Ginsenoside Rh2 composition as well as preparation method and application thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a ginsenoside Rh2 composition as well as a preparation method and application thereof. According to the invention, through artificial intelligence machine learning prediction and molecular simulation prediction of polymers, the ginsenoside Rh2 composition is found after verification, and the ginsenoside Rh2 composition comprises ginsenoside Rh2 and Gelucire 44 / 14. The Gelucire 44 / 14 can promote the solubility of ginsenoside Rh2, and the dissolution rate can be further increased after the Gelucire 44 / 14 is added into SDS to form the ternary solid dispersion. The ternary solid dispersion preparation formed by the ginsenoside Rh2, the Gelucire 44 / 14 and the SDS can promote the intestinal absorption rate, the blood drug concentration in a rat model is improved, and the intake of the ginsenoside Rh2 by Caco-2 cells can be increased by further using a P-glycoprotein inhibitor. The composition can effectively overcome the defects that ginsenoside Rh2 is less in absorption and low in bioavailability clinically.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a ginsenoside Rh2 composition, a preparation method thereof and an application thereof. Background Art

[0002] Ginsenosides are a class of compounds with pharmaceutical activities in ginseng extracts. 20(S)-ginsenoside-Rh2 is one of the ginsenosides and has various biological activities with different mechanisms.

[0003] 20(S)-ginsenoside Rh2 (20(S)-ginsenoside Rh2, 20(S)G-Rh2), with the molecular formula C 36 H 62 O 8 , a molecular weight of 622.9, and a structural formula as follows:

[0004]

[0005] 20(S)G-Rh2 can inhibit the proliferation of MCF-7 breast cancer cells by epigenetically regulating the cell-mediated immune pathway. The research groups of Jianjian Zheng and Zhixian Yu from the First Affiliated Hospital of Wenzhou Medical University demonstrated that Rh2 can regulate SLC7A11 inhibited by IRF1, promoting ferritin deposition and inactivation in hepatic stellate cells. Haitao Yin et al. found that Rh2 can sponge the miR-28-5p / STK4 axis, inactivating the Wnt / β-catenin signal, thereby slowing down the progression of non-small cell lung cancer. The team of Youcheng Zhang studied the mechanism of Rh2 in inhibiting colon cancer, and the results showed that Rh2 can target the mir-150-3p / srcin1 / wnt axis, thereby achieving the purpose of inhibiting colon cancer. In addition, Rh2 can also kill or inhibit esophageal cancer cells, cervical cancer cells, and thyroid cancer cells. Due to the chiral structure of carbon-20, Rh2 exists as chiral isomers (20R)G-Rh2 and 20(S)G-Rh2. Compared with the former, the latter shows more prominent anti-cancer biological activities. In addition, the cytotoxic effect of 20(S)G-Rh2 on normal cells is less than that on tumor cells, which is more friendly to cancer patients.

[0006] However, the water solubility of 20(S)G-Rh2 is low, and its solubility in water is usually undetectable. Therefore, it is very necessary and urgent at this stage in the art to develop a modified preparation that can improve the bioavailability of 20(S)G-Rh2. Summary of the Invention

[0007] In view of the problems of poor water solubility and low bioavailability of 20(S)-G-Rh2, the present invention adopts the solid dispersion technology to significantly improve the dissolution rate and bioavailability of 20(S)-G-Rh2.

[0008] The purpose of the first aspect of the present invention is to provide a ginsenoside Rh2 composition.

[0009] The purpose of the second aspect of the present invention is to provide a preparation method of the composition of the first aspect of the present invention.

[0010] The purpose of the third aspect of the present invention is to provide a product.

[0011] The purpose of the fourth aspect of the present invention is to provide a pharmaceutical composition.

[0012] The purpose of the fifth aspect of the present invention is to provide the application of the composition of the first aspect and / or the product of the third aspect and / or the pharmaceutical composition of the fourth aspect of the present invention.

[0013] The purpose of the sixth aspect of the present invention is to provide an application.

[0014] In order to achieve the above purposes of the present invention, the technical solutions adopted by the present invention are as follows:

[0015] In the first aspect of the present invention, a ginsenoside Rh2 composition is provided, and the preparation raw materials of the preparation include: ginsenoside Rh2 and a polymer.

[0016] Preferably, the ginsenoside Rh2 includes at least one of 20(S)-ginsenoside Rh2 and 20(R)-ginsenoside Rh2.

[0017] Preferably, the ginsenoside Rh2 is 20(S)-ginsenoside Rh2.

[0018] Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, and / or hydroxypropyl methylcellulose.

[0019] Preferably, the mass ratio of the ginsenoside Rh2 to the polymer is 1:(1-10).

[0020] Preferably, the mass ratio of the ginsenoside Rh2 to the polymer is 1:(3-9).

[0021] Preferably, the mass ratio of the ginsenoside Rh2 to the polymer is 1:(5-9).

[0022] Preferably, the mass ratio of ginsenoside Rh2 to the polymer is 1:(4.5 - 5.5).

[0023] Preferably, the polymer includes Gelucire 44 / 14.

[0024] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 is 1:(1 - 10).

[0025] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 is 1:(3 - 9).

[0026] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 is 1:(5 - 9).

[0027] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 is 1:(4.5 - 5.5).

[0028] Preferably, the raw materials for preparing the composition further include a surfactant.

[0029] Preferably, the surfactant includes sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and / or polyethylene glycol ester.

[0030] Preferably, the surfactant includes at least one of sodium dodecyl sulfate and polysorbate.

[0031] Preferably, the mass ratio of the surfactant to ginsenoside Rh2 is (1 - 3):6.

[0032] Preferably, the mass ratio of the surfactant to ginsenoside Rh2 is (2 - 2.8):6.

[0033] Preferably, the mass ratio of the surfactant to ginsenoside Rh2 is (2.2 - 2.6):6.

[0034] Preferably, the composition is a solid dispersion preparation.

[0035] In the second aspect of the present invention, a preparation method of the composition in the first aspect of the present invention is provided, including but not limited to any one of a1) - a5):

[0036] a1) Mix the raw materials;

[0037] a2) Melting method: Heat the raw materials to 60 - 80 °C and obtain the product after mixing.

[0038] a3) Solvent method: Dissolve the raw materials in a solvent, dry to remove the solvent, and obtain the product.

[0039] a4) Solvent - melting method: Add the ginsenoside Rh2 to a solvent to obtain a mixed solution, add the solution to the melted polymer and / or surfactant, and obtain the product after mixing.

[0040] a5) Grinding method: Grind the raw materials together to obtain the product.

[0041] Preferably, the heating temperature is 65 - 75 °C.

[0042] Preferably, the mixing is uniform mixing; further, it is stirring and mixing uniformly.

[0043] Preferably, the solvent includes but is not limited to one or several of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N - methylpyrrolidone, N,N - dimethylformamide, dimethyl sulfoxide, isopropanol, and n - hexane.

[0044] Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying.

[0045] Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid - based polymers, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, and / or hydroxypropyl methylcellulose.

[0046] Preferably, the polymer includes Gelucire 44 / 14.

[0047] Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and / or polyethylene glycol ester.

[0048] Preferably, the surfactant includes at least one of sodium dodecyl sulfate and polysorbate.

[0049] The third aspect of the present invention lies in providing a product, which includes a P - glycoprotein inhibitor and the composition of the first aspect of the present invention.

[0050] Preferably, the P-glycoprotein inhibitor includes, but is not limited to, amiodarone, clarithromycin, cyclosporine, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, ifenprodil, duloxetine, verapamil, cyclosporine A, tamoxifen, valspodar, biricodar, elacridar, glibenclamide, tariquidar, zosuquidar trihydrochloride, piperine, risperidone, polyphyllin VII, atazanavir sulfate, selamectin, solasonine, isoorientin, feruloyl coniferyl ester, vobasine, crocetin, evodiamine, MC70, YS-370, PGP-4008, OY-101, RMS3, RMS5, FM04, P-gp inhibitor 1, P-gp inhibitor 2, P-gp inhibitor 3, P-gp inhibitor 5, P-gp inhibitor 13, P-gp inhibitor 14, D-α-tocopheryl polyethylene glycol succinate, polyoxyethylene castor oil, TW80, and / or poloxamer 407.

