CN104434947B - The pharmaceutical composition of a kind of anti-cholangiocarcinoma and application thereof - Google Patents
The pharmaceutical composition of a kind of anti-cholangiocarcinoma and application thereof Download PDFInfo
- Publication number
- CN104434947B CN104434947B CN201410623889.9A CN201410623889A CN104434947B CN 104434947 B CN104434947 B CN 104434947B CN 201410623889 A CN201410623889 A CN 201410623889A CN 104434947 B CN104434947 B CN 104434947B
- Authority
- CN
- China
- Prior art keywords
- cholangiocarcinoma
- capecitabine
- pharmaceutical composition
- lacto
- benzoic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims abstract description 34
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Classifications
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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
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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
- A61K31/185—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
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- 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
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- 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
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- 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
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- 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
Landscapes
- 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 pharmaceutical composition and the application thereof of a kind of anti-cholangiocarcinoma, this pharmaceutical composition comprises active component and pharmaceutically acceptable auxiliary material, and described active component includes capecitabine and 2 lacto benzoic acid.The present invention is found by experiment that, concertedness can strengthen the effect that inhibiting tumor cell is bred, thus be more beneficial for reaching the therapeutic purposes of anti-cholangiocarcinoma after 2 lacto benzoic acid and capecitabine combination.
Description
Technical field
The present invention relates to a kind of antineoplastic, particularly relate to pharmaceutical composition and the application thereof of a kind of anti-cholangiocarcinoma, belong to
Pharmaceutical technology field.
Background technology
Cholangiocarcinoma (Cholangiocarcinoma) refers to be primary in left and right conjunctive region of hepatic duct to the liver outer bladder of distal common bile duct
Pipe malignant tumour, its cause of disease is unclear, relevant with its possibility of falling ill because have: ulcerative colitis, gall stone,
Clonorchis sinensis infection, choledochocyst etc., these factors can increase the danger of cholangiocarcinoma morbidity.Clinical table
Now predominantly with epigastric discomfort Progressive symmetric erythrokeratodermia jaundice, lose the appetite, become thin, itch etc..Such as tumour ulceration bleeding,
Melena or the fecal occult blood testing positive, anaemia etc. can be had to show.
The grade malignancy of cholangiocarcinoma is high, very low at the European and American areas incidence of disease, but at the incidence of disease of south east asia and China
Become ascendant trend, and wholistic therapy level is very undesirable, so far without satisfied treatment method.Owing to symptom occurring clinically
Later, early diagnosis difficulty, simultaneously because cholangiocarcinoma has the biological characteristics along bile duct wall local infiltration, easily invade liver
Door portion blood vessel and two grades of bile ducts, the chance of radical surgery excision is few (about 15%～20%), causes office after routine operation
Portion recurs, and prognosis poor mean survival time (MST) is 6～12 months, and 5 annual survival rates are 2%～16.5%.At present,
Scholar is had successfully to clone somatostatin receptor II type from cholangiocarcinoma cell strain RBE, NEC, QBC939, SSP-25
(SSTR-2) expression, provides the Research foundation of molecular biology for the medicine that screening suppression cholangiocarcinoma cell is bred.Make
For the chemotherapy of important auxiliary treatment means, cholangiocarcinoma is all insensitive to current conventional chemicotherapy, though there being scholar to report
Some drugs curative effect in a short time still can, but long-term effect is not good, therefore finds new effective chemotherapeutics to improving bile duct
The clinical treatment of cancer has great significance.
Capecitabine (capecitabine) is a kind of new oral fluorouracil mephenesin Carbamate series antineoplastic medicament, warp after being administered orally
Enzymatic reaction, is degraded to 5 FU 5 fluorouracil in tumour cell, plays the antitumor action of high selectivity, to multiple
Entity tumor has stronger activity, is mainly used in the treatment advanced breast cancer knot/carcinoma of the rectum and other solid tumors (peace clinically
Fu Rong, Ge Shengrong, Zhu Deqiu.The pharmacology of capecitabine and Clinical advances [J]. China's new drug is miscellaneous with clinic
Will, 2002,21 (8): 503-507).Recent studies indicate that, gemcitabine associating capecitabine treatment late period cannot
The cholangiocarcinoma patients of operation has preferable short term effect (Wang Yue, gemcitabine associating capecitabine treatment Advanced Bile Duct Cancer
Clinical observation, middle national health medical science, 2011/16).But, gemcitabine needs drip-feed to be administered, long-term note
Penetrate medication and bring great misery to patient, be unfavorable for maintaining the interdependence of patient medication.2-lacto benzoic acid
(2-lactoylaminobenzoic acid) be a kind of from Penicillium fungi Penicillium chrysogenum or
The benzoic acid derivative of isolated in the metabolite of P.notatum bacterial strain, current pharmacological evaluation shows that it has
Good antalgic and inflammation relieving activity, and less to GI spread effect.
