CN101926755A - 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
- Publication number
- CN101926755A CN101926755A CN2009100932912A CN200910093291A CN101926755A CN 101926755 A CN101926755 A CN 101926755A CN 2009100932912 A CN2009100932912 A CN 2009100932912A CN 200910093291 A CN200910093291 A CN 200910093291A CN 101926755 A CN101926755 A CN 101926755A
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- China
- Prior art keywords
- gel
- preparation
- situ
- andrographolide
- potassium
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- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229910052700 potassium Inorganic materials 0.000 title claims abstract description 20
- 239000011591 potassium Substances 0.000 title claims abstract description 20
- 238000011065 in-situ storage Methods 0.000 title claims abstract description 19
- YTHKMAIVPFVDNU-GPTWTFMPSA-N 4-[[(1r,2r,4ar,5r,8as)-2-(3-carboxypropanoyloxy)-1,4a-dimethyl-6-methylidene-5-[(e)-2-(5-oxo-2h-furan-4-yl)ethenyl]-3,4,5,7,8,8a-hexahydro-2h-naphthalen-1-yl]methoxy]-4-oxobutanoic acid Chemical compound C(/[C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@H]([C@]2(COC(=O)CCC(O)=O)C)OC(=O)CCC(O)=O)=C\C1=CCOC1=O YTHKMAIVPFVDNU-GPTWTFMPSA-N 0.000 title claims abstract description 7
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- -1 andrographolide butanedioic acid ester Chemical class 0.000 claims abstract description 14
- 239000000758 substrate Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract 3
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 claims description 54
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000012153 distilled water Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000003292 glue Substances 0.000 claims description 12
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 11
- 239000004299 sodium benzoate Substances 0.000 claims description 11
- 235000010234 sodium benzoate Nutrition 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 7
- 238000001879 gelation Methods 0.000 claims description 7
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
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- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 6
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
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- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 4
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 3
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
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- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
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Landscapes
- Medicinal Preparation (AREA)
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 substantially with Chinese medicine aspect the performance curative effect, and is being better than 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 good control Release Performance widely in addition, what situ-gel was studied abroad comparatively gos deep into and existing sophisticated launch, domestic starting late, also there is how tame research institute to declare the clinical research of this type of preparation, but mainly based on chemicals, 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; the blocking-up inosinic acid is converted into guanyl; and then suppress synthesizing of viral RNA/DNA; to the pneumonia adenovirus type III; influenza virus A 1 type; first 3 types; intestinal syncytial virus and respiratory syncytial virus etc. all have deactivation; can protect lysosome membrane; prevent that lysosome from destroying; the release of Profilin hydrolytic enzyme; suppress to cause inflammation; causing the pain medium discharges; capillary wall permeability due to the antagonism human body inflammatory mediator histamine increases, and synthesizing of inflammation-inhibiting position prostaglandin recovers the sensitivity of heat-sensitive neuron; 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 preparation mainly contains freeze-dried powder, injection, injection at present.According to the literature, 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 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.There are not relevant patent and patent application at present.
Summary of the invention:
The objective of the invention is at 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 is implemented by 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-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 makes 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, fill, promptly.
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 entering 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 preparation is drug administration by injection, and untoward reaction is more serious, patient's poor compliance, and the present invention is by 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:
The following examples are used to further specify the present invention, but they are not to attempt in office where face limits the scope of the 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.
Preparation method: 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.
Embodiment 2:
Prescription is with embodiment 1
Preparation method: 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.
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.
Preparation method: 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.
Preparation method: 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 recipe quantity Andrographolide and stir and make dissolving, a yellow clarification pastille glue, add the benzyl alcohol of 0.5g, stir, moisturizing is to making into 100g, fill, promptly.
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.
Preparation method: 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, fill, promptly.
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.
Preparation method: 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, fill, promptly.
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.
Preparation method: 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, fill, promptly.
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 grouping
Normal group, model group, blank 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,, ask its average, by its basal body temperature it is divided into 7 groups then, 5 every group, keep room temperature constant in the experimentation as normal body temperature in the anus temperature of same measure of time normal rabbits on experiment the previous day and experiment same day.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: * represents with model group significant difference (P＜0.05) is arranged relatively, and * * represents 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 of mouse ear caused by dimethylbenzene xylene inflammation; 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
Dimethylbenzene, 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 grouping
Be divided into model group, blank 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, dimethylbenzene 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 results are shown in 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 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: * represents with model group significant difference (P＜0.05) is arranged relatively, and * * represents with model group utmost point significant difference (P＜0.01) is arranged relatively.
