CN101628903B - Defervescence anti-inflammatory and anti-infection medicine with immunization function, preparation and application thereof - Google Patents
Defervescence anti-inflammatory and anti-infection medicine with immunization function, preparation and application thereof Download PDFInfo
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- CN101628903B CN101628903B CN2009101651102A CN200910165110A CN101628903B CN 101628903 B CN101628903 B CN 101628903B CN 2009101651102 A CN2009101651102 A CN 2009101651102A CN 200910165110 A CN200910165110 A CN 200910165110A CN 101628903 B CN101628903 B CN 101628903B
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Abstract
The invention relates to a defervescence anti-inflammatory and anti-infection medicine with immunization function, a preparation and an application thereof. Andrographolidume derivant is andrographolidume sodium bisulfite hydrate, and the molecular formula of the andrographolidume sodium bisulfite hydrate is C20H29O7SNa.nH2O, wherein n is equal to a number between 0.88 and 3.5. The derivant has better water solubility and better storage stability, and is suitable to prepare treatment or prevention medicines for reducing fever and relieving internal heat of fever, resisting bacteria and diminishing inflammation, resisting virus and allaying fever, and adjusting immunologic function.
Description
Technical field
The present invention relates to medical technical field, specifically provide have the bringing down a fever of immunization, anti-inflammatory, anti-infectives---andrographolidume derivative and preparation thereof and purposes, i.e. deshydroxy dehydrogenation rographolide sulfonate sodium hydrate and preparation and purposes.
Background technology
Present disclosed document has only been reported the l4-deshydroxy-13-dehydrogenation rographolide-12-sodium sulfonate [C that does not contain crystal water
20H
29O
7SNa molecular weight: 436.47] (as: Meng Zhengmu. Acta Pharmaceutica Sinica .1981; 16 (8): 571-575.); Up to the present, still do not have both at home and abroad disclosed bibliographical information to have the bringing down a fever of immunization, anti-inflammatory, anti-infectives andrographolidume derivative---14-deshydroxy-13-dehydrogenation rographolide-12-sulfonate sodium art hydrate or say rographolide bisulfite sodium hydrate [C
20H
29O
7SNanH
2O, n=0.88～3.5].
Summary of the invention
Involved in the present invention is has the bringing down a fever of immunization, anti-inflammatory, anti-infectives---deshydroxy dehydrogenation rographolide sulfonate sodium hydrate, i.e. rographolide bisulfite sodium hydrate and preparation thereof and purposes.Its chemical name is: 14-deshydroxy-13-dehydrogenation rographolide-12-sulfonate sodium hydrate, its molecular formula is C
20H
29O
7SNanH
2O, n=0.88～3.5, n can be 0.88,1,1.25,1.5,2,2.25,2.5,3.0,3.2,3.5 or the numeral between it.
The rographolide sodium sulfite anhy 96 that contains crystal water that the present invention obtains is different from the characteristic that rographolide is insoluble in water; Surprisingly; The rographolide sodium sulfite anhy 96 that does not contain crystal water draws moist far above the rographolide sodium sulfite anhy 96 that contains crystal water, the rographolide bisulfite sodium hydrate that contains crystal water than do not contain crystal water more can be stable existence, be convenient to store and transportation; And at room temperature have good water-solubility, be easy to process water miscible preparation.Distinctive, heat analysis (TG-DTA) collection of illustrative plates of hydrate of the present invention can find out that weightless platform has the corresponding endotherm(ic)peak of intensive, and the thermogram spectrum demonstrates rographolide sodium sulfite anhy 96 0.88 hydrate, 1 hydrate (C
20H
29O
7SNaH
2O), 1.25 hydrates, rographolide sodium sulfite anhy 96 1.5 hydrates, rographolide sodium sulfite anhy 96 2 hydrate (C
20H
29O
7SNa2H
2O), rographolide sodium sulfite anhy 96 2.5 hydrate (C
20H
29O
7SNa2.5H
2O), rographolide sodium sulfite anhy 96 3 hydrate (C
20H
29O
7SNa3H
2O) etc., match with karl Fischer method mensuration moisture result and hot analytical results.Crystalline hydrate of the present invention has identical chromatographic behavior under same HPLC condition; After the hydrate dissolving with different embodiments of the invention; In twos or a plurality of compound solution mix the back sample introduction; Under the testing conditions that Ben Wenben adopts, in detectable concentration range, main peak all is shown as unimodal on the HPLC collection of illustrative plates.