At present, 2-lacto benzoic acid is not still had to report for antineoplastic document, more not by itself and other anticarcinogens
The document report of anti-cholangiocarcinoma after combination.
Content of the invention
In view of most of tumor Drugs are drug administration by injection clinically, the treatment adding patient is painful, the therefore present invention
Purpose be by research provide a kind of for anticancer oral drugs.
Capecitabine, as oral antineoplastic, is mainly used in treating advanced breast cancer knot/carcinoma of the rectum clinically, and poison is secondary
Act on bigger.In order to play the antitumor efficacy of capecitabine, reducing its toxic and side effect, the present inventor is by reducing simultaneously
The consumption of capecitabine, and by itself and 2-lacto benzoic acid use in conjunction, although to breast after having been surprisingly found that the two medication
Other malignant tumours such as gland cancer, colon cancer are without preferable therapeutic action, but have the antiproliferative of Synergistic to cholangiocarcinoma
Effect.Based on this research, it is an object of the invention to provide pharmaceutical composition and the application thereof of a kind of anti-cholangiocarcinoma.
The object of the present invention is achieved like this: the pharmaceutical composition of a kind of anti-cholangiocarcinoma, and this pharmaceutical composition comprises activity
Composition and pharmaceutically acceptable auxiliary material, described active component includes capecitabine and 2-lacto benzoic acid.At this
In the preferred technical scheme of invention institute, the active component in this pharmaceutical composition is by capecitabine and 2-lacto benzoic acid
Composition.
The pharmaceutical composition of the present invention relies on 2-lacto benzoic acid and capecitabine to play anti-bile duct as active component
The synergy of cancer, inventor is screened by the amount ratio to both components for the lot of experiments, and result is Ka Peita
When shore and 2-lacto benzoic quality amount ratio are in the range of 0.5-20:1, its anti-cholangiocarcinoma cell propagation
Effect is more preferable；Further, capecitabine and 2-lacto benzoic quality amount ratio are preferably 1.5-10:1.
It is true that for the toxic and side effect reducing capecitabine, the present invention is more likely to reduce the consumption of this active component,
Especially reduce the consumption of capecitabine, therefore in the most preferably external embodiment of the present invention, capecitabine and 2-lactoyl
The quality amount ratio of aminobenzoic acid is 3-5:1.
Clearly as capecitabine and 2-lacto benzoic acid all can absorb concurrent by intestines and stomach with speed faster
Waving biologically active, therefore the pharmaceutical composition of the present invention is oral formulations.Pharmaceutical units preparation can be conventional preparation work
Skill makes pharmacy acceptable any conventional peroral dosage form, such as tablet, granule, capsule, dry suspensoid agent, drips
Ball.For making above-mentioned formulation be capable of, pharmaceutically acceptable auxiliary material need to be added when preparing these formulations, for example: fill
Agent, disintegrant, lubricant, suspending agent, adhesive, sweetener, flavouring etc..Filler includes: starch, pre-glue
Change starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose etc.；Disintegrant includes: starch, pregelatinated form sediment
Powder, microcrystalline cellulose, sodium carboxymethyl starch, PVPP, low-substituted hydroxypropyl cellulose, crosslinked carboxylic first
Base sodium cellulosate etc.；Lubricant includes: magnesium stearate, lauryl sodium sulfate, talcum powder, silica etc.；Suspending
Agent includes: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.；Adhesive bag
Include, starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.；Sweetener includes: saccharin sodium, aspartame,
Sucrose, honey element, enoxolone etc.；Flavouring includes sweetener and various essence.
