CN101926755B - In-situ gel preparation of potassium dehydroandrographolide succinate and preparation method thereof - Google Patents

Abstract

The invention relates to a Chuanhuning in-situ gel preparation and a preparation method thereof. This preparation uses water as the solvent, Chuanhuning in-situ gel prepared from Chuanhuning (dehydroandrographolide succinate half-ester monopotassium salt), in-situ gel matrix recognized in the field and other pharmaceutically necessary pharmaceutical excipients . The Chuanhuning in-situ gel in the present invention is a free-flowing liquid in vitro, and forms a semi-solid gel after the patient takes medicine, which has definite curative effect, stable performance, simple preparation, convenient administration, strong patient compliance, no toxic side effects and adverse reactions , High bioavailability and so on. The invention has good antipyretic and anti-inflammation effects, and can be used as a medicine substitute for Chuanhuning injection in the clinical treatment of viral upper respiratory tract infection and viral pneumonia, and is especially suitable for infants and young children and patients who are inconvenient to take medicine.

Description

Chuanhuning in situ gel preparation and preparation method thereof

Technical field:

The invention belongs to the field of traditional Chinese medicine, and more specifically relates to a Chuanhuning in situ drug with good antipyretic effect and anti-inflammatory effect, which is the first choice for viral upper respiratory tract infection and viral pneumonia, especially for infants and patients who are inconvenient to take medicine. Gel formulation and method for its preparation. the

Background technique:

In recent years, with the large-scale clinical application of traditional Chinese medicine injections, the problem of adverse reactions has become more and more prominent. The 10 varieties of leaf saponin sodium, puerarin and zedoary oil injection were more serious, and their adverse reaction rate accounted for 74.4% of all traditional Chinese medicine injections. Incidents of anaphylactic shock and acute death caused by adverse reactions of traditional Chinese medicine injections have been reported from time to time (Zuo Zhiyan, Analysis of 42 Cases of Adverse Reactions of Traditional Chinese Medicine Injections, China Pharmaceutical Industry, 2007, 16(20): 54). How to solve the problem of adverse reactions of traditional Chinese medicine injections has been a hot topic of debate in the academic circles in the past two years, and it is also the focus and difficulty of scientific research by pharmaceutical workers. One of the solutions is to find a new dosage form of traditional Chinese medicine that can replace traditional Chinese medicine injections, so that it is basically equivalent to traditional Chinese medicine injections in terms of efficacy, and better than traditional Chinese medicine injections in terms of reducing toxicity and adverse reactions. the

Mucosal administration is currently the most widely recognized route of administration that is closest to injection administration. It can at least partially replace traditional Chinese medicine injections in TCM emergencies. Small size, high bioavailability and fast action time. the

In-situ gel refers to the semi-solid or liquid preparation formed by polymer materials administered in a solution or semi-solid state, responding to external stimuli at the site of administration, and undergoing a reversible change in dispersion state or conformation. The in situ gel has the hydrophilic three-dimensional network structure of the gel preparation and good tissue compatibility. At the same time, the unique solution-gel transition properties make it easy to prepare, easy to use, and compatible with the drug site, especially the mucosal tissue. With the advantages of strong affinity and long residence time, combined with a wide range of uses and good controlled release performance, in-situ gels have been deeply researched abroad and mature products have been marketed. It started relatively late in China, and there are also many research and development units. The clinical research of this kind of preparation is declared, but it is mainly based on chemical drugs, and there is no report in the field of traditional Chinese medicine. the