Rographolide bisulfite sodium hydrate of the present invention, for white or off-white color to micro-yellow powder, can stable storage.With above-mentioned rographolide bisulfite sodium hydrate and rographolide sodium sulfite anhy 96 anhydride sample airtight respectively with cillin bottle in carry out accelerated stability test (chromatographic condition: chromatographic column: C
18(150mm * 4.6mm, 5m); Moving phase: methyl alcohol-second eyeball-0.02mol/L potassium dihydrogen phosphate (5: 24: 75); Flow velocity: 1ml/min; Temperature: room temperature; Detect wavelength: 220nm); Unexpectedly find; The content and the related substance of rographolide bisulfite sodium hydrate of the present invention do not have considerable change; Rographolide sodium sulfite anhy 96 anhydride accelerated test 6 months was compared (40 ℃, under the RH75%) with 0 month, the multiple that related substance increases is higher than rographolide bisulfite sodium hydrate.Draw moist test by the Chinese Pharmacopoeia requirement: get rographolide sodium sulfite anhy 96 anhydride and the about 5g of hydrate of the present invention, place the watch-glass of dry constant weight, precision is weighed.25 ℃, relative humidity are 75%; Respectively at test 0h and 48h sampling, calculate the percentage that draws wet weightening finish, the result shows; Anhydride draws moist more much higher than hydrate of the present invention, explains that rographolide bisulfite sodium hydrate of the present invention has better storage stability.The result sees table 1～7.
In addition, the deliquescence of anhydride makes wants secluding air to prevent adhesion etc. when handling, and does not have good sliding like hydrate, improves the operability of preparation.
Table 1. the present invention 3 hydrate accelerated stability test results
Table 2. the present invention 2.5 hydrate accelerated stability test results
Table 3. the present invention 2 hydrate accelerated stability test results
Table 4. the present invention 1.5 hydrate accelerated stability test results.
Table 5. the present invention 1 hydrate accelerated stability test result
Table 6. accelerated stability test result
Table 7. draws the wet test result
Pharmacology test is following:
The influence of the writhing response that 1, Glacial acetic acid min. 99.5 is caused
Get 60 of the Kunming male mices of body weight 18-22g; Be divided into 5 groups at random, the tail intravenously administrable, control group gives saline water; The administration group gives the medicine of the present invention (it is pure to press dry product) of various dose; Injected 0.7% acetic acid 0.2ml/ only in mouse peritoneal in 20 minutes after the last administration, the number of times of observing the writhing response of mouse in 20 minutes is as medicine analgesic curative effect index, and the result sees table 8.
The influence of the writhing response that table 8. pair Glacial acetic acid min. 99.5 causes
2, the mouse hot plate method is caused the influence of pain reaction
20 of the female mices that 55 ± 0.5 ℃ of hot plate methods of learning from else's experience screen divide 2 groups at random, and (it is pure to press dry product, and dosage is 200mg/kg, i.p) to give saline water (i.p) and medicine of the present invention respectively.After 30 minutes, mouse the metapedes action occurs licking and reacts generation bitterly for it, and be respectively latent period: saline water group 26.7 ± 6.9s, and drug group of the present invention is 36.7 ± 8.2s, two groups of differences have significance.
3, dry yeast is caused the influence of rat fever
Get the Wistar rat body weight 180-220g of normal body temperature,, measure the anus temperature every day once, measured the anus temperature once in per 1 hour before the experiment its pre-adaptation 5 days in environment; Continuous 3 times, getting average is normal value, for same rat, selects the double temperature difference to be no more than 0.3 ℃; Promptly can be fever model usefulness, with 40 qualified rats, be divided into 4 groups at random, 10 every group; Each organizes the saline water suspension 10ml/kg of rat equal back subcutaneous injection 20% fresh dry yeast, and after the last administration 6 hours, control group gave saline water; The administration group gives the medicine of the present invention of various dose (mg/kg), and it is pure that dosage is pressed dry product, all intravenously administrable; Measure the anus temperature of 1,2,3,4, the 5 hour rat in injection back, calculate the changing value of its front and back, result such as following table.The administration group compares administration with control group after t check difference all has significance, P＜0.05.The result sees table 9.
Table 9. pair dry yeast causes the influence of rat fever
4, the influence of p-Xylol induced mice ear swelling
Get 30 of the Kunming male mices of body weight 18-22g, be divided into 3 groups at random, 10 every group; Control group administered physiological saline (i.p), administration group give the medicine of the present invention (i.p, all pure by dry product) of various dose (mg/kg) respectively; Each is organized volumetric injection and is 1ml/100g, after the last administration 40 minutes, is coated with 0.5ml YLENE in mouse right ear; Left side ear is coated with distilled water, causes inflammation and puts to death mouse after back 1 hour, gets an auricle in mouse two ear same area respectively with the punch tool of 8mm; Accurate claim fixed, with about the difference of two auricle weight as the swelling degree of otitis.The result shows that the difference of the influence of medicine of the present invention and control group p-Xylol induced mice ear swelling has significance, and the result sees the following form 10.
