly crushed and mixed, only the subsequent steps are different, and the skilled person can select the conventional method according to the composition of the tablet and the preparation requirement.

Claims (7)

1. Chlorogenic acid ethanolamine salt.
2. The chlorogenic acid ethanolamine salt according to claim 1, having a structural formula shown in formula (I):
Figure FDA0001808818100000011
3. a pharmaceutical preparation comprising the ethanolamine chlorogenic acid according to claim 1 and pharmaceutically acceptable excipients.
4. The pharmaceutical formulation of claim 3, wherein the pharmaceutical formulation is in a dosage form comprising a tablet, capsule, lozenge, chewable tablet, multiparticulate and nanoparticulate, gel, solid solution, liposome, film, egg, spray, suspension, solution, syrup, elixir, aqueous solution, anhydrous solution, lyophilized powder for injection, gel, hydrogel, lotion, solution, emulsion, ointment, dusting powder, dressing, foam, film, skin patch, wafer, implant, tampon, fiber, bandage, or microemulsion.
5. Use of the ethanolamine chlorogenic acid salt according to claim 1 in the preparation of medicaments for treating and/or preventing tumors, inflammatory diseases or autoimmune diseases, medicaments for resisting oxidation, aging, musculoskeletal aging or protecting cardiovascular and/or health products.
6. Use according to claim 5, wherein the autoimmune disease is psoriasis, inflammatory-like rheumatoid arthritis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis or organ transplant rejection.
7. The use according to claim 5, wherein the tumor is lung cancer, liver cancer, breast cancer, uterine cancer and brain tumor.
CN201811109914.6A 2018-09-21 2018-09-21 Chlorogenic acid ethanolamine salt and application thereof Pending CN110938001A (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012178A1 (en) * 1999-08-16 2001-02-22 Microplants Co., Ltd Method for isolating chlorogenic acid and 1,4-di-o-caffeoyl-d-(+)-quinic acid
US20080234380A1 (en) * 1992-06-30 2008-09-25 Shapiro Howard K Compositions and method for treatment of chronic inflammatory diseases
CN103998029A (en) * 2011-12-14 2014-08-20 花王株式会社 Method for producing antimicrobial composition
KR20160008125A (en) * 2015-12-15 2016-01-21 충북대학교 산학협력단 Novel Chlorogenic Acid Derivatives and Composition for Treating Inflammatory Disease Comprising the Same
CN105582004A (en) * 2016-01-14 2016-05-18 四川九章生物科技有限公司 Application of chlorogenic acid and/or chlorogenic acid derivative in tumor stem cell treatment drug
CN108276458A (en) * 2018-03-07 2018-07-13 中国科学院烟台海岸带研究所 A kind of Glucosamine chlorogenic acid salt and its preparation method and application

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080234380A1 (en) * 1992-06-30 2008-09-25 Shapiro Howard K Compositions and method for treatment of chronic inflammatory diseases
WO2001012178A1 (en) * 1999-08-16 2001-02-22 Microplants Co., Ltd Method for isolating chlorogenic acid and 1,4-di-o-caffeoyl-d-(+)-quinic acid
CN103998029A (en) * 2011-12-14 2014-08-20 花王株式会社 Method for producing antimicrobial composition
KR20160008125A (en) * 2015-12-15 2016-01-21 충북대학교 산학협력단 Novel Chlorogenic Acid Derivatives and Composition for Treating Inflammatory Disease Comprising the Same
CN105582004A (en) * 2016-01-14 2016-05-18 四川九章生物科技有限公司 Application of chlorogenic acid and/or chlorogenic acid derivative in tumor stem cell treatment drug
CN108276458A (en) * 2018-03-07 2018-07-13 中国科学院烟台海岸带研究所 A kind of Glucosamine chlorogenic acid salt and its preparation method and application

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