TW200412985A - Use of aglycon protopanaxadiol in cancer therapy - Google Patents

Abstract

The present invention provides for the use of aglycon protopanaxadiol (aPPD) in cancer therapy. aPPD is used, in the present invention, in the treatment of human subjects having a multi-drug resistant(MDR) cancer. Also provided is the use of aPPD in combination of one or more other chemotherapeutic agents in the treatment of human subjects having a multi-drug resistant (MDR) cancer. Also provided are pharmaceutical, as well as non-pharmaceutical, compositions comprising aPPD for use in the treatment of human subjects having a multi-drug resistant cancer and pharmaceutical kits comprising such compositions.

Description

200412985 Description of the invention (The description of the invention should state the technical field, prior art, content, embodiments, and drawings of the invention briefly) [Technical field to which the invention belongs] The present invention relates to the second test element of desugared ginseng ( Application of minga 011 ProtoPa prison adiol (aPPD) in cancer treatment. [Previous technology] The resistance of cancer cells to chemotherapy killing is one of the core problems of cancer treatment. It is now clear that at the beginning of diagnosis, tumors in many people already have standard chemotherapy drugs. Drug-resistant cancer cells, this spontaneous drug-resistant mutation, it is estimated that one in every 106 to 107 cancer cells will appear, although the leg mutation and chemotherapy may increase the mutation, And promote tumor progression within a certain number of cancer cells, but the mutation rate seems to have nothing to do with any selective pressure from drug therapy (see Goldie et al., Cancer Treat. Rep., 63 : 1727, 1979; Goldie et al., Cancer Res "44: 3643,1984; Nowell, Cancer Res., 46: 2203, 1986). Only selectively kills tumor cells that are sensitive to drugs, leading to those that are chemically sensitive Treatment of drug-resistant tumors, including drug accumulation reduction (especially Multi-drug resistance), accelerated drug metabolism and other changes in drug metabolism, and Enhanced ability of cell repair drugs to damage (Curt et al ·, Cancer Treat · Rep "68: 87,1984; and Kolate, Science, 231: 220, 1986). The next page (please note and use the continuation page when the invention description page is inadequate) 200412985 The medicines described in the invention pages have drug resistance, and usually also feed other drugs with resistance, and these resistances have different mechanisms of action, This phenomenon is called "multi-drug resistance" (MDR), and it can explain why multiple resistance appears in cancer patients who have previously been treated. The development of drug resistance is a major obstacle encountered in the treatment of cancer. One of the traditional methods to try to circumvent the problem of drug resistance is combination chemotherapy, which uses different active mechanisms and cytotoxic potentials of multiple drugs. Although the combination therapy has been successful in many cases, the need to develop new drugs still exists, especially the ability to kill multi-drug phenotypic fine-drug drugs to treat drug-resistant tumors. A drug with the ability to overcome multidrug resistance, can be used as a chemotherapeutic agent alone or in combination with other drugs. The potential benefit of using this drug in combination with other chemotherapeutics is that it can be used in combination Fewer toxic compounds, cost savings, and synergistic effects are achieved, creating a less frequent treatment. Previous technology has revealed that some compounds obtained from Asian ginseng, American ginseng, panax notoginseng, and other varieties of the ginseng family have the potential to become anticancer drugs (see U.S. Patent

Application No. 09 / 910,887, US Patent No. 5,776,460, Kikuchi Υ et al. (1991) Anti-cancer Drugs. 2: 63-7; Lee KY et al. (1996) Cancer Lett. 110: 193-200 ; Oh M et al. (1999) Int J Oncol. 18: 869-75; Ota T et al. (1997) Life Sci. 60: PL39-88; Continued pages And use continuation page) 200412985 Description of Invention Continued

Nakata H et al. (1998) Jpn J Cancer Res. 89: 733-80; Kim HE et al. (1999) Life Sci. 65: PL33-80; Park JA et al (1997) Cancer Lett. 121: 73- 81, Nakata H et al. (1998) Jpn J Cancer Rep. 89: 733-80, US Patent Application No. 60 / 204,785) ^ Two known ginseng islands: 1C yuan: protopanaxadiol and ginseng III Alcohol (proto-p-atriol) has been shown to have chemosensitizing effect on multidrug resistant cancer cells in vitro (in vitro) in combination with other chemotherapeutic drugs (see 118 · Patent Application Να 09 / 957,082), although the original ginseng erin and the original ginseng triol have the effect of chemosensitizer, but its ability to kill multi-drug phenotype cells has not been disclosed. Therefore, The demand for a multidrug-resistant cancer treatment is still Mitoxantrone, an anti-tumor agent, which can be used as the synthetic acetone of anthraquinone (anthraquinone dye ametantrone). (antracenedione) derivatives, reports indicate that rice Toroxantrone has been used in the treatment of many malignant diseases, including acute non-lymphocytic leukemia, advanced breast cancer, and prostate cancer (see Wiseman and Spencer, Drugs & Aging, 1997 June KX6): 473 ), Mitoxantrone, is commercially available, and its method is as described in U.S. Patent No. 4,197,249. Paclitaxel is a derivatized diterpenoid that can be obtained from Pacific Yew bark and other resources (Taxus brevifolia, see Want et al, J. Am. Chem. Soc .93 -.2325,1971; and Stierle et al .. Science 60: 214-216, ~ T | continued page (when the description page of the invention is insufficient, please note and use the continued page) 200412985 __ Invention description continued page 1993 ), In the treatment, especially in the treatment of cancer, Paditaxd is considered to be able to stabilise the microtubular structure by binding to tubulin (Paclitaxel) The term ") can include naturally occurring molecular analogs, derivatives, and conjugates such as TAXOL ™ 'TAXOTERE ™, Paclitaxel's 10 deacetylated analogs (10- desacetyl analogues) ^ ^ # © (Paclitaxel) ^ PN-desbenzoyUTSR-butoxy carbonyl analogues), Paclit ^ xel_PEG, Paclitoel-dextran (de-Pin) or Paclita'el-TKM (xyl〇s), Paclitaxel can Prepared by many techniques (see WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076, US Patent Nos. 5,294,637, 5,283,253, 5,279,949, 5,274,137, 5 (202,448, 5,200,534, 5,229,529, and EP 590267) or from many commercial sources, including, for example, Sigma Chemical Co., St Louis, Mo ° Cisplatin is an inorganic compound containing the element lead, since cis-uranium (cis- Diamine di ^ | g (II)) (Cis-diaininedichloroplatinum (II)) ^ irCM ^ tg14 (Rosenberg et al.?

