Composition for promoting absorption of insoluble drugs and oral preparation

Abstract

The invention provides a composition for promoting absorption of insoluble drugs and an oral preparation. The composition comprises an andrographolide compound, organic acid, carbonate and cholate. The composition can improve the in-vitro release, intestinal transmittance and oral bioavailability of the indissolvable drug.

Description

Technical Field

[0001] The present invention relates to the field of solubilization of poorly soluble drugs, and more particularly to a composition and an oral preparation for promoting the absorption of poorly soluble drugs. Background Art

[0002] Andrographolide (AG) is a diterpenoid lactone compound extracted from Andrographis paniculata, a plant of the Acanthaceae family. Clinically, it shows good therapeutic effects on inflammation-related diseases such as viral infections, bacillary dysentery, malaria, herpes, fever, laryngitis, and rheumatoid arthritis, and is known as the "natural antibiotic". Currently, andrographolide is mainly used to treat bacterial and viral respiratory infections. In addition, andrographolide also has activities such as anti-tumor and immunomodulation, and has great clinical value.

[0003] Andrographolide has poor water solubility and intestinal permeability, resulting in low oral bioavailability and limiting its further clinical application. To improve the water solubility and oral absorption of andrographolide, many new formulations of andrographolide have been developed. For example, the commercially available andrographolide dropping pills use the solubilization technology of solid dispersion. Other solubilization technologies for andrographolide also include ultrafine comminution technology, cyclodextrin inclusion technology, etc.

[0004] Through research, it is found that the following problems exist in the prior art:

[0005] (1) The solubilization technology of solid dispersion has successfully improved the solubility of andrographolide and masked the bitterness of andrographolide through film coating. However, the solid dispersion preparation technology has problems such as large amount of excipients used, complex preparation process, easy aging, etc., and the dissolution rate decreases significantly after aging;

[0006] (2) The ultrafine comminution technology has limited improvement in the solubility and dissolution rate of andrographolide, and has problems such as low preparation efficiency and high energy consumption;

[0007] (3) Cyclodextrin has low solubility in water and organic solvents, and its hydroxyl groups exhibit an enzyme-like catalytic effect, affecting the stability of the drug and the inclusion efficiency of β-cyclodextrin inclusion complex for andrographolide. Summary of the Invention

[0008] The purpose of the present invention is to provide a composition and an oral preparation for promoting the absorption of poorly soluble drugs, which solve many problems existing in other preparation types of andrographolide compounds in the prior art, improve its solubility in water, improve the dissolution rate and intestinal permeability of poorly soluble drugs, and improve the bioavailability.

[0009] The technical solution adopted by the present invention to solve the technical problem is: a composition for promoting the absorption of poorly soluble drugs, comprising andrographolide compounds, organic acids, carbonates and bile salts.

[0010] In the composition for promoting the absorption of poorly soluble drugs of the present invention, the organic acid is selected from at least one or more of tartaric acid and citric acid; the carbonate is selected from at least one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; the bile salt is selected from at least one or more of taurocholic acid, sodium deoxycholate and ursodeoxycholic acid; the andrographolide compounds include one or more of andrographolide, deoxyandrographolide, neoandrographolide and dehydrated andrographolide.

[0011] Preferably, the organic acid is citric acid.

[0012] Preferably, the carbonate is sodium carbonate or sodium bicarbonate. More preferably, the carbonate is sodium carbonate.

[0013] Preferably, the bile salt is taurocholic acid or sodium deoxycholate. More preferably, the bile salt is sodium deoxycholate.

[0014] Among them, deoxyandrographolide is also called andrographolide A, andrographolide is also called andrographolide B, neoandrographolide is also called andrographolide C, and dehydrated andrographolide is also called andrographolide D. The chemical structures of the four are similar and their physicochemical properties are similar. They are all poorly soluble drugs with extremely poor oral bioavailability. The preparation method of the present invention can significantly improve the water solubility of andrographolide and increase oral absorption. The above four representative andrographolide diterpenoids all have good antipyretic and anti-inflammatory effects and can be used for the development of rapid-acting antipyretic preparation products.

[0015] In the composition for promoting the absorption of poorly soluble drugs of the present invention, the mass ratio of the organic acid to the carbonate is 2-10:5.