[0051] Preferably, the P-glycoprotein inhibitor includes at least one of D-α-tocopheryl polyethylene glycol succinate, polyoxyethylene castor oil, TW80, and poloxamer 407.

[0052] Preferably, the mass ratio of the P-glycoprotein inhibitor to ginsenoside Rh2 in the preparation is 1:(2 - 5); more preferably 1:(2.5 - 3.5).

[0053] Preferably, the P-glycoprotein inhibitor and the preparation exist independently or in combination.

[0054] In the fourth aspect of the present invention, there is provided a pharmaceutical composition comprising the composition of the first aspect and / or the product of the third aspect of the present invention.

[0055] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0056] Preferably, the pharmaceutically acceptable carrier comprises at least one of diluent, adjuvant, excipient, preservative, filler, binder, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, fragrance, antibacterial agent, antifungal agent, lubricant, dispersant, temperature-sensitive material, temperature regulator, pH regulator, adhesive, stabilizer, and suspending aid.

[0057] The fifth aspect of the present invention provides the application of the composition of the first aspect and / or the product of the third aspect and / or the pharmaceutical composition of the fourth aspect of the present invention in any one of b1)-b7) including but not limited to:

[0058] b1) Application in preparing anti-aging products;

[0059] b2) Application in preparing antioxidant products;

[0060] b3) Application in preparing anti-tumor products;

[0061] b4) Application in preparing products for inducing apoptosis;

[0062] b5) Application in preparing products for protecting the heart;

[0063] b6) Application in preparing products for protecting bones;

[0064] b7) Application in preparing products for protecting the liver.

[0065] Preferably, the products include but are not limited to skin care products and health care products.

[0066] Preferably, the tumors include at least one of breast cancer, non-small cell lung cancer, colon cancer, esophageal cancer, cervical cancer, and thyroid cancer.

[0067] The sixth aspect of the present invention provides the application according to any one of (1) to (3):

[0068] (1) Application of Gelucire 44 / 14 in solubilizing ginsenoside Rh2;

[0069] (2) Application of Gelucire 44 / 14 and a surfactant in solubilizing ginsenoside Rh2;

[0070] (3) Application of Gelucire 44 / 14 in preparing a solid dispersion of ginsenoside Rh2.

[0071] Preferably, the ginsenoside Rh2 includes at least one of 20(S)-ginsenoside Rh2 and 20(R)-ginsenoside Rh2.

[0072] Preferably, the ginsenoside Rh2 is 20(S)-ginsenoside Rh2.

[0073] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 in (1) is 1:(0.5 - 4); further preferably 1:(1 - 3).

[0074] Preferably, the application in (1) includes but is not limited to any one of a1)-a5):

[0075] a1) Mix the raw materials;

[0076] a2) Melting method: Heat the raw materials to 60 - 80 °C and obtain after mixing;

[0077] a3) Solvent method: Dissolve the raw materials in a solvent, dry to remove the solvent, and obtain;

[0078] a4) Solvent - melting method: Add the ginsenoside Rh2 to a solvent to obtain a mixed solution, add the solution to the polymer and / or surfactant that has been melted, and obtain after mixing;

[0079] a5) Grinding method: Grind the raw materials together to obtain.

[0080] Preferably, the heating temperature is 65 - 75 °C.

[0081] Preferably, the mixing is uniform mixing; further, it is stirring and mixing uniformly.

[0082] Preferably, the solvent includes but is not limited to one or several of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N - methylpyrrolidone, N,N - dimethylformamide, dimethyl sulfoxide, isopropanol, and n - hexane.

[0083] Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying.

[0084] Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid - based polymers, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, and / or hydroxypropylmethyl cellulose.

[0085] Preferably, the polymer includes Gelucire 44 / 14.

[0086] Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soybean phospholipid deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and / or polyethylene glycol ester.

[0087] Preferably, the surfactant includes at least one of sodium dodecyl sulfate and polysorbate.

[0088] Preferably, the application described in (1) includes a1) mixing the raw materials.

[0089] Preferably, the application described in (1) includes mixing the raw materials with water.

[0090] Preferably, the mixing in (1) is uniform mixing; further, Rh2 is placed in an aqueous solution of Gelucire 44 / 14 and oscillated at 35 - 40 °C for 48 - 96 h.

[0091] Preferably, the mass ratio of the total mass of ginsenoside Rh2 and Gelucire 44 / 14 to the mass of the water in (1) is 1:(20 - 100); further, it is 1:(50 - 100).

[0092] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 in (2) is 1:(0.5 - 4); further, it is 1:(1 - 3).

[0093] Preferably, the surfactant described in (2) includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and / or polyethylene glycol ester.

[0094] Preferably, the surfactant described in (2) includes at least one of sodium dodecyl sulfate and polysorbate.

[0095] Preferably, the surfactant described in (2) includes sodium dodecyl sulfate.

[0096] Preferably, the mass ratio of the surfactant to ginsenoside Rh2 in (2) is (1 - 3):6.

[0097] Preferably, the mass ratio of the surfactant to ginsenoside Rh2 in (2) is (2 - 2.8):6.

[0098] Preferably, the mass ratio of the surfactant to ginsenoside Rh2 in (2) is (2.2 - 2.6):6.

[0099] Preferably, the application described in (2) includes but is not limited to any one of a1) - a5):

[0100] a1) mixing the raw materials;

[0101] a2) melting method: heating the raw materials to 60 - 80 °C and obtaining the mixture after mixing;

[0102] a3) Solvent method: Dissolve the raw materials in a solvent, and dry to remove the solvent to obtain;

[0103] a4) Solvent-melting method: Add the ginsenoside Rh2 to a solvent to obtain a mixed solution, add the solution to the polymer and / or surfactant that has been melted, and obtain after mixing;

[0104] a5) Grinding method: Grind the raw materials together to obtain.

[0105] Preferably, the heating temperature is 65-75 °C.

[0106] Preferably, the mixing is uniform mixing; further, it is stirring and mixing.

[0107] Preferably, the solvent includes but is not limited to one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, and n-hexane.

[0108] Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying.

[0109] Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, and / or hydroxypropylmethyl cellulose.

[0110] Preferably, the polymer includes Gelucire 44 / 14.

[0111] Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and / or polyethylene glycol ester.

[0112] Preferably, the surfactant includes at least one of sodium dodecyl sulfate and polysorbate.

[0113] Preferably, the application in (2) includes a1) mixing the raw materials.

[0114] Preferably, the application in (2) includes mixing the raw materials with water.

[0115] Preferably, (2) the mixing is uniform mixing; further, Rh2, Gelucire 44 / 14 and a surfactant are placed in water and oscillated at 37 °C for 48 - 96 hours.

[0116] Preferably, the mass ratio of the total mass of ginsenoside Rh2 and Gelucire 44 / 14 to the mass of the water in (2) is 1:(20 - 100); further, it is 1:(50 - 100).

[0117] Preferably, the solid dispersion of ginsenoside Rh2 in (3) further contains a surfactant.

[0118] Preferably, the surfactant in (3) includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soybean phospholipid deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and / or polyethylene glycol ester.

[0119] Preferably, the surfactant in (3) includes at least one of sodium dodecyl sulfate and polysorbate.

[0120] Preferably, the surfactant in (3) is sodium dodecyl sulfate.

[0121] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 in (3) is 1:(1 - 10).

[0122] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 in (3) is 1:(3 - 9).

[0123] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 in (3) is 1:(5 - 9).

[0124] Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 in (3) is 1:(4.5 - 5.5).

[0125] Preferably, the mass ratio of Gelucire 44 / 14 to the surfactant in the solid dispersion of ginsenoside Rh2 in (3) is (5 - 25):1; further, it is (10 - 15):1.

