CN106074588A - The combination of Rhizoma Paridis forrestii monomer saponin and pharmaceutical composition and its application in pharmacy - Google Patents

Abstract

Provides [Paris forrestii (Takht.) H.Li] total saponin PFE‑PT3 and monomeric saponin combination PFE‑PT65, which are pharmaceutical compositions of active ingredients, and are used in the preparation of prevention or treatment of drug-resistant breast cancer and application of drugs in drug-resistant nasopharyngeal carcinoma. Paclitaxel total saponins PFE‑PT3 and monomer saponin combination PFE‑PT65 have significant inhibitory effect on doxorubicin-resistant human breast cancer MCF‑7/ADM cells, and the drug resistance index is less than 2; Pharyngeal cancer KBvin cell growth has a significant inhibitory effect, the drug resistance index is less than 2.

Description

Polyphylla polyphylla monomer saponin combination and its pharmaceutical composition and its application in pharmacy

Technical field:

The invention belongs to the technical field of medicine, and in particular relates to the total saponin PFE-PT3 of Pachyphylla saponins and its monomer saponin combination PFE-PT65, its preparation method and its application in the preparation of drugs for preventing or treating drug-resistant tumors.

Background technique:

Paris forrestii (Takht.) H.Li] is a plant of the genus Pachyphylla in the family Trilliumaceae. Its rhizome is used as medicine. It has the effects of clearing away heat and detoxification, reducing swelling and pain, cooling the liver and calming convulsions. It is used to treat carbuncle sores , unknown swollen poison, poisonous snake bite, sore throat, mumps, tonsillitis and big head plague (Zhu Zhaoyun. Yunnan Natural Medicine Illustrated Book. Volume 6. Kunming: Yunnan Science and Technology Press, 2010:127). The patent application "A plant drug for treating cancer and its preparation method and application" (publication number: CN104706896A) discloses that the PFE-PT3 part of Parisia polyphylla has significant anticancer activity; Chemical composition separation and identification method of PFE-PT3" (publication number: CN105106556A) discloses the main chemical composition of PFE-PT3; ) discloses the anti-cancer activity of the fractions of Barley. At present, there is no report on the prevention and treatment of drug-resistant tumors by the combination of total saponins and monomeric saponins of S. longiflora.

Invention content:

The present invention provides the total saponins PFE-PT3 of Pachyphyllum parenchyma and the combination of monomeric saponins PFE-PT65, as well as the pharmaceutical composition in which the above-mentioned combination is an active ingredient, and provides them in the preparation of prevention or treatment of drug-resistant breast cancer and drug-resistant nasopharynx Application in cancer medicine. The total saponins PFE-PT3 and the combination of monomeric saponins PFE-PT65 of Paris polyphylla of the present invention have significant inhibitory effects on the growth of drug-resistant breast cancer cells and drug-resistant nasopharyngeal carcinoma cells.

In order to realize the above-mentioned purpose of the present invention, the present invention provides following technical scheme:

The monomer saponin combination PFE‐PT65 of Parisia lanceolata is obtained from the combination of the chemical components papaya saponin I and saponin III contained in the total saponins of Parisia lanceolata PFE‐PT3 at a molar mass ratio of 1:1.

A pharmaceutical composition, which contains a therapeutically effective amount of papaya monomer saponin combination PFE‐PT65 and a pharmaceutically acceptable carrier.