Nature, 205: 698, 1965; Nature 222: 385, 1972; US Patent No. 4,177,263) since its discovery, it has been used as a chemotherapeutic agent for many years. The mechanism of action of cisplatin in cancer treatment, according to It is believed to be achieved by its combination with DNA to interfere with the repair mechanism, which can lead to cell death. It has been reported that cis-lead beta noon cancer is effective in the treatment of ovarian cancer and testicular nine Cancer (testicular cancer) is more significant, cis-lead can be continued from pages such as R1 (inventory description page is insufficient, please note and use the continuation page) 200412985 Invention description continued page

Acquired by Bristol-Myers Sqmbb, its trade name is platin〇lTM 〇 The above background information is provided based on the purpose that the applicant believes may be related to the present invention, and any of the foregoing information is not intended to constitute a countermeasure against the present invention The prior art (p-sister), all the technical specifications (publication) publications will be placed in the reference of this case. [Content] One of the objects of the present invention is to provide desugared ginsengdiol The use of aglyCOnprOtox panaxadiol (aPPD) for cancer treatment is related to one aspect of the present invention, and here is provided an aglycon protopanaxadiol (aPPD) for patients with multiple diseases. The application of drug resistance to cancer treatment. Consistent with another aspect of the present invention, there is provided a method for inhibiting the proliferation of cancer cells, and a method for treating patients in need of such treatment, the method comprising administering to such patients a combination of therapeutic and synergistic doses Aglycon protop leg xadiol (aPPD) and a chemical treatment [j (chemotherapeutW ^ cells may be multidrug resistant.) In accordance with yet another aspect of the present invention, there is provided a Aglycon protopanaxadiol (aPPD) is used in the manufacture of a drug for treating patients with multidrug-resistant cancer. 5 Continued page (Insufficient pages of the invention, please note and use continued pages) Invention The description 200412985 is consistent with another aspect of the present invention, and here is provided an application of aglycon protopanaxadiol (aPPD) in the manufacture of a non-phamiaceutical composition. The non-pharmaceutical composition can be administered For multidrug resistant cancer patients. Figure 1 provides a non-N dose of deglycosed ginsengdiol lane test element (aglycon protopan axadiol (aPPD) after treatment of multi-drug resistant cancer cells, a graphical representation of cell viability; Figure 2a provides a desugared ginsengdiol lane test element (agiyCon pr〇t〇panaxa (ji. i, aPPD) A graphical representation of cell survival rates after treating multidrug resistant cancer cells; and Figure 2b is a graphical representation of cell survival rates after treating multidrug resistant cancer cells with different doses of paclitexal. Figure 1 shows the cell survival rate of multi-drug resistant cancer cells treated with different sugar-free ginseng glycol lane test cells (agiyCOn pr0topanaxa (ji〇i, aPPD) and ginseng lane test Rh2). Figure 4a. Figure 4a provides a sample of different doses of aglycone glycoside glycosides (aglycopanapadioxin (aPPD), ginsenoside Rh2, and paclitaxel (padit㈣ treatment of non-multidrug resistant drug sensitive) cancer cells. A graphical representation of cell viability. Figure 4b provides a multidrug treatment with different doses of aglycoponin aglycon (aglycoon pronat, aPPD), ginsenoside Rh2, and paclitaxel (paditexal). Graphic representation of cell survival after facial cells. Detailed description is defined unless otherwise determined 'All aspects and scientific terms used by females and the first and second continuation pages involved in this translation (turning the description page is not enough, remembering and making the job page) Invention description continuation page 200412985 People with common knowledge before technology generally understand The meaning is the same. "Multi-drug resistant cancer (MDR)" refers to the primary or acquired resistance of cancer or tumor cells to treatment. Generally, the original type of multi-drug resistance Cancer (Prime MDR) is considered to be a cancer that does not respond to chemotherapy without treatment, and Secondary MDR cancer develops resistance during the course of treatment. It is understood that "multi-drug resistant cancer" refers to drug resistance caused by the following mechanisms: Decreased drug accumulation (eg, excretion of chemotherapy by P-type protein pump) Initiation (eg, active excretion of the chemotherapeutic by a protein pump (P-glycoprotein)), other changes in power metabolism and drug metabolism, and increased cell repair The ability to damage thereof. "Advanced cancer" refers to overt cancer in a patient. This open cancer is often not limited to the local area and does not respond to local treatment methods such as surgery or radiation therapy. "Primary cancer" refers to the original tumor or primary tumor and is usually named after the part of the body it is suffering from. "Metastatic cancer" refers to the type of cancer that has spread from one original site (primary cancer) to other sites (subsequent cancer). In fact, all cancers can develop into metastatic cancer. The term is not limited to any particular type of cancer. "Recurrent cancer" refers to a cancer that is considered to have cured or the disease has recurred. Cancer recurrence can occur in weeks, months, years, or years. The technology in this field The recurrence of cancer as understood by the skilled person refers to the cancer that failed to be treated in the original treatment such as chemotherapy [3 Continued Page (If the Instruction Sheet is inadequate, please note and use the continuation sheet) 200412985 Cell-induced cancer. '' Adjuvant therapy '' refers to a treatment method to increase the therapeutic effect of the main treatment method. In cancer treatment, adjuvant therapy usually refers to chemotherapy or radiation treatment after surgical treatment (primary therapy). For the possibility of killing all cancer cells. Therapeutic use of aglycon Protopanaxadiol (aPPD) The present invention provides the treatment of a person with aglycon glycoside glycoside saponin (aPPD), including multiple Application in patients with multidrug cancer. In one embodiment of the present invention, the desugared ginseng glycol saponin (appD) has

