CN106421795A - Medicinal composition for preventing re-metastasis of primary tumor after excision - Google Patents

Medicinal composition for preventing re-metastasis of primary tumor after excision Download PDF

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CN106421795A
CN106421795A CN201610888807.2A CN201610888807A CN106421795A CN 106421795 A CN106421795 A CN 106421795A CN 201610888807 A CN201610888807 A CN 201610888807A CN 106421795 A CN106421795 A CN 106421795A
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medicine
circulating tumor
tumor cell
medicines
phosphonic acids
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贾力
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • 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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/567—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 substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/074—Ganoderma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/21—Amaranthaceae (Amaranth family), e.g. pigweed, rockwort or globe amaranth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Abstract

The invention provides a combination medicine capable of comprehensively preventing re-metastasis of primary tumor after excision. The combination medicine comprises five types of medicines. The medicines include medicines capable of improving intrinsic tumor immunity functions of organisms, medicines capable of inhibiting the activity of circulating tumor cells in bone marrow, medicines capable of inhibiting circulating tumor cells in blood from being adhered and implanted in endangium, medicines capable of preventing the circulating tumor cells in the blood from being aggregated in blood vessels and medicines capable of reinforcing the structures of tissue matrixes. Different tumor metastasis sites are respectively controlled by each type of medicines. The combination medicine has the advantages that the five types of medicines are optimally combined with one another, and accordingly re-metastasis of the circulating tumor cells in the blood can be effectively and safely prevented after tumor surgery.

Description

The Pharmaceutical composition that prevention primary tumor retransfers after surgery excision
Technical field
The present invention relates to be optimized combination with the medicine of five types, in order to prevent comprehensively, safely or auxiliary Treatment tumour after surgery excision primary tumor for the mammalian subject retransfers (or recurring) again.
Background technology
The defect of existing technologies and beneficial effects of the present invention：Over more than 50 year, other major diseases (heart disease etc.) The death rate significantly (＞ 60%) have dropped, but cancer mortality only reduces about 5%, and wherein the overwhelming majority dies from tumour Transfer.The death causing because of metastases is current one warp happy and peace, in the urgent need to address global, relevant Ji, society and Scientific And Technical Problems.What the research and development of traditional main flow " anticarcinogen " were walked is the stupid late of " anticancer again after cancer metastasis " Route, produces little effect.Chemotherapeutics " effectively " can not efficiently control cancer metastasis at present, and toxic and side effect is big, sick People's quality of the life reduces, and family members bear sharp increase.The more important thing is, " anticarcinogen " at all cannot reversing tumor transporting patient dead Die！The present situation of domestic and international oncotherapy and Existing Defects are simplified and is exactly：Entity tumor can use surgical resection in early days, Its success rate up to more than 95% (need not " anticarcinogen ", unless can not perform the operation！ ).Operation again cannot to metastases When whole body excises the tumor mass having shifted one by one, " anticarcinogen " is also invalid；And tumour patient after surgery excision early stage do not have Have and can remove circulating tumor cell, and prevent the adhesion of circulating tumor cell in the future and the medicine of invasion and attack.Asymptomatic " patient " Have to leave it to chance, until metastases there occurs after 3-5.The possibility retransferring in various tumours 3-5 after surgery Property is 30-70%.Retransferring after comprehensively preventing tumor operation with composition of medicine be an ignored theory, technology and The global great science and technology of product is blank.