The preparation method of PFE‐PT65, a monomeric saponin combination of Polygonum polyphyllum, is to grind the dried rhizome of Polyphylla polyphylla, soak it in 95% ethanol for 7 days, filter, and continue to extract the filter residue for a total of 4 extractions, combine the filtrates, and recover the solvent to obtain Extract PFE-PT1, make PFE-PT1 into a suspension with water, extract with ethyl acetate, recover ethyl acetate, get ethyl acetate extraction part PFE-PT2, continue to use n-butanol for the mother liquor after ethyl acetate extraction Extract and recover n-butanol to obtain the PFE-PT3 of the n-butanol extraction part; take PFE-PT3 and wash it with a gradient of 10:1, 5:1, 3:1, 1:1 chloroform-methanol mixed solvent through silica gel column chromatography Detach and divide into sections to obtain 4 parts Fr.A, Fr.B, Fr.C and Fr.D, take part Fr.B and go through C ₁₈ reverse phase silica gel column chromatography, methanol-water, 10:90→100:0 , get Fr.B ₁ , Fr.B ₂ , Fr.B ₃ , Fr.B ₄ , Fr.B ₅ and Fr.B ₆ 6 fractions; take Fr.B ₃ fraction and pass through LH‐20 gel column layer Analysis, methanol elution, and then silica gel column chromatography 5:1 chloroform-methanol elution to obtain β-ecdysone, take Fr.B ₄ part, use semi-preparative high-performance liquid chromatography to obtain methyl protoflour saponin I and methyl protoflour saponin V, take Fr.B ₅ part, and use semi-preparative high performance liquid chromatography to obtain Pariposide A, paprika saponin II, paprika saponin III, paprika saponin I and paprika saponin V; take Fr .B ₆ part, semi-preparative high performance liquid chromatography purification to obtain the compound PGRR and saponin H, and the above saponin I and saponin III were combined in a molar mass ratio of 1:1 to obtain PFE‐PT65.

The application of the polyphylla monomer saponin combination PFE-PT65 in the preparation of drugs for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma.

Application of the polyphylla monomer saponin combination PFE-PT65 as described in the preparation of drugs for the prevention or treatment of drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, wherein the daily dose of PFE-PT65 is 1-100 mg/kg weight.

The application of PFE-PT65 in the combination of pachyphyllum monomeric saponins as described in the preparation of drugs for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, wherein the daily dosage of PFE-PT65 is 60 mg/kg body weight , prepared as a 20mg ordinary tablet 3 times a day/each time, a 30mg ordinary tablet 2 times a day/each time or a 60mg tablet once a day/each time.

The application of PFE-PT65 in the combination of pachyphyllum monomeric saponins as described in the preparation of drugs for the prevention or treatment of drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, wherein the daily dosage of PFE-PT65 is 90 mg/kg body weight , prepared as a 30mg ordinary tablet 3 times a day/each time, a 45mg ordinary tablet 2 times a day/each time or a 90mg slow-control tablet once a day/each time.

The application of PFE‐PT3, the anticancer active part of Pachyphylla longifolia, in the preparation of drugs for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma.

As described in the application of PFE-PT3 in the preparation of drugs for the prevention or treatment of drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, wherein the daily dosage of PFE-PT3 is 60 mg/kg body weight, prepared as 3 times a day / One 20mg ordinary tablet each time, one 30mg ordinary tablet twice a day/each time or one 60mg tablet once a day/each time.

The application of PFE-PT3 in the preparation of drugs for the prevention or treatment of drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma as described, wherein the daily dosage of PFE-PT3 is 90 mg/kg body weight, prepared as 3 times a day / One 30mg ordinary tablet each time, one 45mg ordinary tablet twice a day/each time, or one 90mg slow-control tablet once a day/each time.

The preparation of PFE-PT3 of the present invention more specifically adopts: long column Paris forrestii (Takht.) H.Li] dry rhizome (4.4kg), soak 7 days with 95% ethanol (13L) after pulverizing, filter, Filter residue continues to extract. A total of 4 extractions were performed, the filtrates were combined, and the solvent was recovered to obtain 550 g of extract (code PFE‐PT1). Make a suspension of PFE‐PT1 with water (2L), extract it with ethyl acetate (2L×3), recover ethyl acetate, and obtain 19g of ethyl acetate extraction fraction (code PFE‐PT2). The mother liquor after ethyl acetate extraction was continued to be extracted with n-butanol (2L×3), and n-butanol was recovered to obtain 290g of n-butanol extraction fraction (code PFE-PT3).

