CN102579423A - Compound medicinal composition for improving oral bioavailability of paclitaxel and application thereof - Google Patents
Compound medicinal composition for improving oral bioavailability of paclitaxel and application thereof Download PDFInfo
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- CN102579423A CN102579423A CN2012100002489A CN201210000248A CN102579423A CN 102579423 A CN102579423 A CN 102579423A CN 2012100002489 A CN2012100002489 A CN 2012100002489A CN 201210000248 A CN201210000248 A CN 201210000248A CN 102579423 A CN102579423 A CN 102579423A
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Abstract
The application is an invention patient divisional application which is applied on January 11, 2011 with the application number 201110004638.9 and is named 'a compound medicinal composition for improving the oral bioavailability of paclitaxel and an application thereof'. The invention discloses a compound medicinal composition for improving the oral bioavailability of paclitaxel and an application thereof. The invention further discloses a medicinal composition containing the compound medicinal composition and a paclitaxel monomer compound. The compound medicinal compound disclosed by the invention can be used for improving the oral bioavailability of the paclitaxel, and can contribute to enhancing the antic-cancer effect of the paclitaxel when used for preparing an anti-cancer medicament. In the compound medicinal composition, the paclitaxel is taken as a main anti-cancer component, and the Chinese medicine-extracted monomer compound is used for restraining the first pass effect of the paclitaxel, so that the oral bioavailability and anti-cancer effect of the paclitaxel are improved. As proved by experimental research, the compound medicinal composition is prepared into an oral medicament, and the blood concentration and anti-cancer effect of orally-taken paclitaxel can be improved.
Description
Technical field
The application is to be 201110004638.9 to application number, and the applying date is on January 11st, 2011, and name is called the dividing an application of application for a patent for invention of " a kind of compound medicament composition and application thereof that improves the paclitaxel oral administration biaavailability ".The present invention relates to field of medicinal compositions, be specifically related to a kind of compound medicament composition and application thereof that improves the paclitaxel oral administration biaavailability.
Background technology
Paclitaxel applies to treat multiple malignant tumor, for example ovarian cancer, cervical cancer, breast carcinoma, laryngeal carcinoma, esophageal carcinoma etc. clinically as a kind of chemotherapy cancer therapy drug with special mechanism.The formulation for paclitaxel that uses clinically at present is injection, because paclitaxel dissolubility in water is very low, and the most of polyoxyethylene castor oil/dehydrated alcohol (1:1 that adopts of the injection that uses now; V/v) improve the dissolubility of paclitaxel as adjuvant, before using with glucose or normal saline solution dilution (Tao Yang, Wu Zongqun. the experiment of antitumor paclitaxel and Clinical advances. Dalian Medical Univ's journal; 2007; 29 (2): 197-199, Tang Fushan, Jiao Haisheng, former Ling Yan etc. formulation for paclitaxel is with progress. Lanzhou University's journal; 2005,31 (2): 97-99).But this injection is because of containing more a large amount of polyoxyethylene castor oils, and discharging histamine during degradation in vivo can cause than severe anaphylactic reaction.Anaphylaxis can be divided into slight anaphylaxis, severe allergic reaction, allergy (being anaphylactic shock) and other symptoms according to clinical manifestation.Slight anaphylaxis generally shows as erubescence, urticaria, erythra, the whole body formication; Severe allergic reaction generally shows as hypotension, tachycardia, uncomfortable in chest, asthma, dyspnea; Symptoms such as anaphylactic shock generally shows as pale complexion, lip cyanosis, dripping sweat, the limbs being moist and cold, can't record blood pressure and pulse even heart beating, respiratory arrest; In addition, also have that blood vessel swells and ache, other symptoms (Liu Chaohui such as chest and limbs pain; Ceng Congyan; 79 routine paclitaxel injections cause the anaphylaxis document analysis. Chinese medicinal application and monitoring, 2010,7 (2): 100-102).The anaphylaxis of paclitaxel injection hinders its clinical practice.