[0016] In the composition for promoting the absorption of poorly soluble drugs of the present invention, the mass ratio of the organic acid to the carbonate is 6-10:5.

[0017] In the composition for promoting the absorption of poorly soluble drugs of the present invention, the mass ratio of the organic acid to the carbonate is 6:5.

[0018] In the composition for promoting the absorption of poorly soluble drugs of the present invention, the mass ratio of the organic acid to the andrographolide compounds is 5-15:1; the mass ratio of the andrographolide compounds to the bile salt can be 5:2-10. Among them, the andrographolide compounds are preferably andrographolide.

[0019] In the composition for promoting the absorption of poorly soluble drugs of the present invention, the mass ratio of the organic acid to the andrographolide compound is 5 to 10:1. Preferably, the mass ratio of the organic acid to the andrographolide compound is 10:1. In the preparation for promoting the absorption of poorly soluble drugs of the present invention, the mass ratio of the andrographolide compound to the bile salt is 5:5 to 10. Preferably, the mass ratio of the andrographolide compound to the bile salt is 5:5. Among them, the andrographolide compound is preferably andrographolide.

[0020] In the composition for promoting the absorption of poorly soluble drugs of the present invention, the configuration conditions of the dissolution apparatus are: the rotation speed is 100 rpm and the temperature is 37 °C;

[0021] In some of the embodiments, when the dissolution medium is pH = 7.4, the dissolution degree of the composition in the dissolution apparatus at 2 h is not less than 85%;

[0022] In some of the embodiments, when the dissolution medium is configured to pH = 1.2, the dissolution degree of the composition in the dissolution apparatus at 2 h is not less than 70%;

[0023] In some of the embodiments, when the dissolution medium is configured to pH = 6.8, the dissolution degree of the composition in the dissolution apparatus at 2 h is not less than 80%.

[0024] In some of the embodiments, the apparent permeability coefficient of the composition in the everted gut sac method experiment at 2 h is not less than 2×10 -6 cm / s; wherein the configuration conditions of the dissolution apparatus are: the rats are male SD rats with a body weight of 220 ± 20 g; the intestinal segment is selected at a position 2 cm behind the duodenum; the blank solution in the intestine is Krebs-Henseleit buffer; the temperature is 37 °C.

[0025] The present invention also provides an oral preparation, comprising the above composition for promoting the absorption of poorly soluble drugs.

[0026] Among them, the oral preparation includes oral solid preparations and oral liquid preparations. The oral solid preparations are tablets, enteric-coated tablets, sustained-release tablets, granules or capsules, and the oral liquid preparations are oral solutions or syrups.

[0027] Implementing the composition for promoting the absorption of poorly soluble drugs and the oral preparation of the present invention has the following beneficial effects: The present invention provides a composition for promoting the absorption of poorly soluble drugs, which can significantly improve the water solubility and intestinal permeability of poorly soluble drugs, thereby improving the oral bioavailability, and can generate bubbles to disperse the drugs, avoiding drug aggregation and precipitation, and has the advantages of simple preparation process and easy industrial production, etc., and can provide new ideas for the research and development of poorly soluble drug preparations, and has extremely high industrial application and development potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The present disclosure also provides drawings related to the technical solutions provided by the present disclosure to illustrate the technical solutions of the present disclosure. The purpose of the drawings and the description is only to describe the present disclosure more clearly, and should not be regarded as a limitation on the scope of protection required by the present disclosure.

[0029] Figure 1 Shows the dissolution test result graph of the drug and the foaming formulation (without bile salt group) in the pH = 7 dissolution medium during the construction and screening process of the present invention;

[0030] Figure 2 Shows the dissolution test result graph of the drug and the foaming formulation (with bile salt group) in the pH = 7 dissolution medium during the construction and screening process of the present invention;

[0031] Figure 3 Shows the dissolution test result graph of the different ratios of the excipients and bile salts in the drug and the foaming formulation in the pH = 7 dissolution medium during the construction and screening process of the present invention;

[0032] Figure 4 Shows the dissolution test result graph of the different types of bile salts and the excipients in the drug and the foaming formulation in the pH = 7 dissolution medium during the construction and screening process of the present invention;

[0033] Figure 5 Shows the dissolution test result graph of an embodiment of the present invention, the andrographolide raw material drug group, and the andrographolide dropping pill group in the pH = 7.4 dissolution medium;