Separation of chemical components contained in PFE-PT3:

Take 180g of PFE-PT3 by silica gel column chromatography and use chloroform-methanol mixed solvent gradient (10:1, 5:1, 3:1, 1:1) to elute and segment to obtain Fr.A (14g), Four parts of Fr.B (101g), Fr.C (45g) and Fr.D (12g). Take 30g of Fr.B part and pass through C ₁₈ reverse phase silica gel column chromatography (methanol-water, 10:90→100:0), to obtain Fr.B ₁ (1.0g), Fr.B ₂ (0.5g), Fr. 6 fractions of B ₃ (0.8g), Fr.B ₄ (4.6g), Fr.B ₅ (16.1g) and Fr.B ₆ (1.0g).

Take 150 mg of Fr.B ₃ part, pass through LH-20 gel column chromatography (methanol elution), and then use silica gel column chromatography to elute with chloroform-methanol (5:1) to obtain β-ecdysone (39.0 mg). Take part 130mg of Fr.B ₄ , and use semi-preparative HPLC (Agilent 1200, Zorbax SB‐C ₁₈ column, 9.4×250mm; methanol‐water, 72:28, flow rate 2mL/min) to obtain the original weight of methyl House saponin I (30.0mg, retention time 25.313min) and methyl protoflour saponin V (14.0mg, retention time 27.236min). Take part 120mg of Fr.B ₅ , and use semi-preparative HPLC (Agilent 1200, Zorbax SB-C ₁₈ chromatographic column, 9.4 × 250mm; Acetonitrile-water, 50:50, flow rate 2mL/min) to obtain Pariposide A (4.5 mg, retention time 12.788min), saponin II (1.4mg, retention time 14.634min), saponin III (14.4mg, retention time 18.070min), saponin I (12.7mg, retention time 21.019min) and Paprika saponin V (4.4mg, retention time 26.029min). Take Fr.B ₆ part 132mg, semi-preparative HPLC (Agilent 1200, Zorbax SB-C ₁₈ chromatographic column, 9.4 × 250mm; Acetonitrile-water, 40:60, flow rate 2mL/min) purification to obtain compound PGRR (4.1mg , retention time 18.421min) and saponin H (9.0mg, retention time 23.587min).

PFE-PT65 was obtained by combining the main components of papaya saponin I and papaya saponin III in PFE‐PT3 in a molar mass ratio of 1:1.

The above-mentioned anticancer active components of the present invention or their pharmaceutically acceptable salts can be administered orally or not, and the dosage varies with different drugs. For the pharmaceutical composition, 1-200 mg per day is more appropriate. It is preferably in the range of 5 to 200 mg.

When administered orally, the active ingredient is first mixed with conventional pharmaceutical adjuvants such as excipients, disintegrants, binders, lubricants, antioxidants, coating agents, colorants, fragrances, surfactants, etc. Mix it and make it into granules, capsules, tablets and other forms for administration; for parenteral administration, it can be administered in the form of injection, infusion or suppository. In preparing the above formulations, conventional formulation techniques can be used.

The dosage of the total saponins or monomeric saponins of S. polyphyllum saponins can be selected 1: the pharmaceutical composition prepared and developed by using the total saponins of S. polyphylla or the combination of monomeric saponins as the active ingredient of the drug, and the daily dosage is 60mg, which can be prepared into 3 times a day/each time a 20mg ordinary tablet, 2 times a day/each time a 30mg ordinary tablet or 1 time a day/each time a 60mg tablet type.

The dosage of the total saponins or monomeric saponins of S. polyphylla can also be selected. 2: Use the total saponins of S. polyphylla or the combination of monomeric saponins as the active ingredient to prepare the developed pharmaceutical composition. The active ingredient sample is used as the active ingredient of the drug, and the daily dosage is 90 mg, which can be prepared as 3 times a day/each time as 1 piece of 30 mg ordinary tablet, 2 times a day/each time as 1 piece of 45 mg ordinary tablet or One 90mg slow-control tablet type once a day/each time.