The present inventor is shown by the result of study of a large amount of in vitro tests, and at the transplanted tumor in nude mice Relative tumor rate of increase, this refers to
Mark aspect, drug combination group is less than lacto benzoic acid group, the independent medication group of capecitabine group two, and difference has statistics
Learning meaning (P < 0.01), this explanation drug combination group curative effect is significantly better than alone capecitabine or 2-lacto benzoic acid is controlled
Treat.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 becomes apparent from, illustrate that therapeutic alliance is more more effective than single therapy, and Small dose injection chemotherapy compares unification
Treatment can heighten the effect of a treatment, and mitigates chemotherapeutics side reaction.Based on the studies above achievement and combine the general of those skilled in the art
Logical technological know-how, the present invention also provides a kind of pharmaceutical applications, it may be assumed that the group of 2-lacto benzoic acid and capecitabine composition
Application in the medicine preparing anti-cholangiocarcinoma for the compound.The part in vitro test step of the present invention and result of the test are as follows:
Human bile duct carcinoma strain QBC939 is placed in the RPMI-1640 nutrient solution containing 10% calf serum cultivation, passes
In 2～3 weeks generations, make 1mL after centrifuging and contain 107～108The suspension of individual cell/mL.34 4～6 week old nude mices, 18～
22g, male and female dual-purpose.Take 1 female mouse therein and 1 male mouse, every nude mice left lower extremity hypodermic injection 0.2mL at random
Tumor cell suspension, after about 1 week, all there is tumor mass in mice with tumor left lower extremity, when tumour length to diameter about 0.8～1.0cm,
Put to death, in super-clean bench, separate tumour, after slightly rinsing, be placed in the RPMI-1640 nutrient solution containing 10% calf serum
In, eye scissors fully shreds, and makes about 1mm3The little tumor mass of size.Every right lower extremity subcutaneous implantation of remaining nude mice is little
Tumor mass, about 2～3 pieces, 3-0 absorbable suture is sewed up, when tumor bearing nude mice lump diameter equal ＞ 0.8cm, nude mice model
Knurl model is successfully established.
Successful for modeling Transplanted tumor model mouse stochastic averagina being divided into four groups, often organizing 8, male and female half and half, each group is respectively
Carry out treating 3 weeks by the tested material of following dosage:
Blank group: every nude mice gavage 1% sodium cellulose glycolate solution 0.1ml/10g；
Lacto benzoic acid group: every nude mice presses the 2-lacto benzoic acid of weight gavage 200mg/kg, with 1%
The suspended rear gavage of sodium cellulose glycolate solution；
Capecitabine group: every nude mice presses the capecitabine of weight gavage 750mg/kg, with 1% sodium cellulose glycolate
The suspended rear gavage of solution；
Drug combination group: every nude mice presses 2-lacto benzoic acid and the 375mg/kg of weight gavage 100mg/kg
Capecitabine, with the 1% suspended rear gavage of sodium cellulose glycolate solution.
It is administered after starting the long and short footpath of the 2nd, the 5th, the 8th, the 11st, the 14th, the 17th, the 20th, 23 days measurement tumours, calculate volume.
Gross tumor volume=1/2 × major diameter × minor axis2.Relative tumour volume (RTV)=Vt/V0 (when wherein Vt is for measuring each time
Gross tumor volume, V0 is for being administered the gross tumor volume of the 0th day).The antitumor evaluation index of medicine be the Relative tumor rate of increase=
(treatment group RTV/ control group RTV) × 100%.Calculating the Relative tumor rate of increase, each group transplanted tumor in nude mice Relative tumor increases
The rate curve of growing is shown in Fig. 1.
As seen from Figure 1, during alone 2-lacto benzoic acid, the tumor killing effect during whole administration is inconspicuous, phase
70% is all higher than to tumor proliferation rate；Alone capecitabine is starting tumor killing effect when being administered preferably, but post-drug period is bright
Aobvious bounce-back, the Relative tumor rate of increase after being administered the last time reaches more than 65%；And give two kinds of drug therapy simultaneously
Drug combination group is with the passage of administration time, and its tumor killing effect is more and more significant, until the phase after being administered the last time
23.2% is dropped to tumor proliferation rate.As can be seen here, can concertedness after 2-lacto benzoic acid and capecitabine combination
Strengthen the effect of inhibiting tumor cell propagation, thus be more beneficial for reaching the therapeutic purposes of anti-cholangiocarcinoma.
Brief description
Fig. 1 is the administration time-Relative tumor rate of increase curve map of each administration group.