Cancers with extremely high malignant potential, or diagnosed with spreading forms, are typical multidrug-resistant types, and some cases of often difficult-to-drug tumors that have been associated with the original type have been reported (Yin L "et al ·; Zhonghua Zhong Liu Za Zhi; 19⑹: 420-2, 1997), for example: lung cancer (55%) (lung), stomach cancer (33%), stomach cancer), esophageal cancer (37%) (esophagus), colorectal cancer (31% ) (colorectal), and thyroid cancer (40%) (thyroid), other types of cancer that have turned into relapsed multidrug-resistant cancers include: breast cancer, prostate cancer (prostate), Hodgkin's and non-13 Continued pages (Notes on the use of the invention description page, please note and use the continuation page) 200412985 _ Description of the invention continued pages Hodgkim & Non-Hodgkhs lymphoma, bladder cancer (leukemia), uterus Endometrial, oropharyngeal, cervical, testis, skin, soft tissue cancer, which does not rule out multidrug Drug-resistant cancers appear in this group of cancers. In addition, in certain types of cancer Here, the frequency of multidrug-resistant cancer has been found to be different, for example, only 20-35% of patients with pancreatic cancer (Permert J ·, et al ·, Acta Oncol; 40 (2_3): 361-70, 2001), relative to 60-80% of breast cancer patients (Hortobagyi GN ·, et al ·, Semin Oncol; 23 (lSiiPpl 1): 53_7, 1996), an example of a tumor that responds to chemotherapy and cannot be penetrated by traditional chemotherapy That is, cancer. On the other hand, although breast cancer often achieves a high rate of patient remission after chemotherapy, it has become a relapsed multidrug-resistant cancer after relapse (Liu X., et al; Zhonghua Yi Xue Za Zhi; 77 (7): 488-90, 1997). In another specific example of the present invention, desugared ginsengdiol saponin (aPPD) is used to treat the original type of hair that is generally resistant to traditional chemotherapy Cancers, including, but not limited to, the following: pancreatic cancer, lung cancer, stomach eancer, esophagus cancer, colon and rectum cancer, Brain cancer, ovary cancer, liver cancer (nver eancer), kidney cancer (kid dney cancer, laryx cancer, bone cancer, multiple myeloma 'and melanoma ° In yet another specific embodiment of the present invention, the desugared ginsengdiol saponin (aPPD) is used for the treatment of Dora-resistant cancer. These cancers are usually worsened from the site of patients who have undergone chemotherapy. 'Including, but not beta, the following cancers are mentioned. (breast cancer), Mf ^ il ^ (pr〇state cancer) > PM ^ ® (bladder cancer) > ^ H ^ (cancer in body of uterus), oral cavity cancer, thyroid cancer (thyr〇) ideancer), cervical cancer Ξ continuation page (if the description page of the invention is insufficient, please note and use the continuation page) invention description page 200412985 (cervix cancer), testis cancer, non-Hodgkin's lymph Tumor (Non-Hodgkins lymphoma), leukemia, Hodgkin's disease, skin cancer, and soft tissue cancer; in yet another specific example of the present invention, Sugar ginsengdiol saponin (aPPD) is used to treat advanced and Shift cancers, this type of cancer is generally resistant, including late and / or phase of the spoon rather _ cancer. The invention is used to treat cancer, and is also applicable to other types of cancer, such as the original type and metastatic multidrug resistant cancer including various tissues and / or organs, including, but not limited to the following tissues or organs: muscle (muscle ), Bone or connective tissues, skin, brain, lungs, the sex organs, the lymphatic or renal systems, breast or Blood cells (mammary or blood cells), liver (liver), digestive tract, pancreas, thyroid or adrenal glands, these conditions may include solid tumors, ovaries, Breast, brain, prostate, colon, stomach, kidney, or testis and other cancers (cancers of the ovary, breast, brain, prostate, colon, stomach, kidney or testicles), Kaposi's sarcoma (Kaposi's muscle oma) '' bile duct Cholangioma, chorioma, neuroblastoma, Wilms' tumor, Hodgkin's disease, melanoma omas), multiple myelomas, lymphatic leukemias, and acute or chronic granulocytic lymphomas ° In another embodiment of the present invention, desugared ginsengdiol saponin ( aPPD) ^ It can be used in combination with one or more chemical treatments, and can also be used as part of a chemotherapy regimen. Continued on the next page (please note and use the continuation page if the description page of the invention is insufficient, 200412985) Page to treat multidrug resistant cancer, according to the present invention, desugared ginseng glycol saponin (aPPD) can be used alone or in combination with other pharmacologically active chemotherapeutic drugs to treat multidrug resistant cancer. As previously mentioned It is said that the combination therapy using standard chemotherapeutic drugs is well known in the prior art and can also be used in combination with desugared ginsengdiol aglycone (aPPD). A large number of chemotherapeutic drugs have been human in the prior art. Known, including those special chemotherapeutics for specific _ cancers, as well as those with a wide range of chemotherapies for cancer Substances such as doxorubicin, mitoxantrone, and irinotecan (CPT-11), chemotherapeutic drugs suitable for the treatment of breast cancer, including, but not limited to, the following drugs: cyclophosphamide, Ifosfamide, cisplatin, carboplatin, 5-fluorouracil (5_FU), taxanes, such as paclitaxel and docetaxel and various anthracydines , Such as doxorubicin and epidoxth rubicin (also called epirubicin), combination therapies using standard chemotherapeutic drugs have been included in the prior art ', for example, epirubicin and paclitaxel or dodoctaxel ) Combined use, or doxorubicin or epirubicin and cyclophosphamide-in combination for the treatment of breast cancer, multiple chemotherapeutic combinations (Polychemotherapeutic regimens) are also useful , For example, doxo · rnbicin / cyclophosphamide / 5-fluorouradl or cyclophosphamid e) / epimbicin / 5-fluorouracil constitutes more than 1 combination therapy and multiple therapies, which can be used in combination with desugared ginseng glycol saponin (aPPD). Cyclophosphamide (cyclophosphamide), mitoxantrone (mitoxantrone) and estrogen mustard (estnh ϊ〇 continuation page (when the invention description