Problems that need to be explained: the pharmaceutical composition involved in the present invention has the influence of many factors on the dosage of active ingredients, for example: the different purposes for prevention and treatment cause the difference of daily dosage; Differences in the severity of the disease lead to differences in daily dosage; differences in gender, age, body surface area, route of administration, frequency of administration, and purpose of treatment result in differences in daily dosage; in addition, the absorption between dosage forms Different from the blood drug concentration, the suitable daily dosage range of the active ingredient used in the present invention is 0.01-150 mg/kg body weight, preferably 1-100 mg/kg body weight. During use, different total dosage regimens of the active ingredients of Polygonum chinensis should be formulated according to the actual needs of different situations of prevention and treatment, and can be divided into multiple or one-time administration methods to complete.

Compared with prior art, the present invention has following excellent effect:

The total saponins PFE‐PT3 of Polyphylla polyphylla and the combination of monomeric saponins PFE‐PT65 have significant inhibitory effects on human breast cancer MCF‐7/ADM cells resistant to doxorubicin, and the drug resistance index is less than 2, which is much lower than that of doxorubicin The drug resistance index of the latter was 50794; the total saponins PFE‐PT3 of Paclitaxel and the combination of monomeric saponins PFE‐PT65 had a significant inhibitory effect on the growth of paclitaxel-resistant human nasopharyngeal carcinoma KBvin cells. The index is less than 2, which is much lower than the paclitaxel resistance index, which is 1799.

detailed description:

The following examples of the present invention are used to further illustrate the substantive content of the present invention, but the present invention is not limited thereto.

Example 1:

1. The preparation of the active site PFE-PT3 of the present invention and the separation of its chemical components:

Preparation of PFE‐PT3: dry rhizomes (4.4kg) of Paris forrestii (Takht.) H.Li, crushed, soaked in 95% ethanol (13L) for 7 days, filtered, and the filter residue was further extracted. A total of 4 extractions were performed, the filtrates were combined, and the solvent was recovered to obtain 550 g of extract (code PFE‐PT1). Make a suspension of PFE‐PT1 with water (2L), extract it with ethyl acetate (2L×3), recover ethyl acetate, and obtain 19g of ethyl acetate extraction fraction (code PFE‐PT2). The mother liquor after ethyl acetate extraction was continued to be extracted with n-butanol (2L×3), and n-butanol was recovered to obtain 290g of n-butanol extraction fraction (code PFE-PT3).

Separation of chemical components contained in PFE-PT3:

Take 180g of PFE-PT3 by silica gel column chromatography and use chloroform-methanol mixed solvent gradient (10:1, 5:1, 3:1, 1:1) to elute and segment to obtain Fr.A (14g), Four parts of Fr.B (101g), Fr.C (45g) and Fr.D (12g). Take 30g of Fr.B part and pass through C ₁₈ reverse phase silica gel column chromatography (methanol-water, 10:90→100:0), to obtain Fr.B ₁ (1.0g), Fr.B ₂ (0.5g), Fr. 6 fractions of B ₃ (0.8g), Fr.B ₄ (4.6g), Fr.B ₅ (16.1g) and Fr.B ₆ (1.0g).

