CN103705926A - Pharmaceutical composition used for preventing primary tumor metastasis after exairesis - Google Patents
Pharmaceutical composition used for preventing primary tumor metastasis after exairesis Download PDFInfo
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract
The invention provides a pharmaceutical composition used for comprehensive prevention of primary tumor metastasis after exairesis. The pharmaceutical composition is composed of five kinds of drugs, which are capable of increasing body internal tumor immune functions, inhibiting marrow internal circulation tumor cell activity, inhibiting adhesion and implantation of circulating tumor cells in blood onto tunica elastica interna, preventing aggregation of circulating tumor cells in blood vessels, and strengthening tissue matrix structures respectively. Each of the five drug is capable of controlling a different point related to tumor metastasis. Optimized combination of the five drugs is capable of preventing tumor cells from metastasis after exairesis effectively and safely.
Description
Technical field
The present invention relates to be optimized combination with the medicine of five types, so as comprehensively, prevention or auxiliary treatment mammalian subject the shifting again of tumor (or recurring again) after excision primary tumor safely.
Background technology
The defect of existing technologies and beneficial effect of the present invention: over more than 50 year, the mortality rate of other major disease (heart disease etc.) significantly (> 60%) has declined, but cancer mortality only reduces approximately 5%, and wherein the overwhelming majority dies from neoplasm metastasis.The death causing because of neoplasm metastasis is current global, economy, society and a Scientific And Technical Problems about happy and peace, in the urgent need to address.What the research and development of traditional main flow " anticarcinogen " were walked is the slow stupid route of " anticancer again after cancer metastasis ", produces little effect.The chemotherapeutics of " effectively " can not be controlled cancer metastasis effectively at present, and toxic and side effects is large, and patient's quality of the life reduces, and family members bear sharp increase.The more important thing is the death that " anticarcinogen " at all cannot reversing tumor transporting patient! The present situation of domestic and international oncotherapy and Existing Defects are simplified and are exactly: early stage entity tumor can be used surgical resection, its success rate can reach more than 95% (need not " anticarcinogen ", unless expert's art not! ).To neoplasm metastasis surgical operation while again cannot whole body excising one by one the tumor mass having shifted, " anticarcinogen " is also invalid; And tumour patient not having in early days after excision can be removed circulating tumor cell, and the prevention adhesion of circulating tumor cell in the future and the medicine of invasion and attack, asymptomatic " patient " have to leave it to chance, until neoplasm metastasis has occurred after 3-5.The probability that various tumors shift in 3-5 after operation is again 30-70%.With composition of medicine comprehensively postoperative the transfer again of prophylaxis of tumours be that the global great science and technology of uncared-for theory, technology and a product is blank!
The chemotherapeutics of tumor can be divided into following a few class at present: 1) the damaged agent (DNA damaging agents) of DNA; 2) tubulin targeting agent (Tubulin-targeted agents) is as paclitaxel etc.; 3) topoisomerase enzyme inhibitor (Topoisomerase inhibitors) is as camptothecine, ABT-888; 4) antimetabolite (Antimetabolites/Nucleosides); 5) monoclonal antibody; 6) epidermal growth factor tyrosine kinase inhibitor is as Bcr-abl tyrosine kinase inhibitor (Gleevec); 7) farnesyl transferase inhibitor (Farnesyl transferase inhibitors; FTI); 8) proteasome inhibitor (proteasome inhibitor); 9) vascular endothelial growth factor receptor inhibitors; 10) matrix metallo-proteinase inhibitor (matrix metalloproteinase inhibitors; MMP); 11) Cycloxygenase-2 (cyclooxygenase-2; COX-2) inhibitor.12) amcinonide (Hormonal agents) is as Tamoxifen; This class medicine really can cause cell (cancerous cell and normal cell) death in isolated test.Targeting class medicine (Targeted drugs; Signaling agents) only the special ethnic group of minority is worked, the tumor of these ethnic groups need give full expression to this target protein, and medicine just can work like this.This has just limited to the scope of application of targeting class medicine.Targeting class medicine is as little in the therapeutic index of neovascularization inhibitor bevacizumab, shows that this type of medicine also has greatly deficiency, comprises patient is produced to serious bone marrow depression.Cytotoxic drug acts on the cancerous cell of rapid division and breeding, but also acts on normal stool tract epithelial cell, hair cell and leukocyte.Tumor cell easily produces Drug tolerance to cytotoxic drug.In a word, " anticarcinogen " achievement in research and development and application is very micro-.