[0034] Figure 6 Shows the dissolution test result graph of an embodiment of the present invention, the andrographolide raw material drug group, and the andrographolide dropping pill group in the pH = 1.2 dissolution medium;

[0035] Figure 7 Shows the dissolution test result graph of an embodiment of the present invention, the andrographolide raw material drug group, and the andrographolide dropping pill group in the pH = 6.8 dissolution medium;

[0036] Figure 8 Shows the test result graph of the difference in cell transmembrane absorption between an embodiment of the present invention and the andrographolide raw material drug group;

[0037] Figure 9 Shows the test result graph of the difference in cell uptake between an embodiment of the present invention and the andrographolide raw material drug group;

[0038] Figure 10 Shows the test result graph of the difference in intestinal permeability rate between an embodiment of the present invention, the andrographolide raw material drug group, and the andrographolide dropping pill group;

[0039] Figure 11Shows the test result graph of an embodiment of the present invention and andrographolide dropping pills group in the anti-yeast-induced fever reaction in SD rats;

[0040] Figure 12 Shows the test result graph of an embodiment of the present invention, andrographolide raw material drug group, and andrographolide dropping pills group in the blood drug concentration in SD rats. Detailed implementation manners

[0041] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are not all of the embodiments.

[0042] The elements and features described in one embodiment of the present invention can be combined with the elements and features shown in one or more other embodiments. It should be noted that, for the sake of clarity, the representation and description of components and processes irrelevant to the present invention and known to those of ordinary skill in the art are omitted in the description.

[0043] The present invention discloses a composition for promoting the absorption of poorly soluble drugs, which includes andrographolide compounds, organic acids, carbonates and bile salts. An organic acid is used as an acid initiator, a carbonate is used as a foaming agent, and a bile salt is used as a surfactant to form a bubble-driven drug delivery system (BDDS). The composition can be prepared by mixing andrographolide compounds, organic acids, carbonates and bile salts with each other.

[0044] Example 1

[0045] Experimental groups 1 to 6 are set up to investigate the screening and foaming effect of carbonates as foaming agents and organic acids as acid initiators, wherein:

[0046] Sodium carbonate is used as the foaming agent in experimental groups 1 to 3. Specifically: tartaric acid, citric acid and sodium carbonate are respectively placed in 3 mL of PBS buffer solution (pH = 6.8) according to the ratios of 2:5, 4:5, 6:5, 8:5, 10:5 to react, and the amount of carbon dioxide generated under no-load (without drugs) is measured.

[0047] Sodium bicarbonate is used as the foaming agent in experimental groups 4 to 6. Specifically: tartaric acid, citric acid and sodium bicarbonate are respectively placed in 3 mL of PBS buffer solution (pH = 6.8) according to the ratios of 2:5, 4:5, 6:5, 8:5, 10:5 to react, and the amount of carbon dioxide generated under no-load (without drugs) is measured.

[0048] Table 1 Foaming height when sodium carbonate is used as the foaming agent

[0049]

[0050] Table 2 Foaming height when sodium bicarbonate is used as the foaming agent

[0051]

[0052] When the ratio of tartaric acid to foaming agent exceeds 2:5, insoluble precipitation will occur at the bottom of the test tube, so it is not selected. From the results of Table 1 and Table 2, it can be seen that the heights of the ratios of citric acid to foaming agent of 6:5, 8:5, and 10:5 are relatively high, and the next step of pH investigation can be carried out.

[0053] Example 2

[0054] Set experimental groups 7 - 12, all used to investigate the pH during the foaming of citric acid. Among them:

[0055] Experimental groups 7 - 9 investigate the sodium carbonate group, and react citric acid and sodium carbonate in 3 ml of PBS buffer solution (pH = 6.8) according to the ratios of 6:5, 8:5, and 10:5 respectively; experimental groups 10 - 12 investigate the sodium bicarbonate group, and react citric acid and sodium bicarbonate in 3 mL of PBS buffer solution (pH = 6.8) according to the ratios of 6:5, 8:5, and 10:5 respectively. Each of the above groups has three parallels. The obtained pH parameters are shown in Table 3.