5) experimental result
By Kunming mouse auricle edema experimental result as seen, 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 instrument, 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 grouping
Be divided into blank group, model group, high dose group, middle dosage group, 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 instrument, record sees 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 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 dosage group | 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: * represents with model group significant difference (P＜0.05) is arranged relatively, and * * represents with model group utmost point significant difference (P＜0.01) is arranged relatively.
5) experimental result
As shown in 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, grouping sees Table 4.Rat anti serum is diluted to 1: 5 and 1: 10 solution with normal saline respectively, both sides intradermal injection after the rat back unhairing, 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/, disconnected neck is put to death behind the 30min, cut 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.Illustrate 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 results are shown in Table 4.
Table 4 rat PCA result of the test of the same race (n=10)
Annotate: * represents with model group significant difference (P＜0.05) is arranged relatively, and * * represents with model group utmost point significant difference (P＜0.01) is arranged relatively.
Claims (15)
1. an in-situ gel preparation of potassium dehydroandrographolisuccinate succinate is characterized in that preparing gained by Andrographolide crude drug and pharmaceutic adjuvant according to certain ratio.
2. claim 1 indication Andrographolide crude drug refers to chemistry POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE (Potassium Dehydroandrographolide Succinate) by name, and molecular formula is C
28H
35KO
10
3. by the described in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that the shared percentage by weight of Andrographolide is 0.01%-20% in the described preparation.
4. by the described in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that the shared percentage by weight of Andrographolide is preferably 5%-15% in the described preparation.
5. by the described in-situ gel preparation of potassium dehydroandrographolisuccinate succinate of claim 1, it is characterized in that the shared percentage by weight of Andrographolide most preferably is 10% in the described preparation.
6. claim 1 indication pharmaceutic adjuvant comprises situ-gel substrate, and necessary adjuvant on other pharmaceuticss.
7. claim 6 indication situ-gel substrate is selected from the material of ion-sensitive type, responsive to temperature type and pH value responsive type.
8. claim 7 indication ion-sensitive type situ-gel substrate comprises one or more of deacetylation gellan gum, sodium alginate, xanthan gum, welan gum or carrageenan.
9. claim 7 indication responsive to temperature type situ-gel substrate comprises one or more in poloxamer, N-N-isopropylacrylamide copolymer, Polyethylene Glycol-PLGA block copolymer or the ethylhydroxyethylcellulose.
10. claim 7 indication pH value responsive type situ-gel substrate comprises one or more in polyacrylic, chitosan and chitosan derivatives, cellulose acetate phthalate ester, the polyacrylamide.
11. adjuvant necessary on described other pharmaceutics of claim 6 comprises
1) thickening agent: be methylcellulose, and one or more of cellulose family such as hydroxypropyl emthylcellulose and cellulose derivative.
2) antioxidant: be one or more of sulfites, thioglycerol, sulfo-sorbic acid, thioglycolic acid, cysteine hydrochloride, ascorbic acid, disodium edetate.
3) plasticizer: one or more of mixture, polyoxyethylene ether castor oil hydrogenated and other common plasticizers of pharmaceutics that comprise polyethylene glycols, glycerol, propylene glycol, TC, glyceride and cithrol.
4) solubilizing agent: comprise hydroxypropyl beta cyclodextrin, poly yamanashi esters, polyoxyethylene fatty acid ester class,, in polyoxyethylene fatty acid alcohol ethers, organic acid and its esters, amide or aminated compounds, polyethylene glycols, the polyhydric alcohol one or more.
5) antiseptic: one or more of oxybenzene esters, chlorobutanol, benzyl alcohol, phenethanol, chlorhexidine acetate, benzalkonium chloride, sodium benzoate, potassium sorbate, thimerosal and quaternary ammonium compound.
6) etc. ooze, etc. open regulator: comprise in mannitol, sorbitol, sodium citrate, the sodium chloride one or more.
7) pH regulator agent: one or more of acids such as diethanolamine, triethanolamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate or hydrochloric acid.
12. the preparation method of an Andrographolide situ-gel is characterized in that making as follows:
(a) by prescription ratio weighting profit requirement 7 described situ-gel substrate and the necessary adjuvant of other pharmaceuticss, 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, fill, promptly.
13. the described Andrographolide in-situ gel of claim 1 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.
14. the described Andrographolide in-situ gel of claim 1 is solution light yellow, clear and bright homogeneous under room temperature and cryogenic conditions, stable in properties is quality controllable; Enter and change clear and bright semi-solid gel in the body into.
15. the described Andrographolide in-situ gel of claim 1 can be used for rectally, dosing eyes, nasal-cavity administration.
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