Result to the clinical trials of 22 of 1990-2004 times is analyzed, (the Clin.Oncol.16:549-560 such as Morgan; 2004) find that current " anticarcinogen " only can make 5 annual survival rates of tumour patient increase by 2.1%.Meanwhile, these medicines are invalid to melanoma, uterus carcinoma, carcinoma of prostate and renal carcinoma.The disappointed result of these anticarcinogens is attributed to: the serious toxicity of medicine itself, and patient's quality of the life declines, and the ability of autoimmune and rehabilitation is subject to the strike of anticarcinogen, and the toleration of tumor cell to medicine.(Lancet 2010 for the people such as Rustin; 376:1155-1163) reported, ovarian cancer patient serum CA125 level after paclitaxel treatment was returned to when normal, be divided at random two groups, early stage chemotherapy group and postpone chemotherapy group.The survival period intermediate value of early stage chemotherapy group (265 people) and delay chemotherapy group (264 people) is respectively 25.7 months and 27.1 months, and two groups of survival period intermediate values are without significant difference.Early stage chemotherapy group patient's survival period intermediate value shortens two months on the contrary, the toxic and side effects of prompting medicine to people.Chemotherapeutics is not the medicine of prophylaxis of tumours hands postoperative metastasis.
Anticarcinogen at present used is invalid to dormancy cancerous cell, and the molluscum contagiosum cancerous cell of the rest period being expelled in Mice Body being grown as Doxorubicin is invalid.Surgical resection and or radiotherapy are taked in people's primary tumor treatment more.The tumor cell of postoperative residue will become rest cell (dormant cells) and be hosted by bone marrow and its hetero-organization.According to U.S.'s disease prevention and control centre (Center for Disease Control, the CDC) report of 2011, (CDC Weekly 60 (09); 269-272,2011), in 2007, the U.S. will have 1,200 ten thousand people to become the survivor after treatment of cancer, and these people are excessive risk ethnic groups of cancer metastasis diffusion.According to Lancet report [1998; 351 (9114): 1451-67], patients with mastocarcinoma in latter 3 years of operation again the probability of recurrence be 40%.According to the postoperative statistics of 20,000 above colorectal cancer patients, the 2 phase colorectal cancer patients relapse rate again of performing the operation in latter 3 years is 74% (J.Clin.Oncol.25:4569-73; 2007).In the 3-5 of primary tumor after excision, be the excessive risk phase of cancer metastasis diffusion, the activated circulating tumor cell of tool wherein forming can be in blood by adhering to tunica intima (adhesion), attack, exosmose (extravasation), form neoplasm metastasis micro-kitchen range until tumor entire transformation spread.Prevent the resurrection of dormancy tumor cell, suppress circulating tumor cell adhesion, attack, exosmose and micro-kitchen range point of forming neoplasm metastasis is characteristic of the present invention! Once tumor shifts diffusion, can reverse without medicine.This is just as preventing that termite population is to the infringement of a luxurious house, effectively preventing method be in Coptotermes formosanus Shtrari. district occurred frequently with bait trapping and killing termites outside luxurious house.Once termite population has been invaded each organ of luxurious house, the late period that it is hard to guard against that has been arrived.The first-selected therapeutic scheme of primary tumor is surgical resection, does not need " anticarcinogen "; When the transfer of tumor is spread after needing chemoprophylaxis operation, there is no again at present the medicine of this respect.The present invention be intended to fill up after chemoprophylaxis tumor operation to shift this uncared-for global great science and technology blank again.
Summary of the invention
The invention provides a kind of comprehensive method of mammalian subject, to prevent and to control or treat primary tumor shifting again after excision.The method comprises and gives the treatment of patient's effective dose or the composition of medicine (code name HAMPT) that prevention primary tumor shifts after excision again, and this composition of medicine is by the ingredients of following five types: the medicine that 1) improves the tumour immunity function of body inherence; 2) can suppress the medicine that bone marrow internal recycle tumor cell (circulating tumor cells, circulating tumor cell) brings back to life; 3) can suppress that circulating tumor cell in blood adheres to and implantation arrives the medicine of tunica intima; 4) medicine that the circulating tumor cell in can anti-Hemostatic Oral Liquid is assembled in blood vessel; 5) thus the structure of strengthening periplast prevents the medicine of circulating tumor cell to the infiltration of periplast.The medicine of each type has been controlled respectively the different loci of neoplasm metastasis above.