[0126] Preferably, the application in (3) includes but is not limited to at least one of a2) - a5):

[0127] a2) Melt method: Heat the raw materials to 60 - 80 °C and obtain the product after mixing.

[0128] a3) Solvent method: Dissolve the raw materials in a solvent, and dry to remove the solvent to obtain;

[0129] a4) Solvent-melting method: Add the ginsenoside Rh2 to a solvent to obtain a mixed solution, add the solution to the polymer and / or surfactant that has been melted, and obtain after mixing;

[0130] a5) Grinding method: Grind the raw materials together to obtain.

[0131] Preferably, the heating temperature is 65-75 °C.

[0132] Preferably, the mixing is uniform mixing; further, it is stirring and mixing.

[0133] Preferably, the solvent includes but is not limited to one or several of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, and n-hexane.

[0134] Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying.

[0135] Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, and / or hydroxypropylmethyl cellulose.

[0136] Preferably, the polymer includes Gelucire 44 / 14.

[0137] Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and / or polyethylene glycol ester.

[0138] Preferably, the surfactant includes at least one of sodium dodecyl sulfate and polysorbate.

[0139] The beneficial effects of the present invention are:

[0140] The present invention discovers that Gelucire 44 / 14 can promote the solubility of 20(S)-ginsenoside-Rh2, and the dissolution rate of 20(S)-ginsenoside-Rh2 can be further increased after forming a ternary solid dispersion with SDS. The ternary solid dispersion preparation formed by 20(S)-ginsenoside-Rh2, Gelucire 44 / 14, and SDS can promote the intestinal absorption rate, increase the blood drug concentration in a rat model, and further use of a P-glycoprotein inhibitor can increase the uptake of 20(S)-ginsenoside-Rh2 by Caco-2 cells. This preparation composition can effectively solve the disadvantages of low absorption and low bioavailability of 20(S)-ginsenoside-Rh2 clinically. Description of the Drawings

[0141] Figure 1 Dissolution curves of the solid dispersion preparations of Examples 3-9 in a pH 6.8 medium: Among them, F1-F7 correspond to Examples 3-9 respectively.

[0142] Figure 2 Dissolution curves of the solid dispersion preparation of Example 7 in different media.

[0143] Figure 3 X-ray diffraction patterns of 20(S)G-Rh2, Gelucire 44 / 14, SDS monomers, a simple physical mixture of the three, and a ternary solid dispersion: Among them, A is 20(S)G-Rh2; B is Gelucire 44 / 14; C is SDS; D is a simple physical mixture of the three; E is a ternary solid dispersion.

[0144] Figure 4 Infrared absorption spectra of 20(S)G-Rh2, Gelucire 44 / 14, SDS monomers, a simple physical mixture of the three, and a ternary solid dispersion: Among them, A is 20(S)G-Rh2; B is Gelucire 44 / 14; C is SDS; D is a simple physical mixture of the three; E is a ternary solid dispersion.

[0145] Figure 5 Effect of P-gp inhibitors on the uptake of ginsenoside Rh2 by Caco-2 cells: Among them, Rh2con is the group without treatment with a P-gp inhibitor; Rh2 P407 is the Rh2 group pre-treated with the P-gp inhibitor P407; Rh2 TW80 is the Rh2 group pre-treated with the P-gp inhibitor TW80; Rh2 Cr is the Rh2 group pre-treated with the P-gp inhibitor Cr; Rh2 TPGS is the Rh2 group pre-treated with the P-gp inhibitor TPGS.

[0146] Figure 6Effect of P-gp inhibitor on the uptake of 20(S)G-Rh2 preparation by Caco-2 cells: Among them, Rh2ZJ con is the Rh2 preparation group without treatment with P-gp inhibitor; Rh2ZJ P407 is the Rh2 preparation group pretreated with P-gp inhibitor P407; Rh2ZJ TW80 is the Rh2 preparation group pretreated with P-gp inhibitor TW80; Rh2ZJ Cr is the Rh2 preparation group pretreated with P-gp inhibitor Cr; Rh2ZJ TPGS is the Rh2 preparation group pretreated with P-gp inhibitor TPGS.

[0147] Figure 7 Relationship between the permeation amount and time of 20(S)G-Rh2 and 20(S)G-Rh2 preparation on Caco-2 cell model: Among them, Rh2 represents the Rh2 group without treatment; Rh2ZJ represents the preparation group of Rh2 treated.

[0148] Figure 8 Curve of the change of blood drug concentration of 20(S)G-Rh2 and 20(S)G-Rh2 preparation with time in rats: Among them, Rh2 represents the Rh2 group without treatment; Rh2ZJ represents the preparation group of Rh2 treated.

[0149] Figure 9 Results of the interaction energy of the solid dispersion system, where F1 represents Example 3; F2 represents Example 4; F3 represents Example 5; F5 represents Example 7.

[0150] Figure 10 Represents all possible hydrogen bonds between 20(S)G-Rh2 and excipients in the solid dispersion system (red represents oxygen atom, blue represents carbon atom, white represents hydrogen atom, yellow represents sulfur atom).

[0151] Figure 11 Results of the number of hydrogen bonds between Rh2 and Gelucire44 / 14, where F1 represents Example 3; F2 represents Example 4; F3 represents Example 5; F5 represents Example 7.

[0152] Figure 12 Represents the number of hydrogen bonds between 20(S)G-Rh2 and SDS or Tween 80 in the solid dispersion system, where F2 represents Example 4; F3 represents Example 5; F5 represents Example 7.

[0153] Figure 13 Represents the average hydrogen bond lifetime in the solid dispersion system, where F2 represents Example 4; F3 represents Example 5; F5 represents Example 7. Detailed implementation mode

[0154] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0155] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturers. The materials and reagents used in the examples are commercially available unless otherwise specified.

[0156] The sources of materials, reagents and instruments used in the following examples are:

[0157] 20(S)-ginsenoside-Rh2 (Jiangsu Yongjian Pharmaceutical Technology Co., Ltd., >98%); PVP K30 (Chongqing Steckeler Material Technology Co., Ltd.); Gelucire 44 / 14 (Gattefossé, France); Plasdone S630 (Ashland (China) Investment Co., Ltd.); P188 (BASF Group, Germany); sodium dodecyl sulfate (SDS, Sinopharm Chemical Reagent Co., Ltd.); polysorbate 80 (TW80, Beijing Bailingwei Technology Co., Ltd.); UltiMate 3000 ultra-high performance liquid chromatograph, Q Exactive quadrupole-electrostatic field orbital trap high-resolution mass spectrometer (Thermo Fisher Scientific, USA); Milli-Q ultrapure water machine (Merek Millipore Corporation); KS-2200DE liquid crystal ultrasonic cleaner (Kunshan Jielimei Ultrasonic Instrument Co., Ltd.); FC5515R high-speed microcentrifuge (OHAUS Corporation, USA); fetal bovine serum, trypsin, penicillin, streptomycin, DMEM culture medium (Gibco Corporation, USA); Hank's balanced salt solution (Hyclone Corporation, USA); Transwell plate (Corning Corporation, USA).

[0158] Example 1 Machine Learning Model Predicts Optimal Polymer

[0159] Previously, the inventors established the "PharmSD" platform (https: / / pharmsd.computpharm.org / ) for predicting the dissolution type, dissolution rate, and stability of solid dispersions based on a machine learning model, which has been published in the literature (Dong J, Gao H, Ouyang D. PharmSD: A novel AI-based computational platform for solid dispersion formulation design. International Journal of Pharmaceutics. 2021;604:120705.).

[0160] The SMILES expression of (20S)G-Rh2 was input into the PharmSD website, and the preparation method was selected as hot melt extrusion. The drug loading rate was set at 0.5, and the drug dose was set at 20 mg with reference to market products. The dissolution conditions were set as 900 mL of phosphate buffer solution (PBS) at pH 6.8 without surfactant, using the paddle method at a rotation speed of 50 rpm. The dissolution of different solid dispersion formulations containing different polymers was predicted. Under the conditions of a preparation temperature of 70°C, a storage condition of 40°C, and a relative humidity of 75% (RH75), the stability of different formulations over 6 months was predicted.