The influence of table 10. p-Xylol induced mice ear swelling
With control group ratio, P＜0.05
5, the monocyte phagocytic function is measured
30 Kunming mouses are divided into 3 groups, 10 every group, through intraperitoneal injection; Control group gives saline water, the medicine of the present invention (all pure) of administration group injection different concns by dry product, for three days on end; Each group was all injected 5% starch 1ml in the 4th day, and injection chicken red blood cell 1ml puts to death mouse after 1 hour more at interval after 1 hour; Draw the peritoneal exudate smear, observe the phagocytic rate of macrophage phagocytic chicken red blood cell behind the Wright's staining, the result shows; Compare difference with control group and have significance, the result sees the following form 11.
The influence of table 11. pair monocyte phagocytic function
6, antivirus action
With Hep-2 cell (5 * 10
5/ L, every hole 0.1ml) placing 96 orifice plates, DMEM respectively is substratum, at 37 ℃, 5%CO
2Cultivate in the incubator, nutrient solution in the hole of inclining next day is with 100TCID
50The adenovirus of/0.1ml (Adv3), respiratory syncytial virus (RSV) and the Sa Qi B of section papova (COXBV) are inoculated Hep-2 cell, 100TCID respectively
50The influenza virus of/0.1ml (FM1) inoculation mdck cell, in 96 orifice plates that grow into monolayer, 37 ℃, 5% CO
2Cultivate in the incubator, hatch after 1 hour and remove liquid, PBS washes flush away virus twice; DMEM is a substratum, adds the medicine of the present invention (all pure by dry product) of nontoxic scope respectively, makes concentration be respectively 10,5 (mg/ml); Every kind of concentration 4 holes; Virus control group and cell control group are set simultaneously, 37 ℃ of constant temperature, observation of cell pathology effect day by day.The result shows that medicine of the present invention has the obvious suppression effect to adenovirus (Adv3), respiratory syncytial virus (RSV), the Sa Qi B of section papova (COXBV) influenza virus (FM1).The result sees table 12.
Table 12. antivirus test result
Annotate: "-" expression cell does not have pathology, and "+" representes intracellular lesion degree
Andrographolidume derivative---rographolide bisulfite sodium hydrate is the preparation method comprise:
Method A. is rographolide water or low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol, rudimentary (C2-C6) ether, and one or more that comprise ether, butyl ether, DIPE, THF are solvent, heating for dissolving; Add one or more or its solution of sodium sulfite anhy 96, S-WAT, Sodium Pyrosulfite, add sulphuric acid soln, be heated to backflow, concentrating under reduced pressure; Cold filtration, filtrating comprises methylene dichloride, trichloromethane, ethylene dichloride with C1-C5 lower halogenated hydrocarbon; Rudimentary (C2-C6) ester is like N-BUTYL ACETATE, ethyl acetate, formic acid second fat, the aromatic hydrocarbon of C6-C9; One or more that comprise benzene, toluene etc. extract 1-5 time, separate organic layer, the water layer filtration; Filtrate decompression concentrates, and adds one or more of water or low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol, rudimentary (C2-C6) ether, stirring; Filter, filtrate decompression is concentrated into dried, is drying to obtain;
Perhaps method B. with the rographolide water or or low mass molecule alcohol C1-C5; Comprise methyl alcohol, ethanol, Virahol, rudimentary (C2-C6) ether; One or more that comprise ether, butyl ether, DIPE, THF are solvent, and heating for dissolving adds solution, the reflux of sodium sulfite anhy 96 or S-WAT or Sodium Metabisulfite or its mixture; Concentrating under reduced pressure; Add one or more of water or low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol, cooled and filtered, gained filtrate direct concentrating under reduced pressure dry these article; Perhaps gained is filtrated with C1-C5 lower halogenated hydrocarbon, comprise methylene dichloride, trichloromethane, ethylene dichloride, rudimentary (C2-C6) ester; Like N-BUTYL ACETATE, ethyl acetate, formic acid second fat, the aromatic hydrocarbon of C6-C9, one or more that comprise benzene, toluene etc. extract 1-5 time; Separate organic layer, water layer filters, and filtrate decompression concentrates near doing; Add one or more of water or low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol, rudimentary (C2-C6) ether, make moltenly, filter; Filtrate decompression is concentrated into dried, is drying to obtain;
Perhaps method C. is evaporated to nearly dry with method A or method B; Perhaps the aromatic hydrocarbon of its desciccate water or C6-C9 or rudimentary (C3-C6) ketone, like acetone, isoamyl ketone; Or low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol; Or the lower halogenated hydrocarbon, like methylene dichloride, trichloromethane, ethylene dichloride, rudimentary (C2-C6) ether, comprise that in ether, butyl ether, the DIPE one or more carry out the one or many recrystallization and promptly get.
Rographolide bisulfite sodium hydrate injection, its preparation method is:
The aseptic subpackaged powder injection of rographolide bisulfite sodium hydrate can prepare according to ordinary method.
The preparation method of freeze-dried powder is: get rographolide bisulfite sodium hydrate, can add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, add injection and blunge and make dissolving, if need; Available pharmaceutically acceptable acid-alkali accommodation pH is 4.0～7.5, adds activated carbon 0.005～0.5% (W/V) and stirs 15～45min, filters; Moisturizing, sterile filtration is by 20～600mg/ bottle (in main ingredient) packing; Lyophilize, tamponade gets finished product.