Describe in detail
The present invention is by giving mammalian subject following composition of medicine, to prevent and to control or treat the risk that primary tumor shifts after excision again.Method according to claim 1 comprises and gives the composition of medicine that the prevention of described patient's effective dose and control or treatment primary tumor are shifted after excision again, and this composition of medicine is by the ingredients of following five types: the medicine that 1) improves the tumour immunity function of body inherence; 2) can suppress the medicine that bone marrow internal recycle tumor cell brings back to life; 3) can suppress that circulating tumor cell in blood adheres to and implantation arrives the medicine of tunica intima; 4) medicine that the circulating tumor cell in can anti-Hemostatic Oral Liquid is assembled in blood vessel; 5) thus the structure of strengthening periplast prevents the medicine of circulating tumor cell to the infiltration of periplast.
The example that can be used for the medicine of the inherent tumour immunity function of raising body of the present invention includes but not limited to following medicine and salt and ester: ginsenoside (Ginsenosides) (Jia et al.Curr.Med.Chem.16:2475-84,2009; Curr.Med.Chem.16:2924-42,2009).Ginsenoside comprises dammarane type [panoxadiol Class and panaxatriol Class compound: Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, notoginsenoside R4, Rs1, Rs2, Rs3, Rs4, Rb1, Rb2, Rc, and oleanane type (protopanaxatriol) compound (Re Rd)], Rf, Rg1, Rg2, Rg3), ganoderan (polysaccharides), ganoderan glycoside (polysaccharopeptides), Ganoderma triterpenoids (triterpenoids), Ganodenic acid (ganoderic acids), Ganolactone (ganolactone), and krestin (Yun Zhi polysaccharopeptide).Being preferred for the medicine that improves the inherent tumour immunity function of body of the present invention is ginsenoside.
The example that can be used for the medicine that inhibition bone marrow internal recycle tumor cell of the present invention brings back to life includes but not limited to following medicine and salt and ester: diphosphate, pyrophosphate and lower than POSTN (Periostat), alendronic Acid (Alendronate), auspicious raw phosphonic acids (Risedronate), group's rice phosphonic acids (Pamidronate), clone phosphonic acids (Clodronate), below phosphonic acids in distress (Etidronate) He Yi nation's phosphonic acids (Ibandronate) and salt and the hydrate of conventional antibacterial dosage.The medicine that is preferred for inhibition bone marrow internal recycle activity of tumor cells of the present invention is alendronic Acid or POSTN.
Can be used for that circulating tumor cell in inhibition blood of the present invention adheres to and implantation includes but not limited to following medicine and salt and ester to the example of the medicine of tunica intima: she takes charge of the steroidal compounds ecdysone (ecdysterone) that ketone, mifepristone, Folium Et Cacumen Murrayae alkaloid comprise yuehchukene, Radix Achyranthis extraction U.S., and S-NITROSOCAPTOPRIL and salt and hydrate.Be preferred for of the present invention class medicine and be beautiful she take charge of ketone.
The example that can be used for the medicine that the circulating tumor cell in inhibition blood of the present invention assembles in blood vessel includes but not limited to following non_steroidal anti_inflammatory drug and salt and ester: aspirin, acetyl aminophenol, celecoxib (celecoxib) and indometacin (indomethacin) and salt and hydrate.Being preferred for of the present invention class medicine is aspirin.
Thereby the circulating tumor cell can be used in the anti-Hemostatic Oral Liquid of reinforcement periplast's structure of the present invention is lysine and salt and hydrate to the medicine of the infiltration of periplast.