[0161] According to the prediction results, the dissolution rates of binary solid dispersions composed of Gelucire 44 / 14, Polymer188 (P188), PVP K30, and PVPVA64 with (20S)G-Rh2 were all close to 70% within 60 minutes. Therefore, the above four polymers were selected for preliminary screening, and PVPVA64 was replaced with Plasdone 630.

[0162] Table 1 Polymer Prediction Results

[0163]

[0164]

[0165] Example 2 Solubility of 20(S)G-Rh2 in Different Polymer Solutions

[0166] Add the drug (20(S)G-Rh2) / polymer (Gelucire 44 / 14, PVP K30, P188, or Plasdone S630) to 8 mL of water at a mass ratio of 1 / 1 or 1 / 3. The compositions of different polymer solutions are shown in Table 1. Each sample is in triplicate. Place the samples in a 37°C water bath oscillator and oscillate for 72 hours. Then, determine the solubility of 20(S)G-Rh2 by high performance liquid chromatography. The detection conditions are as follows: Eclipse XDB C18 column (250 mm × 4.6 mm, 5 μm); the mobile phase is acetonitrile:water = 53:47, the injection volume is 20 μL, the detection wavelength is 203 nm, the column temperature is room temperature, and the flow rate is 1 ml / min. The results are shown in Table 1: 20(S)G-Rh2 was only detected in the Gelucire 44 / 14 solution, and not detected in other polymer solutions (PVP K30, Polymer188, or Plasdone S630), indicating that the concentration of 20(S)G-Rh2 in other polymer solutions is lower than 5.6 μg / mL, which is the lowest limit of the detection range; indicating that Gelucire 44 / 14 has an obvious solubilizing effect on 20(S)G-Rh2, and the solubilizing effect is better with the increase of the dosage. Therefore, Gelucire 44 / 14 was selected as the solubilizer for 20(S)G-Rh2.

[0167] Table 2 Composition and Results of Solubility Investigation Samples

[0168]

[0169] Note: ND: Not detected.

[0170] Example 3 A Solid Dispersion Preparation

[0171] A solid dispersion preparation is made of 60 mg of 20(S)G-Rh2 and 180 mg of Gelucire 44 / 14.

[0172] The preparation method of the above solid dispersion preparation includes the following steps: Take 20(S)G-Rh2 and Gelucire 44 / 14, heat them to 70°C, stir to mix evenly, and obtain a solid dispersion after cooling to room temperature.

[0173] Example 4 A Solid Dispersion Preparation

[0174] A solid dispersion preparation is made of 60 mg of 20(S)G-Rh2, 180 mg of Gelucire 44 / 14, and 24 mg of SDS.

[0175] The preparation method of the above solid dispersion preparation comprises the following steps: Take 20(S)G-Rh2, Gelucire 44 / 14, and SDS, heat them to 70 °C, stir to mix evenly, and obtain a solid dispersion after cooling to room temperature.

[0176] Example 5 A solid dispersion preparation

[0177] A solid dispersion preparation is made of 60 mg of 20(S)G-Rh2, 180 mg of Gelucire 44 / 14, and 24 mg of TW80.

[0178] The preparation method of the above solid dispersion preparation comprises the following steps: Take 20(S)G-Rh2, Gelucire 44 / 14, and TW80, heat them to 70 °C, stir to mix evenly, and obtain a solid dispersion after cooling to room temperature.

[0179] Example 6 A solid dispersion preparation

[0180] A solid dispersion preparation is made of 60 mg of 20(S)G-Rh2 and 300 mg of Gelucire 44 / 14.

[0181] The preparation method of the above solid dispersion preparation comprises the following steps: Take 20(S)G-Rh2 and Gelucire 44 / 14, heat them to 70 °C, stir to mix evenly, and obtain a solid dispersion after cooling to room temperature.

[0182] Example 7 A solid dispersion preparation

[0183] A solid dispersion preparation is made of 60 mg of 20(S)G-Rh2, 300 mg of Gelucire 44 / 14, and 24 mg of SDS.

[0184] The preparation method of the above solid dispersion preparation comprises the following steps: Take 20(S)G-Rh2, Gelucire 44 / 14, and SDS, heat them to 70 °C, stir to mix evenly, and obtain a solid dispersion after cooling to room temperature.

[0185] Example 8 A solid dispersion preparation

[0186] A solid dispersion preparation is made of 60 mg of 20(S)G-Rh2 and 540 mg of Gelucire 44 / 14.

[0187] The preparation method of the above solid dispersion preparation comprises the following steps: Take 20(S)G-Rh2 and Gelucire 44 / 14, heat them to 70 °C, stir to mix evenly, and obtain a solid dispersion after cooling to room temperature.

[0188] Example 9 A solid dispersion preparation

[0189] A solid dispersion preparation is made of 60 mg of 20(S)G-Rh2, 540 mg of Gelucire 44 / 14, and 24 mg of SDS.

[0190] The preparation method of the above solid dispersion preparation includes the following steps: Take 20(S)G-Rh2, Gelucire 44 / 14, and SDS, heat them to 70 °C, stir to mix evenly, and obtain a solid dispersion after cooling to room temperature.

[0191] Effect Example 1 Dissolution of the solid dispersion preparations of Examples 3-9 in a pH 6.8 medium

[0192] Use a dissolution apparatus (ERWEKA, DT820) to conduct a dissolution test. Under the conditions of 37 °C and a rotation speed of 50 rpm, put the solid dispersion preparations of Examples 3-9 equivalent to 10 mg of 20(S)G-Rh2 into 450 mL of pH 6.8 PBS dissolution medium using the paddle method. Take 5 mL of samples at each time point (5, 10, 15, 20, 30, 45, 60, 120 minutes) without replenishing the liquid. All samples are filtered through a 0.45 μm PES filter and detected using HPLC (the detection method is the same as in Example 2). The dissolution test for each formulation is repeated three times. The results are as Figure 1 shown. When Rh2:Gelucire44 / 14 is 1:9, the dissolution is nearly 60% at the highest, while when Rh2:Gelucire44 / 14 is 1:3, the dissolution is only about 33%. Increasing the proportion of Gelucire 44 / 14 significantly increases the dissolution rate, and the solubilization effect of SDS is significantly better than that of Tween 80.

[0193] Effect Example 2 Dissolution of the solid dispersion preparation of Example 7 in different media

[0194] Use an ERWEKA dissolution apparatus to conduct a dissolution test. Under the conditions of 37 °C and a rotation speed of 50 rpm, put the solid dispersion prepared in Example 7 containing 20 mg of 20(S)G-Rh2 into 900 mL of water (Water), 900 mL of hydrochloric acid solution (pH 1.0), 900 mL of acetate buffer solution (pH 4.5), and 900 mL of phosphate buffer solution (pH 6.8) respectively for the dissolution test. Take 5 mL of samples at 5, 10, 15, 20, 30, 45, 60 minutes respectively without replenishing the liquid. All the taken samples are filtered through a 0.45 μm PES filter and detected by HPLC (the detection method is the same as in Example 2). The dissolution test for each medium is repeated three times.

[0195] The results are as Figure 2As shown, the solid dispersion preparation obtained in Example 7 has good dissolution effects in different media. Among them, it dissolves about 60% in 60 minutes in the hydrochloric acid solution with pH 1.0, and in the remaining media, the dissolution degree can reach 80% in 60 minutes. Effect Example 3 Crystal state detection of the solid dispersion preparation of Example 7

[0196] X-ray powder diffraction is an important characterization method for judging the crystal form of drugs. The X-ray diffractometer (Rigaku SmartLab 9kW) was used to test 20(S)G-Rh2, Gelucire 44 / 14, SDS, and their simple physical mixtures (the same as the raw materials for the preparation of Example 7, with the only difference being that the preparation method is to mix the raw materials), and the ternary solid dispersion (obtained in Example 7). Using Cu Kα radiation, the scanning angle was set to 5-90°, and the rate was 10° / min to investigate the crystal state of the samples.