Chuanhuning is a dehydrated Andrographis paniculata produced by reacting with succinic anhydride in a potassium hydroxide pyridine solution using the plant monomer Andrographolide extracted from the Acanthaceae plant Andrographis paniculate (Burm.f.) Nees. Lactone succinate half ester monopotassium salt (Potassium DehydroandrographolideSuccinate), trade name Chuan Hu Ning. Pharmacological studies have proved that Chuanhuning can inhibit inosinic acid-5-phosphate dehydrogenase, block the conversion of inosinic acid to guanylic acid, and then inhibit the synthesis of viral RNA/DNA. Type A3, enteric syncytial virus and respiratory syncytial virus are all inactivated, which can protect lysosomal membranes, prevent lysosomal damage, inhibit the release of proteolytic enzymes, inhibit the release of inflammatory and pain-causing media, and resist The increased permeability of the capillary wall caused by the human inflammatory mediator histamine inhibits the synthesis of prostaglandins at the inflammatory site, restores the sensitivity of heat-sensitive nerves, moves down the body temperature regulation point, and enhances heat dissipation to play an antipyretic effect (Liu Cunling , Observation on the curative effect of Chuanhuning powder injection on 100 cases of bronchopneumonia, Guangzhou Medicine, 1999, 30(1): 65). Clinically, it is often used in the treatment of viral respiratory tract infection and infant viral pneumonia, and has achieved good curative effect. It has become one of the first batch of essential Chinese patent medicines approved by the State Administration of Traditional Chinese Medicine for emergency departments of Chinese medicine hospitals across the country. the

Chuanhuning preparations currently mainly include freeze-dried powder injections, injections, and injections. According to literature reports, the adverse reactions of Chuanhuning for injection are very serious, which brings great hidden dangers to the safe medication of patients. In this patent, Chuanhuning in situ gel is prepared by taking mucosal drug administration as the approach and in situ gel as the means. The preparation is safe and effective, has high bioavailability, stable performance, controllable quality, simple preparation, convenient administration, strong mucous membrane adhesion, easy cleaning, rectal administration does not increase the pain of the patient, and has strong patient compliance. Infants and young children and patients who cannot take medicine or have difficulty taking medicine. There are no relevant patents and patent applications at present. the

Invention content:

The purpose of the present invention is to provide a new product with definite curative effect, stable quality, simple preparation, convenient use, strong patient compliance, no toxic side effects and adverse reactions, and high bioavailability for the serious adverse reactions of Chuanhuning injection administration. — Chuanhuning in-situ gel and its preparation method. The drug has good antipyretic and anti-inflammatory effects, and is the first choice for viral upper respiratory tract infection and viral pneumonia, especially for infants and patients who are inconvenient to take medicine. the

To achieve the above object, the present invention is implemented through the following technical solutions:

1. The prescription of this patent

1) The prescription of the present invention is composed of main drug (Chuanhuning), in-situ gel matrix, other necessary excipients of pharmacy and distilled water. Wherein the main drug Chuanhuning accounts for 0.01%-20% by weight of the present invention, preferably 5-10%, most preferably 10%. the

2) The in-situ gel matrix in the present invention can be one or more combinations of ion-sensitive, temperature-sensitive and pH-sensitive materials, wherein the ion-sensitive in-situ gel matrix includes deacetylated gellan gum , sodium alginate, xanthan gum, Brunei gum or carrageenan; temperature-sensitive in situ gel matrix includes poloxamer, N-isopropylacrylamide copolymer, polyethylene glycol -One or more of PLGA block copolymer or ethyl hydroxyethyl cellulose; pH-sensitive in situ gel matrix including polyacrylic acid, chitosan and its derivatives, cellulose acetate phthalate , one or more of polyacrylamide. the

3) Other pharmacy necessary auxiliary materials in the present invention include one or more thickeners of celluloses such as methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose and derivatives thereof, preferably Sodium carboxymethylcellulose; one or more antioxidants of sulfites, thioglycerol, thiosorbic acid, thioglycolic acid, cysteine hydrochloride, ascorbic acid, preferably disodium edetate; Glycerin, propylene glycol, diethylene glycol monoethyl ether, a mixture of glycerol esters and polyethylene glycol fatty acid esters, polyoxyethylene ether hydrogenated castor oil, etc. One or more plasticizers commonly used in pharmacy, preferably polyethylene glycol Glycols; hydroxypropyl β-cyclodextrin, polysorbates, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohol ethers, organic acids and their salts, amides or amine compounds, polyethylene glycols , one or more solubilizers in polyols, preferably hydroxypropyl β-cyclodextrin; hydroxyphenyl esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, chlorhexidine acetate, benzalkonium chloride, Sodium benzoate, potassium sorbate, thimerosal and one or more preservatives of quaternary ammonium compounds, preferably sodium benzoate, potassium sorbate, most preferably sodium benzoate; mannitol, sorbitol, sodium citrate, chloride One or more isotonic and isotonic regulators of sodium, preferably mannitol; one or more pH regulators of acids such as triethanolamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate or hydrochloric acid , preferably triethanolamine. the