Take 150 mg of Fr.B ₃ part, pass through LH-20 gel column chromatography (methanol elution), and then use silica gel column chromatography to elute with chloroform-methanol (5:1) to obtain β-ecdysone (39.0 mg). Take part 130mg of Fr.B ₄ , and use semi-preparative HPLC (Agilent 1200, Zorbax SB‐C ₁₈ column, 9.4×250mm; methanol‐water, 72:28, flow rate 2mL/min) to obtain the original weight of methyl House saponin I (30.0mg, retention time 25.313min) and methyl protoflour saponin V (14.0mg, retention time 27.236min). Take part 120mg of Fr.B ₅ , and use semi-preparative HPLC (Agilent 1200, Zorbax SB-C ₁₈ chromatographic column, 9.4 × 250mm; Acetonitrile-water, 50:50, flow rate 2mL/min) to obtain Pariposide A (4.5 mg, retention time 12.788min), saponin II (1.4mg, retention time 14.634min), saponin III (14.4mg, retention time 18.070min), saponin I (12.7mg, retention time 21.019min) and Paprika saponin V (4.4mg, retention time 26.029min). Take Fr.B ₆ part 132mg, semi-preparative HPLC (Agilent 1200, Zorbax SB-C ₁₈ chromatographic column, 9.4 × 250mm; Acetonitrile-water, 40:60, flow rate 2mL/min) purification to obtain compound PGRR (4.1mg , retention time 18.421min) and saponin H (9.0mg, retention time 23.587min).

2. Utilize high-performance liquid chromatography (HPLC) technology to measure the main chemical composition content of PFE-PT3, the model of high-performance liquid chromatography is Agilent 1200, is equipped with diode array (DAD) detector, and chromatographic column selects Agilent C ₁₈ column ( 4.6mm×150mm, 5μm), the detection method refers to the method of the 2015 edition of "The Pharmacopoeia of the People's Republic of China" (Part 1). The test results are shown in Table 1.

Table 1. Contents of main chemical components of PFE‐PT3

2. The preparation of PFE‐PT65, a monomeric saponin combination of Paris polyphylla of the present invention:

PFE-PT65 was obtained by combining the main components of papaya saponin I and papaya saponin III in PFE‐PT3 in a molar mass ratio of 1:1.

Example 2:

The cytotoxic activity was determined by the modified MTT method. Cells in the logarithmic growth phase were seeded in 96-well culture plates. After culturing for 24 h in a 5% CO ₂ incubator, add the test sample. An equal volume of normal saline was added to the negative control group, and doxorubicin or paclitaxel was added to the positive control group. After culturing for 48 hours, MTT was added at 10 μL/well. After continuing to cultivate for 4 hours, add the triple solution [10% SDS-5% isobutanol-0.012mol/l HCL (W/V/W)], 100 μL/well, let it stand overnight, use a microplate reader at 570nm, 630nm double The OD value of each well was measured at the wavelength. Actual OD value=experimental well OD value-blank control well OD average value; cell proliferation inhibition rate (%)=100%-(actual OD value of sample well/actual OD value of negative control well)×100%; use GWBASIC software Calculate the _IC50 value of the sample. Drug resistance index (Resistance Index, RI) = IC ₅₀ of the drug-resistant cell line/IC ₅₀ of the sensitive cell line.

The experimental results are shown in Table 2 and Table 3. Paprika saponin I, papaya saponin Ⅲ, PFE‐PT3 and PFE‐PT65 all had a good inhibitory effect on doxorubicin-resistant breast cancer MCF‐7/ADM cells, and the drug resistance index was less than 2. In contrast, The doxorubicin resistance index was 50794. PFE‐PT3 and PFE‐PT65 also had a good inhibitory effect on the growth of paclitaxel-resistant nasopharyngeal carcinoma KBvin cells, and the drug resistance index was less than 2, while the paclitaxel resistance index was 1799.

Table 2. Inhibitory effects of total saponins, monomeric saponins and their combinations on the growth of doxorubicin-resistant breast cancer MCF‐7/ADM cells

Table 3. Inhibitory effect of total saponins of Paclitaxel on the growth of paclitaxel-resistant nasopharyngeal carcinoma KBvin cells

Example 3:

Prepare the medicine for the treatment of cancer: total saponins PFE‐PT3 of Pachyphyllum lanceolata, add sodium carboxymethyl starch, appropriate amount of starch, granulate the starch paste, dry, granulate, add appropriate amount of talcum powder, mix evenly, compress into tablets (each 0.5 g, which is equivalent to 3g of the rhizome of Polyphylla longifolia), 2 tablets each time, 3 times a day.