[0197] The X-ray diffraction pattern of the sample powder was used to analyze the crystal morphology of the ternary solid dispersion. As Figure 3 shown, 20(S)G-Rh2 has obvious crystal form diffraction peaks. Gelucire 44 / 14 has two sharp inherent peaks between 15° and 25°. SDS has a single diffraction peak near 6° and a peak cluster between 20° and 25°. The diffraction peaks of the physical mixture show that SDS still exists in crystal form. Although the characteristic peaks are small, it can still be proved. The characteristic peaks of 20(S)G-Rh2 are not obvious in the simple physical mixture. Only the diffraction peaks of Gelucire 44 / 14 exist in the ternary solid dispersion, and the diffraction peaks of 20(S)G-Rh2 and SDS are not found, indicating that both exist in amorphous form.

[0198] Effect Example 4 Fourier transform infrared spectroscopy scanning of the solid dispersion preparation of Example 7

[0199] Fourier transform infrared spectroscopy scanning was performed using Nicolet iS10 (Thermo Fisher Scientific). The samples included 20(S)G-Rh2, Gelucire 44 / 14, SDS, and their simple physical mixtures (the same as the raw materials for the preparation of Example 7, with the only difference being that the preparation method is to mix the raw materials), and the ternary solid dispersion (obtained in Example 7). An appropriate amount of the sample was added to KBr powder, pressed into tablets, and the resolution was set to 4 cm -1 -1, and the scanning wavelength was 4000 cm -1 -500 cm -1 -1. The samples were scanned separately, the number of scans was 4, and the average value was the final infrared scanning spectrum.

[0200] The results are as Figure 4As shown in A, 20(S)G-Rh2 has a broad absorption peak at 3600 - 3200 cm -1 There is a broad absorption peak, which is the intermolecular bonding absorption peak of alcohol hydroxyl groups. At 1649.4 cm -1 There is a stretching vibration absorption peak of C═C. At 1453.6 cm -1 There is a bending vibration of C-H. Figure 4 In B is the infrared absorption spectrum of Gelucire44 / 14, and its main component is PEG-32 laurate. Figure 4 In C is the unique absorption peak of the sulfate bond in sodium dodecyl sulfate (1082.4 cm- 1 , 994.2 cm -1 and 634.5 cm -1 ). In Figure 4 In D, a peak appears at 1107.4 cm-1. However, in Figure 4 In E, all the characteristic peaks of the sulfate bond disappear, indicating that the sulfate bond may form hydrogen bonds with other molecules.

[0201] Cell uptake experiment of the solid dispersion preparation of Example 5 and Example 7 of the effect

[0202] Caco-2 cells were purchased from Wuhan Punosai Life Science Co., Ltd. Caco-2 cells were seeded in 6-well plates at a density of 2×10 5 cells per well and cultured for 2 days under the culture conditions of 37 °C and 5% CO 2 . They were divided into the Rh2 group (Rh2) and the Rh2 preparation group (Rh2ZJ). Only 20(S)G-Rh2 was added to the Rh2 group, and the solid dispersion preparation obtained in Example 7 was added to the Rh2ZJ group.

[0203] When the cell density reached 80%, the cells were washed once with HBSS. Four kinds of HBSS containing 1% (m / v) of P-gp inhibitor were added to the dosing wells of the Rh2 group and the Rh2 preparation group respectively. The four P-gp inhibitors were D-α-tocopheryl polyethylene glycol succinate (TPGS), polyoxyethylene castor oil (Cr), polysorbate 80 (TW80), and poloxamer (Poloxamer407, P407). HBSS without 1% P-gp inhibitor was added to the blank wells of the Rh2 group and the Rh2 preparation group respectively, and they were incubated in an environment of 37 °C and 5% CO 2 for 30 minutes.

[0204] The cells were washed once with blank HBSS. HBSS containing 100 μM (20S)G-Rh2 solution was added to the Rh2 group, and HBSS containing the preparation solution equivalent to 100 μM (20S)G-Rh2 was added to the preparation group, and they were placed at 37 °C and 5% CO2 Incubate in the environment for 60 minutes.

[0205] Aspirate the HBSS of the Rh2 group and the Rh2 preparation group, and wash the cells three times with blank HBSS. Add 0.4 mL of deionized water to each well, freeze-thaw repeatedly 3 times at -80 °C, sonicate for 15 min, aspirate 0.2 mL of the cell suspension from each well, add 0.8 mL of methanol, place it in a 1.5 mL centrifuge tube, centrifuge at 15000 r / min at 4 °C for 10 min, take the supernatant and transfer it to a new 1.5 mL centrifuge tube, and dry it with nitrogen for testing.

[0206] Dissolve the dried cell suspension with 100 μl of the preparation solution. The preparation solution consists of methanol: 0.1% (V / V) formic acid water (formic acid: water = 3:7). Vortex and mix well, centrifuge at 15000 r / min at 4 °C for 10 min, transfer 90 μl of the supernatant to the liner, and detect the content of Rh2 by LC-MS. The detection conditions are as follows: Ascentis Express 90A C18 chromatographic column (50 mm × 3.0 mm, 2.7 μm); the mobile phase is 0.1% (V / V) formic acid water (B) - acetonitrile (C), dilute formic acid water with acetonitrile, linear gradient elution: 0 min - 10 min, 85% - 81% B; 10 min - 13 min, 81% - 75% B; 13 min - 18 min, 75% - 72% B; 18 min - 22 min, 72% - 70% B; 22 min - 25 min, 70% - 65% B; 25 min - 30 min, 65% - 60% B; 30 min - 38 min, 60% - 40% B, 38 min - 45 min, 40% - 20% B; 45 min - 53 min, 20% - 0% B; 53 min - 60 min, 0% - 85% B, flow rate 0.4 mL / min; column temperature 35 °C; injection volume 10 μL. ESI ion source; negative ion mode; spray voltage -6 kV; drying gas temperature 400 °C; sheath gas flow rate 40 L / min; auxiliary gas flow rate 10 L / min; scanning mode is Full MS; mass scanning range m / z 150 - 2000; mass resolution 70 000.

[0207] As Figure 5 、 Figure 6 shown, the presence of the four P-gp inhibitors all increased the accumulation of (20S)G-Rh2 and (20S)G-Rh2 solid dispersion preparations in Caco-2 cells to varying degrees. Among them, the effect of TPGS was the greatest, and the accumulation of (20S)G-Rh2 in the Rh2 group and the Rh2ZJ group in the cells reached 0.22 μg / mL and 0.33 μg / mL respectively, increasing by 100% and 150% respectively. And compared with Figure 5 、 Figure 6, it can be concluded that the ability of these four P-gp inhibitors to enhance the uptake of Rh2 by Caco-2 cells is in the order of TPGS > Cr > TW80 > P407. This indicates that P-gp inhibitors can indeed enhance the ability of Caco-2 cells to uptake Rh2. It can be considered that P-gp inhibitors have a certain promoting effect on the intestinal absorption of ginsenoside Rh2, can be used as a means to improve the bioavailability of Rh2, and the promoting effect on Rh2 preparations is better than that on pure Rh2.

[0208] Cell Penetration Experiment of the Solid Dispersion Preparation in Effect Example 6 and Example 7

[0209] Caco-2 cells were placed in an incubator with a culture condition of 37°C and 5% CO 2 and cultured. The culture medium was high-glucose DMEM + 10% FBS + 1% double antibiotics. Caco-2 cells were seeded in a 6-well transwell plate at a density of 2×10 5 cells per well. 1.5 mL of DMEM culture medium was added dropwise to the apical side, and 2.6 mL of DMEM culture medium was added to the basolateral side. The cells were cultured in an incubator at 37°C for 6 h. The apical medium was discarded and 1.5 mL of DMEM culture medium was replenished; then the bottom medium was discarded, and 2.6 mL of fresh culture medium was replenished to the basolateral side. In the first four days, the above medium replacement steps were repeated every two days. After that, the medium was changed daily, and the cells were continuously cultured for 21 days.

