CN105147696A - Anti-breast cancer granules combining metformin hydrochloride and gdc 0941 and a preparation method thereof - Google Patents
Anti-breast cancer granules combining metformin hydrochloride and gdc 0941 and a preparation method thereof Download PDFInfo
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- CN105147696A CN105147696A CN201510394804.9A CN201510394804A CN105147696A CN 105147696 A CN105147696 A CN 105147696A CN 201510394804 A CN201510394804 A CN 201510394804A CN 105147696 A CN105147696 A CN 105147696A
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- metformin hydrochloride
- gdc0941
- breast cancer
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Abstract
The invention discloses anti-breast cancer granules combining metformin hydrochloride and gdc 0941. Active components of the anti-breast cancer granules are metformin hydrochloride and gdc 0941. The anti-breast cancer granules further comprise pharmaceutically acceptable auxiliary materials. The anti-breast cancer granules are simple to prepare, easy to operate, lower in cost and economical and practical; the anti-breast cancer granules are portable, dissolve fast, are well absorbable and take effect fast. In-vitro antitumor tests show that anti-cancer activities of the metformin hydrochloride and gdc 0941 are synergistic, the combination of the metformin hydrochloride and gdc 0941 provides high anti-cancer activity, high cost of a single dose can be decreased, and the anti-breast cancer granules are worthy of clinical popularization.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of solid orally ingestible being active component with metformin hydrochloride and gdc0941.
Background technology
The discovery of the novelty teabag of known drug is an important directions of new drug development; as the metformin (Metformin) of type 2 diabetes mellitus patient initial therapy choice drug; there is low price, cross patent protection period, safety and the advantage be widely used.And its potentiality on oncotherapy, also become a focus recently.A lot of observational study report discloses, and accept the diabetics of Or Metformin In Treating, Tumor incidence and mortality rate all have reduction.In the report of Evans, the diabetics accepting Or Metformin In Treating compares the patient not accepting Or Metformin In Treating, and the former amounts to 8170 objects of observation than the latter's cancered risk reduction 4.3%(two groups).ZODIAC(hereby Waller Diabetes Clinic patient integrate existing nursing care plan) in research, author reports that the standard cancer case fatality rate of all patients is 1.47 and the danger ratio of metformin group drops to 0.43.And show that the consumption often increasing by 1 gram of metformin just can reduce the conclusion of the danger ratio of the cancer case fatality rate of 42%.Meanwhile, a large amount of preclinical models also demonstrate that metformin has obvious growth inhibited effect to multiple cancerous cell and mouse tumor model.Nearest research confirms, metformin also has effect to breast carcinoma stem cell, and overcomes the drug resistance to Trastuzumab because breast carcinoma stem cell causes.
Breast carcinoma is the common cancer that women ranks the first.The recent statistics data display of U.S. CA:ACancerJournalforClinicians magazine announcement in 2012, the U.S. estimates there will be 226870 routine women's suffers from breast in 2012, account for 29% of women's de novo malignancy, rank female malignant sickness rate first.In China Beijing, Shanghai, Tianjin etc., metropolitan statistics display breast carcinoma is the modal malignant tumor of China women equally, and sickness rate is in ascendant trend year by year.Therefore study the effect of metformin anti-breast cancer and there is certain realistic meaning.But find in process metformin being developed as a kind of cancer therapy drug, metformin, under physiological dose, is difficult to as a kind of independent cancer therapy drug.Therefore being necessary that selection is a kind of can have synergistic medicine to carry out administering drug combinations to reduce the dosage of metformin with metformin.
The anticancer mechanism of the metformin disclosed mainly can be divided into direct effect (non-insulin dependence) and indirect action (insulin dependency) two kinds.In indirect action, metformin suppresses transcribing of the crucial glyconeogenesis gene of liver by AMPK mediation, and stimulated muscle to the picked-up of glucose, thus reduces fasting glucose and insulin.Because insulin has mitogenesis effect, the normal high level expression Insulin receptor INSR of tumor cell, therefore the effect of metformin reduction insulin level plays pivotal role in its active anticancer.In direct effect, metformin reduces mTOR signal level by activating AMPK thus inhibits the synthesis of cell protein.MTOR is main " the synthesis person " of somatomedin and nutrient signal, is the critical mediator of PI3K/Akt/mTOR signal path, and this signal path is one of the most common molecular network out of control of human tumor.The AMPK activation of metformin mediation result in the suppression of mTOR signal path, the crucial effector molecule phosphorylation in its downstream reduces, eukaryotic initiation factor 4E associated proteins (4E-BPs), Ribosomal protein (S6Ks) and the suppression to total protein synthesis and a large amount of different carcinoma cell line proliferation.