page is insufficient, please note and use the continuation page) 200412985 invention description (M stomach mustine) is well known Drugs suitable for the treatment of prostate cancer, cyclophosphamide, vincristine, doxorubicin and etoposide are suitable for the treatment of small cdl 1 and gc caer , Etoposide) combined with cisplatin (ckplatin) or carboplatin to treat small cell lung cancer. When treating gastric or esophageal cancer, doxorubicin or epirubicin and cisplatin (dsplatin) and 5-fluorouracil (fluorouracil) combination is also effective, in the treatment of colon cancer, use CPT-11 alone or in combination with 5-fluorourine-steep (fluoro (H flat il) drugs) Use, or use oxaliplatin in combination with 5-fluorouracil-derived drugs, other combinations ^ (cyclophosphamide) > ^ »(d〇- xorubicin) > (vincristine) ^ (prednisone) Doxorubicin, bleomytin, vincristine, and DTIC for Hodgkin's disease, and a combination of Cisplatin or carboplatin with gemcitabine and paclitaxel (paditaxel), docetaxel, vi-nordbine, or etoposide, or a combination of non-small cell lung pancers (aPPD) can be used to treat subjects who have already received chemotherapy, and 疋 to treat subjects who have not received chemotherapy (chemotherapy naive subjects). Therefore, in a specific embodiment of the present invention, aglycone glycoside saponin (aPPD) ) Can be used as part of adjuvant therapy. In a further example of the present invention, desugared ginsengdiol saponin is used to treat subjects who have received one or more courses of chemotherapy. Continued page (Invention When the description page is insufficient, please note and use the continuation page) 200412985 _ Description of the invention The continuation page of the drug group decoration isolates and purifies the deglycoside ginsenoside saponin (aPPD) from natural resources. For example, as described in J. No. 4,157,894 in the United States, a pharmaceutically active compound can be passed through a physiologically acceptable carrier, a diluent, or an excipient. Or a vehicle, combined with a pharmaceutical composition for administration. The pharmaceutical composition may also be composed of desugared ginsengdiol aglycone (aPPD) and one or more chemotherapeutic drugs for simultaneous administration of a certain subject. The pharmaceutical composition of the present invention can be used by inhalation, spray, or by directly dosage units in dosage unit formulations, using traditional non-toxic pharmaceutically acceptable carriers, adjuvants and media Orally, topically, parenterally, injections here include subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections ) Inftision techniques 〇 The pharmaceutical composition may be in a form suitable for oral use, for example, in the form of tablets, troches, cough drops (lozenges), aqueous or oily suspensions (aqueous or oily suspensions) , Dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, the drug group intended to be used orally , Can be prepared according to methods known in the field of pharmaceutical production, in order to refine the preparation And delicious, can also be continued from the sweetener (sweetening Ιϊ) (inventory description page is insufficient, please note and use the continuation page) invention description continued page 200412985 agents), flavoring agents, pigments and preservatives One or more drugs are selected from the group of agents (reservhg agents), and the tablets containing the active ingredients are mixed with appropriate, non-toxic, suitable non-toxic acceptable excipients, such as: carbonated fishing ( calcium carbonate), sodium carbonate, lactose, f§ (calcium phosphate), or sodium diphosphate (hert diluents), such as maize lions om st muscle h), Or alginic acid granulating and disintegrating agents, binding agents such as starch, gelatine or acacia & binding agents > Magnesium stearate 'lubricating agents for steric acid or talc, tablets can Uncoated or coated with tablets using known techniques to delay its digestion and absorption in the gastrointestinal tract to provide the same lasting treatment, for example, can Glyceryl monostearate and glyceryl distearate are used as a sustained-release substance. Pharmaceutical compositions intended for oral use can also be in the form of hard white gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as carbon (§1611111 carbonate), calcium phosphate or kaolin The pharmaceutical composition intended to be used orally can also be in the form of soft white gelatin capsules, the active ingredients of which are combined with water or oil such as peanut oil >, liquid paraffm, and dive oil 7] Aqueous suspensions contain active compounds and are compatible with the appropriate surface _ III] Continued pages (if the description page is not enough, please note and use the continued page) 200412985 Invention description _ page mixed, this Class excipients include: such as sodium carboxymethylcellu-lose, methyl cellulose, hydropropylmethyl cellulose (1 ^ (11 * (职 (^ 1-methylcellulose) Suspension drugs such as sodium alginate, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia, fractions of naturally-occurring phosphatide Disposing or wetting agents, such as lecithin, or concentrated alkylene oxides and fatty acids such as polyoxyethylene stearate, olyoxy and yette stearate Products, or concentrated products such as ethylene oxide of hepta-decaethyleneoxycetanol and long-chain aliphatic alcohols, or ethylene oxide such as polyoxyethylene sorbitol monooleate pxide) and concentrated products of partial esters extracted from fatty acids and hexitol, or ethylene oxide such as polyoxyethylene soibitan monooleate and A concentrated product of partial est㈣ of mono-esters extracted from fatty acids and hexitol anhydrides. Aqueous suspensions may contain one or more fS such as ethyl or p-hydroxybenzoic acid. N-propylp-hydroxy-benzoate preservatives, one or more coloring agents, one or more Drug (flavouring agents) or one or more, such as sucrose (sucrose) or saccharin (saccharin) sweetness together! K sweetening agents) Oily suspensions can be obtained by using vegetable oils such as peanut oil, olive oil, sesame oil, coconut oil, or liquid oil ! mm (Note when the invention description sheet is not enough, please note and use the continuation sheet) 200412985 _ The invention description is prepared by suspending active ingredients in mineral oil of liquid paraffin. Oily suspension can be Contains thickening agents such as beeswax, hard