[0056] Table 3 pH values of different foaming agent systems with citric acid as the acid initiator

[0057]

[0058] From the results of Table 3, it can be seen that when the mass ratio of citric acid to sodium carbonate is 6:5 in the six groups, the pH is closest to the pH of the human small intestine (pH = 6.8). Therefore, the mass ratio of citric acid to sodium carbonate of 6:5 is selected as the foaming prescription.

[0059] Example 3

[0060] Set experimental groups 13 - 19, all used to investigate the drug loading of the foaming formulation. Among them:

[0061] Experimental groups 13 - 16 all investigate the drug loading of the foaming formulation (without bile salts), and experimental groups 17 - 19 all investigate the drug loading of the foaming formulation (with bile salts). Specific operations:

[0062] Group without bile salts: Taking andrographolide (AG) as an example of the drug, its content was fixed at 5 mg. Citric acid was used as the acid initiator and sodium carbonate was used as the foaming agent. The mass ratio of citric acid to sodium carbonate in this foaming formulation was 6:5. The mass ratios of the drug to the acid initiator citric acid in the foaming formulation (including the acid initiator and the foaming agent, calculated based on the mass of citric acid) were 1:5, 1:10, and 1:15. An experiment was carried out using a dissolution tester; the dissolution medium was 250 mL / cup of deionized water with pH = 7, the rotation speed was 100 rpm, at a temperature of 37 °C, samples were taken at 5, 15, 30, 60, 90, and 120 min. Immediately after taking 2 mL, 2 mL of deionized water at 37 °C was added. The 2 mL of the taken sample was filtered through a 0.22 μm filter membrane, and the initial filtrate was discarded. The remaining was used as the sample, and the content of andrographolide was detected by high performance liquid chromatography (HPLC). After obtaining the data, the dissolution rate was calculated and plotted. The results are as Figure 1 shown.

[0063] Group with bile salts: The content of andrographolide (AG) was fixed at 5 mg, and the bile salt was fixed as sodium deoxycholate with a mass of 5 mg. Citric acid was used as the acid initiator and sodium carbonate was used as the foaming agent. The mass ratio of citric acid to sodium carbonate in this foaming formulation was 6:5. The mass ratios of the drug to citric acid in the foaming acid formulation were set as 1:5, 1:10, and 1:15 respectively. An experiment was carried out using a dissolution tester, and the conditions and detection methods were the same as those in the group without bile salts. The results are as Figure 2 shown.

[0064] From Figure 1 the results, it can be seen that there is no difference among the three ratios when the drug and the foaming formulation do not contain bile salts; Figure 2 after adding bile salts, with the bile salt fixed, the mass ratio of the drug, citric acid to the bile salt of 1:10:1 is better than other groups. Therefore, the best effect is achieved when the drug-excipient ratio is determined as "the mass ratio of the drug to citric acid in the foaming formulation is 1:10".

[0065] Example 4

[0066] Experimental groups 20 - 23 were set up to investigate the drug-bile salt ratio, where:

[0067] In experimental groups 20 - 23, the bile salt was fixed as sodium deoxycholate (SDC), and the ratios of the drug and excipients in the foaming formulation to the bile salt were investigated. Specific operation: The content of andrographolide was fixed at 5 mg, and the citric acid in the foaming formulation was ten times the mass of andrographolide. The foaming formulation included 50 mg of citric acid and 41.7 mg of sodium carbonate, and their mass ratio was 6:5. The mass ratios of the drug to the bile salt could be 5:2, 5:5, and 5:10. The experiment was measured using a dissolution tester, and the conditions and detection methods were the same as those in Example 3. The results are shown in Figure 3 .

[0068] From Figure 3As can be seen from the results, among the four different ratios of drug to bile salt, the effect of 5:2 is lower than that of the other three groups; there is no difference between the ratios of 5:5 and 5:10, so 5:5 with less mass is selected as the prescription. Therefore, the ratio of "drug, citric acid in the foaming formula, and bile salt is 5:10:5" has the best effect.

[0069] Example 5

[0070] Experimental group 24 - 26 and the control group were used to investigate the types of bile salts, where:

[0071] The content of andrographolide was fixed at 5 mg, and the citric acid in the foaming formula was fixed at ten times the mass of andrographolide. The foaming formula included 50 mg of citric acid and 41.7 mg of sodium carbonate, and the mass ratio of the two was 6:5. The mass of different bile salts was 5 mg each, that is, the mass ratio of drug to bile salt was 5:5. Taurocholic acid (TCA), sodium deoxycholate (SDC), and sodium ursodeoxycholate (UDCA) were selected for investigation. The dissolution was measured using a dissolution tester, and the conditions and detection methods were the same as those in Example 3. The results are shown in Figure 4 .