PI3K/Akt/mTOR signal path is the drug development target spot of very attractive, there is this path targeted drug a series of just under development, comprise PI3K/mTOR double inhibitors, the mono-inhibitor of PI3K, the mono-inhibitor of mTOR and Akt inhibitor etc., and existing medicine to enter the I/II phase clinical.The medicine GDC0941 that this project intends adopting is the PI3K inhibitor having very much application prospect developed by U.S.'s technique for gene engineering (Genetech) company.One of main anticancer mechanism of metformin is exactly suppress mTOR by activating AMPK, and communicate with the effect of PI3K/Akt/mTOR signal pathway inhibitor part, is therefore necessary to combine the effect whether having collaborative increase anticancer both checking.
Summary of the invention
Technical problem to be solved by this invention is for above-mentioned deficiency of the prior art, anti-breast cancer granule and the preparation method of a kind of conbined usage metformin hydrochloride and gdc0941 are provided, it is simple that this oral formulations has composition, the feature of convenient drug administration, persistent, stable curative effect.
Realizing main technical schemes of the present invention is:
The anti-breast cancer granule of conbined usage metformin hydrochloride and gdc0941, its active component is metformin hydrochloride and gdc0941.
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, described metformin hydrochloride and gdc0941 weight ratio are that 1:0.5-3(is preferred, and metformin hydrochloride and gdc0941 weight ratio are 1:1).
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, also comprises pharmaceutically acceptable adjuvant.
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, described adjuvant is disintegrating agent (preferred starch, usage ratio is metformin hydrochloride: diluent=1:0.9-1.5).
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, the weight ratio of described metformin hydrochloride and diluent is 1:1.2.
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, described adjuvant is adhesive (preferably 10% starch slurry, usage ratio is metformin hydrochloride: adhesive=1:0.1-0.2).
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, the weight ratio 1:0.15 of described metformin hydrochloride and adhesive.
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, described adjuvant is disintegrating agent (preferred carboxymethyl starch sodium, usage ratio is metformin hydrochloride: disintegrating agent=1:0.04-0.08).
Described conbined usage metformin hydrochloride and the anti-breast cancer granule of gdc0941, preferred scheme is, the weight ratio of described metformin hydrochloride and disintegrating agent is 1:0.06.
Present invention also offers the preparation method of the anti-breast cancer granule of conbined usage metformin hydrochloride and gdc0941, it is characterized in that, step is as follows:
(1) metformin hydrochloride and gdc0941 were pulverized 60-100 mesh sieve (preferred, to pulverize 80 mesh sieves), stand-by;
(2) made for step (1) medicated powder and diluent and disintegrating agent are mixed, then add adhesive make gently hold agglomerating, the light pressure i.e. soft material of loose shape, soft material mechanical presses is passed through 20 object screen clothes, obtained wet granular, then put the normal pressure case inner drying of 70-80 DEG C, dry granule crosses 16 mesh sieve granulate, pack, obtains granule.
Compared with prior art, the solid orally ingestible antitumor activity preventing and treating breast carcinoma provided by the invention is remarkable, and toxic and side effects is little, has enriched prior art, for adding a kind of potential anti-breast cancer new drug clinically, there is social meaning and the economic implications of highly significant.Specifically, be embodied in:
1, the present invention is prepared simply, and operate easy, cost is lower, economical and practical;
2, the present invention verifies through antitumor activity in vitro, and the active anticancer of metformin hydrochloride and gdc0941 has synergistic function, and both couplings have higher active anticancer, and clinic is promoted;
3, the made granule of the present invention is easy to carry, and stripping is fast, good absorbing, instant effect.
Detailed description of the invention
Now further describe implementation process of the present invention and effect test by following examples, embodiment is only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
embodiment 1the anti-breast cancer granule of conbined usage metformin hydrochloride and gdc0941, is prepared from primarily of following bulk drugs: metformin hydrochloride 40g, gdc094120g, starch 48g, 10% starch slurry 8g, carboxymethyl starch sodium 2.4g.