Oral bioavailability of taxol is low, is the major reason that hinders the developmental research of paclitaxel oral formulations.Along with going deep into of research; Find the low reason of paclitaxel oral administration biaavailability except its poorly water-soluble, paclitaxel is another major reason that reduces its oral administration biaavailability as the substrate of a kind of running efflux protein of intestinal P-glycoprotein (P-gp).The efflux pump effect of P-gp makes paclitaxel be absorbed into the blood minimizing.Therefore, utilization P-gp inhibitor improves oral bioavailability of taxol by extensive utilization, but used P-gp inhibitor is the compound monomer of drug effect at present, has limitation for the utilization of cancer patient.For example, ciclosporin A (CsA) is a kind of immunosuppressant, is the substrate of P-gp simultaneously, can effectively improve oral bioavailability of taxol, but because CsA has certain untoward reaction, limits its application as the P-gp inhibitor.So screening multiple P-gp inhibitor with clinical application, available property, low toxic and side effects is the important research work that breaks through this technical bottleneck.
Simultaneously, Cytochrome P450 (CYP) is the metabolic enzyme of paclitaxel, CYP2C wherein, and the 3A hypotype is main metabolic enzyme (Jennifer Spratlin, Michael B. Sawyer; Pharmacogenetics of paclitaxel metabolism. Oncology/Hematology, 2007, (61) 222-229).In the oral absorption process, be metabolized to 6 Alpha-hydroxy paclitaxels, 3 '-p-hydroxyl paclitaxel and 6 α by the CYP of gastrointestinal tract and liver, 3 '-p-hydroxyl paclitaxel, Rahman etc.
[9]Research shows that Cytochrome P450 2C8 (CYP2C8) mainly is metabolized to 6 Alpha-hydroxy paclitaxels with paclitaxel; (Cresteil T such as Cresteil; Monsarrat B, Alvinerie P, Treluyer JM; Vieira I, Wright M. Taxol metabolism by human liver microsomes:identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res 1994; 54 (2): 386 – 92) metabolism of the main corresponding 3 '-p-hydroxyl paclitaxel of Cytochrome P450 3A4 (CYP3A4); (Harris JW such as Harris; Rahman A; Kim BR, Guengerich FP, Collins JM. Metabolism of taxol by human hepatic microsomes and liver slices:participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 1994; 54 (15): 4026 – 35) find that Cytochrome P450 3A4 (CYP3A4) only participates in the metabolism of 3 '-p-hydroxyl paclitaxel, does not participate in the metabolic process of 6 Alpha-hydroxy paclitaxels.Though its metabolite is different, be the hydroxylation metabolism product.3 kinds of main metabolites do not have cytotoxicity for tumor cell; But has cytotoxicity (Henningsson A for the human bone marrow cell; Karlsson MO, Vigano L, Gianni L; Verweij J, Sparreboom A. Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol 2001; 19 (20): 4065 – 73).
(Baker SD such as Baker SD; Verweij J; Rowinsky EK, et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991 –, 2001. J Natl Cancer Inst 2002; 94 (24): 1883 – 8) report, the paclitaxel metabolism has only the paclitaxel of 5-10% to eliminate through kidney mainly by oxidative metabolism and bile excretion.
In sum, the subject matter of oral absorption paclitaxel concentrates on the oxidative metabolism with Cytochrome P450 that effluxes of P-gp mediation, and in other words, the gastrointestinal tract in the first pass effect, liver and gallbladder are the low relevant organs of paclitaxel oral administration biaavailability.So effectively improve the paclitaxel bioavailability, key is the P-gp hypotype and the CYP hypotype that effectively suppress relevant in intestinal, liver and the gallbladder.So the inhibitor of utilization cell absorbing model and the effective low toxicity of whole animal experimentation could fundamentally solve the problem of paclitaxel oral absorption.Along with Chinese medicine gos deep into what clinicing aspect was studied, Chinese medicine monomer has the characteristics of its low toxic and side effects as the utilization of P-gp, CYP inhibitor or derivant, helps becoming the monomer compound oral administration preparation with the paclitaxel compatible combination.But do not see that Chinese medicine monomer and paclitaxel compatibility process the report of the clear and definite compound preparation of mechanism (pharmaceutical composition).
Summary of the invention
The objective of the invention is to absorb problems such as the bioavailability that exists in the paclitaxel is low according to existing oral, provide a kind of can improve the paclitaxel oral administration biaavailability, metabolic when reducing first pass effect to paclitaxel, have a compound medicament composition low toxic and side effects, that can improve blood drug level.
A further object of the invention is to provide and contains above-mentioned taxol drug that can compound medicament composition.
