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CN104434947A - Anti-cholangiocarcinoma medicine composition and application thereof - Google Patents

Anti-cholangiocarcinoma medicine composition and application thereof Download PDF

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Publication number
CN104434947A
CN104434947A CN201410623889.9A CN201410623889A CN104434947A CN 104434947 A CN104434947 A CN 104434947A CN 201410623889 A CN201410623889 A CN 201410623889A CN 104434947 A CN104434947 A CN 104434947A
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capecitabine
cancer
lacto
pharmaceutical composition
biliary duct
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CN201410623889.9A
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CN104434947B (en
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林绪涛
任莉
张长习
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Binzhou Medical University Hospital
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Binzhou Medical University Hospital
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    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic 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
    • A61K31/185—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
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses an anti-cholangiocarcinoma medicine composition and an application thereof. The medicine composition comprises active components and pharmaceutically acceptable auxiliary materials, wherein the active components comprise capecitabine and 2-lactoyl aminobenzoic acid. By virtue of tests, according to the anti-cholangiocarcinoma medicine composition disclosed by the invention, the effects of cooperatively enhancing the anti-cancer cell proliferation can be achieved by combining 2-lactoyl aminobenzoic acid and capecitabine, so that the treatment purpose of resisting cholangiocarcinoma can be achieved more beneficially.