The chemotherapeutics of current tumour can be divided into following a few class：1) the damaged agent (DNA damaging agents) of DNA； 2) tubulin targeting agent (Tubulin-targeted agents) is such as taxol etc.；3) topoisomerase enzyme inhibitor (Topoisomerase inhibitors) is such as camptothecine, ABT-888；4) antimetabolite (Antimetabolites/ Nucleosides) ；5) monoclonal antibody；6) EGF tyrosine kinase inhibitor such as Bcr-abl tyrosine-kinase Enzyme inhibitor (Gleevec)；7) farnesyl transferase inhibitor (Farnesyl transferase inhibitors； FTI) ；8) proteasome inhibitor (proteasome inhibitor)；9) vascular endothelial growth factor receptor inhibitors； 10) NMPI (matrix metalloproteinase inhibitors；MMP) ；11) epoxy Change enzyme-2 (cyclooxygenase-2；COX-2) inhibitor.12) amcinonide (Hormonal agents) as Tamoxifen ；This kind of medicine can cause cell (cancer cell and normal cell) dead in isolated test really.Targeting class Medicine (Targeteddrugs；Signaling agents) only to minority, special ethnic group works, and the tumour of these ethnic groups need to be filled Dividing and expressing this target protein, such medicine just can work.This has just limited to the range of targeting class medicine.Targeting class medicine is as newly The therapeutic index of angiogenic inhibitor bevacizumab is little, shows that this type of medicine also has greatly deficiency, including produce patient seriously Bone marrow suppression.Cytotoxic drug acts on the cancer cell of division and breeding rapidly, but it is thin also to act on normal gut epithelium Born of the same parents, hair cell and leucocyte.Tumour cell is easily generated drug tolerance to cytotoxic drug.In a word, " anticarcinogen " is in research and development Upper achievement is little with application.
The result of the clinical testing of 22 times of 1990-2004 is analyzed, (the Clin.Oncol.16 such as Morgan ：549-560 ；2004) find that current " anticarcinogen " is only capable of making 5 annual survival rates of tumour patient to increase by 2.1%.Meanwhile, this A little medicines are invalid to melanoma, the cancer of the uterus, prostate cancer and kidney.The disappointed result of these anticarcinogens is attributed to：Medicine The serious toxicity of thing itself, patient's quality of the life declines, and the ability of autoimmunity and rehabilitation is hit by anticarcinogen, and tumour The tolerance to medicine for the cell.Rustin et al. (Lancet 2010；376 ：1155-1163) reported, by ovary carninomatosis People when serum CA125 level returns to normal after paclitaxel treatment, is randomly divided into two groups, in early days chemotherapy group and prolonging Slow chemotherapy group.In early days chemotherapy group (265 people) and postpone chemotherapy group (264 people) median survival be respectively 25.7 months and 27.1 months, two groups of median survival were without significant difference.The median survival of chemotherapy group patient shortens two months on the contrary in early days, prompting The toxic and side effect to people for the medicine.Chemotherapeutics be not prevention tumor operation after transfer medicine.
Presently used anticarcinogen is invalid to dormancy cancer cell, if Doxorubicin is to the dormancy being expelled in Mice Body The murine mammary cancer cells of phase length is invalid.Surgical resection and or radiotherapy are taked in the primary tumor treatment of people more.Postoperative residual Remaining tumour cell will become rest cell (dormant cells) and be hosted by marrow and its hetero-organization.Pre-according to U.S.'s disease Prevent and control centre (Center for Disease Control, CDC) report (the CDC Weekly 60 (09) of 2011； 269-272,2011), in 2007, U.S. of 1,2,000,000 will be had to become treatment of cancer after survivor, these people are cancers The excessive risk ethnic group of disease transfer diffusion.Report [1998 according to Lancet；351(9114) ：1451-67], patients with mastocarcinoma is at hand The probability recurring again in postoperative 3 years is 40%.According to the postoperative statistics of more than 20,000 colorectal cancer patients, 2 phase colorectal cancer patients hands In postoperative 3 years, recurrence rate is 74% (J.Clin.Oncol.25 again：4569-73 ；2007).Primary tumor is at surgery excision After 3-5 in be cancer metastasis diffusion the excessive risk phase, the active circulating tumor cell wherein being formed can be in blood By adhering to endangium (adhesion), invasion and attack, extravasation (extravasation), forming micro-stove of metastases until swelling Knurl entire transformation is spread.Prevent resurrection, the adhesion of suppression circulating tumor cell, invasion and attack, the extravasation of dormancy tumour cell and formed Micro-stove point of metastases is the characteristic of the present invention！Tumour once shifts diffusion, can reverse without medicine.This is just as preventing termite population As infringement to a luxurious house, effectively preventing method be at termite district occurred frequently bait trapping and killing termites outside luxurious house.Once white Ant colony has invaded each organ of luxurious house, the late period that it is hard to guard against that has been arrived.Outside the first-selected therapeutic scheme of primary tumor is Section's surgery excision, it is not necessary to " anticarcinogen "；There is no again this side when the transfer needing chemoprophylaxis Post operation tumour is spread at present The medicine in face.It is contemplated that fill up after chemoprophylaxis tumor operation to retransfer this ignored global great science and technology empty In vain.