(1) metformin hydrochloride and gdc0941 were pulverized 60 mesh sieves, stand-by;
(2) made for step (1) medicated powder and starch and carboxymethyl starch sodium are mixed, then add 10% starch slurry make gently hold agglomerating, the soft material that namely light pressure falls apart, soft material mechanical presses is passed through 20 object screen clothes, obtained wet granular, then put the normal pressure case inner drying of 70-80 DEG C, dry granule crosses 16 mesh sieve granulate, pack, obtains granule.
embodiment 2the anti-breast cancer granule of conbined usage metformin hydrochloride and gdc0941, is prepared from primarily of following bulk drugs: metformin hydrochloride 40g, gdc0941120g, starch 48g, 10% starch slurry 8g, carboxymethyl starch sodium 2.4g.
(1) metformin hydrochloride and gdc0941 were pulverized 100 mesh sieves, stand-by;
(2) made for step (1) medicated powder and starch and carboxymethyl starch sodium are mixed, then add 10% starch slurry make gently hold agglomerating, the soft material that namely light pressure falls apart, soft material mechanical presses is passed through 20 object screen clothes, obtained wet granular, then put the normal pressure case inner drying of 70-80 DEG C, dry granule crosses 16 mesh sieve granulate, pack, obtains granule.
embodiment 3the anti-breast cancer granule of conbined usage metformin hydrochloride and gdc0941, is prepared from primarily of following bulk drugs: metformin hydrochloride 40g, gdc094180g, starch 48g, 10% starch slurry 8g, carboxymethyl starch sodium 2.4g.
(1) metformin hydrochloride and gdc0941 were pulverized 80 mesh sieves, stand-by;
(2) made for step (1) medicated powder and starch and carboxymethyl starch sodium are mixed, then add 10% starch slurry make gently hold agglomerating, the soft material that namely light pressure falls apart, soft material mechanical presses is passed through 20 object screen clothes, obtained wet granular, then put the normal pressure case inner drying of 70-80 DEG C, dry granule crosses 16 mesh sieve granulate, pack, obtains granule.
embodiment 4the anti-breast cancer granule of conbined usage metformin hydrochloride and gdc0941, is prepared from primarily of following bulk drugs: metformin hydrochloride 40g, gdc094140g, starch 48g, 10% starch slurry 8g, dried starch 2.4g.
(1) metformin hydrochloride and gdc0941 were pulverized 80 mesh sieves, stand-by;
(2) made for step (1) medicated powder and starch and carboxymethyl starch sodium are mixed, then add 10% starch slurry make gently hold agglomerating, the soft material that namely light pressure falls apart, soft material mechanical presses is passed through 20 object screen clothes, obtained wet granular, then put the normal pressure case inner drying of 70-80 DEG C, dry granule crosses 16 mesh sieve granulate, pack, obtains granule.
experimental example:to the mensuration of the cytotoxic activity of MCF-7 Human Breast Cancer Cells
Adopt mtt assay, measure metformin hydrochloride, gdc0941 and two medicines associating (metformin hydrochloride+gdc0941) cytotoxic activity to MCF-7 Human Breast Cancer Cells (Shanghai Inst. of Cytobiology, Chinese Academy of Sciences provides), calculate IC
50value.Testing drug level used is, metformin hydrochloride and gdc0941 establish 6 Concentraton gradient respectively, be respectively 10,20,40,60,80,100 μm of ol/L, combined concentration is (10+10), (20+20), (40+40), (50+50), (60+60), (80+80), (100+100) μm ol/L.Each concentration establishes 3 multiple holes, test repetition 3 times.
Result shows, and metformin hydrochloride, gdc0941 and two medicines associating (metformin hydrochloride+gdc0941) all have inhibitory action in various degree to human breast cancer cell growth, obtain the IC of its 48h according to regression analysis
50value is respectively 93.27 μ g/mL, 72.48 μ g/mL, 8.27 μ g/mL.Relatively three groups of IC
50be worth known, drug combination group has comparatively significant cytotoxic activity (P < 0.05) to MCF-7 Human Breast Cancer Cells, illustrate that the granule that conbined usage metformin hydrochloride and gdc0941 are prepared from has significant tumor killing effect, and two kinds of active ingredient combination successfuls of using comparatively single component is good, two kinds of active ingredient exerts summation action in made granule.