In composition of medicine Therapeutic Method described in the invention, the single dosage form administration of active component one-tenth capable of being combined of above five types, or can from five types, as separate dosage forms, separate administration by preferred a kind of active component.When using separate dosage forms to separate the scheme of administration, separate dosage forms at one time (simultaneously) or stagger the time respectively (continuous) gives above medicine.This drug regimen comprises all these type of medically acceptable route of administration, dosage form and dosage.Although preferred this medicine of 5 types dosage regimen with once a day time, but the present invention also comprises various other dosage regimens, as once a day, secondary or the separate dosage forms that repeatedly gives above single combination dosage forms or separate, to maintain effective blood drug concentration.The single peroral dosage form being preferably combined into by the active component of above five types.Other embodiments of the present invention comprise the Pharmaceutical composition with one or more pharmaceutically acceptable carriers.
In this article, " salt " of medicine means organic or inorganic alkali and the reacted compound of free acid of medicine.The salt particularly forming as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium by cation, and the salt forming with ammonia, amine (as ethylenediamine, N-methyl glucoside amine, diethanolamine, diethylamine, phenethylamine).
In this article, " the treatment effective dose " of medicine means that medicine can produce to patient (animal or human) the comparatively safe dosage of pharmacological action." the prevention effective dose " of medicine means the dosage that medicine preventable disease occurs.
Compound described in the invention can have one or more chiral centres, also can be used as racemic modification, racemic mixture and occurs as each diastereomer or enantiomer, within all these type of isomeric form and composition thereof are all included in the scope of the invention.The crystal formation of compound described in the invention can be used as polymorphic and exists, and can also form solvate with water or conventional organic solvent.This type of solvate and hydrate, and within anhydrous composition is all included in the scope of the invention.Compound described in the invention can contain olefinic double bonds (as yuehchukene).Except as otherwise noted, otherwise comprise E and Z geometric isomer.
With anticarcinogen composite reagent or separate medication when reaching auxiliary for treating cancer, the dosage of medicine of the present invention should be selected according to many factors, comprises that patient's type, race, age, body weight, sex and tumor are found and neoplasm staging during excision; Route of administration; Patient's renal function and liver function; And the particular compound or its salt or the ester that use.At this, the definition of anticarcinogen comprises medicine, microtubule inhibitors, topoisomerase, antimetabolite and the hormone drug that destroys DNA.
Two or more different activating agents one are used to conjoint therapy, must consider medicine effect separately and the interaction that their combinations are reached together, thereby determine and can prevent safely, resist or stop treatment effective dose or the prevention effective dose shifting again after tumor operation.The effective dose of combination depends on many factors, comprises the activity of the particular compound for combining, the metabolic stability of compound and when effect length, patient's specified disease symptom age, body weight, general health situation, sex, diet, administering mode and time, concrete dosage level and administration frequency and excretion rate.
In order to prevent and treat disease, medicine of the present invention can be made into the dosage form that oral administration, part, parenteral, suction, spraying, per rectum or transvaginal give active component (alone or in combination) with pharmaceutically acceptable other carrier.Parenteral medication comprises subcutaneous injection, intravenous injection, intramuscular injection, intracisternal injection or infusion methods.
Single medicine of the present invention or composition of medicine can adopt the form that is applicable to orally using, as tablet, buccal tablet, lozenge, water or oil suspension, dispersible powder or granule, Emulsion, hard capsule or soft capsule, solution, syrup and elixir.Can be prepared into the compositions orally using according to the known any method of Pharmaceutical composition preparation field, in order to obtain exquisite good to eat pharmaceutical formulation, such composition comprises one or more preparations that is selected from sweeting agent, correctives, coloring agent and antiseptic conventionally.These excipient can be diluent, as lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate; Granulation agent and disintegrating agent, as corn starch or alginic acid; Binding agent, as starch, gelatin or arabic gum; And lubricant, as magnesium stearate, stearic acid or Pulvis Talci.Tablet is coating or can coating not.Coating can postpone the decomposition of medicine in gastrointestinal tract, thus the action time of prolong drug.For example, the up time postpones material as glyceryl monostearate or distearin.
It should be appreciated by those skilled in the art that in the situation that not deviating from ultimate principle of the present invention and scope, can carry out various changes, change, modification, replacement, deletion or interpolation to this method.For example, the reaction of the mammalian subject for the treatment of by the compounds of this invention or compositions due to any indication is different, and the effective dose outside given dose listed above is also applicable.Equally, whether the concrete pharmacological reaction of observing can there is pharmaceutical carrier according to selected particular active compounds, and the preparation type using and administering mode and difference.These changes or difference object according to the invention and practice.