paraffin or cetyl alcohol, the aforementioned sweetening agents and / or flavoring agents The addition can increase the palatability of oral preparations. These pharmaceutical compositions can be preserved by adding anti-oxidants such as ascorbic acid. Dispersible powders M | i (granules) ^ * «7ic ^ or wetting agent) suitable for preparing an aqueous suspension, a suspension drug and one or more antiseptics are mixed and prepared, suitable The dispersant or wetting agent refers to the above-mentioned examples of medicines, and additional excipients such as sweeteners, flavoring agents, and pigments can also be added thereto. The pharmaceutical composition of the present invention may also be in the form of an oil-water emulsion, and the portion of the oil may be a vegetable oil such as peanut oil, olive oil, or a mineral such as liquid paraffin Mineral oil, or a mixture of these oils, suitable emulsifying agents can be naturally truncated gums such as gum tragacanth and gum acacia, which can be Such as soy beans, lecithin, naturally-occurring phosphatides, esters or partial esters extracted from fatty acids and hexitol anhydrides, such as Sorbitan monooleate, as well as the oxidation of the above partial esters and polyoxyethylene sorbitan monooleate, such as polyoxyethylene sorbitan monooleate, continued. When using, please note and use the continuation sheet) 200412985-Description of the invention Continuation sheet Concentrated products of ethylene, emulsions can also contain sweeteners and flavoring agents. Syrups and elixirs can be prepared from a complete set of products such as glycerol, propylene glycol, sorbitol, or sucrose, and the preparation can contain pain Demulcent, preservative, and / or flavoring and coloring. The pharmaceutical composition can be prepared in the form of a sterile injectable aqueous or oleaginous suspension, which can be prepared according to known techniques by using a suitable dispersant or wetting agent, as well as the aforementioned suspension drugs, sterile injection The preparation may be a sterile injectable solution or suspension derived from a non-toxic acceptable diluent or solvent, such as a 1,3 · butanediol solution, acceptable acceptable media and solvents, including but not limited to the following: Water, compound sodium chloride injection (Ringer, s solution), lactated Ringer's solution and isotonic sodium dichlorite solution (isotonic sodirnn chloride solution) ^ Sterile, non-volatile oil in suspension medium , And different irritating and non-volatile oils such as mono-glycerides or diglycerides. In addition, fatty acids such as oleic add can also be used for injectable combinations. Preparation. Other pharmaceutical compositions and methods for preparing pharmaceutical compositions are known and described in the prior art in this field, for example, have been published by Williams & Wilkins, Philidelphia, PA (2000), by Gennaro, A. By Lippincott ⑽ · 7¾ ^

Practice of Pharmacy) (Originally known as "Remingtons Pharmaceutical Sciences") Γϊτΐ Continued pages (Insufficient invention pages, please note and use continuation pages) 200412985 Continued pages of invention description

I Non-pharmaceutical composition An important aspect of the present invention is that desugared ginseng glycol saponin (aPPD) can be treated with a suitable pharmaceutically acceptable medium such as buffer, solvent, diluent, inert Carrier inert carrier, crdme (cream), or can be prepared using non-pharmaceutical compositions for use, non-pharmaceutical compositions can be in the following forms, such as natural pharmaceutical composition (nutm-ceutical composition), food, health Food, natural health products, functional foods, nutrition supplements (nuMti〇nal supplement), diet supplements (herbal supplements), herbs (herb), alternative therapies (altematiye medicine), And a naturopathic product. In a specific embodiment of the present invention, the non-pharmaceutical composition may include a therapeutically effective dose of desugared ginseng diol ionophore (aPPD) in a pharmaceutically acceptable medium, and here The disclosed non-pharmaceutical compositions are typically 'tablets, capsules, or ointment forms & administration of drugs and agents According to the present invention, in order to treat multi-drug resistant cancer, the subject to be treated is treated with a therapeutically effective dose of devinelated ginseng glycol saponin (aPPD) or a pharmaceutical composition containing deglyconated ginsenoside aglycon (aPPD). Sugar ginseng glycol saponin (aPPD) or □ I containing desugared ginseng glycol aglycone (aPI &D; D)] Continued pages (Insufficient invention pages, please note and use continued pages) 200412985 Description of the invention ^ Page pharmaceutical composition, which can be administered according to traditional chemotherapy. The dosage of desugared ginsengdiol aglycone (aPPD) is based on the size of the cancer M to be treated and the size of the subject, and skilled practitioners can easily do this. Make a decision, however, in the treatment of different types of cancer, the dosage and frequency of the drug can be determined according to the actual situation according to the technology known in the art. Pharmaceutical Kits The present invention can also provide desugared ginseng. Diglycosides (aPPD) therapeutic kits for multidrug resistant cancer treatment, individual components of the element will be packaged in separate containers Together with these containers, there are instructions in a format prescribed by a government agency that regulates the production, use, or sale of drugs and biological products, which reflects the government agency's approval for the production, use, or sale of human drugs. When the components of a drug component are When one or more liquid solutions are used, the liquid solution may be an aqueous solution, such as a sterile aqueous solution. In this case, the container means may be an inhaler, a syringe, or a syringe. , Pipette, eye dropper, or other similar devices (apparatus), the pharmaceutical composition can be administered to the subject via these fibers. The component of the drug element may also be in a dry or lyophilized form, and the drug element may additionally contain a suitable solvent to reduce the lyophilized component. The drug element of the present invention may also include 1 191 pages (Invention Explanation Page) When not enough, please note and use the continuation sheet) 200412985 Description of the