Rographolide bisulfite sodium hydrate and injection freeze-dried powder, aseptic subpackaged powder injection, the preparation of a unitary dose (specification is 50-800mg) is dissolved in the 10-15ml water, and its pH value is between 4.0～7.5.
Rographolide bisulfite sodium hydrate injection with small volume and preparation technology thereof: water and pharmaceutically acceptable additives are penetrated in the filling of rographolide bisulfite sodium hydrate; For example: pharmaceutically acceptable pH regulator agent, pharmaceutically acceptable oxidation inhibitor, rare gas element; The sterilization injection with small volume is processed in filtration, degerming, and its pH value is between 4.0～7.5.
Its pharmaceutically acceptable pH regulator agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases; Also can be generalized Lewis acid or alkali; Can contain one or several; Can be hydrochloric acid, phosphoric acid, propionic acid, acetic acid and acetate, like sodium-acetate etc.; Lactic acid and lactic acid pharmaceutical salts, Citric Acid pharmaceutical salts, yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide, Pottasium Hydroxide, phosphoric acid salt, tartrate and pharmaceutical salts thereof, borax, boric acid, Succinic Acid, caproic acid, hexanodioic acid, FUMARIC ACID TECH GRADE, maleic acid, trihydroxy-aminomethane, diethylolamine, thanomin, Yi Bingchunan, HSDB 338,2-amino-2-(methylol) 1; Ammediol amine, 1; 2-hexanediamine, N-methyl grape amine, Diisopropylamine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts are like in glucuronic acid, glucono-, lactobionic acid, oxysuccinic acid, threonic acid, glucoheptonic acid, amino acid and the amino acid salts etc. one or several.
Its pharmaceutically acceptable oxidation inhibitor and stablizer can be sulfurous acid, sulphite, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate; Organosulfur compound thiocarbamide, gsh, Sulfactin, Thiovanic acid and salt, thiolactic acid and salt, thio-2 acid and salt, phenol compound; Like gallic acid and salt, coffic acid, caffeiate, FLA, ferulate, di-t-butyl Pyrogentisinic Acid, 2; 5-resorcylic acid, 2,5-resorcylic acid salt, phenol or derivatives thereof, Whitfield's ointment or its salt; Amino acid with and salt; Xitix and ascorbate salt, saccharosonic acid and erythorbate, vitamin PP, tartrate, nitrate salt, phosphoric acid salt, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, like in EDTA disodium, EDTA four sodium, N-two (2-hydroxyethyl) glycocoll etc. one or several.
Its pharmaceutically acceptable isotonic regulator can be one or more in glucose, fructose, Xylitol, sorbyl alcohol, N.F,USP MANNITOL, Nulomoline, SANMALT-S, Expex, sodium-chlor, Repone K, the Sodium.alpha.-hydroxypropionate etc.
Source and the degerming mode of reducing phlegm and internal heat can be the gac that adds dosing amount 0.005～3% source of reducing phlegm and internal heat, and millipore filtration degerming and pressure sterilizing also can adopt heat sterilization, the source of reducing phlegm and internal heat.In the hyperfiltration process; That ultra-fine filter can be selected for use is flat, rolling, tubular type, tubular fibre formula or circle boxlike etc.; Preferred rolling and tubular fibre formula ultra-fine filter; It is after 50,000 to 300,000 filter membrane is removed most of heat generation material and bacterium that relative molecular mass is held back in employing, adopts the ultra-filtration membrane of holding back relative molecular mass 4000～30000 to remove the residue thermal source again, the ultra-filtration membrane of preferred relative molecular mass 4000～10000.
Rographolide bisulfite sodium hydrate of the present invention; Be applicable to the application in the medicine of following treatment that caused humans and animals is infected of preparation or prevention: preparation is used for clearing heat and detoxicating; Azelaic Acid; Application in antiviral, as to bring down a fever, the regulate immunologic function treatment or the medicine of prevention; Promptly be used for the upper and lower respiratory tract infection of preparation treatment, intestinal tract infections, meningitis, myocarditis, pericarditis; Comprise flu, acute bronchitis, acute episode of chronic bronchitis and pneumonia, respiratory tract infection and due to heating, otitis media, parotitis, pharyngitis, tonsillitis, meningitis, myocarditis, pericarditis, influenza, dysentery, intestinal tract infections, acute gastroenteritis, pyelonephritis, urethritis, rotavirus enteritis, by virus, inflammation caused by bacterial infection and the application that improves the medicine of immunity function etc.
Consumption usage: generally speaking,, get medicine 0.020～1.2g of the present invention in 20～500 milliliters of 0.9% sodium-chlor or 5～10% glucose, do intravenous injection or instillation, every day 1～2 time in the adult; Get medicine 0.020～1.0g of the present invention and be dissolved in the water for injection, intramuscularly, every day 1～2 time; Children's amount of reducing by half is above to be used.