[0210] Caco-2 cells: The culture medium was changed 12 h before the experiment. The Rh2 group (Rh2) and the Rh2 preparation group (abbreviated as Rh2ZJ) were prepared separately, and the culture medium was preheated to 37°C. Before the experiment, the Caco-2 cell monolayer was rinsed and equilibrated with HBSS buffer for 30 minutes. The volumes of the apical cavity (Apical, AP) and the basolateral cavity (Basolateral, BL) were 1.5 mL and 2.6 mL, respectively. The transendothelial electrical resistance (TEER) value was measured at 37°C using an epithelial cell voltmeter.

[0211] The TEER value measured at 21 d was 623 Ω. Existing literature (Kan L, Capuano E, Fogliano V, et al. Inhibition of α-glucosidases by tea polyphenols in rat intestinal extract and Caco-2 cells grown on Transwell[J]. Food Chemistry, 2021, 361:130047.) has shown that when the TEER value is greater than 500 Ω, it is considered that the Caco-2 cell monolayer has formed and is dense enough to perform transport experiments.

[0212] (1) Detection from the apical side to the basolateral side (Apical-to-Basolateral, AP-BL)

[0213] Discard the top medium and the bottom medium. Add 1.5 mL of HBSS buffer containing 20 μM (20S)G-Rh2 or the solid dispersion preparation of Example 7 equivalent to 20 μM (20S)G-Rh2 to the AP side of the transwell plate, and add 2.6 mL of blank HBSS buffer to the BL side. Take 1 mL of samples from the BL side for detection at 15, 30, 60, 90, and 120 min. After each sampling, supplement with an equal volume of freshly preheated (37 °C) HBSS buffer.

[0214] (2) Detection from the basolateral side to the apical side (Basolateral-to-apical, BL-AP)

[0215] Discard the top medium and the bottom medium. Add 2.6 mL of HBSS buffer containing 20 μM (20S)G-Rh2 or the solid dispersion preparation of Example 7 equivalent to 20 μM (20S)G-Rh2 to the BL side of the transwell plate, and add 1.5 mL of blank HBSS buffer to the AP side. Take 1 mL of samples from the AP side for detection at 15, 30, 60, 90, and 120 minutes. After each sampling, supplement with an equal volume of freshly preheated (37 °C) HBSS buffer.

[0216] In the permeability experiment, the present invention utilizes the characteristics of Caco-2 cells, whose structure and biochemical functions are similar to those of human small intestinal epithelial cells and contain enzyme systems related to the small intestinal brush border epithelium, to construct a monolayer cell structure model similar to the small intestinal epithelium and conduct transport experiments on Rh2 from both sides of the membrane.

[0217] The results showed that the BL-AP of the Rh2ZJ group was lower than that of the Rh2 group at the same time, while the AP-BL of the Rh2 group was higher than that of the Rh2ZJ group at the same time. Combining Table 3, the ratio of the secretion permeability coefficient to the absorption permeability coefficient (EfR value) of Rh2ZJ at each time point was significantly lower than that of Rh2 at the same time point.

[0218] According to the literature (Wu Xiaofang, et al. Transport study of lipoamide and lipoic acid in Caco-2 cell monolayer model. Chinese Medical Journal. 2020.04.08): The apparent permeability coefficient (P app ) can represent the absorption ability of a substance. When the P app value < 1×10 -7 , it means that the substance is not easily absorbed; when 1×10 -7 < P app value < 1×10 -6 , it means that the absorption of the substance is average; when the P app value > 1×10 -6 , it means that the substance is relatively easily absorbed. It can be seen that the absorption effects of both drugs are average, but since the P app values of Rh2ZJ at each time point are all greater than the P app values of Rh2, Rh2ZJ is more conducive to absorption than Rh2.

[0219] According to the literature (Wang Sulian, et al. Absorption and transport study of crocetin in Caco-2 cell model. Chinese Journal of Clinical Pharmacology. 2018.08.17), when the EfR value of a substance is between 0.5 and 1.5, the transport mode of the substance is mainly passive transport; when the EfR value of the substance > 1.5, the transport mode of the substance is mainly active transport. Since the EfR values of both Rh2 and Rh2ZJ are greater than 1.5, it indicates that there may be bidirectional transport of Rh2 and Rh2ZJ in the small intestine, and it is speculated that there may be efflux. And the EfR values of Rh2 at each time point are all greater than those of Rh2ZJ, indicating that the efflux of Rh2 is more serious than that of Rh2ZJ, and the bioavailability of Rh2ZJ is higher than that of Rh2. This study is the first to compare the transport contents of Rh2ZJ and Rh2, which can effectively make up for the disadvantages of low absorption and low bioavailability of Rh2 in clinical practice. * in Table 3 indicates p < 0.05.

[0220] Table 3 Comparison of Papp and EfR values of Rh2 and Rh2ZJ across Caco-2 monolayer cell model

[0221]

[0222]

[0223] Pharmacokinetics Experiment of Effect Example 7

[0224] Six male SD rats were adaptively fed for 7 days and fasted overnight without water restriction on the day before drug administration. The rats were randomly divided into two groups: the Rh2 group and the Rh2 preparation group, and fasted overnight without water restriction 24 h before the experiment. The rats were perfused intragastrically at a dose of 30 mg / kg 20(S)G-Rh2 (Rh2 group) or the solid dispersion preparation of Example 7 equivalent to 30 mg / kg 20(S)G-Rh2 (Rh2 preparation group). Blood samples were collected from the abdominal aorta of the two groups of rats at 0.083 h, 0.17 h, 0.33 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, and 48 h. At each blood sampling time point, 3 rats were sampled in parallel, and 2 mL of blood was taken from each rat into a heparin tube. The collection tube was gently inverted and shaken to mix the blood. The blood sample was naturally cooled for 20 min, centrifuged at 3000 rpm for 10 min at 4°C, and the supernatant was plasma, which was stored at -80°C.

[0225] Sample treatment: Take 600 μL of plasma, add 30 μL of internal standard dilution solution (200 ng / mL astragaloside IV dissolved in methanol), vortex for 30 s, then add 60 μL of 0.1 mol / L NaOH solution and vortex to mix evenly. Add 1.5 mL of n-butanol to the above solution, shake and extract for 2 min, centrifuge at 2000 r / min for 10 min, transfer the upper organic solvent to a new EP tube, dry it under nitrogen, re-dissolve it with 150 μL of methanol, and filter through a membrane (PVDF, 0.22 μm) for determination.

[0226] Preparation of quality control samples: Prepare 1 mg / mL 20(S)G-Rh2 reference substance (stock solution) → Gradient dilute it with methanol to 40, 200, 1000, 4000, 20000, 50000, 100000 ng / mL (reference substance gradient dilution solution) → Dilute it with blank plasma to obtain Rh2 concentrations of 2, 10, 50, 200, 1000, 2500, 5000 ng / mL to get the standard working solution. Internal standard stock solution: 1 mg / mL astragaloside IV (dissolved in methanol) → 200 ng / mL internal standard dilution solution (diluted with methanol). Take 200 μL of the standard working solution, add 10 μL of the internal standard dilution solution, vortex for 30 s, then add 20 μL of 0.1 mol / L NaOH solution and vortex to mix evenly. Add 500 μL of n-butanol to the above solution, shake and extract for 2 min, centrifuge at 2000 r / min for 10 min at 4°C, transfer 500 μL of the upper organic solvent to a new EP tube, dry it at 45°C, re-dissolve it with 150 μL of methanol, and filter through a membrane (PVDF, 0.22 μm) to obtain quality control samples with different concentrations for standard curve detection.

[0227] Rh2 reference solution (containing internal standard): Take 100 μL of the 20(S)G-Rh2 reference stock solution and 10 μL of the internal standard stock solution, add 890 μL of methanol, mix well, filter through a membrane for determination (the concentration of 20(S)G-Rh2 in the reference is 0.1 mg / mL, and the internal standard is 0.01 mg / mL).