Content of the invention
The present invention provides mammalian subject a kind of comprehensive method, to prevent and to control or treatment primary tumor Retransferring after surgery excision.The method includes the treatment giving patient effective amounts or prevention primary tumor at surgery excision After the composition of medicine (code name HAMPT) that retransfers, this composition of medicine is made up of the medicine of following five types：1) body is improved The medicine of inherent tumour immunity function；2) can suppress circulating tumor cell in marrow (circulating tumor cells, Circulating tumor cell) medicine that brings back to life；3) circulating tumor cell in blood can be suppressed to adhere to and implantation arrives endangium Medicine；4) can the medicine assembled in intravascular of the circulating tumor cell in anti-Hemostatic Oral Liquid；5) strengthen periplast structure from And prevent the medicine of the infiltration to periplast for the circulating tumor cell.The medicine of each of the above type controls metastases respectively Different loci.The technological core of the present invention is the composition of medicine researched and developed for the circulating tumor cell of trace in blood.
Describe in detail：The present invention is by giving mammalian subject following composition of medicine, to prevent and control or treat former The risk that the property sent out tumour retransfers after surgery excision.Prevention that the method includes giving described patient effective amounts and control or The composition of medicine that treatment primary tumor retransfers after surgery excision, this composition of medicine is by the medicine group of following five types Become：1) improve in body the medicine of tumour immunity function；2) medicine that circulating tumor cell brings back to life in marrow can be suppressed； 3) circulating tumor cell in blood can be suppressed to adhere to the medicine with implantation to endangium；4) can circulation in anti-Hemostatic Oral Liquid The medicine that tumour cell is assembled in intravascular；5) strengthen the structure of periplast thus prevent circulating tumor cell to tissue base The medicine of the infiltration of matter.
The interior example at the medicine of tumour immunity function of body that improves that can be used for the present invention includes but is not limited to following medicine Thing and salt thereof and ester：Ginsenoside (Ginsenosides) (Jia et al.Curr.Med.Chem.16：2475-84,2009 ；Curr.Med.Chem.16 ：2924-42,2009).Ginsenoside includes dammarane type [panoxadiol and panaxatriol Compound：Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, notoginsenoside R4, Rs1, Rs2, Rs3, Rs4, Rb1, Rb2, Rc, ] and oleanane type (protopanaxatriol) compound (Re, Rf, Rg1, Rg2, Rg3), GL-B Rd) (polysaccharides), GL-B glucoside (polysaccharopeptides), ganodenic acid (triterpenoids), spirit Sesame acid (ganoderic acids), Ganolactone (ganolactone) and coriolan (YunZhi polysaccharopeptide).The interior medicine in tumour immunity function of improved body being preferred for the present invention is ginseng soap Glycosides.
Can be used for the example of medicine that circulating tumor cell in the suppression marrow of the present invention brings back to life including but not limited to following Medicine and salt thereof and ester：Diphosphate, pyrophosphate and less than commonly using the POSTN (Periostat) of antibacterial dosage, A Lun phosphine Acid (Alendronate), auspicious raw phosphonic acids (Risedronate), send rice phosphonic acids (Pamidronate), clone phosphonic acids (Clodronate), strategic point below phosphonic acids (Etidronate) and adopted nation's phosphonic acids (Ibandronate) and salt thereof and hydrate.Preferably Medicine for circulating tumor cell activity in the suppression marrow of the present invention is alendronic acid or POSTN.
The circulating tumor cell that can be used in the suppression blood of the present invention adheres to the reality with implantation to the medicine of endangium Example includes but is not limited to agents and salt thereof and ester：Metapristone, mifepristone, kamuning alkaloid include yuehchukene, The steroidal compounds ecdysone (ecdysterone) that achyranthes aspera extracts, and Snopori and salt thereof and hydrate.Preferably use It is metapristone in this class medicine of the present invention.
Can be used for the example of medicine that the circulating tumor cell in the suppression blood of the present invention assembles in intravascular include but It is not limited to following non_steroidal anti_inflammatory drug and salt thereof and ester：Aspirin, Paracetamol, Sai-Mi-Xi-Bu (celecoxib) With indocin (indomethacin) and salt thereof and hydrate.This class medicine being preferred for the present invention is aspirin.