Description of drawings
Fig. 1 is the thermogram spectrum of rographolide sodium sulfite anhy 96 2 hydrates.
Fig. 2 is the thermogram spectrum of rographolide sodium sulfite anhy 96 2.5 hydrates.
Fig. 3 is the thermogram spectrum of rographolide sodium sulfite anhy 96 3 hydrates.
Fig. 4 is the thermogram spectrum of rographolide sodium sulfite anhy 96 1.5 hydrates.
Fig. 5 is the thermogram spectrum of rographolide sodium sulfite anhy 96 1 hydrate.
Test condition: the Setsys of Setaram company 16, the about 5mg of sample size, heat-up rate: 10K/min, N
2Flow velocity: 50ml/min, room temperature～400 ℃.
Fig. 6 be rographolide sodium sulfite anhy 96 2 hydrates carbon-13 nmr spectra (
13C-NMR) collection of illustrative plates (600MHz).
Fig. 7 be rographolide sodium sulfite anhy 96 2 hydrates carbon-13 nmr spectra (
1H-NMR, D
2O) collection of illustrative plates.
Fig. 8 is the nucleus magnetic resonance DEPT spectrum (400MHz) of rographolide sodium sulfite anhy 96 2 hydrates.
Embodiment
Being prepared in the 1000ml three-necked flask of embodiment 1 rographolide sodium sulfite anhy 96 2 hydrates adds ethanol 220ml, methyl alcohol 30ml and rographolide 100g, and heating for dissolving adds the aqueous solution 150ml of sodium sulfite anhy 96 (30g); Be heated to and refluxed 30 minutes, concentrating under reduced pressure is closely dried, and adding distil water 400ml makes dissolving, cooled and filtered; Filtrating is with chloroform extraction 3 times, and each 100ml separates chloroform layer, the water layer filtration; Filtrate decompression concentrates near doing, and adds 1: 1 ethanol and aqueous isopropanol, and heating makes molten; Cooling is filtered, and filtrate decompression is concentrated near doing, and filters; Use ethanol and DIPE to carry out recrystallization again as solvent, about 100 ℃ of solidss dry 2-4 hour off-white color crystalline powder 86.3g, fusing point: 226.2-228.4 ℃ of decomposition (correction), UV spectrum: λ
H2O Max203nm (ε, 10500), ESI-MS:m/z:436; Ir spectra: v
KBr MaxCm
-13446,2939,2870,1756,1644,1200,1143,898; It is 7.73% that the Ka Shi method is measured moisture; Heat is analyzed TG-DTA: platform is weightless about 7.52%, and result's (theoretical value 7.63%) that this and sample contain 2 crystal water (sees accompanying drawing 1) in limit of error.Ultimate analysis theoretical value: C 50.84%, H7.04%, Na4.87%S6.79%; Measured value: C 50.78%, H7.11%, Na4.81%S6.72%;
H-NMR (D
2O) δ 7.69 (1H CH-CH2-O-C, 14), δ 4.91 (2H C=CH2,17), δ 4.82 (1H C=CH2--O; 15B), and δ 4.68 (1H C=CH2--O, 15A), δ 3.91 (1H CH-SO3Na), δ 3.83 (1H C-CH-OH; 3), δ 3.28 (2H C-CH2-OH, 19), δ 0.97 (3H CH
2OH-C-CH
3, 18), δ 0.54 (3H C-CH
3, 20); Carbon-13 nmr spectra (
13C-NMR) and DEPT spectrum: 20 of total carbon numbers, 2 of primary carbons, secondary carbon 8, tertiary carbon 5, quaternary carbon 5;
13C-NMR (D
2O): 174.3-C
16, 150.4-C
14, 145.7-C
8, 126.7-C
13, 104.9-C
17, 77.5-C
3, 70.3-C
15, 61.2-C
19, 52.7-C
9, 52.3-C
5, 50.5-C
12, 40.3-C
4, 36.5-C
10, 35.5-C
7, 34.4-C
1, 24.8-C
2, 23.3-C
11, 21.8-C
6, 19.8-C
18, 12.3-C
20(ppm).