[0072] From Figure 4 the results, it can be seen that the dissolution-promoting effect of sodium ursodeoxycholate (UDCA) is lower than that of the other two groups; sodium deoxycholate (SDC) is slightly better than taurocholic acid (TCA), so sodium deoxycholate (SDC) is selected as the best. Therefore, the final mass ratio of "andrographolide, citric acid, sodium carbonate, and sodium deoxycholate is 5:50:42:5" is determined as the best formula in the composition, where the mass ratio of citric acid to sodium carbonate is 6:5.

[0073] Example 6

[0074] Experimental group 27 and three control groups were set up. Among them, experimental group 27 was a bubble-driven drug delivery system group (BDDS) composed of the composition of the best formula determined in Example 5, and the control groups were the andrographolide raw material drug group (AG) and the commercially available preparation dropping pill group (DP). Both experimental group 27 and the two control groups contained 5 mg of andrographolide.

[0075] (1) Dissolution test in a dissolution medium with pH = 7.4 (simulating the blood environment)

[0076] Take a certain amount of phosphate buffer solution and add it to a 1000 ml beaker, add a certain amount of deionized water, measure the pH using a pH meter, and then add hydrochloric acid or deionized water to adjust until the pH is 7.4 to obtain a dissolution medium with pH = 7.4.

[0077] Experiments were carried out using a dissolution tester. The samples were andrographolide raw material (AG) containing 5 mg of andrographolide, andrographolide dripping pills (DP), and the bubble-driven drug delivery system (BDDS) of andrographolide. The dissolution medium at pH = 7.4 was 250 mL / cup, the rotation speed was 100 rpm, and at a temperature of 37 °C, samples were taken at 5, 15, 30, 60, 90, and 120 min. Immediately after taking 2 mL, 2 mL of the dissolution medium at pH = 7.4 and 37 °C was replenished. The 2 mL of the taken sample was filtered through a 0.22 μm filter membrane, and the initial filtrate was discarded. The remaining was used as the sample, and the content of andrographolide was detected by HPLC. After obtaining the data, the dissolution rate was calculated and plotted. The results are as Figure 5 shown.

[0078] (2) Dissolution test in a dissolution medium at pH = 1.2 (simulating the gastric environment)

[0079] Take 3.8 mL of 6×10 -2 mol / L hydrochloric acid and add it to a 1000 mL beaker. Then continue to add deionized water until it reaches 500 mL. Use a pH meter to measure the pH, and then add hydrochloric acid or deionized water for adjustment until the pH is 1.2 to obtain a dissolution medium at pH = 1.2.

[0080] According to the steps in the dissolution experiment in the dissolution medium at pH = 7.4 in (1) above, the in vitro dissolution curves of the experimental group 27 and the two control groups in the medium at pH = 1.2 were obtained. The results are as Figure 6 shown.

[0081] (3) Dissolution test in a dissolution medium at pH = 6.8 (simulating the intestinal environment)

[0082] Take a certain amount of phosphate buffer solution and add it to a 1000 mL beaker. Add a certain amount of deionized water, use a pH meter to measure the pH, and then add hydrochloric acid or deionized water for adjustment until the pH is 6.8 to obtain a dissolution medium at pH = 6.8.

[0083] According to the steps in the dissolution experiment in the dissolution medium at pH = 7.4 in (1) above, the in vitro dissolution curves of the experimental group 27 and the two control groups in the medium at pH = 6.8 were obtained. The results are as Figure 7 shown.

[0084] Comprehensively Figure 5 、 Figure 6 and Figure 7 From the results, it can be seen that in different pH media, the 2-hour cumulative dissolution rate of the bubble-driven drug delivery system group (BDDS) as the experimental group in the three groups is significantly better than that of the commercially available andrographolide dripping pills (DP) with better performance.

[0085] In the group with the dissolution medium at pH = 7.4, the bubble-driven drug delivery system group as the experimental group

[0086] The 2-hour cumulative dissolution rates of (BDDS) were 3.37 and 1.76 times those of andrographolide raw material drug (AG) and dripping pills (DP), respectively, and the dissolution rate was significantly improved.

