CN101926755B - In-situ gel preparation of potassium dehydroandrographolide succinate and preparation method thereof - Google Patents
In-situ gel preparation of potassium dehydroandrographolide succinate and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an in-situ gel preparation of potassium dehydroandrographolide succinate and a preparation method thereof. The preparation is prepared from potassium dehydroandrographolide succinate (dehydration andrographolide butanedioic acid ester single sylvite half), in-site gel substrates recognized in the field, and other pharmaceutic adjuvants necessary for other pharmacy by using water as a solvent. In-situ gel of potassium dehydroandrographolide succinate is liquid freely moving outside a body, and forms semisolid gel after patients take the gel. The invention has the advantages of definite effect, stable performance, simple preparation, convenient administration, strong compliance for patients, no toxic and side effect, no untoward effect, high bioavailability, and on the like. The in-situ gel preparation has good antipyretic and antiinflammatory action, can be used for clinically treating viral respiratory tract infection and viral pneumonia, can be used as alternative medicine for potassium dehydroandrographolide succinate injection, and is particularly suitable for infants and patients who have trouble in taking medicine.
Description
Technical field:
The invention belongs to the field of Chinese medicines; More specifically relate to a kind of have good bring down a fever effect and antiinflammatory action; For viral upper respiratory tract infection and viral pneumonia, especially infant and the in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of the patient's of being inconvenient to take medicine first-selected medication and preparation method thereof.
Background technology:
In recent years; Along with Chinese medicine large scale application clinically; The problem of untoward reaction also more and more highlights; Wherein Andrographolide, QINGKAILING, Herba Houttuyniae, compound Salviae Miltiorrhizae, MAILUONING, SHUANGHUANLIAN, the Radix Astragali, beta-aescin sodium, puerarin and 10 kinds of Oleum Curcumae injection are even more serious, and its untoward reaction rate accounts for 74.4% of whole Chinese medicines.Report (Zuo Zhiyan, 42 routine Chinese medicine analysis of adverse reactions, Chinese Pharmaceutical, 2007,16 (20): 54) are arranged when causing the incident of patient's anaphylactic shock, acute death because of the Chinese medicine untoward reaction.How solving Chinese medicine untoward reaction problem, is the focus of academia arguement in nearly 2 years, also is the emphasis and the difficult point of pharmacy worker scientific research simultaneously.One of its solution route makes it suitable basically with Chinese medicine aspect the performance curative effect, and is being superior to Chinese medicine aspect reduction toxicity and the minimizing untoward reaction for seeking the Chinese medicine novel form that can substitute Chinese medicine.
Mucosal drug delivery be at present by consistent approve near a kind of route of administration of drug administration by injection; At least can partly substitute Chinese medicine and be applied to tcm emergency; The performance its quick-acting in; Avoid its side effect and first pass effect, have also that dosage is little, bioavailability is high and characteristics such as action time is fast.
After situ-gel is meant that macromolecular material is with solution or semi-solid state administration, stimulate to external world at agents area to respond, the reversible conversion of dispersity or conformation takes place, the semisolid of formation or liquid preparation.Situ-gel has the hydrophilic three-dimensional net structure and the favorable tissue compatibility of gel preparation; Simultaneously; Unique solution-gel conversion character make its have concurrently preparation simple, easy to use, with agents area advantages such as particularly the mucous membrane tissue affinity is strong, the holdup time is long, purposes and better controlling Release Performance widely in addition, situ-gel study abroad comparatively deeply and have a sophisticated launch; Domestic starting late; Also have how tame research institute to declare the clinical research of this type of preparation, but be main with chemicals mainly, the field of Chinese medicines does not still have report.