invention Continuation of the eastward direction of the target drug use equipment, regardless of the type and number of containers, the device can be an inhaler (syringe), aspiration (syringe), aspiration Pipette, forceps, measured spoon, eye dropper, or any other medically acceptable delivery vehicle. Further, the drug element is administering the drug to the subject In addition, one or more other chemotherapeutic drugs may also be included for use in combination with desugared ginseng glycol saponin (aPPD). To facilitate a better understanding of the present invention, the following examples are given. These enumerated examples should be understood as illustrative purposes only, and therefore, these examples should not limit the scope of the present invention in any way. [Embodiment] Cytotoxicity measurement is performed using standard microculture tetrazolium assay (MTT). The exponential growth of tumor cells (including multi-drug drug cell lines) is used to perform microdrops. Microtiter plate cultures were cultured in 96-wdl plates (1.2-103 cells per well), cultured at 37 ° C overnight, and then the test compound was added— Desaccharified ginseng glycol saponin (aPPD), cells. After 24 hours treatment, add MTT test to stain MTT handle according to standard methods of known technology | (3- (4,5-dimethylthiazolyl thiathiaUyl) -.- Biphenyltetrazolium tetrazolium bromide in saline, to determine the number of cells in each well. Example 1: Desaccharified Ginseng Dimu noodles aPPD) to more than one cancer treatment ~ 2 〇1 Continued page (Note when the Instruction Sheet is inadequate, please note and use the continuation sheet) Invention Description Continued 200412985 Different doses of desugared ginsengdiol saponin (aPPD) against human multidrug resistant breast cancer MCF7r cells and Mesothelioma ) MS_1 dirty fine line processing, after 24 hours of cell viability by MTT assay is calculated. Figure 1 illustrates the effect of different doses of desugared ginsenoside saponin (aPPD) in treating drug-sensitive human mesothelioma cell line MS-1 and human multidrug resistant breast cancer; cell line] y〇7r In comparison, before determining the cell survival rate, each group of cells was treated with desugared ginsengdiol lane tester (aPPD) at a dose of 6 pg / ml, 12 pg / ml, 24 pg / ml, and 48 pg / ml for 24 hours. After treatment, it is clear that desugared ginseng glycol saponin (aPPD) caused cancer cell death in a dose-dependent manner and reached almost 100% killing at high doses. Example 2: Comparison of Desugared Ginseng Second Marketing Test (apPD) and Zi Na In this experiment, the effect of the treatment of multidrug-resistant cells by desugared ginseng glycol saponin (aPPD) was compared with the previously known The chemotherapeutic drug paclitaxel (Paclitaxd's treatment effect in technology) was compared to prove the efficacy of desugared ginsengdiol aglycone (aPpD) in treating multi-drug resistant cancer cells. Figure 2a. Ginseng: Cell effect (MCF7f) is used to clarify the therapeutic effect, using non-removed sugar-free ginsengdiol lane test (appD), to perform multi-drug resistant cancer cells (MCF7r) and drug-sensitive breast cancer (MCF7) Treatment, before the calculation of cell hoof ratio in the greenhouse MTT method g, use the doses of 6, η,%, and Yuca 1 u to continue; human page (say that I do n’t make a brain, I ’ll move the title page) 200412985 __ 发明 发明 的 脱Sugar ginseng glycol saponin (aPPD) is treated for 24 hours. Unlike traditional chemical treatment paclitaxel, deglycosyl ginseng glycol saponin (aPPD) is also effective on drug-sensitive cells and drug-resistant cells. Figure 2b illustrates the effect of paclitaxd on the same human breast cancer cells used in the example of Figure 2a. Different doses of paclitaxel were used against human multidrug resistant breast cancer magnetic field cells MCF7r and drugs. MCF7 cells were treated with sensitive cancer cells. Before calculating the cell survival rate by the MTT method, they were treated with paclitaxel at a dose of (U, 1, 10, 100, and 1000 nM for 24 hours, and paclitaxel). ) Has significant cytotoxicity to drug-sensitive cells, but it has a much smaller effect on the drug drug cells. As shown in Figures 2a and 2b, deglycosyl ginsenodiol saponin (aPPD) is effective against multidrug-resistant cancer cells and The cytotoxic effect of drug-sensitive cancer cells is similar. In contrast, the effect of paclitaxel is significantly inhibited in the drug drug cancer cells. Example 3: Comparison of ginseng 2 and test element (aPPD O Rh2 ginseng county comparison chart) Thirdly, it is shown that desugared ginseng glycol saponin (aPPD) has stronger tumor suppressive effect than Rh2 ginsenoside. The cytotoxicity of desugared ginseng glycol saponin (aPPD) and Rh2 ginsenoside is in melanoma B16 (melanoma) cells. in A comparison was made, using different doses of desugared ginsenoside saponin (aPPD) and plant ginsenoside to treat cancer cells, and the cell survival rate was measured after 24 hours of treatment. Γ221 continued page Please note and use the continuation page) 200412985 Description of the invention Continuation page Example 4: Zinuo (Paditaxd Fenbei and dirty ginseng dikan aglycone (aPPD) and ginseng soap trial enhanced effect comparison Figure 4a and 4b illustrate Paclitaxel ) When combined with desugared ginsengdiol lane test element (aPPD> and Rh2 ginsenosides) to treat drug sensitive (MCF7) and drug resistant (MCF7r) human breast cancer cells, cytotoxicity is enhanced. Cancer cells may be treated differently. Paclitaxel was treated alone, or 20 pg / ml Rh2 panaxaside and 6 pg / ml desugared ginseng glycol aglycone (aPPD) were treated with paclitaxel together. Both compounds significantly increase the cytotoxicity caused by Paclitaxd, but the synergistic effect of desugared ginseng glycol aglycone (aPPD) and paclitaxd is significantly more effective and powerful, and the synergy is in drug resistance The tumor cells (MCF7r) are the most intense. The following table shows the IC50 of Rh2 ginsenoside and desugared ginsenoside saponin (aPPD) versus paclitexel in drug sensitive cells (MCF7) and drug resistant cell line (MCF7r). It is worth noting that the synergistic effect of the three compounds, especially the desugared ginseng glycol saponin (aPPD), is much more significant in drug-resistant cell lines than in drug-sensitive cell lines. Cell paclitaxel Rh2 aPPD strain used alone (20 μ ^ ηιΐ) (6 μ ^ / πύ) MCF7 225 nM 61.6 ηΜ 12.5 