Rographolide 100g is got in the preparation of embodiment 2 rographolide sodium sulfite anhy 96s 3 hydrates, adds ethanol 220ml, and isopropyl ether 30ml heats in the 1000ml three-necked flask; Drip 2M sodium sulfite aqueous solution 150ml, reflux half a hour, behind the concentrating under reduced pressure, with chloroform and dichloromethane extraction 3 times; Each 150ml separates organic layer, and water layer filters, and filtrate decompression concentrates; Add ethanol, cooling is filtered, filtrate decompression concentrate as for; Dry under the room temperature, get sample 82 grams, fusing point: 215.5-218.6 ℃ (proofreading and correct), UV spectrum: λ
H2O Max203nm (ε, 10500), ESI-MS:m/z:436; Ir spectra: v
KBr MaxCm
-13446,2939,2870,1756,1644,1200,1143,898; It is 12.26% that the Ka Shi method is measured moisture, and heat is analyzed TG-DTA: platform is weightless about 11.31%, and result's (theoretical value 11.03%) that this and sample contain 3 crystal water (sees accompanying drawing 3) in limit of error; Ultimate analysis theoretical value: C 48.97%, H7.19%, Na4.69%S6.54%; Measured value: C 49.08%, H7.26%, Na4.63%S6.62%; Carbon-13 nmr spectra (
13C-NMR) and DEPT spectrum: total carbon number 20, primary carbon 2, secondary carbon 8, tertiary carbon 5, quaternary carbon 5.
Being prepared in the three-necked flask of embodiment 3 rographolide sodium sulfite anhy 96s 2.5 hydrates adds rographolide 20g and ethanol 55ml, methyl alcohol 5ml, and heating makes dissolving, adds 2M sodium sulfite aqueous solution 30ml under stirring; Heating, backflow 0.6h, concentrating under reduced pressure is with chloroform and dichloromethane extraction 3 times; Each 100ml separates organic layer, and water layer filters, and is evaporated near doing; With ethanol and isopropyl alcohol mixed solvent (1: 2) crystallization, filter, the dry off-white powder 16g that gets is soluble in water about 72 ℃; Fusing point: 219.3-222.6 ℃ of decomposition (not proofreading and correct); UV spectrum: λ
H2O Max203nm (ε, 10500), ESI:m/z:436; Ir spectra: v
KBr MaxCm
-13446,2939,2870,1756,1644,1200,1143,898; Moisture (Ka Shi method): 9.26%; Heat is analyzed TG-DTA: platform is weightless about 9.82%%, and result's (theoretical value 9.36%) that this and sample contain 2.5 crystal water (sees accompanying drawing 3) in limit of error; Ultimate analysis theoretical value: C 49.89%, H7.12%, Na4.77%S6.66%; Measured value: C 49.81%, H7.20%, Na4.64%S6.57%.
The preparation of embodiment 4 rographolide sodium sulfite anhy 96s 1.5 hydrates drops into rographolide hydrate 15g and Sodium Metabisulfite 4.7g in the reaction flask, adds 85% ethanol 120ml, and butyl ether 20ml stirs, heating; Stirring, back flow reaction 35-60min are evaporated near doing, and add the several times water dissolution, and refrigeration is spent the night; Filter, filtrating chloroform extraction 2-3 time filters filtrating, and concentrating under reduced pressure is closely dried; Use the mixed solvent crystallization of ethanol and chloroform again, cooling is filtered, and drains; 80 ℃ dry 10-16 hour the off-white color crystalline powder, soluble in water, fusing point: 226.8～228.7 ℃ (proofread and correct), UV spectrum: λ
H2O Max203nm (ε, 10500), ESI:m/z:436; Ir spectra: v
KBr MaxCm
-13500,1755,1643,1200,1153,899; It is 5.92% that the Ka Shi method is measured moisture; Heat is analyzed TG-DTA: platform is weightless about 6.01%, and result's (theoretical value 5.83%) that this and sample contain 1.5 crystal water (sees TG-DTA accompanying drawing 3) in limit of error.Ultimate analysis theoretical value: C 51.82%, H6.96%, Na4.96%S6.92%; Measured value: C 51.74%, H7.06%, Na5.07%S6.79%.
Within 150 ℃, Vanadium Pentoxide in FLAKES is a siccative with rographolide bisulfite sodium hydrate, and vacuum-drying got rographolide sodium sulfite anhy 96 anhydride more than 10 hours.
Embodiment 6 with rographolide hydrate 10g and Sodium Metabisulfite in molar ratio example (2: 1) drop in the reaction flask, add ethanol 80ml and THF 30ml, heating, about stirring, backflow 50min, question response finishes; Concentrating under reduced pressure, with chloroform extraction 3 times, each 100ml separates chloroform layer, and water layer filters; Concentrating under reduced pressure adds dissolve with ethanol, and cooling is filtered, filtrate decompression concentrate as for; The gained solid is added water make dissolving, place Freeze Drying Equipment, freezing 3～6 hours, make temperature reach-35～-65 ℃; Making the interior vacuum tightness of machine is 2～30Pa, and low-temperature vacuum drying 24～48 hours rises to temperature about 30 ℃, vacuum-drying 4～10 hours; Get off-white powder, soluble in water, fusing point: 226.3～228.5 ℃ (proofreading and correct), UV spectrum: λ
H2O Max203nm (ε, 10500), ESI:m/z:436; It is 5.96% that the Ka Shi method is measured moisture, and platform was weightless about 5.83% before heat was analyzed TG-DTA:175 ℃, and this and sample contain the result of 1.5 crystal water in limit of error.Ultimate analysis theoretical value: C 51.82%, H6.96%, Na4.96%S6.92%; Measured value: C 51.71%, H7.09%, Na5.10%S7.07%.