Description

A kind of pharmaceutical composition of anti-cancer of biliary duct and application thereof
Technical field
The present invention relates to a kind of antitumor drug, particularly relate to a kind of pharmaceutical composition and application thereof of anti-cancer of biliary duct, belong to medical art.
Background technology
Cancer of biliary duct (Cholangiocarcinoma) refers to and is primary in the extrahepatic bile ducts malignant tumor of left and right conjunctive region of hepatic duct to distal common bile duct, its cause of disease it be unclear that, with its morbidity may be relevant because of have: ulcerative colitis, cholelithiasis, Clonorchis sinensis infect, choledochal cyst etc., and these factors can increase the danger that cancer of biliary duct is fallen ill.Clinical manifestation be mainly with epigastric discomfort Progressive symmetric erythrokeratodermia jaundice, inappetence, become thin, pruritus etc.As hemorrhage in tumor ulceration, the performance such as melena or the fecal occult blood testing positive, anemia can be had.
The grade malignancy of cancer of biliary duct is high, very low at European and American areas sickness rate, but becomes ascendant trend at the sickness rate of south east asia and China, and wholistic therapy level is very undesirable, so far without satisfied Therapeutic Method.Owing to occurring that symptom is more late clinically, early diagnosis difficulty, simultaneously because cancer of biliary duct has the biological characteristics along bile duct wall local infiltration, easy infringement Hilar blood vessel and secondary bile duct, the chance few (about 15% ~ 20%) of radical surgery excision, cause local recurrence after routine operation, prognosis poor mean survival time (MST) is 6 ~ 12 months, and 5 annual survival rates are 2% ~ 16.5%.At present, existing scholar successfully clones the expression of somatostatin receptor II type (SSTR-2) from cholangiocarcinoma cell strain RBE, NEC, QBC939, SSP-25, for screening suppresses the medicine of cholangiocarcinoma cell propagation to provide molecular biological Research foundation.As the chemotherapy of important auxiliary treatment means, cancer of biliary duct is all insensitive to chemicotherapy conventional at present, though have scholar report some drugs in a short time curative effect still can, long-term effect is not good, therefore finds new effective chemotherapeutics and has great significance to the clinical treatment improving cancer of biliary duct.
Capecitabine (capecitabine) is a kind of new oral fluorouracil mephenesin Carbamate series antineoplastic medicament, through enzymatic reaction after oral, 5-fluorouracil is degraded in tumor cell, play the antitumor action of high selectivity, stronger activity is had to multiple entity tumor, be mainly used in treatment advanced breast cancer knot/rectal cancer and other solid tumors (An Furong, Ge Shengrong, Zhu Deqiu clinically.The pharmacology of capecitabine and Clinical advances [J]. Chinese Journal of New Drugs and Clinical Remedies, 2002,21 (8): 503-507).Research in recent years shows, gemcitabine associating capecitabine is treated the cholangiocarcinoma patients cannot performed the operation late period and is had good short term effect (Wang Yue, the clinical observation of gemcitabine associating capecitabine treatment Advanced Bile Duct Cancer, middle national health medical science, 2011/16).But gemcitabine needs intravenous drip administration, long-term injecting drug use brings great misery to patient, is unfavorable for the interdependence maintaining patient medication.2-lacto benzoic acid (2-lactoylaminobenzoic acid) a kind ofly from the metabolite of Penicillium fungus Penicillium chrysogenum or P.notatum bacterial strain, is separated the benzoic acid derivative obtained, it is active that current pharmacological evaluation shows that it has good antalgic and inflammation relieving, and less to gastrointestinal stimulation.
At present, still there is no 2-lacto benzoic acid for antineoplastic bibliographical information, more not by the bibliographical information of anti-cancer of biliary duct after itself and other anticarcinogen coupling.
Summary of the invention
In view of most of tumor Drugs is drug administration by injection clinically, the treatment adding patient is painful, therefore the object of the invention is to provide a kind of for anticancer oral drugs by research.
Capecitabine, as oral antitumor drug, be mainly used in treatment advanced breast cancer knot/rectal cancer clinically, and toxic and side effects is larger.In order to play the antitumor efficacy of capecitabine, reduce its toxic and side effects simultaneously, the present inventor is by reducing the consumption of capecitabine, and by itself and 2-lacto benzoic acid use in conjunction, after medication both finding although unexpected to other malignant tumor such as breast carcinoma, colon cancer without good therapeutical effect, cancer of biliary duct is had to the anti-proliferative effect of Synergistic.Based on this research, the object of the present invention is to provide a kind of pharmaceutical composition and application thereof of anti-cancer of biliary duct.
The object of the present invention is achieved like this: a kind of pharmaceutical composition of anti-cancer of biliary duct, and this pharmaceutical composition comprises active component and pharmaceutically acceptable adjuvant, and described active component comprises capecitabine and 2-lacto benzoic acid.In technical scheme preferred for this invention, the active component in this pharmaceutical composition is made up of capecitabine and 2-lacto benzoic acid.
Pharmaceutical composition of the present invention relies on 2-lacto benzoic acid and capecitabine as the synergism of the anti-cancer of biliary duct of active ingredient exerts, inventor is screened by the amount ratio of lot of experiments to these two kinds of components, result be the benzoic quality amount ratio of capecitabine and 2-lacto in the scope of 0.5-20:1 time, the better effects if of its anti-cholangiocarcinoma cell propagation; Further, capecitabine and the benzoic quality amount ratio of 2-lacto can be preferably 1.5-10:1.
In fact, in order to reduce the toxic and side effects of capecitabine, the present invention is more prone to the consumption reducing this active component, especially reduces the consumption of capecitabine, therefore, in the most preferred external embodiment of the present invention, capecitabine and the benzoic quality amount ratio of 2-lacto are 3-5:1.
Obviously, because capecitabine and 2-lacto benzoic acid all can be absorbed with speed faster and play biological activity by gastrointestinal tract, therefore pharmaceutical composition of the present invention is oral formulations.Pharmaceutical units preparation can be that conventional preparation process makes the acceptable any conventional peroral dosage form of pharmaceutics, such as tablet, granule, capsule, dry suspension, drop pill.For enabling above-mentioned dosage form realize, the acceptable adjuvant of pharmacy need be added when preparing these dosage forms, such as: filler, disintegrating agent, lubricant, suspending agent, binding agent, sweeting agent, correctives etc.Filler comprises: starch, pregelatinized Starch, lactose, mannitol, chitin, microcrystalline Cellulose, sucrose etc.; Disintegrating agent comprises: starch, pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose etc.; Lubricant comprises: magnesium stearate, sodium lauryl sulphate, Pulvis Talci, silicon dioxide etc.; Suspending agent comprises: polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, agar, hydroxypropyl emthylcellulose etc.; Binding agent comprises, starch slurry, polyvinylpyrrolidone, hydroxypropyl emthylcellulose etc.; Sweeting agent comprises: saccharin sodium, Aspartane, sucrose, cyclamate, enoxolone etc.; Correctives comprises sweeting agent and various essence.