Following embodiment further illustrates the present invention, but the present invention is not limited only to this:
The specific embodiment 1:
B16-F10 Mus melanoma cell strain tends to form at mouse lung tissue the transfer of tumor cell.After B16-F10 Mus melanoma cell strain is cultivated, add 0.02%EDTA that it is suspended, with every mL, contain 7x10
4the Cell sap of cell is slowly injected by mouse tail vein.This inject first 3 days and injection after every day and high dose low to mouse stomach composition of medicine.After cell injection, the 14th day ether put to death mice.Get lung, 10% formalin is processed, cut sections for microscopic examination, and the lung B16-F10 cell colony counts of administration group is obviously less than the matched group of not administration, and the increase of the minimizing of cell bacterium colony and the dosage of composition of medicine is directly proportional.This experiment shows that composition of medicine has the effect that B16-F10 tumor cell is transferred to lung that suppresses.
The specific embodiment 1:
The tablet preparation of composition of medicine: will contain oleanane type ginsenoside Rg3 (100mg), POSTN (10mg), beautiful she take charge of ketone (2mg), aspirin (25mg) and lysine (10mg) isoreactivity composition mix with microcrystalline Cellulose (100mg) and modified corn starch (100mg) and be prepared into granule after sieve.Granule after sieving mixes with modified corn starch (100mg) and magnesium stearate (1mg), then mixture is pressed into tablet.
Claims (8)
1. the composition of medicine therapy that can comprehensively prevent primary tumor to shift again after excision, it is characterized in that this composition of medicine is by five types, the ingredients that side effect is very little: the medicine that improves the tumour immunity function of body inherence, the medicine that can suppress bone marrow internal recycle activity of tumor cells, can suppress that circulating tumor cell in blood adheres to and implantation arrives the medicine of tunica intima, the medicine that circulating tumor cell in can anti-Hemostatic Oral Liquid is assembled in blood vessel, thereby the structure that can strengthen periplast prevents the medicine of circulating tumor cell to the infiltration of periplast.
2. composition of medicine according to claim 1, the wherein said medicine that improves the inherent tumour immunity function of body can be selected from a kind of in dammarane type (comprising panoxadiol Class and panaxatriol Class) ginsenoside, oleanane type ginsenoside, ganoderan, ganoderan glycoside, Ganoderma triterpenoids, Ganodenic acid, Ganolactone and krestin.
3. composition of medicine according to claim 1, the wherein said medicine that suppresses bone marrow internal recycle activity of tumor cells can be selected from diphosphate, pyrophosphate and a kind of lower than in the POSTN (Periostat) of conventional antibacterial dosage, alendronic Acid (Alendronate), auspicious raw phosphonic acids (Risedronate), group's rice phosphonic acids (Pamidronate), clone phosphonic acids (Clodronate), below phosphonic acids in distress (Etidronate) He Yi nation's phosphonic acids (Ibandronate) and salt and hydrate.
4. composition of medicine according to claim 1, wherein said suppress that circulating tumor cell in blood adheres to and implantation to the medicine of tunica intima can be selected from beautiful she take charge of ketone, mifepristone, from the alkaloid of Folium Et Cacumen Murrayae extraction, from the ecdysone (Ecdysterone) of Radix Achyranthis extraction, and a kind of in S-NITROSOCAPTOPRIL and salt and hydrate.
5. composition of medicine according to claim 1, the medicine that the wherein said circulating tumor cell suppressing in blood is assembled in blood vessel can be selected from non_steroidal anti_inflammatory drug, comprises a kind of in aspirin, acetyl aminophenol, celecoxib (Celecoxib) and indometacin (Indomethacin) and salt and hydrate.
6. composition of medicine according to claim 1, the wherein said medicine of strengthening periplast's structure is lysine and salt and hydrate.
7. composition of medicine according to claim 1 can be used as dosage form separately administration simultaneously respectively.
8. composition of medicine according to claim 1 can be used as and forms single dosage form.
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| CN201210379714.9A CN103705926A (en) | 2012-10-08 | 2012-10-08 | Pharmaceutical composition used for preventing primary tumor metastasis after exairesis |
| CN201610888807.2A CN106421795A (en) | 2012-10-08 | 2012-10-08 | Medicinal composition for preventing re-metastasis of primary tumor after excision |
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