CN102309486A - The anti-cancer of pancreas effect and the pharmaceutical preparation thereof of piperine - Google Patents

Abstract

The invention discloses the new medical use of piperine aspect anti-cancer of pancreas, also disclosing with the piperine simultaneously is that pharmaceutical raw material is prepared into acceptable drug preparation clinically such as tablet, capsule, pill, injection.Piperine pharmaceutical preparation of the present invention contains the piperine of 1%-99% and the pharmaceutical excipient of 99%-1% (comprising the medicine that other compatibility is used).Piperine provided by the invention and pharmaceutical preparation thereof have good anti-cancer of pancreas effect, show that the vitro human pancreatic cancer cell is had obvious inhibiting activity, and the transplanted tumor in nude mice of this tumor cell is had significant antitumor activity.In addition, the active component of this pharmaceutical preparation is a Chinese medicine extract, abundant raw material and have the little advantage of toxic and side effects.

Description

The anti-cancer of pancreas effect and the pharmaceutical preparation thereof of piperine

One, technical field

The present invention relates to application and the pharmaceutical preparation thereof of piperine (Piperine) aspect anti-cancer of pancreas medicine, belongs to the field of Chinese medicines.

Two, background technology

Malignant tumor is the commonly encountered diseases and the frequently-occurring disease of serious threat human health, and the exploitation of cancer therapy drug has become the key subjects of new drug research in this century.At present, from plant, seek the antitumor drug of high-efficiency low-toxicity, become the emphasis of domestic and international antitumor drug research.We find that in the screening antineoplastic drugs process piperine has the effect of very strong inhibition pancreatic cancer cell and solid tumor growth.

Piperine is mainly derived from Piperaceae plants such as black pepper, is white crystalline powder.130～133 ℃ of fusing points are dissolved in acetic acid, benzene, ethanol and chloroform, are slightly soluble in ether.Piperine molecular weight: 285.34; Molecular formula: C ₁₇H ₁₉NO ₃Chemical name: (E, E)-1-[5-(1,3-Benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]-piperidine; (E, E)-1-[5-(1,3-benzo dioxolanes-5-yl)-1-oxo-2,4-pentadienyl]-piperidines.

Chemical structural formula:

Before the present invention, do not find with the piperine to be feedstock production pharmaceutical dosage form and the report that is used to prevent and treat the cancer of pancreas disease.Piperine is almost non-toxic, and natural resources of Chinese medicinal materials is very abundant, is a kind of very promising antitumor drug.

Three, summary of the invention

One of the object of the invention has provided the pharmaceutical preparation of piperine;

Two of the object of the invention has provided the antineoplastic new usage of piperine.

The objective of the invention is to realize through following technical scheme:

Pharmaceutical preparation of the present invention contains the piperine of 1%-99% and the excipient of 99%-1% (medicine that comprises other adapted); Preferably contain the piperine of 20%-80% and the excipient of 80%-20% (medicine that comprises other adapted), preferably contain the piperine of 60%-70% and the excipient of 40%-30% (medicine that comprises other adapted).

Press practice of pharmacy, can piperine of the present invention be prepared into the various clinical pharmaceutical dosage form as anti-cancer of pancreas medicine, comprise the dosage form of oral formulations or parenterai administration.Said oral formulations selects any in tablet, capsule, pill, granule, microcapsule tablet, suspensoid, drop pill, oral liquid; Said parenterai administration dosage form is selected from a kind of in the middle of injection, aerosol, suppository or the subcutaneous administration dosage form.

Adjuvant in the anti-cancer of pancreas medicine of the present invention is meant conventional excipient, like solvent, disintegrating agent, correctives, antiseptic, coloring agent, binding agent etc.The medicine that other compatibility in the antitumor drug of the present invention is used, the piperine that refers to effective dose is certain medicine material, again compatibility other allowed the Chinese medicine or the chemical drugs that share.

Piperine pharmaceutical preparation of the present invention has anti-cancer of pancreas effect, is to be confirmed through following pharmacodynamics test.

Test Example 1 has been investigated the inhibitory action of piperine to external pancreatic cancer cell

Cell: human pancreas cancer epithelial cell (PANC-1).For ocean institute of Chinese Academy of Sciences marine drug laboratory provides.

Medicine and reagent: ocean institute of piperine (Piperine) Chinese Academy of Sciences marine drug laboratory provides white powder; 5-fluorouracil (5-FU) Nantong elite pharmaceutical Co. Ltd product, lot number is 100402; MTT (SIGMA, USA); DMSO (SIGMA, USA); Trypsin SIGMA, USA); RPMI1640 (GIBCO, Invitragen Co., USA); DMEM (GIBCO, Invitragen Co., USA); The top grade hyclone (GIBCO, Invitragen Co., USA); Superfine hyclone Fetal Bovine Serum (Hyclone).