Example 4:

Prepare the medicine for treating cancer, and mix according to the following weight percentages: total saponins PFE‐PT3 of Pachyphyllum polyphylla account for 20‐80%, dispersant 2‐20%, disintegrant 3‐5%, emulsifier 3‐8% , 0.2-2% binder, 0.5-10% wetting agent, and the rest are fillers. Then, an anticancer drug whose active ingredient is PFE-PT3 is prepared according to a conventional drug preparation method.

Example 5:

Prepare the medicine for treating cancer: Polyphylla polyphylla monomer saponin combination PFE‐PT65, add sodium carboxymethyl starch, appropriate amount of starch, granulate the starch paste, dry, granulate, add appropriate amount of talcum powder, mix well, and compress into tablets (each Tablet 0.5g, equivalent to 3g of Rhizome of Polyphyllum longifolia), 2 tablets each time, 3 times a day.

Embodiment 6:

Combination pharmaceutical dosage forms of Papilionaceae saponins‐tablets:

The preparation of the drug combination tablet of the total saponins PFE‐PT3 of Polyphylla polyphylla or/and the combination of monomeric saponins PFE‐PT65: use the above composition as the active ingredient of the drug, and use the excipients described in Table 3 as the preparation of the combination drug tablet According to the ratio of the excipient ingredients, each tablet sample containing 5-60 mg of the above-mentioned active combined drug ingredients is made. Table 4 shows the formula ratio of ordinary tablets:

Table 4 Raw material and excipient formulations of the total saponins and monomeric saponins of Paris polyphylla combined drug tablet

The method for preparing the active ingredients and excipients and auxiliary materials in the table into tablet preparations of different doses is to uniformly mix several excipients and auxiliary materials with the raw material drug, and add an appropriate amount of 1% sodium hydroxymethylcellulose solution to make a soft material. Sieve and granulate, dry the wet granules and sieve for granulation, add magnesium stearate and talcum powder, mix evenly, and press into tablets to obtain.

Embodiment 7:

Combination of Active Components of Papilionaceae-Capsules:

Preparation of pharmaceutical combination capsule preparations containing total saponins PFE‐PT33 and/or monomeric saponin combination PFE‐PT65 of Polyphylla lanceolata as active ingredients: using PFE‐PT33 or/and PFE‐PT65 as active ingredients of the drug, using Table 5 Several excipients are used as adjuvant components for preparing combination drug tablets, and the capsule preparations containing 5-50 mg of active pharmaceutical ingredients are made in each capsule according to the proportioning ratio. Table 5 provides the formula ratio of common capsule preparations:

Table 5 Raw material and excipient formulations of total saponins and monomeric saponins of Paris polyphylla combined drug capsule preparation

The method of preparing a certain number of active ingredient samples in the table and excipients and auxiliary materials into capsule preparations is: mix several excipients and auxiliary materials with the active combination of S. chrysogenum, and add an appropriate amount of 1% sodium hydroxymethyl cellulose solution , made into wet granules, dried, sieved and granulated, added with magnesium stearate, mixed evenly, and packed into capsules; or directly combined with total saponins PFE‐PT33 or monomeric saponins without using granulation steps PFE-PT65 is mixed evenly with several excipients, sieved, and directly packed into capsules.