Andrographolide is that the plant monomer andrographolide (Andrographolide) that extracts in the employing acanthaceous plant Herba Andrographis [Andrographis paniculate (Burm.f.) Nees] is a raw material; React in the potassium hydroxide pyridine solution with succinic anhydrides; The POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE (Potassium DehydroandrographolideSuccinate) that generates, commodity are called Andrographolide.Pharmacological research proof Andrographolide can suppress inosinic acid-5-phosphate dehydrogenase, and the blocking-up inosinic acid is converted into guanyl, and then suppresses the synthetic of viral RNA/DNA; Pneumonia adenovirus type III, influenza virus A 1 type, first 3 types, intestinal syncytial virus and respiratory syncytial virus etc. are all had deactivation, can protect lysosome membrane, prevent that lysosome from destroying; The release of CKIs hydrolytic enzyme suppresses to cause inflammation, causes the pain medium and discharge, and the capillary wall permeability due to the antagonism human body inflammatory mediator histamine increases; Synthesizing of inflammation-inhibiting position prostaglandin recovered the sensitivity of heat-sensitive neuron, and the body temperature set point moves down; Heat radiation strengthens and a refrigeration function (Liu Cunling, Andrographolide injectable powder treatment bronchopneumonia 100 routine observation of curative effect, Guangzhou medicine; 1999,30 (1): 65).Usually be used for the treatment of viral respiratory tract infection and infant viral pneumonia clinically, obtain good efficacy, become one of first batch of indispensable Chinese patent medicine of national hospital of traditional Chinese hospital's emergency department of State Administration of Traditional Chinese Medicine's approval at present.
Chuanhuning prepn mainly contains freeze-dried powder, injection, injection at present.According to bibliographical information, the untoward reaction of injection Andrographolide is very serious, brings great hidden danger for patient's safe medication.This patent is an approach with the mucosal drug delivery, is means with the situ-gel, has prepared the Andrographolide situ-gel.Said preparation is safe and effective, bioavailability is high, stable performance, quality controllable, preparation is simple, convenient drug administration, mucosa adhesion property are strong, easy to clean; The per rectum administration does not increase patient's misery; Patient's compliance is strong, is particularly useful for infant and the patient of the difficulty of can not taking medicine or take medicine.No related patent U.S. Patent No. and patent application at present.
Summary of the invention:
The objective of the invention is to the untoward reaction of Andrographolide drug administration by injection seriously, the spy provides that a kind of determined curative effect, steady quality, preparation are simple, easy to use, patient's compliance strong, have no side effect and untoward reaction, new product---Andrographolide situ-gel and preparation method thereof that bioavailability is high.This medical instrument has good analgesic, antiinflammatory action, for viral upper respiratory tract infection and viral pneumonia, especially infant and the patient's of being inconvenient to take medicine first-selected medication.
For achieving the above object, the present invention implements through following technical proposals:
1. the prescription of this patent
1) prescription of the present invention is made up of the adjuvant and the distilled water of principal agent (Andrographolide), situ-gel substrate, other pharmaceutics necessity.Wherein the principal agent Andrographolide accounts for 0.01%～20% of percentage by weight of the present invention, and is preferred 5～10%, and most preferably 10%.
2) the original position gel-type vehicle can be one or more couplings of the material of ion-sensitive type, responsive to temperature type and pH value responsive type among the present invention, and wherein ion-sensitive type situ-gel substrate comprises one or more of deacetylation gellan gum, sodium alginate, xanthan gum, welan gum or carrageenan; Responsive to temperature type situ-gel substrate comprises one or more in poloxamer, N-Isopropylacrylamide copolymer, Polyethylene Glycol-PLGA block copolymer or the ethylhydroxyethylcellulose; PH value responsive type situ-gel substrate comprises one or more in polyacrylic, chitosan and derivant thereof, cellulose acetate phthalate ester, the polyacrylamide.