[0087] In the dissolution medium with pH = 1.2 simulating the gastric environment and the dissolution medium with pH = 6.8 simulating the intestinal environment, the bubble-driven drug delivery system group (BDDS) as the experimental group also performed excellently. Under the three pH media, BDDS showed better dissolution-promoting effects than DP in all three pH environments. Compared with free AG and the commercial preparation DP, the dissolution rates of BDDS were increased by 3.6 times and 2.1 times on average, respectively.

[0088] Example 7

[0089] An experimental group 28 and a control group were set up. Among them, the experimental group 28 was the bubble-driven drug delivery system group (BDDS) composed of the optimal formulation composition determined in Example 5; the control group was the andrographolide raw material drug group (AG).

[0090] Caco-2 cells (human colon adenocarcinoma cells) were cultured in a 12-well plate for 21 days to measure their electrical resistance, meeting the requirements of the transmembrane transport experiment. The Transwell chambers were grouped, with three replicates in each group. To the A side of different groups, the AG group and the BDDS group were added, and each group contained 20 μmol / L of andrographolide in an equivalent amount. Samples were taken at 15, 30, 45, 60, 90, and 120 min after drug administration, and the content of andrographolide was determined. The results were as Figure 8 shown.

[0091] Figure 8 The measurement results showed that there was a significant difference between the BDDS group and the AG group, proving that the absorption amount of the experimental group BDDS was significantly increased compared with that of the andrographolide raw material drug AG.

[0092] Example 8

[0093] Experimental groups 29 to 33 were set up to investigate the cell uptake efficiency, where:

[0094] Caco-2 cells were seeded into a 6-well plate (2×10 5Cells / well) were allowed to adhere overnight. When the cell density reached 90%, the original culture medium was discarded. For the group without inhibitor (Free AG, AG+SDC, AG+CA+Na2CO3, BDDS), 2 mL of DMEM medium was added, and for the group with inhibitor (300 μM UDCA+BDDS), 2 mL of DMEM medium containing 300 μM ursodeoxycholic acid (UDCA) was added. Incubation was carried out at 37 °C for 30 min. After washing with PBS, 2 mL of DMEM medium containing free AG, AG+SDC, AG+CA+Na2CO3 and BDDS was added to each well, with each group containing 200 μmol / L of andrographolide. After incubation at 37 °C for 2 h, the cells were washed with PBS, sonicated in 300 μL of 80% methanol for 20 min, and then centrifuged at 19,000×g for 10 min to collect the supernatant. The content of AG in the cell lysate was determined by HPLC. The results are as Figure 9 shown.

[0095] Figure 9 The determination results showed that there was a significant difference between the BDDS group and the Free AG, AG+SDC, AG+CA+Na2CO3 groups. The uptake efficiency of the andrographolide bubble-driven drug delivery system group (BDDS) was 3.67, 3.36, and 3.29 times higher than that of the andrographolide raw material drug group (Free AG), the group with only increased bile salt (AG+SDC), and the group with only increased foaming agent (AG+CA+Na2CO3), indicating that the andrographolide raw material drug could not achieve the same uptake effect as the andrographolide bubble-driven drug delivery system after only increasing bile salt (SDC) or foaming formula (CA and Na2CO3), proving that the andrographolide bubble-driven drug delivery system described in the present invention has a significant improvement in uptake efficiency compared to the andrographolide raw material drug. And after pre-administering the inhibitor (ursodeoxycholic acid, UDCA), the uptake efficiency of the BDDS group decreased significantly, proving that the solubilization and absorption-promoting effects of the foaming components and bile salts in the andrographolide bubble-driven drug delivery system complement each other and are indispensable.

[0096] Example 9

[0097] Experimental group 34 and two control groups were set up. Among them, experimental group 34 was the bubble-driven drug delivery system group (BDDS) composed of the composition of the optimal formula determined in Example 5; the control groups were the andrographolide raw material drug group (AG) and the andrographolide dropping pill group (DP).

