CN102274238B - Pharmaceutical composition for treating pancreatic cancer - Google Patents

Abstract

The invention discloses a pharmaceutical composition for treating pancreatic cancer, and the pharmaceutical composition comprises gemcitabine and tetrahydropyrimidine or tetrahydropyrimidine derivatives used as active ingredients, wherein the tetrahydropyrimidine derivatives include 1,4,5,6-tetrahydro-2-methyl-5-hydroxy-4-pyrimidinecarboxylic acid and the like. The mass ratio of gemcitabine to tetrahydropyrimidine or tetrahydropyrimidine derivatives in the composition is 3:1. The inventor found in pharmacodynamic studies that the combination of gemcitabine and tetrahydropyrimidine or tetrahydropyrimidine derivatives in a certain proportion has distinct therapeutic effect on pancreatic cancer. Tetrahydropyrimidine or tetrahydropyrimidine derivatives can improve the therapeutic effect of gemcitabine on pancreatic cancer, and can reduce the toxicity of gemcitabine.

Description

A kind of pharmaceutical composition of treating cancer of pancreas

Technical field

The present invention relates to a kind of pharmaceutical composition of treating cancer of pancreas.

Background technology

Tumor is one of common disease that threatens human health; Be only second to cardiovascular disease; Research about tumor has obtained bigger progress, developed the method such as various radiotherapies, chemotherapy of multiple treatment tumor, but all there is limitation in various medicine and therapy; Be difficult to reach the effect of radical cure, and be prone to drug resistance and side effect.The tumor mortality rate still occupy first of the various diseases.The tool data show, existing 3,000,000 people of China in 2006 die from cancer, and tumor incidence still is in ascendant trend, and rejuvenation trend is arranged.In less than the time in 20 years, China's tumor incidence has risen 69% according to statistics, and mortality rate has risen 29.4%.Therefore, the new developing effective tumor treating medicaments of research is still the main direction of present oncotherapy.

Solid tumor is generally adopted the method for excision, but excision is bigger to patient's damage, and is difficult to guarantee that excision is clean, after tumor tissues occurred soaking into adhesion, obscure boundary excision difficulty was higher, and some cerebral tissue solid tumor excision risk is higher.Radiotherapy also is one of common method in oncotherapy; But it is comparatively serious to injury of human, often causes patient's system to descend; Prognosis mala; Be difficult to bear the side effect of chemotherapy for the part patient, and radiotherapeutic effect is also unsatisfactory, and cost issues also is one of reason of its application of restriction.Therefore the Drug therapy to tumor is still the method for the most generally using.

The annual newly-increased tumor patient of China reaches 1,600,000-1,700,000 people in recent years, and sum is about 4,500,000 people.Its M & M all presents ascendant trend." the Chinese health statistics summary in 2009 " of health ministry issue shows, in the special rates of part cities and counties top ten disease death in 2008, it is the first that malignant tumor occupy, and become the healthy No.1 killer of harm humans.

Although there have been many antitumor drug, and have more chemical compound to come to light to have antitumor action.But; Most of antitumor drug are owing to lack ideal selectivity; In inhibition or killing tumor cell; Human normal tissue cell also had suppress or damaging action, thereby have more side effect, add effect, plus cisplatin in treatment ovarian cancer or the carcinoma of testis inductive neurotoxicity of institute and the nephrotoxicity thereof etc. of bone marrow toxicity due to the cyclophosphamide chemotherapy regimen like cardiac toxicity, the cisplatin of anthracene nucleus class antitumor antibiotic amycin.Therefore, how when keeping and improving the antitumor drug curative effect, reducing its toxic action is the emphasis of antitumor drug research and development.

Gemcitabine is the classization thing of deoxycytidine, belongs to CCSA, is the choice drug of the unresectable cancer of pancreas of present clinical treatment, uses very extensively clinically.

But; Because gemcitabine lacks targeting property; It is extensive in each tissue distribution of health to take the back; Therefore, its side effect is also more relatively, like anemia, leucocytes reduction, thrombocytopenia, liver transaminase disorder, albuminuria and hematuria, edema/peripheral edema, alopecia, drowsiness, the constipation etc. of suffering from diarrhoea.Side effect widely is the principal element of restriction gemcitabine clinical practice.

The English ectoin by name of tetrahydropyrimidine, CAS number is 96702-03-3, chemistry by name 1,4; 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 2-Methyl-1,4,5; 6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1; 4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid is the amino acid derivativges of finding in 1985; Discovered in recent years, it has certain mitigation to allergic disease, maybe be relevant with its moisture-keeping function.In addition tetrahydropyrimidine has been used to cosmetics, as preserving moisture or suntan lotion.

Summary of the invention

To above-mentioned prior art, the purpose of this invention is to provide a kind of pharmaceutical composition of treating cancer of pancreas, a kind of specifically antineoplastic pharmaceutical compositions that contains gemcitabine and tetrahydropyrimidine or tetrahydropyrimidinederivatives derivatives.

For realizing above-mentioned purpose, the technical scheme that the present invention adopts is:

A kind of treatment cancer of pancreas pharmaceutical composition is made up of gemcitabine and tetrahydropyrimidine or tetrahydropyrimidinederivatives derivatives and pharmaceutically acceptable carrier.