The present inventor is shown by the result of study of a large amount of in vitro tests, in this index of the transplanted tumor in nude mice Relative tumor rate of increase, drug combination group is less than lacto benzoic acid group, the independent medication group of capecitabine group two, difference has statistical significance (P<0.01), and this illustrates that drug combination group curative effect is significantly better than alone capecitabine or the treatment of 2-lacto benzoic acid.And in drug combination group, capecitabine or the benzoic dosage of 2-lacto are all the half of independent medication group, but tumor killing effect is more obvious, illustrates that therapeutic alliance is more effective than single therapy, and Small dose injection chemotherapy can heighten the effect of a treatment than single chemotherapy, alleviate chemotherapeutics side reaction.Based on above-mentioned achievement in research and in conjunction with the ordinary technical knowledge of those skilled in the art, the present invention also provides a kind of pharmaceutical applications, that is: the application of the compositions of 2-lacto benzoic acid and capecitabine composition in the medicine of the anti-cancer of biliary duct of preparation.Part in vitro tests step of the present invention and result of the test as follows:
The RPMI-1640 culture fluid that human bile duct carcinoma strain QBC939 is placed in containing 10% calf serum is cultivated, goes down to posterity 2 ~ 3 weeks, make 1mL after centrifugal containing 10 7~ 10 8the suspension of individual cell/mL.34 4 ~ 6 week age nude mice, 18 ~ 22g, male and female dual-purpose.Get 1 female Mus wherein and 1 male Mus at random, the tumor cell suspension of every nude mice left lower extremity subcutaneous injection 0.2mL, after about 1 week all there is tumor block in mice with tumor left lower extremity, when tumor grows to diameter about 0.8 ~ 1.0cm, put to death, in super-clean bench, separate tumor, after slightly rinsing, be placed in the RPMI-1640 culture fluid containing 10% calf serum, eye scissors fully shreds, and makes about 1mm 3the tubercle block of size.Remaining nude mice every right lower extremity subcutaneous implantation tubercle block, about 2 ~ 3 pieces, 3-0 absorbable suture is sewed up, and when tumor bearing nude mice lump diameter equal > 0.8cm, Nude Mouse Model is successfully established.
Successful for modeling Transplanted tumor model mice stochastic averagina is divided into four groups, often organizes 8, male and female half and half, each group carries out treatment 3 weeks by the tested material of following dosage respectively:
Blank group: every nude mice gavage 1% Carboxymethyl cellulose sodium solution 0.1ml/10g;
Lacto benzoic acid group: every nude mice presses the 2-lacto benzoic acid of weight gavage 200mg/kg, with gavage after 1% Carboxymethyl cellulose sodium solution suspendible;
Capecitabine group: every nude mice presses the capecitabine of weight gavage 750mg/kg, with gavage after 1% Carboxymethyl cellulose sodium solution suspendible;
Drug combination group: every nude mice presses the 2-lacto benzoic acid of weight gavage 100mg/kg and the capecitabine of 375mg/kg, with gavage after 1% Carboxymethyl cellulose sodium solution suspendible.
Within after administration starts the 2nd, 5,8,11,14,17,20,23 day, measure the long and short footpath of tumor, calculate volume.Gross tumor volume=1/2 × major diameter × minor axis 2.Relative tumour volume (RTV)=Vt/V0 (wherein Vt is gross tumor volume when measuring each time, and V0 is the administration gross tumor volume of the 0th day).The antitumor evaluation index of medicine is the Relative tumor rate of increase=(treatment group RTV/ matched group RTV) × 100%.Calculate the Relative tumor rate of increase, each group transplanted tumor in nude mice Relative tumor rate of increase curve is shown in Fig. 1.
As seen from Figure 1, during alone 2-lacto benzoic acid, the tumor killing effect during whole administration is not obvious, and the Relative tumor rate of increase is all greater than 70%; The tumor killing effect of alone capecitabine when starting administration is better, but post-drug period obviously rebounds, and the Relative tumor rate of increase the last time after administration reaches more than 65%; And giving the passing of drug combination group along with administration time of two kinds of Drug therapys simultaneously, its tumor killing effect is more and more significant, until the Relative tumor rate of increase the last time after administration drops to 23.2%.As can be seen here, concertedness can strengthen the effect that inhibiting tumor cell breeds after 2-lacto benzoic acid and capecitabine coupling, thus more be conducive to the therapeutic purposes reaching anti-cancer of biliary duct.
Accompanying drawing explanation
Fig. 1 is the administration time-Relative tumor rate of increase curve chart of each administration group.
Detailed description of the invention
Be below the preparation embodiment of some preparation that pharmaceutical composition of the present invention comprises, technical scheme of the present invention is done to laying down a definition further and illustrating, but protection scope of the present invention be not limited to following examples.Every do not deviate from the present invention's design change or equivalent substituting include within protection scope of the present invention.
The preparation of embodiment 1 dispersible tablet
Preparation technology: take capecitabine, 2-lacto benzoic acid by recipe quantity, take microcrystalline Cellulose as filler, cross-linking sodium carboxymethyl cellulose is disintegrating agent, 5%PVP 60% alcoholic solution is adhesive, and micropowder silica gel is fluidizer, with fluid-bed marumerization, then tabletting, to obtain final product.
The preparation of embodiment 2 granule
Preparation technology: take the capecitabine of recipe quantity, 2-lacto benzoic acid, starch, dextrin, cane sugar powder mix homogeneously.Separately be incorporated in mixed-powder by 80% appropriate ethanol, mix homogeneously, soft material processed, makes wet grain by 18 order nylon mesh, and about 60 DEG C dry, and 20 mesh sieve granulate, subpackage, to obtain final product.
The preparation of embodiment 3 tablet
Preparation technology: first capecitabine and beta-schardinger dextrin-are put into mortar ground and mixed even, add carboxymethyl starch sodium, amylum pregelatinisatum mix homogeneously successively, finally add the mixing of 2-lacto benzoic acid, make binding agent with the ethanol solution of 5%PVP to granulate, 40 DEG C of dryings, granulate, adds the mixing of differential silica gel, tabletting, to obtain final product.
The preparation of embodiment 4 tablet
Preparation technology: medicinal iron oxide red and capecitabine, 2-lacto benzoic acid are crossed 80 mesh sieves respectively, take by recipe quantity, mix homogeneously, then mix homogeneously by the equivalent method of progressively increasing with hydroxypropyl cyclodextrin, cross 60 mesh sieves, then mix homogeneously with all the other adjuvants of recipe quantity, survey semi-finished product content, calculate sheet weight, tabletting, to obtain final product.