3) the necessary adjuvants of other pharmaceuticss comprise one or more thickening agent of cellulose family such as methylcellulose, sodium carboxymethyl cellulose and hydroxypropyl emthylcellulose and derivant thereof, preferably carboxymethyl cellulose sodium among the present invention; Sulfites, thioglycerol, sulfo-sorbic acid, thioglycolic acid, cysteine hydrochloride, ascorbic acid, one or more antioxidant, preferred disodium edetate; One or more pharmaceutics common plasticizers of the mixture of glycerol, propylene glycol, TC, glyceride and cithrol, polyoxyethylene ether hydrogenated castor wet goods, preferred polyethylene glycols; The solubilizing agent of one or more in hydroxypropyl beta cyclodextrin, poly yamanashi esters, polyoxyethylene fatty acid ester class, polyoxyethylene fatty acid alcohol ethers, organic acid and its esters, amide or aminated compounds, polyethylene glycols, the polyhydric alcohol, preferred hydroxypropyl beta cyclodextrin; The antiseptic of one or more of oxybenzene esters, chlorobutanol, benzyl alcohol, phenethanol, chlorhexidine acetate, benzalkonium chloride, sodium benzoate, potassium sorbate, thimerosal and quaternary ammonium compound; Preferred sodium benzoate, potassium sorbate, most preferably sodium benzoate; In mannitol, sorbitol, sodium citrate, the sodium chloride one or more etc. ooze, etc. open regulator, preferred mannitol; The pH regulator agent of one or more of acids such as triethanolamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate or hydrochloric acid, preferred triethanolamine.
2. moulding process of the present invention
The present invention processes as follows:
(a) get situ-gel substrate and the necessary adjuvant of other pharmaceuticss in the prescription ratio, put in the part distilled water, the adjusting pH value is put the refrigerator and cooled Tibetan and is made dissolving fully.
(b) in the glue of above-mentioned preparation, add the Andrographolide crude drug in the prescription ratio, stir, regulate pH value, get a yellow clarification pastille glue.
(c) distilled water is supplied recipe quantity, gets yellow clear and bright glue, and fill promptly gets.
Wherein:
The used alkali of this law can be sodium hydroxide, triethanolamine, sodium bicarbonate.
Transfer pH to 5.5～6.5 to make dissolving in the step (a).
Regulate pH to 5.5～6.5 (preferred 5.8～6.2) of Andrographolide situ-gel glue in the step (b).
3. the product of the present invention's preparation is main galenic pharmacy quality control index with gelation temperature, and its gelation temperature scope is 33～37 ℃; The assay method of gelation temperature has viscometer determining method and rheometer measurement method.
4. the product of the present invention's preparation is solution yellow, clear and bright homogeneous under room temperature and cryogenic conditions, and stable in properties is quality controllable; Change clear and bright semi-solid gel into after getting into rectum.
The present invention has good bring down a fever effect and antiinflammatory action, is the first-selected medication of viral upper respiratory tract infection and viral pneumonia, is particularly useful for infant and is inconvenient to the patient that takes medicine.The tradition Chuanhuning prepn is drug administration by injection, and untoward reaction is more serious, patient's poor compliance, and the present invention is through mucosal drug delivery, and not only drug effect is remarkable, and can reduce the occurrence probability of original adverse effect greatly, alleviates patient's medication misery.
The specific embodiment:
Following embodiment is used to further specify the present invention, but they are not to attempt manner in office to limit scope of the present invention.
Embodiment 1:
Prescription: Andrographolide 30.0g, poloxamer 40719.0g, poloxamer 1886.0g, sodium benzoate 0.5g, triethanolamine is an amount of, and distilled water complements to 100g.
Method for preparing: after getting the recipe quantity sodium benzoate and being dissolved in an amount of distilled water, add the recipe quantity Andrographolide, regulate about pH to 5.8, Andrographolide water liquid; Get recipe quantity poloxamer 188 and put in the Andrographolide water liquid,, add recipe quantity poloxamer 407 again prior to stirring and dissolving under the room temperature; After stirring makes and is uniformly dispersed, put 4 ℃ of refrigerator and cooled and hide more than the 48h, get yellow clear and bright solution; Regulate pH to 5.8～6.2, moisturizing is to making into 100g, and fill promptly gets.
Embodiment 2:
Prescription is with embodiment 1
Method for preparing: get recipe quantity sodium benzoate, poloxamer 188, poloxamer 407 and put in an amount of distilled water, stir make be uniformly dispersed after, put 4 ℃ of refrigerator and cooled and hid 24 hours; Add the recipe quantity Andrographolide after getting transparent glue, regulate pH to 5.8～6.2, moisturizing is to making into 100g; Fill promptly gets.