[0098] Rats were fasted for 12 h, and the intestinal segment 2 cm after the duodenum was taken. After washing with KRB (Krebs-Henseleit) buffer solution, it was everted and tied into a sac with cotton thread, and 1.5 mL of KRB was added to the sac-like intestinal tube

[0099] (Krebs-Henseleit) solution. After checking that there was no leakage from the intestinal sac, the intestinal sac was transferred to a 15 mL centrifuge tube containing 10 mL of the drug solution. Oxygen was introduced during the experiment, and the temperature was maintained at 37 °C for 2 h. 300 μL of the sample was taken from inside the intestinal sac, and after treatment of the taken intestinal fluid, HPLC detection was carried out. After the experiment, the intestinal tube was cut open, and the intestine was naturally unfolded and flattened on filter paper, and the length and width were measured, and the absorption surface area was recorded. It can be calculated from the apparent permeability coefficient that the apparent permeability coefficients of the AG, DP, and BDDS groups were 0.83×10 -6 cm / s, 1.55×10 -6 cm / s, 2.93×10 -6 cm / s, as shown in Figure 10 .

[0100] From the experimental conclusions, it can be seen that both DP and BDDS can improve the intestinal absorption of andrographolide, and the absorption-promoting effect of BDDS is more obvious and has a significant difference from the raw drug AG group (P<0.05). It shows that the BDDS group can promote the dissolution and release of the drug and enhance the transmembrane ability of the drug, thereby improving the absorption of andrographolide.

[0101] Example 10

[0102] An experimental group 35, a blank control group, a model group, and a positive control group were set up, where:

[0103] The relevant solution was prepared according to the required drug dosage for rats (the AG dosage for each rat was 50 mg / kg).

[0104] The experimental group 35 was the BDDS group prepared from the optimal formulation composition determined in Example 5. The corresponding amounts of citric acid, anhydrous sodium carbonate, sodium deoxycholate, and andrographolide for each rat were weighed, mixed evenly, filled into small animal gavage capsules, and immediately gavaged.

[0105] Study on fever induction in rats and antipyretic effect after administration: SD rats with a body weight of 120±20 g were screened and randomly divided into a normal group (control, NC), a model group (model), an andrographolide dropping pill group (DP), and an andrographolide bubble-driven drug delivery system group (BDDS). The rats in the dropping pill group and the andrographolide bubble-driven drug delivery group were gavaged with andrographolide dropping pills and the andrographolide bubble-driven drug delivery system respectively, and the dosage was 50 mg / kg of andrographolide. The rats in the blank group and the model group were gavaged with an equal volume of distilled water.

[0106] On the morning of the experimental day, the body temperature was measured twice, and the average value was taken as the basal body temperature. Subsequently, a 20% (i.e., 200 g / L) suspension of beer yeast in physiological saline was subcutaneously injected at the back of the neck at a dose of 10 mL / kg to induce fever in rats, and the blank control group was subcutaneously injected with an equal volume of physiological saline. At 3 - 8 h after animal modeling, the rectal temperature of each group of rats was measured every hour. The measured body temperature was compared with the basal body temperature, and the change value of body temperature △℃ (measured body temperature value - basal body temperature value) was calculated.

[0107] In addition, after measuring the rectal temperature at the 3 - h time point, the corresponding dose of the therapeutic drug (administered by gavage) was given to each rat, and the blank and model groups were given the same volume of distilled water. The results are shown in Table 4 and Figure 11 as follows.

[0108] Table 4 Effects of andrographolide on body temperature of young rats with yeast-induced fever model (n = 8)

[0109]

[0110] Note: Compared with the blank control group, ### p < 0.001, # p < 0.05 compared with the model group, * p < 0.05, ** p < 0.01, *** p < 0.001.

[0111] Based on the results in Table 4 and Figure 11 it can be seen that after subcutaneous injection of 20% yeast suspension on the back, the body temperature of the model group and other groups increased significantly after 3 h, and the average body temperature change value of the model group exceeded 0.4℃ at 3 h, indicating successful modeling.

[0112] Taking the andrographolide dropping pill group as the positive control group, the temperature increase values of the BDDS group were significantly lower than those of the model group at 6 - 8 h after administration (P < 0.05), and the antipyretic effect lasted for more than 5 h, showing a better antipyretic effect than andrographolide dropping pills. It can be seen that BDDS improved the oral bioavailability of andrographolide, demonstrating the superiority of the bubble-driven technology.

[0113] In summary, the andrographolide bubble-driven drug delivery system (BDDS) can effectively reduce fever and lower the body temperature of rats with yeast-induced fever.