Embodiment 7 gets rographolide sodium sulfite anhy 96 2 hydrate 20Kg (by anhydride), adds glucose or N.F,USP MANNITOL or Xylitol 2.0～5g and adds fresh water for injection 160～320L and stir and make dissolving, and using pharmaceutically acceptable acid or alkali to regulate pH is 5.0～6.5; Add activated carbon 0.01～0.5% (W/V) and stir 15～45min; Filter, moisturizing to 200～400L is with 0.22 micron filtering with microporous membrane; By 50mg/ bottle, 100mg/ bottle or 200mg/ bottle or 400mg/ bottle or 600mg/ bottle (in main ingredient) packing; Lyophilize, tamponade gets finished product.
Embodiment 10 rographolide bisulfite sodium hydrate (by anhydride) 10.2g add cysteine hydrochloride 0.8g, EDTA disodium 0.1g; Add injection and blunge and make dissolving, it is 5.5～6.8 that 2M lactic acid is regulated pH with Sodium.alpha.-hydroxypropionate, adds activated carbon 0.01% (W/V) stirring 15～45min; Filter, moisturizing is held back the ultrafiltration membrance filter of relative molecular mass 4000-8000 to 250ml with 0.22 micron filtering with microporous membrane or employing; Press the packing of 2-5ml/ bottle, sterilize finished product.
Embodiment 11 rographolide bisulfite sodium hydrate (by anhydride) 10g add injection and blunge and make dissolving, add activated carbon 0.01% (W/V) and stir 15～45min; Filter, moisturizing is held back the ultrafiltration membrance filter of relative molecular mass 4000-8000 to 200ml with 0.22 micron filtering with microporous membrane or employing; Press the packing of 2-5ml/ bottle; Lyophilize, tamponade gets finished product.
The preparation of embodiment 12 rographolide bisulfite sodium hydrate high-capacity injections takes by weighing glucose 500g and adds in the water for injection; Stirring makes dissolving fully, adds the gac of dosing amount 0.05%, heats about 10-30 minute; Put cold, through sand filtration rod filtering decarbonization; After dissolving fully with fresh water for injection rographolide bisulfite sodium hydrate (in the rographolide sodium sulfite anhy 96) 10.1g, mix, add hydrochloric acid L-halfcystine 1g with above-mentioned filtrating; EDTA disodium 0.2g regulates the pH value in the scope of 3.2-6.0 with the 1M lactic acid solution, adds the injection water to 5000ml; The gac that adds dosing amount 0.01%, about heated and stirred 10-30 minute, filtering decarbonization; Perhaps adopt the ultrafiltration membrance filter of holding back relative molecular mass 4000-8000 through the smart filter of 0.22um millipore filtration again, after work in-process are chemically examined, treated that its content, pH value and clarity are qualified; Embedding is in the vial of 50ml or 100ml or 200ml; Sterilization, finished product inspection, packing promptly gets.
The preparation of embodiment 13 rographolide bisulfite sodium hydrate sodium-chlor transfusion: with rographolide bisulfite sodium hydrate (by anhydride) 10g, sodium-chlor 85g, Sodium Pyrosulfite 1.1g, EDTA disodium 0.2g, add in the water for injection, stir to make and dissolve fully; Citric Acid and liquor sodii citratis with 1M are regulated the pH value in the scope of 4.0-6.5, add the injection water to 10000ml, add the gac of dosing amount 0.05%; About heated and stirred 10-30 minute, filtering decarbonization perhaps adopts the ultrafiltration membrance filter of holding back relative molecular mass 4000-8000 through the smart filter of 0.22um millipore filtration again; Chemically examine through work in-process; After treating that its content, pH value and clarity are qualified, embedding is sterilized in the vial of 50ml or 100ml or 200ml; Finished product inspection, packing promptly gets.
The variation that is appreciated that a lot of details is possible, and therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to the foregoing description.
Claims (10)
1. rographolide bisulfite sodium hydrate, its molecular formula is C
20H
29O
7SNanH
2O, n=1,1.5,2,2.5,3, its be used to prepare have the bringing down a fever of immunization, anti-inflammatory, anti-infectives.
2. rographolide bisulfite sodium hydrate according to claim 1 is characterized in that: rographolide bisulfite sodium hydrate is rographolide sodium sulfite anhy 96 3 hydrates.
3. rographolide bisulfite sodium hydrate according to claim 1 is characterized in that: rographolide bisulfite sodium hydrate is rographolide sodium sulfite anhy 96 2.5 hydrates.
4. rographolide bisulfite sodium hydrate according to claim 1 is characterized in that: rographolide bisulfite sodium hydrate is rographolide sodium sulfite anhy 96 2 hydrates.