Embodiment 3:
Prescription: Andrographolide 10g, poloxamer 40720.0g, poloxamer 1881.0g, hydroxypropyl beta cyclodextrin 6.0g, sodium benzoate 0.5g, triethanolamine is an amount of, and distilled water complements to 100g.
Method for preparing: after getting recipe quantity sodium benzoate, hydroxypropyl beta cyclodextrin 6.0g and being dissolved in an amount of distilled water, remaining operating procedure and method are with embodiment 2.
Embodiment 4:
Prescription: with embodiment 3.
Method for preparing: take by weighing the poloxamer 188 of recipe quantity, put in the high purity water, stir and make dissolving; Take by weighing the poloxamer 407 of recipe quantity again, put wherein, stirring makes and is uniformly dispersed, and puts 4 ℃ of cold preservations in the refrigerator, makes into the homogeneous glue.Slowly inject above-mentioned glue after hydroxypropyl beta cyclodextrin placed high purity water dissolving, stir, add triethanolamine gradually and transfer to 6.5-7.5 to pH value in right amount.Add the stirring of recipe quantity Andrographolide and make dissolving, get a yellow clarification pastille glue, add the benzyl alcohol of 0.5g, stir, moisturizing is to making into 100g, and fill promptly gets.
Embodiment 5:
Prescription: Andrographolide 7.5g, deacetylation gellan gum 10.0g, hydrochloric acid cysteine 0.5, sodium benzoate 0.5g, sodium hydroxide is an amount of, and distilled water complements to 100g.
Method for preparing: get the recipe quantity Andrographolide and put in an amount of distilled water, regulate about pH to 7 and make dissolving, get Andrographolide water liquid; After getting recipe quantity sodium benzoate, hydrochloric acid cysteine 0.5 and being dissolved in Andrographolide water liquid, add the deacetylation gellan gum of recipe quantity, stir to make and be uniformly dispersed; Put 4 ℃ of refrigerator and cooled and hide more than 3 days, get light yellow clear and bright solution, regulate pH to 6.5～7.5; Moisturizing is to making into 100g, and fill promptly gets.
Embodiment 6:
Prescription: Andrographolide 15g, sodium alginate 12.0g, disodium edetate 0.6g, benzalkonium chloride 0.05g, sodium hydroxide is an amount of, and distilled water complements to 100g.
Method for preparing: get the recipe quantity Andrographolide and put in an amount of distilled water, regulate about pH to 7 and make dissolving, get Andrographolide water liquid; After getting recipe quantity disodium edetate, benzalkonium chloride and being dissolved in Andrographolide water liquid, add the sodium alginate of recipe quantity, stir to make and be uniformly dispersed; Put 4 ℃ of refrigerator and cooled and hide more than 3 days, get light yellow clear and bright solution, regulate pH to 6.5～7.5; Moisturizing is to making into 100g, and fill promptly gets.
Embodiment 7:
Prescription: Andrographolide 5.0g, carbopol 9402.0g, sodium carboxymethyl cellulose 0.05g, disodium edetate 0.6g, Potassium Benzoate 1.0g, diethanolamine is an amount of.
Method for preparing: after getting recipe quantity disodium edetate, Potassium Benzoate and being dissolved in suitable quantity of water, add the carbopol 940 and the sodium carboxymethyl cellulose of recipe quantity, stir to make and be uniformly dispersed, put 4 ℃ of refrigerator and cooled and hide, transparent glue; Add the recipe quantity Andrographolide, stir, diethanolamine is regulated pH to 6.5-7.5, and moisturizing is to making into 100g, and fill promptly gets.
Embodiment 8:
Prepare in-situ gel preparation of potassium dehydroandrographolisuccinate succinate according to embodiment 4 methods; Carry out the animal model pharmacodynamic study---the analgesic experiment of rabbit; This experiment is based on the pharmacodynamics comparative study of the present invention and potasium dehydroandrographolisuccinate succinate injection, and purpose is in order to further specify the present invention, but does not limit protection scope of the present invention.