Said tetrahydropyrimidinederivatives derivatives is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.

The mass ratio of said gemcitabine and tetrahydropyrimidine or tetrahydropyrimidinederivatives derivatives is 3:1.

When the discovery that the inventor is surprised under study for action, tetrahydropyrimidine and derivant thereof and gemcitabine were made up according to a definite proportion, tetrahydropyrimidine and derivant thereof can significantly improve the drug effect of gemcitabine, and reduced its untoward reaction.

Tetrahydropyrimidine described in the technical scheme of the present invention, English ectoine by name, CAS number is 96702-03-3, chemistry by name 1; 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 2-Methyl-1,4; 5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5; 6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid.1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and this is that those skilled in the art are known.

The specific embodiment

Below in conjunction with embodiment the present invention is done further explanation.Should be understood that following examples only are used to explain the present invention, rather than restriction protection scope of the present invention.

The preparation of embodiment 1 tetrahydropyrimidine and gemcitabine composition tablet

Fill a prescription as follows:

Tetrahydropyrimidine 20g

Gemcitabine 60g

Microcrystalline Cellulose 20g

Magnesium stearate 10g

Polyvinylpyrrolidone 20g

The tetrahydropyrimidine and the gemcitabine of prescription are crossed 150 μ m sieve, and it is subsequent use that adjuvant is crossed 180 μ m sieve; Tetrahydropyrimidine and gemcitabine are mixed with microcrystalline Cellulose, successively mix with polyvinylpyrrolidone, magnesium stearate, tabletting gets final product behind the mix homogeneously.

Embodiment 21, and 4,5, the preparation of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and gemcitabine composition tablet

1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 10g

Gemcitabine 30g

Microcrystalline Cellulose 10g

Differential silica gel 10g

Sodium lauryl sulphate 5 g

With 1,4,5 of prescription, it is subsequent use that 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and gemcitabine are crossed 180 μ m sieve; With sieve 1,4,5, press large stretch ofly behind 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and gemcitabine and the microcrystalline Cellulose mixing, after granulate obtains smaller particles, add sodium lauryl sulphate and differential silica gel, the mixing tabletting gets final product.

Embodiment 31, and 4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and gemcitabine compound injection and preparation

1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 40g

Gemcitabine 120g

Polyethylene Glycol 150ml

Water for injection adds the injection water to 1000ml

Preparation technology:

Cillin bottle, plug are slightly washed earlier, and the back is qualified to visible foreign matters with the filterable water for injection fine purifiation of warp 0.45 μ m microporous filter membrane, then dry for standby.

, dosing adds 1,4,5 of recipe quantity in irritating, 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic, and Polyethylene Glycol 50 ml dissolve it fully, as solution 1.

In another dosing is irritated, add the gemcitabine of recipe quantity, Polyethylene Glycol 100 ml dissolve it fully, as solution 2.

Solution 2 is merged in the adding solution 1, and 80 ℃ were heated 10 minutes, and added to the full amount of water for injection mixing after the cooling.

Embodiment 4 tetrahydropyrimidines and gemcitabine pharmaceutical composition are to pancreas in rat treatment for cancer evaluation of effect

Human pancreas cancer cell strain Patu 8988 is put into the RPMI-1640 complete medium that contains 10 % to be cultivated.The take the logarithm human pancreas cancer cell strain of trophophase is by every 5 * 10 ⁶Individual tumor cell inoculation is set up tumor model in nude mouse axillary fossa place.

Get 60 of the successful nude mouses of modeling, measure gross tumor volume, be divided into 3 groups at random, 20 every group, first group of subcutaneous injection gives normal saline; Second group of subcutaneous injection gives gemcitabine, and dosage is 2mg/kg; The 3rd group of subcutaneous injection gives embodiment the injection of 3 preparations, presses gemcitabine and calculates, and dosage is 2mg/kg.Every treated animal, administration every day 1 time, successive administration 12 days is measured gross tumor volume after the administration, calculate tumour inhibiting rate, and adds up during each treated animal administration and administration finishes the mortality rate in back 10 days.

The result sees the following form.

Respectively organize tumour inhibiting rate (%) and each treated animal mortality rate (%) after table 1 administration

Divide into groups	Tumour inhibiting rate	Mortality rate
			First group	0	100
Second group	47	50
			The 3rd group	79	10

Visible from table 1, the compositions antitumor action of embodiment 3 preparations is significantly higher than gemcitabine, and toxicity is littler than gemcitabine, and the prompting tetrahydropyrimidine can improve the curative effect of gemcitabine and reduce the toxic action of gemcitabine.

Claims (1)

1. pharmaceutical composition of treating cancer of pancreas; It is characterized in that being made up of gemcitabine and tetrahydropyrimidine or tetrahydropyrimidinederivatives derivatives and pharmaceutically acceptable carrier, said tetrahydropyrimidinederivatives derivatives is 1,4; 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic; The mass ratio of said gemcitabine and tetrahydropyrimidine or tetrahydropyrimidinederivatives derivatives is 3:1.