Claims (8)

1. a pharmaceutical composition for anti-cancer of biliary duct, this pharmaceutical composition comprises active component and pharmaceutically acceptable adjuvant, it is characterized in that, described active component comprises capecitabine and 2-lacto benzoic acid.
2. the pharmaceutical composition of anti-cancer of biliary duct according to claim 1, it is characterized in that, described active component is made up of capecitabine and 2-lacto benzoic acid.
3. the pharmaceutical composition of anti-cancer of biliary duct according to claim 1 or 2, it is characterized in that, in described active component, capecitabine and the benzoic quality amount ratio of 2-lacto are 0.5-20:1.
4. the pharmaceutical composition of anti-cancer of biliary duct according to claim 3, it is characterized in that, in described active component, capecitabine and the benzoic quality amount ratio of 2-lacto are 1.5-10:1.
5. the pharmaceutical composition of anti-cancer of biliary duct according to claim 4, it is characterized in that, in described active component, capecitabine and the benzoic quality amount ratio of 2-lacto are 3-5:1.
6. the pharmaceutical composition of anti-cancer of biliary duct according to claim 1 or 2, it is characterized in that, described pharmaceutical composition is oral formulations.
7. the pharmaceutical composition of anti-cancer of biliary duct according to claim 6, it is characterized in that, described oral formulations comprises tablet, granule, capsule, dry suspension and drop pill.
The application of compositions in the medicine of the anti-cancer of biliary duct of preparation of 8.2-lacto benzoic acid and capecitabine composition.
CN201410623889.9A 2014-11-07 2014-11-07 The pharmaceutical composition of a kind of anti-cholangiocarcinoma and application thereof Expired - Fee Related CN104434947B (en)

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PT1101755E (en) * 1998-07-24 2005-02-28 Teijin Ltd ANTRANILIC ACID DERIVATIVES
CA2485430C (en) * 2002-05-14 2011-12-06 Xenova Limited Process for the preparation of a hydrate of an anthranilic acid derivative
US7705049B2 (en) * 2004-01-21 2010-04-27 New York University Methods for treating non-melanoma cancers with PABA
CN103864638B (en) * 2012-12-14 2015-12-09 沈阳药科大学 A kind of benzoic acid derivative and its preparation method and application

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