1) instrument and reagent
The WMY-01 digital thermometer, Shanghai Medical Instrument and Meter Factory
The typhoid Vi polysaccharide vaccine, Beijing Tiantan Bio-pharmaceuticals goods company (lot number 2008030901)
The Andrographolide injectable powder, 200mg/, Heilungkiang Di Long Pharma Inc. (lot number 061124-1)
Andrographolide in-situ gel (lot number 08093001) is pressed embodiment 4 preparations
Blank gel does not add the principal agent preparation by embodiment 4 methods.
The indomethacin bolt, 100mg/ grain, Beijing ten thousand brightness Pharmaceuticaies (lot number 070503)
2) laboratory animal
Male large ear rabbit, 35,2.0-2.5kg, Beijing tonneau experimental animal is cultured factory.
3) laboratory animal is divided into groups
Normal group, model group, blank control group, high dose group, low dose group, positive drug group, injection dosage form group, 5 every group.
4) experimental technique
Behind the rabbit fasting 48h, in the anus temperature of same measure of time normal rabbits on experiment the previous day and experiment same day, ask its average as normal body temperature, by its basal body temperature it is divided into 7 groups then, 5 every group, the maintenance room temperature is constant in the experimentation.Press the dosage of 0.5ml/kg and give the tame rabbit ear along quiet notes typhoid Vi polysaccharide vaccine, vaccine is promptly seen 1.0-1.5 ℃ of rectal temperature rising, more than the lasting 6h after injecting 1h.
After treating body temperature rise behind the injection vaccine 1h; By high (1.4g/kg), low (0.7g/kg) dosage and rabbit body weight difference rectal perfusion Andrographolide situ-gel and indomethacin suppository (10mg/kg), the injection dosage form is pressed the dosage lumbar injection potasium dehydroandrographolisuccinate succinate injection of 100mg/kg.After the administration, the anus temperature of every rabbit is calculated the different body temperature difference averages (Δ T) constantly of each group 1,2,3,4, in the 6h time point determining group, sees table 1.
5) experimental result
Above statistical data shows, the Andrographolide gel has the fever in rabbits that causes because of the Salmonella typhoid Vi vaccine and significantly to separate thermal effect (P＜0.05) behind administration 1h, shows that rectally can reach onset really and act on rapidly.
Table 1. rabbit different time body temperature changes (n=5)
Annotate: * representes with model group significant difference (P＜0.05) is arranged relatively, and * * representes with model group utmost point significant difference (P＜0.01) is arranged relatively.
Embodiment 9:
Prepare in-situ gel preparation of potassium dehydroandrographolisuccinate succinate according to embodiment 4 methods; Carry out the animal model pharmacodynamic study---the influence that the mouse ear caused by dimethylbenzene xylene is scorching; This experiment is based on the pharmacodynamics comparative study of the present invention and potasium dehydroandrographolisuccinate succinate injection; Purpose is in order to further specify the present invention, but does not limit protection scope of the present invention.
1) instrument and reagent
The rustless steel card punch, self-control
The precise electronic balance, Ao Haosi (Shanghai) company
Xylene, analytical pure, Beijing Chemical Plant
Indomethacin suppository, 100mg/ grain, Beijing ten thousand brightness Pharmaceuticaies (lot number 070503)
The Andrographolide injectable powder, 200mg/, Heilungkiang Di Long Pharma Inc. (lot number 061124-1)
Andrographolide gel (lot number 08093001) is pressed embodiment 4 preparations
Blank gel does not add the principal agent preparation by embodiment 4 methods.
2) laboratory animal
Kunming mouse, 100, Institute of Experimental Animals, Chinese Academy of Medical Sciences
3) laboratory animal is divided into groups
Be divided into model group, blank control group, high dose group, low dose group, positive controls (indomethacin), injection dosage form group, at least 10 every group.
4) experimental technique
Behind the Kunming mouse rectally 60min, xylene 0.02ml evenly is applied to the mouse right ear positive and negative, behind the 15min mice dislocation is put to death; Cut two ears, punching is weighed, and is the swelling degree with auris dextra sheet and left auricle weight difference; The result is good; There is notable difference in model group two auricle weight differentials with the administration group more than 10mg, the result sees table 2.