[0228] Detection conditions: Ascentis Express 90A C18 chromatographic column (50 mm × 3.0 mm, 2.7 μm); the mobile phase is 0.1% (V / V) formic acid water (B) - acetonitrile (C), dilute formic acid water with acetonitrile, linear gradient elution: 0 min - 10 min, 85% - 81% B; 10 min - 13 min, 81% - 75% B; 13 min - 18 min, 75% - 72% B; 18 min - 22 min, 72% - 70% B; 22 min - 25 min, 70% - 65% B; 25 min - 30 min, 65% - 60% B; 30 min - 38 min, 60% - 40% B, 38 min - 45 min, 40% - 20% B; 45 min - 53 min, 20% - 0% B; 53 min - 60 min, 0% - 85% B, flow rate 0.4 mL / min; column temperature 35 °C; injection volume 10 μL. ESI ion source; negative ion mode; spray voltage -6 kV; drying gas temperature 400 °C; sheath gas flow rate 40 L / min; auxiliary gas flow rate 10 L / min; scanning mode is Full MS; mass scanning range m / z 150 - 2000; mass resolution 70 000.

[0229] According to Table 4 and Figure 8 Show. In the first 4 h, the concentration of 20(S)G-Rh2 in the blood of male SD rats in the Rh2 preparation group was higher than that in the blood of mice in the Rh2 group; at 6 h - 48 h, the concentration curves of Rh2 in the blood of rats in the Rh2 preparation group and 20(S)G-Rh2 in the blood of rats in the Rh2 group were basically the same. Combining the above experimental results, it shows that the Rh2 preparation is more soluble in blood and more easily absorbed than Rh2. * in Table 4 indicates p < 0.05.

[0230] Table 4 Pharmacokinetic parameters of Rh2 and Rh2ZJ in SD rats

[0231]

[0232] Effect Example 8 Examples 3, 4, 5, 7 Molecular simulation

[0233] Molecular dynamics simulations were performed using GROMACS 2021.5 software, adopting the all-atom method, and the formation process included three steps. First, based on the experimental mass ratio, the crystal structures of the drug and polymer chains were randomly inserted into a vacuum box. Table 5 illustrates four different simulation systems. Next, energy minimization was performed on all initial systems using the steepest descent method, with the maximum force set to 100 kJ·mol-1nm-1. Finally, 20 annealing cycles were carried out between 300 and 343 K, and 2 ns isothermal isobaric ensemble (NVT) simulations were performed.

[0234] Table 5 Initial system combinations (number of molecules)

[0235]

[0236] Figure 9 The interaction energies of four solid dispersion systems are shown, and the structures with different colored borders represent the most stable conformations of each system. After undergoing the annealing process, the molecules tend to aggregate and form tight clusters. The energies of these systems increase in the order of Example 7 < Example 4 < Example 5 < Example 3. The interaction energy of the most stable conformation in the formulation of Example 7 is equal to -16060 kJ / mol, followed by Example 4 (-13683.9 KJ / mol), Example 5 (-10606.3 kJ / mol), and Example 3 (-6349.06 kJ / mol). These results indicate that the ability of the polymer excipient in the Example 7 system to disrupt the crystalline region of 20(S)-G-Rh2 is the strongest, which is consistent with the experimental results. The study adopted the geometric criteria for hydrogen bonds (H-bonds), i.e., RDonor-acceptor ≤ 0.35 nm and αH-donor-acceptor ≤ 30°. Figure 10 shows all possible hydrogen bonds between Rh2 and excipients in the ternary solid dispersion system, while Figure 11 、 Figure 12 and Figure 13The corresponding number of H-bonds and the average lifetime are shown. The H-bond analysis and lifetime calculation were based on the last 500 ps of the NVT simulation process. It was found that the number of H-bonds between 20(S)G-Rh2 and Gelucire44 / 14 decreased in the order of Example 3 (F1) > Example 5 (F3) > Example 7 (F5) > Example 4 (F2), while the number of H-bonds between 20(S)G-Rh2 and the third additive decreased in the order of Example 7 > Example 4 > Example 5. The addition of the third additive significantly led to the formation of H-bonds with 20(S)G-Rh2, thus reducing the number of H-bonds between 20(S)G-Rh2 and Gelucire44 / 14 and decreasing their interaction. In addition, the H-bond lifetime between SDS-Rh2 was the longest, followed by tween80-Rh2 and Gelucire44 / 14-Rh2, indicating that SDS could form the most stable H-bonds with 20(S)G-Rh2.

[0237] Based on these results, the simulation showed that the order of obtaining the amorphous TSD was Example 7 > Example 4 > Example 5 > Example 3, which was consistent with the results of the dissolution experiment. In addition, the H-bonds between 20(S)G-Rh2 excipient molecules stabilized the amorphous solid dispersion, which was consistent with the predicted results.

Claims

1. A ginsenoside Rh2 composition, the preparation raw materials of the composition comprising: ginsenoside Rh2 and a polymer; Preferably, the ginsenoside Rh2 includes at least one of 20(S)-ginsenoside Rh2 and 20(R)-ginsenoside Rh2; Preferably, the ginsenoside Rh2 is 20(S)-ginsenoside Rh2.

2. The composition according to claim 1, wherein: The polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; Preferably, the polymer includes Gelucire 44 / 14.

3. The composition according to claim 1, wherein: The mass ratio of the ginsenoside Rh2 to the polymer is 1:(1-10); Preferably, the mass ratio of the ginsenoside Rh2 to the polymer is 1:(3-9); Preferably, the mass ratio of the ginsenoside Rh2 to the polymer is 1:(5-9); Preferably, the mass ratio of the ginsenoside Rh2 to the polymer is 1:(4.5-5.5).

4. The composition according to claim 1, wherein: The preparation raw materials of the composition further include a surfactant; Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soybean phospholipid deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, polyethylene glycol ester; Preferably, the surfactant includes at least one of sodium dodecyl sulfate and polysorbate; Preferably, the mass ratio of the surfactant to the ginsenoside Rh2 is (1-3):6; Preferably, the mass ratio of the surfactant to the ginsenoside Rh2 is (2-2.8):6; Preferably, the mass ratio of the surfactant to the ginsenoside Rh2 is (2.2-2.6):

6.

5. The preparation method of the ginsenoside Rh2 composition according to any one of claims 1-4, including but not limited to any one of a1)-a5): a1) Mix the raw materials; a2) Melting method: Heat the raw materials to 60-80°C and obtain after mixing; a3) Solvent method: Dissolve the raw materials in a solvent, dry to remove the solvent, and obtain; a4) Solvent-melting method: Add the ginsenoside Rh2 to a solvent to obtain a mixed solution, add the solution to the melted polymer and / or surfactant, and obtain after mixing; a5) Grinding method: Grind the raw materials together and obtain; Preferably, the heating temperature is 65-75°C; Preferably, the mixing is uniform mixing; further it is stirring and mixing; Preferably, the solvent includes but is not limited to one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, and n-hexane; Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying.

6. A product, comprising a P-glycoprotein inhibitor and the composition according to any one of claims 1 to 4; The P-glycoprotein inhibitor includes but is not limited to amiodarone, clarithromycin, cyclosporine, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, ifenprodil, duloxetine, verapamil, cyclosporine A, tamoxifen, fostamatinib, biricodar, elacridar, glibenclamide, tariquidar, zosuquidar trihydrochloride, piperine, risperidone, polyphyllin VII, atazanavir sulfate, selamectin, solasonine, isoorientin, coniferyl ferulate, acronycine, catapol, rutaecarpin, MC70, YS-370, PGP-4008, OY-101, RMS3, RMS5, FM04, P-gp inhibitor 1, P-gp inhibitor2, P-gp inhibitor 3, P-gp inhibitor 5, P-gp inhibitor 13, P-gp inhibitor 14, D-α-tocopheryl polyethylene glycol succinate, polyoxyl castor oil, TW80, poloxamer 407; Preferably, the P-glycoprotein inhibitor includes at least one of D-α-tocopheryl polyethylene glycol succinate, polyoxyl castor oil, TW80, and poloxamer 407.