[0114] Example 11

[0115] An experimental group 36 and two control groups were set up. Among them, the experimental group 36 was the bubble-driven drug delivery system (BDDS) composed of the optimal formulation composition determined in Example 5; the control group was andrographolide dropping pills (DP).

[0116] Mechanistic study on the in vivo metabolism of drugs: SD male rats weighing 220±20 g were selected and randomly divided into two groups, DP and BDDS, with 6 rats in each group. After fasting for 12 h, the rats were given drugs by gavage, and the dosage was the equivalent dose of andrographolide in rats on the clinical dosing day (40 mg / kg). After the rats were given drugs by gavage, at the time points of 0.25, 0.5, 0.75, 1, 2, 3, 4, 8, 12, and 24 h, 0.3 mL of blood was collected from the orbital cavity and placed in an EP tube containing sodium heparin. The blood was centrifuged at 5000 rpm for 10 min, and the plasma was taken and stored frozen at -20°C. Methanol was used to extract andrographolide from the plasma, and then the samples were detected by ultra-high performance liquid chromatography-mass spectrometry. After data processing and analysis, see Table 5, Figure 12 .

[0117] Table 5 Pharmacokinetic parameters of the drug in rats (n = 6)

[0118]

[0119] The experimental results showed that within 24 h of the total experimental time, the AUC (area under the blood concentration-time curve) of the BDDS group was higher than that of the commercially available preparation DP, indicating that BDDS could promote the absorption of andrographolide and improve the oral bioavailability.

[0120] It should be understood that those skilled in the art can make improvements or transformations according to the above description, but these improvements or transformations should fall within the protection scope of the appended claims of the present invention.

Claims

1. A composition for promoting the absorption of poorly soluble drugs, characterized in that, It includes andrographolide compounds, organic acids, carbonates and bile salts.

2. The composition for promoting the absorption of poorly soluble drugs according to claim 1, wherein The organic acid is selected from at least one or more of tartaric acid and citric acid; the carbonate is selected from at least one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; the bile salt is selected from at least one or more of taurocholic acid, sodium deoxycholate and ursodeoxycholic acid; the andrographolide compounds include one or more of andrographolide, deoxyandrographolide, neoandrographolide and dehydrated andrographolide.

3. The composition for promoting the absorption of poorly soluble drugs according to claim 1 or 2, characterized in that, The mass ratio of the organic acid to the carbonate is 2 - 10:

5.

4. The composition for promoting the absorption of poorly soluble drugs according to claim 3, wherein, The mass ratio of the organic acid to the carbonate is 6 - 10:

5.

5. The composition for promoting the absorption of poorly soluble drugs according to claim 4, wherein The mass ratio of the organic acid to the carbonate is 6:

5.

6. The composition for promoting the absorption of poorly soluble drugs according to claim 2, wherein The mass ratio of the organic acid to the andrographolide compounds is 5 - 15:1; the mass ratio of the andrographolide compounds to the bile salt can be 5:2 - 10.

7. The composition for promoting the absorption of poorly soluble drugs according to claim 6, characterized in that, The mass ratio of the organic acid to the andrographolide compounds is 5 - 10:1; the mass ratio of the andrographolide compounds to the bile salt is 5:5 - 10.

8. The composition for promoting the absorption of poorly soluble drugs according to any one of claims 1-7, characterized in that, The configuration conditions of the dissolution apparatus are: the rotation speed is 100 rpm and the temperature is 37 °C; When the dissolution medium is configured to have a pH of 7.4, the dissolution rate of the composition in the dissolution apparatus at 2 h is not less than 85%; When the dissolution medium is configured to have a pH of 1.2, the dissolution rate of the composition in the dissolution apparatus at 2 h is not less than 70%; When the dissolution medium is configured to have a pH of 6.8, the dissolution rate of the composition in the dissolution apparatus at 2 h is not less than 80%.

9. An oral preparation, characterized in that, It includes the composition for promoting the absorption of poorly soluble drugs according to any one of claims 1 - 8.

10. The oral preparation according to claim 9, characterized in that, The oral preparation includes oral solid preparations and oral liquid preparations. The oral solid preparations are tablets, enteric-coated tablets, sustained-release tablets, granules or capsules, and the oral liquid preparations are oral solutions or syrups.

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