Table 2. Kunming mouse auricle edema experiment (n=10)
| Group | Number of animals (only) | Dosage (mg/kg) | Swelling degree (mg) |
| Model group (water) | 10 | 3750 | 12.8±5.20 |
| Blank control group | 10 | 3750 | 10.3±4.22 |
| The positive drug group | 10 | 30 | 8.2±3.46* |
| The injection group | 10 | 250 | 7.6±2.76* |
| Low dose group | 10 | 1250 | 7.4±4.74* |
| High dose group | 10 | 3750 | 5.4±3.31** |
Annotate: * representes with model group significant difference (P＜0.05) is arranged relatively, and * * representes with model group utmost point significant difference (P＜0.01) is arranged relatively.
5) experimental result
Visible by Kunming mouse auricle edema experimental result, the Andrographolide gel has the tangible scorching reaction of anti-caused by dimethylbenzene xylene (P＜0.01 or 0.05), with positive drug and injection dosage form there was no significant difference.
Embodiment 10:
Prepare in-situ gel preparation of potassium dehydroandrographolisuccinate succinate according to embodiment 4 methods; Carrying out the animal model pharmacodynamic study---the rat paw chondrus ocellatus Holmes causes scorching influence; This experiment is based on the pharmacodynamics comparative study of the present invention and potasium dehydroandrographolisuccinate succinate injection; Purpose is in order to further specify the present invention, but does not limit protection scope of the present invention.
1) instrument and reagent
Threeway volumetric measurement appearance, self-control
High activity dried yeast, Guangdong Dan Baoli Yeast Co., Ltd's (lot number 20070615)
Indomethacin suppository, 100mg/ grain, Beijing ten thousand brightness Pharmaceuticaies (lot number 070503)
The Andrographolide injectable powder, 200mg/, Heilungkiang Di Long Pharma Inc. (lot number 061124-1)
Andrographolide gel (lot number 08093001) is pressed embodiment 4 preparations
Blank gel does not add the principal agent preparation by embodiment 4 methods.
2) laboratory animal
70 of Wistar rats, Beijing Vital River Experimental Animals Technology Co., Ltd.
3) laboratory animal is divided into groups
Be divided into blank control group, model group, high dose group, middle dose groups, low dose group, positive controls (indomethacin), injection dosage form group, every group more than at least 10.
4) experimental technique
After water 24h is can't help in the rat fasting; Before experiment, measure right back sufficient sole of the foot volume, as normal foot sole of the foot volume, afterwards in right back sufficient plantar subcutaneous injection 15% yeast suspension 0.1ml; Rectally immediately; Observe 6h, respectively at 1,2,4, the 6h time point measures the rat paw volume with threeway volumetric measurement appearance, write down and see table 3.
Table 3 rat toes swelling experiment (n=10)
| Group | Dosage (mg/kg) | 1h(ml) | 2h(ml) | 4h(ml) | 6h(ml) |
| Model group | ? | 0.870±0.286 | 0.765±0.314 | 0.530±0.262 | 0.365±0.208 |
| Blank control group | 2g/kg | 0.680±0.136 | 0.685±0.175 | 0.390±0.160 | 0.145±0.104 |
| The positive drug group | 20mg/kg | 0.700±0.196 | 0.620±0.280 | 0.395±0.195 | 0.165±0.192 * |
| The injection group | 100mg/kg | 0.705±0.201 | 0.665±0.215 | 0.305±0.154 * | 0.090±0.097 ** |
| Low dose group | 1.0g/kg | 0.730±0.243 | 0.625±0.303 | 0.430±0.235 | 0.180±0.200 |
| Middle dose groups | 2.0g/kg | 0.678±0.170 | 0.672±0.156 | 0.311±0.163 * | 0.183±0.079 * |
| High dose group | 3.0g/kg | 0.690±0.185 | 0.625±0.162 | 0.405±0.165 | 0.175±0.160 * |
Annotate: * representes with model group significant difference (P＜0.05) is arranged relatively, and * * representes with model group utmost point significant difference (P＜0.01) is arranged relatively.