Can be used for the present invention strengthens periplast's structure thus the circulating tumor cell in anti-Hemostatic Oral Liquid to periplast The medicine of infiltration be lysine and salt thereof and hydrate.
In composition of medicine treatment method described in the invention, the active component of above five types is combined into single Formulation is administered, or can separate administration as separate dosage forms by preferably a kind of active component from five types.When the independent agent of use When type separates the scheme being administered, separate dosage forms can give in same time (i.e. simultaneously) or respectively staggering time (i.e. continuous) Above medicine.This drug regimen includes this type of medically acceptable methods of administration all, formulation and dosage.Although preferably The medicine of this 5 type is with dosage regimen while once a day, but present invention additionally comprises other dosage regimens various, as often It once, twice or more times give above single combination dosage forms or separate dosage forms separately, to maintain effective blood drug concentration. The single peroral dosage form preferably being become by the active ingredient combinations of above five types.Other embodiments of the present invention include with one Kind or the Pharmaceutical composition of multiple pharmaceutically acceptable carrier.
Herein, " salt " of medicine means organic or inorganic alkali and the reacted compound of free acid of medicine.Especially
It is the salt being formed with cation such as sodium, potassium, aluminium, calcium, lithium, magnesium, zinc and tetramethylammonium, and with ammonia, amine (such as ethylenediamine, N- Methyl glucose osamine, diethanol amine, diethylamine, phenyl ethylamine) salt that formed.
Herein, " the treatment effective dose " of medicine means that medicine can produce pharmacological action to patient (animal or people) Comparatively safe dosage." 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 centre, it is possible to as racemic modification, racemic Mixture and occurring as each diastereomer or enantiomer, this type of isomeric form all and mixture thereof are included in the present invention Within the scope of.The crystal formation of compound described in the invention can exist as polymorphic, can also be with water or conventional organic molten Dosage form becomes solvate.This type of solvate and hydrate, and anhydrous composition is included within the scope of the present invention.This Bright described compound can contain olefinic double bonds (such as yuehchukene).Unless otherwise stated, include that E and Z geometry is different Structure body.
With anticancer agents medication or when separately medication is to reach auxiliary for treating cancer, the dosage of the medicine of the present invention should Select according to many factors, including tumour when patient class, race, age, body weight, sex and tumour discovery and excision is divided Phase；Method of administration；The renal function of patient and liver function；And the particular compound that uses or its salt or ester.Here, anticarcinogen Definition includes medicine, microtubule inhibitors, topoisomerase, antimetabolite and the hormone drug destroying DNA.
Two or more different activating agents are used for conjoint therapy together, it is necessary to consider the respective effect of medicine and by it Combine the interaction reaching together, so that it is determined that retransfer after can preventing, resist or stop tumor operation safely controls Treat effective dose or prevention effective dose.The effective dose of combination depends on many factors, including for the particular compound of combination Activity, compound metabolic stability and effect when length, the specified disease symptom age of patient, body weight, general health, Sex, diet, administering mode and time, concrete dosage level and administration frequency and excretion rate.
In order to prevent and treating disease, medicine of the present invention can be fabricated to per os with other carriers pharmaceutically acceptable Clothes, locally, parenteral, suck, spraying, per rectum or Via vagina give the formulation of active component (alone or in combination).Stomach and intestine Externally applied drug includes hypodermic injection, intravenous injection, intramuscular injection, intracisternal injection or infusion methods.
The single medicine of the present invention or composition of medicine can use the form being suitable for orally using, as tablet, lozenge, lozenge, Water or oil suspension, dispersible pulvis or granula, emulsion, hard shell capsules or soft capsule, solution, syrup and elixir.Can be according to medicine It is prepared as the composition orally using by method any known to composition preparation field, in order to obtain exquisite good to eat medicinal system Agent, such composition generally comprises one or more preparations selected from sweetener, flavouring, colouring agent and preservative.These are composed Shape agent can be diluent, such as lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate；Granulation agent and disintegrant, as corn forms sediment Powder or alginic acid；Adhesive, such as starch, gelatin or Arabic gum；And lubricant, such as magnesium stearate, stearic acid or talcum powder.Piece Agent can not be coated or can be coated.Coating can postpone medicine decomposition in the gastrointestinal tract, thus extends the effect of medicine Time.For example, the up time postpones material such as glycerin monostearate or distearin.