Another purpose of the present invention is to provide the application of above-mentioned compound medicament composition.
Above-mentioned purpose of the present invention is achieved through following technical scheme:
A kind of compound medicament composition that improves the paclitaxel oral administration biaavailability; Comprise the Chinese medicine extraction monomeric compound, said Chinese medicine extraction monomeric compound is the two or more mixture in deoxyschizandrin, schisantherin B and piperine, naringenin, apigenin, genistein, biochanin, baicalin, kaempferol, catechin, curcumin, silymarin, emodin, chlorogenic acid, glycyrrhizic acid, psoralen, the epimedium aglucone.
A kind of pharmaceutical composition that contains above-mentioned compound medicament composition and paclitaxel monomeric compound, the mass ratio of said paclitaxel monomeric compound and Chinese medicine extraction monomeric compound is 1:1 ~ 100, is processed into oral formulations.
The molecular formula of paclitaxel: C47H51NO14
Chemical name:: 5 β, 20-epoxy-1,2 α, 4,7 β, 10 β, 13 α-hexahydroxy taxane-11-alkene-9-ketone-4,10-diacetate esters-2-benzoate-13 [(2 ' R, 3 ' S)-N-benzoyl-3-phenylisoserine ester]
Physicochemical property: white crystals body powder.Odorless, tasteless.Water insoluble, be soluble in chloroform, acetone and other organic solvent.
The present invention has the inhibiting Chinese medicine monomer of P-gp through the screening of MDR1-MDCK II cell model; And tentatively illustrate its mechanism of action through the expression of ATPase; Through the blood drug level of rat after its medicine of body experimentation makes up in twos, carry out the antitumor drug effect screening of nude mice experimentation drug regimen at last; Finally, through having the medicine that improves paclitaxel oral administration biaavailability and anti-tumor activity below repeatedly screening is confirmed: schisantherin B, deoxyschizandrin, piperine, naringenin, apigenin, genistein, biochanin, baicalin, kaempferol, catechin, curcumin, silymarin, emodin, chlorogenic acid, glycyrrhizic acid, psoralen, epimedium aglucone etc.
The compound medicament composition that the present invention improves the paclitaxel oral administration biaavailability can be used to improve the paclitaxel oral administration biaavailability, can also be used to improve the anticancer effect of paclitaxel.
The present invention becomes anticarcinogen through above-mentioned compound medicament composition being combined with the paclitaxel monomeric compound, preparing, and can be used for prevention or treatment Cancerous disease.
Compared with prior art, the present invention has following beneficial effect:
The present invention not only effectively improves oral bioavailability of taxol through the Chinese medicine monomer combination, and improves its anti-tumor activity.
At first; Through the activity of two-way conveyer method research Chinese medicine monomer at the MDR1-MDCK of P-gp high expressed II cell model; And the expression through western blot technical measurement P-gp ATPase, according to it ATPase activity is categorized as P-gp with Chinese medicine monomer and suppresses or adjusting control agent; It suppresses first pass effect in the research of body rat experiment through it again, finds under study for action, compare with oral paclitaxel matched group, and behind the Chinese medicine monomer compatibility, the C of paclitaxel
Max, pharmacokinetics index such as AUC is significantly increased, and explains that it has the effect that suppresses first pass effect, increases the oral absorption of paclitaxel.After it had the first pass effect inhibitory action in confirmation, the drug effect of the negative tumor nude mice experimentation compositions of utilization, result showed after the paclitaxel compatibility Chinese medicine monomer, to have more significant function of tumor inhibition than independent oral paclitaxel.
Toxicity research shows that with the paclitaxel injection contrast, indexs such as the mortality rate of compositions (paclitaxel compatibility Chinese medicine monomer), body weight have significant advantage, explain that the toxic and side effects of drug regimen is low.
Drug regimen of the present invention can be through 2 or above Chinese medicine monomer compatibility paclitaxel or its oral administration biaavailability of its extract enhancing.
Oral formulations of the present invention can be oral liquid, tablet, capsule, granule; The crude drug of medicine of the present invention (paclitaxel and above-mentioned various active substance) can add various conventional adjuvant required when preparing different dosage form, is prepared into oral formulations like disintegrating agent, binding agent, lubricant, fluidizer etc.
The present invention screens different drug combination, because the clear and definite relatively multiformity with combination of its mechanism of action can be selected suitable drug regimen according to various cancers and relevant disease flexibly, help the popularization of the present invention at clinical application.