5) experimental result
Can know that by this experiment behind the Andrographolide gel single-dose, middle dosage (2g/kg) and heavy dose of (3g/kg) can bring into play significant anti-yeast proinflammatory effect (P＜0.05) between 4h to 6h.
Embodiment 11:
Prepare in-situ gel preparation of potassium dehydroandrographolisuccinate succinate according to embodiment 4 methods; Carry out rat passive cutaneous anaphylaxis, PCA of the same race (PCA) experiment; This experiment is based on the contrast of potasium dehydroandrographolisuccinate succinate injection and sensitivity response of the present invention; Purpose is in order to further specify the present invention to reducing the untoward reaction of Andrographolide medication, but does not limit protection scope of the present invention.
Laboratory animal: SD rat, male and female half and half, SPF level (body weight: 200-250g, Basic Theories of Chinese Medicine institute of Chinese department of Chinese medicine institute animal center provides)
Experimental technique: 1) the sero-fast preparation of rat: 15 of rats, be divided into 3 groups, first group is the normal saline group, and second group is situ-gel group (1.6g/kg), and the 3rd group is injection group (1.6g/kg).Inject 0.5ml normal saline and injection respectively for first group and the 3rd group, second group feeds 0.5ml Andrographolide situ-gel from anus, and once a day, administration is after 21 days altogether, and with sacrifice of animal, femoral artery is got blood.The serum of every group of 5 animals is mixed, put cryogenic refrigerator and preserve.2) P of Rats CA test: 30 of rats are divided into 3 groups at random, and 10 every group, table 4 divides into groups to see.Rat anti serum is diluted to 1: 5 and 1: 10 solution with normal saline respectively, both sides intradermal injection behind the rat back QUMAO, every some 0.1ml.Behind the 48h each Mus respectively intravenous injection contain above-mentioned 3 kinds of test liquids of 0.5% AZO-blue; Dosage is 1ml/, and disconnected neck is put to death behind the 30min, cuts skin of back; Be soaked in 5ml acetone after shredding: in normal saline (7: the 3) liquid; Jolting frequently, centrifugal behind the 48h, get supernatant and measure absorbance at ultraviolet-visible spectrophotometer wavelength 610nm place.
Experimental result: compare with normal saline, the skin indigo plant that potasium dehydroandrographolisuccinate succinate injection causes is dyed degree to be increased, and significant difference is all arranged; Andrographolide situ-gel group does not cause that then the skin indigo plant degree of dying increases, with normal saline group there was no significant difference.Explain that in-situ gel preparation of potassium dehydroandrographolisuccinate succinate significantly reduces the occurrence probability of the irritated untoward reaction of rat than potasium dehydroandrographolisuccinate succinate injection.The result sees table 4.
Table 4 rat PCA result of the test of the same race (n=10)
Annotate: * representes with model group significant difference (P＜0.05) is arranged relatively, and * * representes with model group utmost point significant difference (P＜0.01) is arranged relatively.
Claims (8)
1. in-situ gel preparation of potassium dehydroandrographolisuccinate succinate is characterized in that: said in-situ gel preparation of potassium dehydroandrographolisuccinate succinate is made up of Andrographolide crude drug, situ-gel substrate, adjuvant and distilled water that other pharmaceutics is necessary; Wherein, said Andrographolide crude drug refers to chemistry POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE by name, and molecular formula is C
28H
35KO
10, account for 0.01%～20% of weight of formulation percentage ratio; Said situ-gel substrate is one or more couplings in the material of ion-sensitive type, responsive to temperature type and pH value responsive type; Wherein, described ion-sensitive type situ-gel substrate be deacetylation gellan gum, sodium alginate, xanthan gum, welan gum or carrageenan one or more; Described responsive to temperature type situ-gel substrate is selected from one or more in poloxamer, N-Isopropylacrylamide copolymer, Polyethylene Glycol-PLGA block copolymer or the ethylhydroxyethylcellulose; Described pH value responsive type situ-gel substrate is selected from one or more in chitosan, cellulose acetate phthalate ester, the polyacrylamide.