Instrument: ultra cold storage freezer (Nature, USA), cell culture incubator (SANYO, Japan); Inverted microscope (NIKON, Japan), ELIASA (Bio-Tek Instruments; Inooski, VT, USA); The PH meter (Thermo orion, USA), superclean bench (FLC-Harbin Dong Lian instrument plant).

Experimental technique mtt assay: tumor cell line is gone down to posterity according to the conventional method cultivation, collect the exponential phase cell, regulate concentration of cell suspension 5 * 10 ⁴About individual/ml.Cell suspension is added in 96 well culture plates, and each hole adds 180 μ l, place 37 ℃ of constant incubators to cultivate 24 h after.Respectively piperine and 5-FU are made into the solution of variable concentrations with cell culture medium, experimental group adds each concentration piperine (with 5-FU as positive controls) 20 μ l/ holes, establishes 4 parallel holes for every group, and establishes blank well (cell culture medium) with zeroing.37 ℃ of incubators, cultivate 48 h after, with liquid-transfering gun liquid in 96 orifice plates is cleaned every hole, back and adds MTT (1 mg/ml) 30 μ l, put CO ₂Incubator is cultivated 4 h for 37 ℃, supernatant discarded, and every hole adds DMSO 150 μ l, puts shaking table and shakes up 30 min, detects under 492 nm with ELIASA, utilizes the SPSS statistical software, calculates cell mortality, asks for IC ₅₀

Result of the test shows; Through the SPSS software statistics; The piperine of variable concentrations has inhibitory action in various degree to the human pancreas cancer epithelial cell (PANC-1) that is used to test, and is certain dose-dependence, and the piperine of variable concentrations is to suppression ratio, the IC of pancreatic cancer cell ₅₀Value sees table 1 for details.

The piperine of table 1 variable concentrations is to the suppression ratio of pancreatic cancer cell

Test Example 2 piperines are to the tumor-inhibiting action of pancreatic cancer cell transplanted tumor in nude mice

Laboratory animal: the BALB/c nude mice is available from Shanghai Slac Experimental Animal Co., Ltd., and animal licence numbering: SYXK (Shanghai) 2010-0047, totally 20, in 7 ~ 9 ages in week, body weight 20 ~ 22g is male Mus.Animal feeding and experiment are raised in the Affiliated Hospital of Qingdao University Experimental Animal Center for no special pathogen level barrier system.

Tumor cell inoculation: the human pancreas cancer epithelial cell (PANC-1) of the trophophase of taking the logarithm is processed tumor cell suspension (1 * 10 ⁷Individual/as ml), to implant BALB/c male nude mouse armpit subcutaneous (about 0.3ml/ only), situation such as inoculation back routine observation mice spirit, diet and defecation.After going down to posterity once, with the aseptic taking-up of tumor tissues and be cut into big or small identical 2mm ³Fritter, it is subcutaneous to be seeded in the nude mice armpit with the trocar.

Test is divided into groups and method: the major diameter of vernier caliper measurement tumor nodule (a), minor axis (b), by formula V=a * b ²* 0.52 calculates gross tumor volume, when subcutaneous transplantation tumor length to 100 mm ³After, selecting tumor nude mice of the same size, nude mice is weighed is divided into 3 groups with the table of random number method, is respectively negative control group, positive controls, piperine group, every group of 5 nude mices.Respectively piperine and 5-FU are made into the solution of variable concentrations, drug level and concrete the grouping as follows: (1) negative control group: lumbar injection 0.2ml normal saline with cell culture medium; (2) positive drug matched group: the 5-FU of lumbar injection 30mg/kg; (3) piperine group: 15mg/kg lumbar injection.Injection in per 3 days is once injected 10 times continuously, behind last administration 24 h, takes out the tumor piece, and it is heavy to measure tumor, calculates average tumor control rate at last.Adopt the SPSS software statistics, test data is with (average ± standard deviation) expression, and P is a significant difference significance criterion of meaning less than 0.01.Result of the test is seen table 2.

Table 2 piperine is to the inhibitory action result of the test of PANC-1 transplanted tumor in nude mice (`X ± SD)

Annotate: compare * * P < 0.01 * P < 0.05 with matched group

Visible by table 2; The transplanted tumor in nude mice of piperine treatment group and 5-FU treatment group has all received inhibition in various degree than matched group; The piperine group is superior to positive drug matched group (5-FU) 30mg/kg administration with the tumor killing effect of 15mg/kg administration; In addition, the piperine group is very little to the influence of nude mice body weight, shows that tentatively piperine does not have obvious toxic-side effects.