ηΜ (3.65 fold) (18 fold) MCF7r 929.8 ηΜ 0.208 ηΜ 0.315 ηΜ (4470 fold) (29517 fold) ) 231 continuation page (please note and use the continuation page when the description page of the invention is insufficient) 200412985 _ Description page of the invention Although various specific examples of the present invention are disclosed here, according to the common knowledge of those skilled in the art Many changes and modifications can be made within the scope of the present invention. For example, the present invention includes all optical isomers and outer rotation forms of Sapogenin protopanaxadiol. Such modifications include replacement with known equivalents. In any aspect of the present invention, the same result is obtained by the same method. The digital range includes those defining the range. In the scope of the patent application, the word "contains" is used as an open editor. Basically equivalent to the phrase "including, but not limited to." [Schematic description] Figure 1 provides a sugar-free ginsengdiol lane with a large dose It is a graph showing the cell survival rate of multi-drug resistant cancer cells treated with aglycon protopanaxadiol (aPPD); Figure 2a provides a multi-drug treatment of glycosylated ginsengdiol lanes (agipyCOn prot0panaxadioi, aPPD) A graphical representation of cell survival rates after drug-resistant cancer cells; and Figure 2b provides a graphical representation of cell survival rates after treatment of multidrug-resistant cancer cells with different doses of paclitexai. ! 1 amount of aglyCon protopanaxadioi (aPPD) and ginseng soap! CRh2 treatment of multidrug resistant cancer cells, the cell survival rate. Figure 4a provides Graphic representation of cell viability of non-multidrug resistant (drug-sensitive) cancer cells treated with agiyeon protatopanaxadioi (aPPD), ginseng lane ltRh2, and paclitexal Figure 4b provides a test method for a brewed ginsengdiol in different agents (aglycon protopanaxadiol, □ 3 sequel (please note and use the continuation sheet when the invention description page is insufficient, 200412985 aPPD) ,people After saponins Rh2 and paclitaxel (Paclitexal) treatment of multidrug resistant cancer cells, the cell viability illustrated ° 25

Claims (1)

200412985 Apply for a patent Fan Yuanΐ · A kind of desugared ginsengdiol saponin is used for cancer treatment, which is an effective therapeutic dose of desugared ginseng glycol saponin (aPPD fetal therapy for patients with multi-drug resistant cancer. 2 · The use of desugared ginseng glycol saponin as described in item 1 of the scope of patent application is cancer treatment, and the multi-drug resistant cancer referred to is advanced cancer. 3. As described in item 1 of the scope of patent application, desugared ginseng 2 The use of alcohol saponin is cancer treatment, and the multi-drug resistant cancer referred to is a snoring disease. 4. The use of desugared ginseng glycol saponin as described in item 1 of the patent application scope is cancer treatment. Multidrug resistant cancers are selected from the group of primary cancers containing the following cancers: pancreatic cancer, lung cancer, stomach cancer, esophagus cancer '' colon and rectal cancer (colon and rectum cancer) '' brain cancer (brain c sister cer), ovarian cancer (ovaiy cancer), liver cancer (liver cancer), kidney cancer (larynx cancer, bone cancer), multiple myeloma (multiple myeloma), and melanoma melanoma) 〇5. The use of desugared ginsengdiol aglycone as described in item 1 of the scope of the patent application is for cancer treatment, and there are many of them referred to »[drug cancer, which is selected from the group of recurrent cancers containing the following cancers Middle: pancreatic cancer, lung cancer, stomach cancer, esophagus cancer, colon and rectal cancer, brain cancer, brain cancer, Ovarian cancer, liver cancer, kidney cancer, laryx cancer, bone cancer, multiple myeloma, and melanoma, breast Cancer (breast cancer), prostate cancer (prostate ~ n continuation page (when the application page is not enough to use, please note and use Gu) 200412985 __ please request patent range continuation page cancer), bladder cancer, uterus Cancer in body of utefus, oral cavity cancer, thyroid cancer, cervix cancer, testis cancer, non-Hodgkin's lymphoma (Non -Hodgkins lymphoma), white blood (Leukemia), Hodgkin's disease (Hodgkin's disease), skin cancer (skin cancer), and soft tissue cancers (soft tissue cancer). 6. · The use of a kind of desugared ginsengdiol alloside for cancer treatment is a combination of desugared ginseng glycol saponin (aPPD) with one or more chemotherapeutic drugs in an effective therapeutic dose to treat patients with multidrug cancer. patient. 7. As stated in item 6 of the scope of patent application, the multi-drug resistant cancer referred to is advanced cancer. 8. As mentioned in item 6 of the scope of patent application, the multi-drug resistant cancer referred to is type 1 cancer. 9. As described in item 6 of the scope of the patent application, the multidrug-resistant cancer referred to in it is selected from the group of primary cancers that contain the following cancers: pancreatic cancer, lung cancer Stomach cancer, esophagus cancer, colon and rectum cancer, brain cancer, ovary cancer, liver cancer, kidney cancer ), Larynx cancer, bone cancer, multiple myeloma, and melanoma. 10. According to item 6 of the scope of the patent application, the multi-drug resistant cancer referred to therein is selected from the group of recurrent cancers containing the following cancers: pancreatic cancer, lung cancer, Stomach cancer, esophagus cancer, colon and rectum cancer, brain cancer, ovary cancer, _ \ T] Continued pages (Patent application page When inadequate use, please note and use the continuation page) 200412985 __—_ Patent Application Continuation Page Liver Cancer (kidney cancer), Kidney Cancer (larynx cancer), Bone Cancer (bone c⑽cer), Multiple myeloma, melanoma, breast cancer, prostate cancer, bladder cancer, cancer in body of uterus, oral cancer ( oral cavity cancer, thyroid cancer, cervdx cancer, testis cancer, non-Hodgkins lymphoma, leukemia, ho Hodgkin's disease s disease), skin cancer, and soft tissue cancer ° 11. As described in any one of claims 1 to 10 in the scope of patent application, wherein the intended use is for patients with multi-drug resistant cancer For the treatment of sick money. 