2. according to the said in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that the shared percentage by weight of Andrographolide is 5%-15% in the described preparation.
3. according to the said in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that the shared percentage by weight of Andrographolide is 10% in the described preparation.
4. according to the said in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that adjuvant necessary on described other pharmaceutics is:
1) thickening agent: be methylcellulose, and one or more of hydroxypropyl emthylcellulose;
2) antioxidant: be one or more of thioglycerol, sulfo-sorbic acid, thioglycolic acid, cysteine hydrochloride, ascorbic acid, disodium edetate;
3) plasticizer: be the mixture of glycerol, propylene glycol, TC, glyceride and cithrol, in the polyoxyethylene ether castor oil hydrogenated one or more;
4) solubilizing agent: be in hydroxypropyl beta cyclodextrin, organic acid, amide, the polyhydric alcohol one or more;
5) antiseptic: be in chlorobutanol, benzyl alcohol, phenethanol, chlorhexidine acetate, benzalkonium chloride, sodium benzoate, potassium sorbate, the thimerosal one or more;
6) etc. ooze, etc. open regulator: be in mannitol, sorbitol, sodium citrate, the sodium chloride one or more;
7) pH regulator agent: be in diethanolamine, triethanolamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate or the hydrochloric acid one or more.
5. like the method for preparing of each described a kind of Andrographolide situ-gel among the claim 1-4, it is characterized in that processing as follows:
(a) get the necessary adjuvant of said Andrographolide crude drug, situ-gel substrate and other pharmaceutics in the prescription ratio, put in the part distilled water, the adjusting pH value is put the refrigerator and cooled Tibetan and is made dissolving fully;
(b) in the above-mentioned glue for preparing, add the Andrographolide crude drug in the prescription ratio, stir, regulate pH value, get a yellow clarification pastille glue;
(c) distilled water is supplied recipe quantity, gets the clear and bright glue of yellowish-brown, and fill promptly gets.
6. according to the said in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that described Andrographolide in-situ gel is main galenic pharmacy quality control index with gelation temperature, its gelation temperature scope is 33～37 ℃; The assay method of gelation temperature has viscometer determining method and rheometer measurement method.
7. according to the said in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that described Andrographolide in-situ gel is solution light yellow, clear and bright homogeneous under room temperature and cryogenic conditions, stable in properties, quality controllable; Get in the body and change clear and bright semi-solid gel into.
8. according to the said in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that described Andrographolide in-situ gel can be used for rectally, dosing eyes, nasal-cavity administration.
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| CN102727565A (en) * | 2011-04-07 | 2012-10-17 | 中国中医科学院中药研究所 | Aidi temperature/pH-sensitive in-situ gel preparation and preparation method thereof |
| CN102258458A (en) * | 2011-07-06 | 2011-11-30 | 陕西新药技术开发中心 | Rectal in-situ gel for abating fever and preparation method thereof |
| CN102552678A (en) * | 2012-03-13 | 2012-07-11 | 中国中医科学院中药研究所 | Injectable red ginseng and dwarf lilyturf tuber temperature sensitive in-situ gel preparation and preparation method thereof |
| CN102727423A (en) * | 2012-06-20 | 2012-10-17 | 贵州大学 | Betaxolol hydrochloride ion-sensitive eye-use in-situ gel and preparation method thereof |
| CN104721234A (en) * | 2013-12-20 | 2015-06-24 | 舒梅 | Periplaneta Americana extract product ion-activated in-situ gel and preparation method thereof |
| CN112190542B (en) * | 2020-10-22 | 2022-01-28 | 艾威药业(珠海)有限公司 | Aqueous in-situ gel ophthalmic preparation for treating xerophthalmia |
| CN113520995B (en) * | 2021-08-16 | 2023-03-10 | 海南鑫开源医药科技有限公司 | Ion-sensitive in-situ gel for eyes, and preparation method and application thereof |
| CN115607508B (en) * | 2022-09-09 | 2024-03-15 | 杭州医学院 | Nasal administration preparation for preventing and treating pneumonia caused by influenza A virus and preparation method and application thereof |
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