2. Forming process of the present invention

The present invention is made by following method:

(a) Take the in-situ gel matrix and other pharmaceutically necessary excipients according to the proportion of the prescription, put them in some distilled water, adjust the pH value, and put them in the refrigerator for complete dissolution. the

(b) Add Chuanhuning crude drug into the above-mentioned prepared glue solution according to the prescription ratio, stir, and adjust the pH value to obtain a yellow clear drug-containing glue solution. the

(c) Distilled water to make up the prescription amount to obtain a yellow clear glue solution, which is filled and ready to be obtained. the

in:

The alkali used in this method can be sodium hydroxide, triethanolamine, sodium bicarbonate. the

In step (a), adjust the pH to 5.5-6.5 to dissolve. the

In step (b), adjust the pH of Chuanhuning in-situ gel solution to 5.5-6.5 (preferably 5.8-6.2). the

3. The product prepared by the present invention takes the gelation temperature as the main pharmaceutical quality control index, and its gelation temperature range is 33 to 37° C.; the determination methods of the gelation temperature include a viscometer measurement method and a rheometer measurement method. the

4. The product prepared by the present invention is a yellow, clear and uniform solution at room temperature and low temperature, with stable properties and controllable quality; it turns into a clear semi-solid gel after entering the rectum. the

The invention has good antipyretic effect and anti-inflammation effect, is the first choice for viral upper respiratory tract infection and viral pneumonia, and is especially suitable for infants and patients who are inconvenient to take medicine. Traditional Chuanhuning preparations are all administered by injection, with serious adverse reactions and poor patient compliance. The present invention not only has significant drug efficacy, but also greatly reduces the incidence of adverse drug reactions of the original drugs and relieves patients' pain in medication through mucosal administration. the

Detailed ways:

The following examples serve to further illustrate the invention, but they are not intended to limit the scope of the invention in any way. the

Example 1:

Prescription: Chuanhuning 30.0g, poloxamer 40719.0g, poloxamer 1886.0g, sodium benzoate 0.5g, appropriate amount of triethanolamine, distilled water to make up to 100g. the

Preparation method: Dissolve the prescribed amount of sodium benzoate in an appropriate amount of distilled water, add the prescribed amount of Chuanhuning, adjust the pH to about 5.8, and obtain Chuanhuning water; take the prescribed amount of poloxamer 188, put it in the Chuanhuning aqueous solution, and stir to dissolve at room temperature , then add the prescribed amount of poloxamer 407, stir to disperse evenly, refrigerate in a refrigerator at 4°C for more than 48 hours to obtain a yellow and clear solution, adjust the pH to 5.8-6.2, add water to make it 100g, and fill it. the

Example 2:

Prescription is the same as embodiment 1

Preparation method: Take the prescribed amount of sodium benzoate, poloxamer 188, and poloxamer 407, put them in an appropriate amount of distilled water, stir to disperse evenly, and refrigerate in a refrigerator at 4°C for 24 hours. After obtaining a transparent glue, add the prescribed amount of Chuanhuning. Adjust the pH to 5.8-6.2, add water to make it 100g, fill it, and get it. the

Example 3:

Prescription: Chuanhuning 10g, poloxamer 40720.0g, poloxamer 1881.0g, hydroxypropyl β-cyclodextrin 6.0g, sodium benzoate 0.5g, triethanolamine amount, distilled water to make up to 100g. the

Preparation method: Dissolve 6.0 g of sodium benzoate and 6.0 g of hydroxypropyl β-cyclodextrin in the prescribed amount of distilled water, and the remaining operating steps and methods are the same as in Example 2. the

Example 4:

Prescription: with embodiment 3. the

Preparation method: Weigh the prescribed amount of Poloxamer 188, put it in high-purity water, stir to dissolve; then weigh the prescribed amount of Poloxamer 407, put it in it, stir it to disperse evenly, put it in the refrigerator at 4°C, and make it into a uniform glue. Dissolve hydroxypropyl β-cyclodextrin in high-purity water and slowly inject it into the above-mentioned glue solution, stir evenly, and gradually add an appropriate amount of triethanolamine until the pH value is adjusted to 6.5-7.5. Add the prescribed amount of Chuanhuning and stir to dissolve to obtain a yellow clear drug-containing glue, add 0.5g of benzyl alcohol, stir evenly, replenish water until it becomes 100g, fill it, and get ready. the

Embodiment 5:

Prescription: Chuanhuning 7.5g, deacetylated gellan gum 10.0g, cysteine hydrochloride 0.5g, sodium benzoate 0.5g, sodium hydroxide amount, distilled water to make up to 100g. the

Preparation method: Take the prescribed amount of Chuanhuning, put it in an appropriate amount of distilled water, adjust the pH to about 7 to dissolve it, and obtain Chuanhuning aqueous solution; take the prescribed amount of sodium benzoate and cysteine hydrochloride 0.5 and dissolve it in the Chuanhuning aqueous solution, add the prescribed amount of deacetyl Melt gellan gum, stir to disperse evenly, refrigerate in a refrigerator at 4°C for more than 3 days to obtain a light yellow clear solution, adjust pH to 6.5-7.5, add water to make it 100g, fill it, and get ready. the

Embodiment 6:

Prescription: Chuanhuning 15g, sodium alginate 12.0g, edetate disodium 0.6g, benzalkonium chloride 0.05g, sodium hydroxide amount, distilled water to make up to 100g. the

Preparation method: Take the prescribed amount of Chuanhuning, put it in an appropriate amount of distilled water, adjust the pH to about 7 to dissolve it, and obtain Chuanhuning water; take the prescription amount of edetate disodium and benzalkonium chloride and dissolve it in Chuanhuning water, then add the prescribed amount of seaweed Sodium bicarbonate, stir to disperse evenly, refrigerate in a refrigerator at 4°C for more than 3 days to obtain a light yellow clear solution, adjust the pH to 6.5-7.5, add water to make it 100g, fill it, and get it. the

Embodiment 7:

Prescription: Chuanhuning 5.0g, Carbopol 9402.0g, sodium carboxymethylcellulose 0.05g, disodium edetate 0.6g, potassium benzoate 1.0g, appropriate amount of diethanolamine. the

Preparation method: Dissolve the prescribed amount of edetate disodium and potassium benzoate in an appropriate amount of water, add the prescribed amount of Carbopol 940 and sodium carboxymethyl cellulose, stir to disperse evenly, and refrigerate at 4°C to obtain Transparent glue; add the prescribed amount of Chuanhuning, stir evenly, adjust the pH to 6.5-7.5 with diethanolamine, add water to make it 100g, fill it, and get ready. the

Embodiment 8:

Chuanhuning in situ gel preparation was prepared according to the method of Example 4, and animal model pharmacodynamics research-rabbit antipyretic experiment was carried out. This experiment was based on the comparative study of the pharmacodynamics of the present invention and Chuanhuning injection, and the purpose was to further illustrate the present invention. invention, but does not limit the scope of protection of the present invention. the

1) Instruments and reagents

WMY-01 digital thermometer, Shanghai Medical Instrument Factory

Typhoid Vi polysaccharide vaccine, Beijing Tiantan Biological Products Company (batch number 2008030901)

Chuanhuning powder injection, 200mg/piece, Heilongjiang Dilong Pharmaceutical Company (batch number 061124-1)

Chuanhuning in-situ gel (batch number 08093001) is prepared according to Example 4

Blank gel, prepared according to the method of Example 4 without adding the main drug. the

Indomethacin suppository, 100mg/capsule, Beijing Wanhui Pharmaceutical (batch number 070503)

2) Experimental animals

Male big-eared white rabbits, 35, 2.0-2.5kg, Beijing Tongli Experimental Animal Breeding Factory. the

3) Grouping of experimental animals

Normal group, model group, blank group, high-dose group, low-dose group, positive drug group, injection group, 5 rats in each group. the