Detailed description of the invention
The following is the preparation embodiment of some preparation that pharmaceutical composition of the present invention includes, technical scheme is done into
One step lays down a definition and illustrates, but protection scope of the present invention is not limited to following example.Every without departing substantially from structure of the present invention
Change or the equivalent replacement thought are included within protection scope of the present invention.
The preparation of embodiment 1 dispersible tablet
Preparation technology: weigh capecitabine, 2-lacto benzoic acid by recipe quantity, with microcrystalline cellulose as filler,
Ac-Di-Sol is disintegrant, and 5%PVP 60% ethanol solution is binder, and superfine silica gel powder is glidant,
With fluid-bed marumerization, then compressing tablet, to obtain final product.
The preparation of embodiment 2 granule
Preparation technology: weigh the capecitabine of recipe quantity, 2-lacto benzoic acid, starch, dextrin, cane sugar powder mixing
Uniformly.It is separately incorporated in 80% appropriate ethanol in mixed-powder, mixes, softwood processed, by 18 mesh nylon sieve series
Become wet grain, about 60 DEG C dryings, the 20 whole grains of mesh sieve, packing, to obtain final product.
The preparation of embodiment 3 tablet
Preparation technology: first capecitabine and beta-schardinger dextrin are put into ground and mixed in mortar uniform, be sequentially added into carboxymethyl
Sodium starch, amylum pregelatinisatum mix, and are eventually adding 2-lacto benzoic acid and mix, with the absolute ethyl alcohol of 5%PVP
Solution is made adhesive and is pelletized, 40 DEG C of dryings, whole grain, adds differential silica gel to mix, and compressing tablet to obtain final product.
The preparation of embodiment 4 tablet
Preparation technology: medicinal iron oxide red is crossed respectively 80 mesh sieves, by place with capecitabine, 2-lacto benzoic acid
Just amount weighs, and mixes, then mixes by the equivalent method of progressively increasing with hydroxypropyl cyclodextrin, excessively 60 mesh sieves, then with
Remaining auxiliary material of recipe quantity mixes, and surveys semi-finished product content, calculates tablet weight, compressing tablet, to obtain final product.
Claims (4)
1. the pharmaceutical composition of an anti-cholangiocarcinoma, this pharmaceutical composition comprises active component and pharmaceutically acceptable auxiliary material, it is characterized in that, described active component is made up of capecitabine and 2-lacto benzoic acid, and in described active component, capecitabine and 2-lacto benzoic quality amount ratio are 3-5:1.
2. the pharmaceutical composition of anti-cholangiocarcinoma according to claim 1, it is characterised in that described pharmaceutical composition is oral formulations.
3. the pharmaceutical composition of anti-cholangiocarcinoma according to claim 2, it is characterised in that described oral formulations is selected from tablet, granule, capsule, dry suspensoid agent or dripping pill.
Application in the medicine preparing anti-cholangiocarcinoma for the composition of 4.2-lacto benzoic acid and capecitabine composition.
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| CN1319086A (en) * | 1998-07-24 | 2001-10-24 | 帝人株式会社 | Anthranilic acid derivatives |
| WO2005070043A2 (en) * | 2004-01-21 | 2005-08-04 | New York University | Methods for treating non-melanoma cancers with paba |
| CN1665806A (en) * | 2002-05-14 | 2005-09-07 | 埃克森诺瓦有限公司 | Medicine compound |
| CN103864638A (en) * | 2012-12-14 | 2014-06-18 | 沈阳药科大学 | Benzoic acid compound, and preparation method and application thereof |
-
2014
- 2014-11-07 CN CN201410623889.9A patent/CN104434947B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1241181A (en) * | 1996-10-18 | 2000-01-12 | 埃克森诺瓦有限公司 | Pharmaceutical compounds |
| CN1319086A (en) * | 1998-07-24 | 2001-10-24 | 帝人株式会社 | Anthranilic acid derivatives |
| CN1665806A (en) * | 2002-05-14 | 2005-09-07 | 埃克森诺瓦有限公司 | Medicine compound |
| WO2005070043A2 (en) * | 2004-01-21 | 2005-08-04 | New York University | Methods for treating non-melanoma cancers with paba |
| CN103864638A (en) * | 2012-12-14 | 2014-06-18 | 沈阳药科大学 | Benzoic acid compound, and preparation method and application thereof |
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