Solid orally ingestible compositions of the present invention significantly can suppress the growth of MCF-7 Breast Cancer Cell, and the compatible rear tumor killing effect of the composition that this solid orally ingestible comprises has synergistic function compared with individually dosed.
It should be pointed out that detailed description of the invention is the more representational example of the present invention, obvious technical scheme of the present invention is not limited to above-described embodiment, can also have a lot of distortion.Those of ordinary skill in the art, with the present invention clear and definite disclosed or according to undoubted the obtaining of the written description of file, the claimed scope of this patent all should be thought.
Claims (10)
1. the anti-breast cancer granule of conbined usage metformin hydrochloride and gdc0941, is characterized in that, active component is metformin hydrochloride and gdc0941.
2. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 1 and gdc0941, it is characterized in that, described metformin hydrochloride and gdc0941 weight ratio are that 1:0.5-3(is preferred, and metformin hydrochloride and gdc0941 weight ratio are 1:1).
3. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 1 and 2 and gdc0941, is characterized in that, also comprises pharmaceutically acceptable adjuvant.
4. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 3 and gdc0941, is characterized in that, described adjuvant is diluent (preferred starch, usage ratio is metformin hydrochloride: diluent=1:0.9-1.5).
5. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 4 and gdc0941, is characterized in that, the weight ratio of metformin hydrochloride and diluent is 1:1.2.
6. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 3 and gdc0941, is characterized in that, described adjuvant is adhesive (preferably 10% starch slurry, usage ratio is metformin hydrochloride: adhesive=1:0.1-0.2).
7. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 5 and gdc0941, is characterized in that, the weight ratio 1:0.15 of metformin hydrochloride and adhesive.
8. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 3 and gdc0941, it is characterized in that, described adjuvant is disintegrating agent (preferred carboxymethyl starch sodium, usage ratio is metformin hydrochloride: disintegrating agent=1:0.04-0.08).
9. the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 7 and gdc0941, is characterized in that, the weight ratio of metformin hydrochloride and disintegrating agent is 1:0.06.
10. the preparation method of the anti-breast cancer granule of conbined usage metformin hydrochloride according to claim 1 and 2 and gdc0941, it is characterized in that, step is as follows:
(1) metformin hydrochloride and gdc0941 were pulverized 60-100 mesh sieve (preferred, to pulverize 80 mesh sieves), stand-by;
(2) made for step (1) medicated powder and diluent and disintegrating agent are mixed, then add adhesive make gently hold agglomerating, the soft material that namely light pressure falls apart, soft material mechanical presses is passed through 20 object screen clothes, obtained wet granular, then put the normal pressure case inner drying of 70-80 DEG C, dry granule crosses 16 mesh sieve granulate, pack, obtains granule.
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Cited By (3)
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| WO2019232403A1 (en) * | 2018-06-01 | 2019-12-05 | Cornell University | Combination therapy for pi3k-associated disease or disorder |
| WO2020076432A1 (en) * | 2018-10-08 | 2020-04-16 | Genentech, Inc. | Methods of treating cancer with pi3k alpha inhibitors and metformin |
| JP2021532139A (en) * | 2018-07-23 | 2021-11-25 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Treatment method for cancer with GDC-0077, a PI3K inhibitor |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019232403A1 (en) * | 2018-06-01 | 2019-12-05 | Cornell University | Combination therapy for pi3k-associated disease or disorder |
| CN113194752A (en) * | 2018-06-01 | 2021-07-30 | 康奈尔大学 | Combination therapy for PI3K related diseases or disorders |
| JP2021532139A (en) * | 2018-07-23 | 2021-11-25 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Treatment method for cancer with GDC-0077, a PI3K inhibitor |
| WO2020076432A1 (en) * | 2018-10-08 | 2020-04-16 | Genentech, Inc. | Methods of treating cancer with pi3k alpha inhibitors and metformin |
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Address after: 744300, Gansu Province, Dingxi District, Liberty Street, No. 54 Wen Yuan District, building 2, 1-202 Applicant after: Li Rongqin Address before: Kang Hong Lu 250000 Shandong province Ji'nan city high tech Development Zone No. 758 Applicant before: Li Rongqin |
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Application publication date: 20151216 |