7. The product according to claim 6, characterized in that: The mass ratio of the P-glycoprotein inhibitor to the ginsenoside Rh2 in the composition in the P-glycoprotein inhibitor and the composition is 1:(2-5); further 1:(2.5-3.5); Preferably, the P-glycoprotein inhibitor and the composition exist independently or in admixture.

8. A pharmaceutical composition, comprising the composition according to any one of claims 1 to 4 and / or the product according to any one of claims 6 to 7; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier includes at least one of a diluent, an adjuvant, an excipient, a preservative, a filler, a binder, a disintegrant, a wetting agent, an emulsifier, a suspending agent, a sweetening agent, a flavoring agent, a fragrance, an antibacterial agent, an antifungal agent, a lubricant, a dispersant, a temperature-sensitive material, a temperature regulator, a pH regulator, an adhesive, a stabilizer, and a suspending aid.

9. Use of the composition according to any one of claims 1 to 4 and / or the product according to claims 6 to 7 and / or the pharmaceutical composition according to claim 8 in any one of b1)-b7) including but not limited to: b1) Application in the preparation of anti-aging products; b2) Use in the preparation of antioxidant products; b3) Use in the preparation of anti-tumor products; b4) Use in the preparation of products for inducing apoptosis; b5) Use in the preparation of products for protecting the heart; b6) Use in the preparation of products for protecting bones; b7) Use in the preparation of products for protecting the liver; Preferably, the products include but are not limited to skin care products and health care products; Preferably, the tumors include at least one of breast cancer, non-small cell lung cancer, colon cancer, esophageal cancer, cervical cancer, and thyroid cancer.

10. The use according to any one of (1) to (3): (1) The use of Gelucire 44 / 14 in solubilizing ginsenoside Rh2; (2) The use of Gelucire 44 / 14 and a surfactant in solubilizing ginsenoside Rh2; (3) The use of Gelucire 44 / 14 in the preparation of a solid dispersion of ginsenoside Rh2; Preferably, the ginsenoside Rh2 includes at least one of 20(S)-ginsenoside Rh2 and 20(R)-ginsenoside Rh2; Preferably, the ginsenoside Rh2 is 20(S)-ginsenoside Rh2; Preferably, the use described in (1) includes but is not limited to any one of a1)-a5): a1) Mix the raw materials; a2) Melting method: Heat the raw materials to 60-80°C and obtain after mixing; a3) Solvent method: Dissolve the raw materials in a solvent, dry to remove the solvent, and obtain; a4) Solvent-melting method: Add the ginsenoside Rh2 to a solvent to obtain a mixed solution, add the solution to the polymer and / or surfactant that has been melted, and obtain after mixing; a5) Grinding method: Grind the raw materials together and obtain; Preferably, the heating temperature is 65-75°C; Preferably, the mixing is uniform mixing; further, it is stirring and mixing; Preferably, the solvent includes but is not limited to one or several of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, and n-hexane; Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying; Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and polyethylene glycol ester; Preferably, the use described in (1) includes a1) Mix the raw materials; Preferably, the application in (1) includes mixing the raw materials with water; Preferably, the mixing in (1) is uniform mixing; further, Rh2 is placed in an aqueous solution of Gelucire 44 / 14 and oscillated at 35 - 40 °C for 48 - 96 h; Preferably, the mass ratio of the total mass of ginsenoside Rh2 and Gelucire 44 / 14 to the mass of the water in (1) is 1:(20 - 100); further, it is 1:(50 - 100); Preferably, the mass ratio of ginsenoside Rh2 to Gelucire 44 / 14 in (2) is 1:(0.5 - 4); further, it is 1:(1 - 3); Preferably, the surfactant in (2) includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soybean phospholipid deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, polyethylene glycol ester; Preferably, the surfactant in (2) includes at least one of sodium dodecyl sulfate and polysorbate; Preferably, the mass ratio of the surfactant to ginsenoside Rh2 in (2) is (1 - 3):6; Preferably, the mass ratio of the surfactant to ginsenoside Rh2 in (2) is (2 - 2.8):6; Preferably, the mass ratio of the surfactant to ginsenoside Rh2 in (2) is (2.2 - 2.6):6; Preferably, the application in (2) includes but is not limited to any one of a1) - a5): a1) Mix the raw materials; a2) Melting method: Heat the raw materials to 60 - 80 °C and obtain after mixing; a3) Solvent method: Dissolve the raw materials in a solvent, dry to remove the solvent, and obtain; a4) Solvent - melting method: Add ginsenoside Rh2 to a solvent to obtain a mixed solution, add the solution to the polymer and / or surfactant that has been melted, and obtain after mixing; a5) Grinding method: Grind the raw materials together and obtain; Preferably, the heating temperature is 65 - 75 °C; Preferably, the mixing is uniform mixing; further, it is stirring and mixing evenly; Preferably, the solvent includes but is not limited to one or several of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N - methylpyrrolidone, N,N - dimethylformamide, dimethyl sulfoxide, isopropanol, n - hexane; Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying; Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, polyethylene glycol ester; Preferably, the application in (2) includes a1) mixing the raw materials; Preferably, the application in (2) includes mixing the raw materials with water; Preferably, the mixing in (2) is uniform mixing; further, Rh2, Gelucire 44 / 14 and the surfactant are placed in water and shaken at 35 - 40 °C for 48 - 96 h; Preferably, the mass ratio of the total mass of ginsenoside Rh2 and Gelucire 44 / 14 to the mass of the water in (2) is 1:(20 - 100); further, it is 1:(50 - 100); Preferably, the solid dispersion of ginsenoside Rh2 in (3) further contains a surfactant; Preferably, the surfactant in (3) includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, polyethylene glycol ester; Preferably, the surfactant in (3) includes at least one of sodium dodecyl sulfate and polysorbate; Preferably, the mass ratio of ginsenoside Rh2 and Gelucire 44 / 14 in (3) is 1:(1 - 10); Preferably, the mass ratio of ginsenoside Rh2 and Gelucire 44 / 14 in (3) is 1:(3 - 9); Preferably, the mass ratio of ginsenoside Rh2 and Gelucire 44 / 14 in (3) is 1:(5 - 9); Preferably, the mass ratio of ginsenoside Rh2 and Gelucire 44 / 14 in (3) is 1:(4.5 - 5.5); Preferably, the mass ratio of Gelucire 44 / 14 to the surfactant in the solid dispersion of ginsenoside Rh2 in (3) is (5 - 25):1; further, it is (10 - 15):1; Preferably, the application in (3) includes but is not limited to any one of a2) - a5): a2) Melt method: heating the raw materials to 60 - 80 °C and obtaining the product after mixing; a3) Solvent method: dissolving the raw materials in a solvent, drying to remove the solvent, and obtaining the product; a4) Solvent - melt method: adding ginsenoside Rh2 to a solvent to obtain a mixed solution, adding the solution to the polymer and / or surfactant that has been melted, and obtaining the product after mixing; a5) Grinding method: co - grinding the raw materials and obtaining the product; Preferably, the heating temperature is 65 - 75 °C; Preferably, the mixing is uniform mixing; further, it is stirring and mixing evenly; Preferably, the solvent includes but is not limited to one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, ether, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, and n-hexane; Preferably, the drying includes at least one of evaporation drying, spray drying, and freeze drying; Preferably, the polymer includes but is not limited to polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, Gelucire 44 / 14, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose; Preferably, the surfactant includes but is not limited to sodium dodecyl sulfate, calcium stearate, triethanolamine stearate, magnesium lauryl sulfate, sodium octadecyl fumarate, sodium taurocholate, sodium ursodeoxycholate, lecithin, soy lecithin deoxycholate, alkylbenzene sulfonate, benzalkonium chloride, benzalkonium bromide, poloxamer, polysorbate, span, benzethonium, myrj, polyoxyethylene castor oil, and polyethylene glycol ester.

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