The specific embodiment
Come further to explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
Embodiment 1 effect experiment
MDR1-MDCK II cell model experimental result:
Be determined at UPLC-MS/MS under the effect of variable concentrations Chinese medicine monomer, concentration is the paclitaxel of l μ M is transported to the AP face through the MDRI-MDCKII cell monolayer concentration.BL-AP transports apparent infiltration coefficient P
AppValue is seen table 1.Experimental result shows that various Chinese medicine monomer have certain inhibition paclitaxel and efflux.
The infiltration coefficient of the various Chinese medicine monomer of table 1
The influence heavy of Chinese medicine ingredients associating paclitaxel oral administration to people's lung cancer A549 cell transplanted tumor in nude mice tumor:
After administration finished, each medication group tumor weight average was lower than matched group, and the result sees table 2,3.Except that paclitaxel suspension oral gavage group, heavy the comparing with matched group of the tumor of all the other each groups all has significant difference.
Table 2 nude mice experimental tumor tumor and suppression ratio
Body weight change before and after the administration of table 3 nude mice
The preparation of embodiment 2 capsules
The ratio of each crude drug:
Paclitaxel 10 gram glycyrrhizic acids 10 grams
Method for preparing:
Behind the drug regimen mix homogeneously, adopt " mixing method of progressively increasing " and the starch-mixed adding appropriate amount of starch of 1980 grams to stir, add an amount of Pulvis Talci, mixing, the encapsulated capsule of processing is processed 2000 of capsules altogether.
Embodiment 3 particulate preparations
The ratio of each crude drug:
Paclitaxel 10 gram glycyrrhizic acids 10 grams
Method for preparing:
Behind the drug regimen mix homogeneously, adopt " mixing method of progressively increasing " and the starch-mixed adding appropriate amount of starch of 1980 grams to stir, granulate, drying is processed granule, is distributed into 2000 bags.
The preparation of embodiment 4 tablets
The ratio of each crude drug:
Paclitaxel 10 gram glycyrrhizic acids 10 grams
Method for preparing:
Step 1)～3) with embodiment 1;
Behind the drug regimen mix homogeneously, adopt " mixing method of progressively increasing " and the starch-mixed adding appropriate amount of starch of 1980 grams to stir, add an amount of Pulvis Talci, magnesium stearate, the tablet machine tabletting is processed 4000.
The preparation of embodiment 5 capsules
The consumption of the glycyrrhizic acid among the embodiment 1 is adjusted into 20 grams, and all the other are with embodiment 1.
The preparation of embodiment 6 capsules
The consumption of the glycyrrhizic acid among the embodiment 1 is adjusted into 200 grams, and all the other are with embodiment 1.
Claims (8)
1. a medicine that improves the paclitaxel oral administration biaavailability is characterized in that the extraction monomeric compound for biochanin A.
2. a pharmaceutical composition that comprises paclitaxel is characterized in that said pharmaceutical composition comprises the medicine of paclitaxel monomeric compound and the described raising paclitaxel of claim 1 oral administration biaavailability.
3. the pharmaceutical composition that comprises paclitaxel according to claim 2, the mass ratio that it is characterized in that said paclitaxel monomeric compound and Chinese medicine extraction monomeric compound is 1:1 ~ 100.
4. the pharmaceutical composition that comprises paclitaxel according to claim 3 is characterized in that said compositions through conventional method, adds adjuvant, and preparation becomes peroral dosage form.
5. the pharmaceutical composition that comprises paclitaxel according to claim 4 is characterized in that said peroral dosage form is tablet, (soft) capsule, pill, oral liquid, syrup, granule, powder, unguentum, drop pill, slow releasing preparation or controlled release preparation.
6. the application of the described medicine of claim 1 in improving the paclitaxel oral administration biaavailability.
7. the application of the described medicine of claim 1 in the anticancer rate that improves paclitaxel.
8. the described application of pharmaceutical composition in preparation prevention or treatment Cancerous disease that comprises paclitaxel of claim 2.
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| SEAN X. PENG, DAVID M. RITCHIE: "Altered Oral Bioavailability and Pharmacokinetics of", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| 张明发等: "甘草酸的抗肿瘤作用", 《上海医药》 * |
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Application publication date: 20120718 |