4) Experimental method

After the rabbits fasted for 48 hours, the rectal temperature of normal rabbits was measured at the same time on the day before the experiment and on the day of the experiment, and the average value was calculated as the normal body temperature, and then divided into 7 groups according to their basal body temperature, with 5 rabbits in each group. The room temperature was kept constant during the process. According to the dose of 0.5ml/kg, intravenously inject typhoid Vi polysaccharide vaccine into the ears of rabbits. One hour after the injection of the vaccine, the rectal temperature will rise by 1.0-1.5°C and last for more than 6 hours. the

One hour after the injection of the vaccine, when the body temperature rises, according to the high (1.4g/kg) and low (0.7g/kg) doses and the rabbit body weight, rectal infusion of Chuanhuning in situ gel and indomethacin suppository (10mg/kg) , intraperitoneally inject Chuanhuning injection at a dose of 100mg/kg for the injection dosage form. After administration, the rectal temperature of each rabbit in the group was measured at 1, 2, 3, 4, and 6 h time points, and the average temperature difference (ΔT) of each group at different times was calculated, as shown in Table 1. the

5) Experimental results

The above statistics show that Chuanhuning gel has obvious antipyretic effect on rabbit fever caused by typhoid Vi vaccine 1 hour after administration (P<0.05), indicating that rectal administration can indeed achieve rapid onset of effect. the

Table 1. Body temperature changes of rabbits at different times (n=5)

Note: * means there is a significant difference compared with the model group (P<0.05), ** means there is a very significant difference compared with the model group (P<0.01). the

Embodiment 9:

According to the method of Example 4, Chuanhuning in situ gel preparation was prepared, and animal model pharmacodynamics research was carried out—the impact of xylene-induced inflammation on the mouse ear. This experiment was based on the comparative study of the pharmacodynamics of the present invention and Chuanhuning injection, with the purpose of In order to further illustrate the present invention, but not limit the protection scope of the present invention. the

1) Instruments and reagents

Stainless steel hole punch, homemade

Electronic precision balance, Ohaus (Shanghai) Co., Ltd.

Xylene, analytically pure, Beijing Chemical Plant

Indomethacin suppository, 100mg/tablet, Beijing Wanhui Pharmaceutical (batch number 070503)

Chuanhuning powder injection, 200mg/piece, Heilongjiang Dilong Pharmaceutical Company (batch number 061124-1)

Chuanhuning gel (batch number 08093001) is prepared according to Example 4

Blank gel, prepared according to the method of Example 4 without adding the main drug. the

2) Experimental animals

Kunming mice, 100, Institute of Experimental Animals, Chinese Academy of Medical Sciences

3) Grouping of experimental animals

They were divided into model group, blank group, high-dose group, low-dose group, positive control group (indomethacin), and injection group, with at least 10 rats in each group. the

4) Experimental method

After 60 minutes of rectal administration to Kunming mice, 0.02ml of xylene was evenly applied to the front and back of the right ear of the mice. After 15 minutes, the mice were killed by dislocation, and both ears were cut off, punched and weighed. The weight difference of the tablet is the degree of swelling, and the result is good. The weight difference of the two ears of the model group is more than 10 mg, which is significantly different from that of the administration group. The results are shown in Table 2. the

Table 2. Kunming mouse auricle swelling experiment (n=10)

group Number of animals (only) Dose (mg/kg) Degree of swelling (mg) model group (water) 10 3750 12.8±5.20 blank group 10 3750 10.3±4.22 Positive drug group 10 30 8.2±3.46* 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**

Note: * means there is a significant difference compared with the model group (P<0.05), ** means there is a very significant difference compared with the model group (P<0.01). the

5) Experimental results

According to the results of Kunming mouse ear swelling test, Chuanhuning Gel has obvious anti-xylene-induced inflammatory response (P<0.01 or 0.05), and there is no significant difference from the positive drug and injection dosage form. the

Embodiment 10:

Chuanhuning in situ gel preparation was prepared according to the method of Example 4, and animal model pharmacodynamics research was carried out——the influence of rat paw carrageen-induced inflammation. This experiment was based on the comparative study of the pharmacodynamics of the present invention and Chuanhuning injection. The purpose is to further illustrate the present invention, but not to limit the protection scope of the present invention. the

1) Instruments and reagents

Three-way volume measuring instrument, self-made

Highly active dry yeast, Guangdong Danbaoli Yeast Co., Ltd. (batch number 20070615)