Above-mentioned isolated test and bulk testing show that piperine all has the obvious suppression effect to stripped with whole man's pancreatic cancer cell (PANC-1), and does not have obvious toxic-side effects, and the prompting piperine is a kind of very promising anti-cancer of pancreas medicine.

Four, the specific embodiment

The preparation of embodiment 1 tablet

Piperine 1000g, medical starch 100g, mix homogeneously is granulated as binding agent with an amount of ethanol, drying, through the pelletizing machine granulate, tabletting, every 0.30g, oral, each 1-2 sheet, twice of every day.

The preparation of embodiment 2 capsules

Piperine 1000g, medical starch 100g, mix homogeneously is granulated as binding agent with an amount of ethanol, and drying is crossed 120 mesh sieve granulate, dress 0# capsule, every 0.300g, each oral 1-2 grain, twice of every day.

The preparation of embodiment 3 drop pills

Polyethylene Glycol ₄₀₀₀400g melts in water-bath, adds piperine raw material 250g; Stir, in the impouring insulating tube, regulate thermostat; Make medicinal liquid under 80-90 ℃, splash in the liquid paraffin that cooled off (temperature ± 4 ℃), after dripping off, with blotting liquid paraffin on the pill impouring filter paper; Add a small amount of Pulvis Talci again, mixing gets 10000 of piperine drop pill.Oral, one time four, three times on the one, one after each meal.

The preparation of embodiment 4 granules

Piperine raw material 100g, starch 1000g, Icing Sugar 500g, mix homogeneously is used an amount of alcohol granulation, and drying, granulate, packing promptly get.Oral, a 5g, twice on the one.

The preparation of embodiment 5 microencapsule tablets

Take by weighing stearic acid 12g and 18ml Herba Origani oil respectively as compound recipe capsule material, take by weighing piperine 80g as capsule core material, through the spray congealing encystation, capsule directly is 10-100 μ m with compressed air.With microcapsule and microcrystalline Cellulose mixing, add the mixed encystation material of 12% ethyl cellulose alcoholic solution then, process granule through 18 order nylon mesh; In oven dry below 50 ℃, placed exsiccator interior 24 hours, add 1%-3% magnesium stearate tabletting; Get the piperine microencapsule tablet, sheet heavily is 0.4g, and is oral; A 1-2 sheet, twice on the one.

The preparation of embodiment 6 injections

Piperine 40g, propylene glycol 50ml, PEG400 100ml, water for injection 600ml; Mix, heating in water bath 30 minutes adds benzyl alcohol 90ml, and reuse water for injection adds to 1800ml; In ultrasound wave, handled 10 minutes, in water-bath, heated 30 minutes, adjust pH is 5.5-6.5; Filter, embedding, sterilization promptly gets.Every 3ml, intramuscular injection, a 3ml, twice on the one.

Claims (9)

1. pharmaceutical preparation that is used to treat cancer of pancreas is characterized in that containing the piperine of treating effective dose and one or more pharmaceutically acceptable pharmaceutical excipients, or can with the other medicines of piperine prescription.

2. pharmaceutical preparation according to claim 1, but it is characterized in that containing piperine and the pharmaceutical excipient of 99%-1% or the medicine of other prescription of 1%-99%.

3. pharmaceutical preparation according to claim 2, but it is characterized in that containing piperine and the pharmaceutical excipient of 80%-20% or the medicine of other prescription of 20%-80%.

4. pharmaceutical preparation according to claim 3, but it is characterized in that containing piperine and the pharmaceutical excipient of 40%-30% or the medicine of other prescription of 60%-70%.

5. pharmaceutical preparation according to claim 1 is characterized in that said medicine is the dosage form of oral formulations or parenterai administration.

6. pharmaceutical preparation according to claim 5 is characterized in that said oral formulations is selected from any in tablet, pill, capsule, granule, microcapsule tablet, suspensoid, drop pill, the oral liquid.

7. pharmaceutical preparation according to claim 5 is characterized in that said parenterai administration dosage form is selected from any in the middle of injection, aerosol, suppository or the subcutaneous administration dosage form.

8. the application of piperine in the anti-cancer of pancreas medicine of preparation.

9. according to Claim 8 purposes is characterized in that said anti-cancer of pancreas is meant the growth that suppresses human pancreas cancer epithelial cell (PANC-1) and nude mice transplanted tumor thereof.