5. rographolide bisulfite sodium hydrate according to claim 1 is characterized in that: rographolide bisulfite sodium hydrate is rographolide sodium sulfite anhy 96 1.5 hydrates.
6. rographolide bisulfite sodium hydrate according to claim 1 is characterized in that: rographolide bisulfite sodium hydrate is rographolide sodium sulfite anhy 96 1 hydrate.
7. the preparation method of rographolide bisulfite sodium hydrate according to claim 1, it is characterized in that: the preparation method comprises:
Method A. is with rographolide water or C
1-C
5Low mass molecule alcohol, C
2-C
6In the rudimentary ether one or more are solvent, and heating for dissolving adds one or more or its solution of sodium sulfite anhy 96, S-WAT, Sodium Pyrosulfite, add sulphuric acid soln, be heated to backflow, and concentrating under reduced pressure, cold filtration, filtrating is used C
1-C
5Lower halogenated hydrocarbon, C
2-C
6Lower member ester, C
6-C
9Aromatic hydrocarbon in one or more extract 1-5 time, separate organic layer, water layer filters, filtrate decompression is concentrated, adds water or C
1-C
5Low mass molecule alcohol, C
2-C
6One or more of rudimentary ether stir, and filter, and filtrate decompression is concentrated into dried, is drying to obtain;
Perhaps method B. is with rographolide water or C
1-C
5Low mass molecule alcohol, C
2-C
6One or more of rudimentary ether are solvent; Heating for dissolving; Dropping adds solution, the reflux of sodium sulfite anhy 96 or S-WAT or Sodium Metabisulfite or its mixture, and concentrating under reduced pressure adds one or more of low mass molecule alcohol of water or C1-C5; Cooled and filtered, gained filtrate direct concentrating under reduced pressure dry these article; Perhaps gained filtrating is used C
1-C
5Lower halogenated hydrocarbon, C
2-C
6Lower member ester, C
6-C
9Aromatic hydrocarbon in one or more extract 1-5 time, separate organic layer, water layer filters, filtrate decompression concentrates near dried, adds water or C
1-C
5Low mass molecule alcohol, C
2-C
6One or more of rudimentary ether make moltenly, filter, and filtrate decompression is concentrated into dried, is drying to obtain;
Perhaps method C. is evaporated to nearly dry with method A or method B, perhaps its desciccate water or C
6-C
9Aromatic hydrocarbon or C
3-C
6Lower ketones or C
1-C
5Low mass molecule alcohol or methylene dichloride, trichloromethane, ethylene dichloride, C
2-C
6In the rudimentary ether one or more carry out once or several times recrystallization promptly get.
8. the purposes of rographolide bisulfite sodium hydrate according to claim 1 is characterized in that: rographolide bisulfite sodium hydrate is used to prepare injection freeze-dried powder, or aseptic subpackaged powder injection or great transfusion preparation, or little water needle injection.
9. the purposes of rographolide bisulfite sodium hydrate according to claim 8; It is characterized in that said injection freeze-dried powder, aseptic subpackaged powder injection are: the preparation that specification is the unitary dose of 50-800mg is dissolved in the 10-15ml water, and its pH value is between 4.0～7.5.
10. rographolide bisulfite sodium hydrate according to claim 1 is used for the application of the medicine of Azelaic Acid, antiviral, the treatment of bringing down a fever, regulate immunologic function or prevention in preparation.
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| CN101830835A (en) * | 2010-03-26 | 2010-09-15 | 刘力 | Sodium paeonol sulfonate crystalline hydrate as well as preparation method and application thereof |
| CN103156840B (en) * | 2012-04-12 | 2015-07-08 | 江西青峰药业有限公司 | Once preparation method of composite of 17-hydrogen-9-dehydro-andrographolidume-3-sodium (or potassium) disulfate and 17-hydrogen-9-dehydro-andrographolidume-3, 19-sodium (or potassium) disulfate, and purposes of prepared medicine |
| CN103145658A (en) * | 2012-04-12 | 2013-06-12 | 江西青峰药业有限公司 | One-step preparation method of composition of sodium (or potassium) 17-hydro-9-dehydroandrographolide-3-sulphate, sodium (or potassium) 17-hydro-9-dehydroandrographolide-19-sulphate and sodium (or potassium) 17-hydro-9-dehydroandrographolide-3,19-disulfate, and use of the composition in drug preparation. |
| CN103156841A (en) * | 2012-04-12 | 2013-06-19 | 江西青峰药业有限公司 | Compound of 17-hydrogen-9-dehydrogenation andrographolide-3-sulphate sodium (or potassium) and 17-hydrogen-9-dehydrogenation andrographolide-19-sulphate sodium (or potassium) and preparation drug purposes thereof |
| CN111635383B (en) * | 2020-07-07 | 2023-01-24 | 郑州大学 | Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate and preparation method thereof |
| CN112279841A (en) * | 2020-10-28 | 2021-01-29 | 谢天龙 | Antiviral andrographolide derivative and preparation method thereof |
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