12. As described in any one of claims 1 to 11 of the scope of patent application, wherein the target of treatment is a patient who has received one or more previous chemotherapy courses. 13. · A kind of desugared ginsengdiol saponin is used for cancer treatment, which is produced by desugared ginsengdiol alloside (aPPD) to treat patients with multidrug_cancer. 14. As described in item 13 of the scope of patent application, the multi-drug resistant cancer referred to is advanced cancer. 15. As described in item 13 of the scope of the patent application, the multi-drug resistant cancer referred to is a metastatic cancer. 16. As described in item 13 of the scope of the patent application, the multi-drug resistant cancer referred to therein is selected from the group of primary cancers containing the following cancers: pancreatic cancer, iung cancer, gastric cancer (stomach cancer), esophagus cancer, colon and rectum continuation pages (please note and use continuation pages when the patent application page is not enough, 200412985 Φ please enroll in the patent scope of colon and rectum cancer, Brain cancer, ovary cancer, liver cancer, kidney cancer, larynx eancer, bone cancer, multiple myeloma And melanoma 〇17. As described in item 13 of the scope of the patent application, the multi-drug resistant cancer referred to is selected from the group of recurrent cancers containing the following cancers: pancreatic cancer (pancreatic cancet) , Lung cancer, stomach cancer, esophagus cancer, colon and rectum cancer, brain cancer, ovary cancer, liver cancer '' Kidney (kidney cancer) `` larynx cancer, bone cancer '' multiple myeloma, and melanoma, breast cancer, prostate cancer, bladder cancer (bladder cancer), cancer in body of uterus, oral cavity cancer, thyroid cancer, cervix cancer, testis cancer, non-hejie Non-Hodgkins lymphoma, leukemia, Hodgkin's disease, skin cancer 'and soft tissue cancer ° 18.-a kind of deglycosed ginseng II The use of glycosides for cancer treatment is based on the production of non-glycosides of panaxadiol glycosides (aPPD) for the treatment of patients with multidrug-resistant cancer. 19. As described in item 18 of the scope of patent application, the multi-drug resistant cancer referred to is advanced cancer. 20. The multi-drug resistant cancer referred to in item 18 of the scope of the patent application is a metastatic cancer. £ J continuation page (please note and use the continuation page when the patent application page is insufficient, 200412985 ~ 丨 ............ =: — patent application park continuation page 21 As described in item 18 of the scope of patent application, the multi-drug resistant cancer referred to is selected from the group of primary cancers containing the following cancers: pancreatic cancer, lung cancer, stomach cancer ), Esophagus cancer, colon and rectum cancer, brain cancer, ovarian cancer, liver cancer, kidney cancer, laryngeal cancer ( larynx cancer, bone cancer, multiple myeloma, and melanoma ° 22. As described in item 18 of the scope of patent application, wherein the multi-drug resistant cancer line is selected from the group consisting of In the recurring cancer group of the following cancers: pancreatic cancer, lung cancer, stomach cancer, esophagus cancer, colon and rectum cancer, moon cancer (brain cancer), nest cancer (ovary cancer), liver cancer (liver can cer), kidney cancer, laryx cancer, bone cancer, multiple myeloma, and melanoma, breast cancer, anterior cancer [| Adenocarcinoma (prostate cancer), bladder cancer (cancer in body of uterus), oral cavity cancer (thyroid cancer), cervix cancer (cervix cancer), testicular nine cancer (testis cancer), Non-Hodgkins lymphoma, leukemia, Hodgkin's disease, skin cancer, and soft tissue cancer 23. As described in item 18 of the scope of the patent application, the non-pharmaceutical composition therein may be an appropriate ^ tLUmmm (buf £ cr) ^ ^ (solvent) ^ ^^ [J (diluent) ^ inert carrier ), Oil, creme, or can be prepared using substances. 24. As described in item 18 of the scope of patent application, the non-pharmaceutical composition can be in the following form, ^ 5 ~ 1 continuation page (please note and use the continuation page when the scope of patent application page is not enough, please note and use the continuation page) 200412985 Patent Fanpu continuation pages such as nutraceutical composition, food, health food, natural health food, functional food, nutrition supplement, Knutritional supplement, food supplement (diet town supplement), herbal supplement (herbal supplement), herbs, alternative mediches, and mturopathic products. 25. As described in item 18 of the scope of patent application, the non-pharmaceutical composition may include tablets. ), Powder, suspension, emulsion, capsule, granule, troche, pill, liquid, alcohol paste ^ irit), syrup, # ®K (lemonade), solution, drop, ointment, ointment, 6ral solution or elixir, Plaster Suppositories (suppository), aerosol (aerosol), a liniment (liniment), lotion (lotion), filling _ (Enema), or a group of selected hybrid. 26. A drug element for treating patients with multidrug resistant cancer. 27. As described in item 6 of the scope of the patent application, the other chemotherapeutic drugs referred to therein are selected from the group consisting of aminoglutethimide, amsa-crine, anastrozole, Asparaginase, erwinia ^ BCG, bicalutamide, bleomycin, byserelin, busulfan, capecitabine, carbbjplatin, carnmstine , Chlorambucil, cisplatin, cladribine, clodronate, cyclophosphamide, cyproterone, cyproterone, cytarabine ( cytarabine), dacarbazine, dactinomycift, daunorubicin, diethylstilbestrol, docetaxel, doxorubicin (cont.) (Please note and use the continuation page when applying) 200412985-Patent application for doxorubicin, epirubicin, estramustine, etoposide, eximetin (exemes) e), Phils (filgmst peak rabine), fludrocortisone, fluorouracil (5-FU), ftuoxymesterone, flutamide, gemcitabine, goserelin ), Hydroxyurea, idarubicin, ifosfamide, imatinib, interferon-alfa, irinotecan, letrozole, leucovorin , Leuprolide, levamisole, lomustine, mechlorethamine, medro-xyprogesterone, megestrol, melphalan ( melphalan), mercaptopurine, mesna, methotrexate, mitomycin, o-chlorobenzene-p-chlorobenzenedioxyethane (mitotane), rice Mitu-xantrone, nilutamide, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, methyl T hydrazine (procarbazine), raltitrexed, rituxi ^ nab, streptozotocin (s treptozocin), tamoxifen, t0mozolomide, teni-poside, thioguanine, thiotepa, topotecan, trastuzumab, tretinoin, vinblastine, vhcrist (R), vindesine, and vinorelbine.