It should be appreciated by those skilled in the art that in the case of without departing substantially from the general principle of the present invention and scope, can be to this Method carries out various change, change, modification, replacement, deletion or adds.For example, chemical combination of the present invention is used due to any indication The reaction of the mammalian subject of thing or composition treatment is different, and the effective dose outside given dose listed above also can be fitted With.Equally, it was observed that concrete pharmacological reaction whether can there is pharmaceutical carrier according to selected particular active compounds, with And use preparation type and administering mode and different.These changes or difference meet the purpose of the present invention and practice.
Following embodiment is further elucidated with the present invention, but the present invention is not limited only to this：
Detailed description of the invention 1
B16-F10 mouse melanoma cell strain tends to be formed the transfer of tumour cell at mouse lung tissue.B16-F10 mouse After melanoma cell strain is cultivated, add 0.02% EDTA to make it suspend, contain 7x10 with every mL4The cell liquid of cell is by little Caudal vein is slowly injected.Inject first 3 days at this and composition of medicine with high dose low to mouse stomach every day after injection.In After cell infusion, the 14th day ether puts to death mouse.Take lung, 10% formalin process, cut sections for microscopic examination, the lung B16-of administration group The control group that F10 cell colonies quantity is not considerably less than administered, and the increasing of the dosage of the minimizing of cell colonies and composition of medicine Addition direct ratio.This experiment shows that composition of medicine has the effect to lung for the suppression B16-F10 Nasopharyngeal neoplasms.
Detailed description of the invention 1
Prepared by the tablet of composition of medicine：Will be containing oleanane type ginseng sapoglycoside Rg 3 (100mg), POSTN (10mg), her department beautiful Ketone (2mg), aspirin (25mg) and lysine (10mg) isoreactivity composition are beautiful with microcrystalline cellulose (100mg) and modification Rice starch (100mg) sieves after mixing and being prepared as particle.Particle after sieving and modified corn starch (100mg) and tristearin Then mixture is pressed into tablet by acid magnesium (1mg) mixing.

Claims (1)

1. one kind is comprehensively prevented the composition of medicine that primary tumor retransfers after surgery excision, it is characterised in that：By five Class medicine forms：Improve in body the medicine of tumour immunity function, in suppression marrow circulating tumor cell activity medicine, Circulating tumor cell in suppression blood adheres to exist with the circulating tumor cell in implantation to the medicine, anti-Hemostatic Oral Liquid of endangium Medicine and the reinforcement structure of periplast that Ink vessel transfusing is assembled thus the medicine that prevents the infiltration to periplast for the circulating tumor cell Thing；
Described improve in body the medicine of tumour immunity function be GL-B, GL-B glucoside, ganodenic acid, glossy ganoderma One in acid, Ganolactone and coriolan；
In described suppression marrow, the medicine of circulating tumor cell activity is diphosphate, pyrophosphate, alendronic acid (Alendronate), auspicious raw phosphonic acids (Risedronate), send rice phosphonic acids (Pamidronate), clone phosphonic acids (Clodronate), in strategic point below phosphonic acids (Etidronate) and adopted nation's phosphonic acids (Ibandronate) and salt thereof and hydrate A kind of；
Circulating tumor cell in described suppression blood adhere to and implantation to the medicine of endangium be mifepristone, from kamuning In the alkaloid extracting, the ecdysone (Ecdysterone) extracting from achyranthes aspera, and Snopori and salt thereof and hydrate One；
The medicine that circulating tumor cell in described anti-Hemostatic Oral Liquid is assembled in intravascular is Paracetamol, celecoxib (Celecoxib) one and in indocin (Indomethacin) and salt thereof and hydrate；
The described reinforcement structure of periplast thus prevent the medicine of the infiltration to periplast for the circulating tumor cell from being lysine.
CN201610888807.2A 2012-10-08 2012-10-08 Medicinal composition for preventing re-metastasis of primary tumor after excision Pending CN106421795A (en)

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CN106420693B (en) * 2016-09-19 2019-06-04 福州大学 Ginsenoside ROApplication in preparation metastases prophylactic agent
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