Indomethacin suppository, 100mg/tablet, Beijing Wanhui Pharmaceutical (batch number 070503)

Chuanhuning powder injection, 200mg/piece, Heilongjiang Dilong Pharmaceutical Company (batch number 061124-1)

Chuanhuning gel (batch number 08093001) is prepared according to Example 4

Blank gel, prepared according to the method of Example 4 without adding the main drug. the

2) Experimental animals

70 Wistar rats, Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

3) Grouping of experimental animals

They were divided into blank group, model group, high-dose group, middle-dose group, low-dose group, positive control group (indomethacin), and injection group, with at least 10 rats in each group. the

4) Experimental method

After the rats were fasted for 24 hours, the volume of the right hind paw was measured before the experiment, as the normal volume of the paw, and then 0.1ml of 15% yeast suspension was subcutaneously injected into the right hind paw, administered rectally immediately, and observed for 6 hours. The paw volume of the rats was measured with a three-way volume measuring instrument at the time points of 1, 2, 4, and 6 hours respectively, and the records are shown in Table 3. the

Table 3 Rat toe swelling test (n=10)

group Dose (mg/kg) 1h(ml) 2h(ml) 4h(ml) 6h(ml) model group the 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 Positive drug group 20mg/kg 0.700±0.196 0.620±0.280 0.395±0.195 0.165±0.192 ^* 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 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 ^*

Note: * means there is a significant difference compared with the model group (P<0.05), ** means there is a very significant difference compared with the model group (P<0.01). the

5) Experimental results

It can be seen from this experiment that after a single administration of Chuanhuning Gel, the medium dose (2g/kg) and high dose (3g/kg) can exert a significant anti-yeast inflammatory effect between 4h and 6h (P<0.05). the

Example 11:

Prepare Chuanhuning in situ gel preparation according to the method of Example 4, and carry out the same passive skin allergy (PCA) experiment in rats. This experiment is based on the contrast of Chuanhuning injection and the sensitization of the present invention, and the purpose is to further illustrate the present invention's effect on Reduce the adverse reactions of Chuanhuning medication, but do not limit the protection scope of the present invention. the

Experimental animals: SD rats, half male and half male, SPF grade (weight: 200-250g, provided by the Animal Center of the Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences)

Experimental method: 1) Preparation of rat antiserum: 15 rats were divided into 3 groups, the first group was the normal saline group, the second group was the in situ gel group (1.6g/kg), and the third group was the Injection group (1.6g/kg). The first group and the third group were injected with 0.5ml of normal saline and injection solution, and the second group was given 0.5ml of Chuanhuning in situ gel from the anus, once a day, after a total of 21 days of administration, the animals were sacrificed, and blood was collected from the femoral artery . The sera of 5 animals in each group were mixed and stored in a low-temperature refrigerator. 2) Rat PCA test: 30 rats were randomly divided into 3 groups, 10 rats in each group. The groups are shown in Table 4. Rat antiserum was diluted with normal saline to 1:5 and 1:10 solutions, and injected intradermally on both sides of the back of the rat after hair removal, 0.1ml per point. After 48h, each mouse was intravenously injected with the above-mentioned 3 kinds of test solutions containing 0.5% Evans blue respectively, the dose was 1ml/only, and after 30min, the neck was cut off to kill, the back skin was cut off, cut into pieces and soaked in 5ml acetone: normal saline (7 : 3) in the solution, shake from time to time, centrifuge after 48h, take the supernatant and measure the absorbance at a wavelength of 610nm in an ultraviolet-visible spectrophotometer. the

Experimental results: Compared with normal saline, Chuanhuning Injection increased the degree of skin blue staining, and there was a significant difference; while Chuanhuning in situ gel group did not cause the increase of skin blue staining, and there was no significant difference from the normal saline group. It shows that Chuanhuning in situ gel preparation can significantly reduce the incidence of allergic adverse reactions in rats compared with Chuanhuning injection. The results are shown in Table 4. the

Table 4 The same PCA test results in rats (n=10)

Note: * means there is a significant difference compared with the model group (P<0.05), ** means there is a very significant difference compared with the model group (P<0.01). the

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.