Claims (10)

1. The monomer saponin combination PFE‐PT65 of Paris polyphylla is obtained from the combination of the chemical components papaya saponin I and papaya saponin III contained in the total saponins of Paris polyphylla in PFE‐PT3 at a molar mass ratio of 1:1. 2. The pharmaceutical composition, which contains the polyphylla polyphylla monomer saponin combination PFE-PT65 described in claim 1 and a pharmaceutically acceptable carrier in a therapeutically effective amount. 3. The preparation method of PFE‐PT65, a combination of monomeric saponins of Polyphylla lanceolata, crushed dried rhizomes of Paris polyphylla, soaked them in 95% ethanol for 7 days, filtered, and continued to extract the filter residue for a total of 4 extractions, combined the filtrates, and recovered the solvent , to obtain the extract PFE-PT1, PFE-PT1 is made into a suspension with water, extracted with ethyl acetate, and the ethyl acetate is recovered to obtain the ethyl acetate extraction part PFE-PT2, and the mother liquor after the ethyl acetate extraction is continued to use normal Butanol extraction, recover n-butanol, get n-butanol extraction part PFE-PT3; take PFE-PT3 and use 10:1, 5:1, 3:1, 1:1 chloroform-methanol mixed solvent for silica gel column chromatography Gradient elution, sectioning, to get Fr.A, Fr.B, Fr.C and Fr.D4 parts, take the part of Fr.B through C ₁₈ reverse phase silica gel column chromatography, methanol-water, 10:90→100 :0, get Fr.B ₁ , Fr.B ₂ , Fr.B ₃ , Fr.B ₄ , Fr.B ₅ and Fr.B ₆ 6 fractions; take Fr.B ₃ fraction and pass through LH‐20 gel Column chromatography, methanol elution, and then silica gel column chromatography 5:1 chloroform-methanol elution to obtain β-ecdysone, take Fr.B ₄ part, use semi-preparative high-performance liquid chromatography to obtain the original methyl heavy building Saponin I and methyl protoflour saponin V, take Fr.B ₅ part, and use semi-preparative high-performance liquid chromatography to obtain Pariposide A, patriotic saponin II, patriotic saponin III, paprika saponin I and paprika saponin V; Part Fr.B ₆ was taken and purified by semi-preparative high performance liquid chromatography to obtain compound PGRR and saponin H, and the above saponin I and saponin III were combined at a molar mass ratio of 1:1 to obtain PFE‐PT65. 4. The application of the saponin combination PFE-PT65 described in claim 1 in the preparation of drugs for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma. 5. the application of the saponin combination PFE-PT65 of Paris polyphylla monomer as claimed in claim 4 in the preparation of the medicine for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, it is characterized in that the daily dose of PFE-PT65 The dose is 1-100mg/kg body weight. 6. The application of the saponin combination PFE-PT65 of Paris polyphylla monomer as claimed in claim 4 in the preparation of the medicine for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, characterized in that PFE-PT65 is given daily The dose is 60mg/kg body weight, prepared as 3 times a day/each time a 20mg ordinary tablet, 2 times a day/each time a 30mg ordinary tablet or once a day/each time a 60mg tablet agent. 7. The application of the saponin combination PFE-PT65 as claimed in claim 4 in the preparation of drugs for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, characterized in that PFE-PT65 is given daily The dose is 90mg/kg body weight, prepared into 3 times a day/each time a 30mg ordinary tablet, 2 times a day/each time a 45mg ordinary tablet or 1 time a day/each time a 90mg slow control tablet. 8. The application of PFE-PT3, the anti-cancer active part of Pachyphylla spp., in the preparation of drugs for the prevention or treatment of drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma. 9. The application of PFE-PT3 as claimed in claim 8 in the preparation of drugs for preventing or treating drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, characterized in that the daily dosage of PFE-PT3 is 60 mg/kg body weight, Prepared into 3 times a day/each time a 20mg ordinary tablet, 2 times a day/each time a 30mg ordinary tablet or once a day/each time a 60mg tablet. 10. the application of PFE-PT3 as claimed in claim 8 in the medicine of preparation prevention or treatment drug-resistant breast cancer or drug-resistant nasopharyngeal carcinoma, it is characterized in that PFE-PT3 daily dosage is 90mg/kg body weight, It is prepared into a 30mg ordinary tablet three times a day/each time, a 45mg ordinary tablet twice a day/each time or a 90mg slow-control tablet once a day/each time.