CN103356504A - 4-Amino-2-trifluoromethylphenylretinoate self-microemulsion and preparation method thereof - Google Patents
4-Amino-2-trifluoromethylphenylretinoate self-microemulsion and preparation method thereof Download PDFInfo
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- CN103356504A CN103356504A CN2012101050742A CN201210105074A CN103356504A CN 103356504 A CN103356504 A CN 103356504A CN 2012101050742 A CN2012101050742 A CN 2012101050742A CN 201210105074 A CN201210105074 A CN 201210105074A CN 103356504 A CN103356504 A CN 103356504A
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Abstract
The invention relates to a technology of improving the in-vitro dissolution of an indissolvable medicament, discloses a self-microemulsion, and especially discloses an ATPR (4-Amino-2-Trifluoromethyl Phenyl Retinoate) self-microemulsion and a preparation method thereof. The ATPR self-microemulsion is characterized by being prepared from the following components by weight percent: 0.1-20% of ATPR, 1-30% of oil phase, 40-85% of surfactant and 1-40% of cosurfactant. The self-microemulsion and the preparation method provided by the invention have the following beneficial effects: the solubility of the medicament is improved by the ATPR self-microemulsion drug release system, the medicament is dissolved in oil drops and thus protected and the stability of the medicament in vivo is improved, the surfactant is capable of changing the liquidity of the cell membrane and improving the membrane permeability of the medicament, so that the in-vivo absorption of the medicament is increased and the relative bioavailability of the medicament is improved. Besides, the solid self-microemulsion is capable of improving the phenomena of softening and oil leakage of the traditional soft capsules and enhancing the stability of the preparation.
Description
Technical field
The present invention relates to a kind of self-microemulsion, particularly 4-amino-2-trifluoromethyl-phenyl retinate self-microemulsion and preparation method thereof.
Background technology
Human life in the malignant tumor serious threat, " the 6th the academic conference of Chinese tumor " update shows, the annual new discovery cancer patient of China has more than 220 ten thousand people, dead more than 160 ten thousand people, the tumor mortality rate has risen 29.42% over nearly 20 years, for the medical expense of tumor, every year can be up to more than 1,500 hundred million yuan.Tumor is a kind of cell differentiation obstacle disease, and its key problem is that Normocellular differentiation is blocked, no matter at form, function, metabolism, behavior aspects similar undifferentiated embryonic cell all.Think always that for a long time tumor cell in case generate, is tumor cell just forever, what make can not the breaking up of tumor people's nature expects only having lethal measure could treat tumor.Chemotherapy and radiation is as traditional malignant tumor and leukemic treatment means, its main mechanism is by destroying copying, transcribe and modifying of DNA hereditary material, suppress and kill and wound the cell of high proliferation state, also can produce lethal effect to the normal cell that is in vegetative state, thereby cause the serious untoward reaction such as bone marrow depression (incidence rate 45%), digestive tract reaction (incidence rate 100%), alopecia (incidence rate 40%), hepatorenal damage.Therefore, for further improving anticancer therapeutic, reducing its toxicity, developing new treatment means is problem in the urgent need to address clinically.
Nineteen sixty Pierce finds that at first the mouse testis teratocarcinoma cell can spontaneously be divided into optimum normal cell, has started the induction research of malignant tumor.Friend in 1971 has reported that friend's cell induced differentiation by dimethyl sulfoxide (DMSO), and hemoglobin is synthetic to be increased, and has confirmed the possibility of Differentiation Induction in vitro.The differentiation of inducing of so-called tumor cell refers in the presence of differentiating inducer, and many signs of the form of malignant cell, biology or biochemistry aspect are all to Normocellular direction differentiation, even is transformed into normal cell fully.1996～2007 years whole world has been held altogether 8 worlds and has been induced the differentiation meeting, has formulated the research direction of tumor inducing differentiation.
At present, the whole world has been applied to the clinical differentiation agent of effectively inducing approximately 30 kinds, and wherein retinoid compounds (Retinoic acids) is a kind of important differentiation agent of inducing, and existing 8 kinds are used for the treatment of cancer and leukemia so far.1988, Shanghai retinoic acid cooperative groups is at first used all-trans-retinoic acid (all-trans retinoic acid, ATRA) induction-differential therapy Human acute promyelocytic leukemia, obtain significant curative effect, and become one of choice drug of the malignant tumor such as treatment leukemia, oral leukoplakia.Other there are some researches show that retinoid compounds also can induce differentiation and the apoptosis of the tumor cells such as hepatocarcinoma, uterus carcinoma, lymphoma, pulmonary carcinoma, cancer of pancreas, osteosarcoma.
But along with the retinoid medicinal application is increasingly extensive, the skin that ATRA causes, mucosal injury, feel sick, untoward reaction and fast-developing drug resistance and the high relapse rates such as vomiting, poor appetite, Abdeminal pain, headache, joint, myalgia, numeration of leukocyte increase, retinoic acid syndrome (RARS), greatly limited the application of medicine.Therefore the structure of retinoid medicine is launched a large amount of modification work both at home and abroad, up to now, develop a lot of eutherapeutic retinoids medicines, chemical compound fenretinide (the Fenretinide of Johnson Co. exploitation wherein, 4-HPR) its toxicity is low far beyond other retinoid compounds, but life-time service, and the drug resistance incidence rate is low, multiple solid tumor all there is direct inhibitory action, has entered at present clinical trial abroad.
This seminar is take the latest Progress of domestic and international retinoid compounds as background, 25 of a series of retinoic acid derivatives that contain electron withdraw group-trifluoromethyl or trifluoromethoxy with independent intellectual property rights have been designed and synthesized take fenretinide as starting point, and with ' HNMR, ' 3CNMR and MS carry out structural confirmation.Subsequently, observe the novel retinoid derivant synthesize to leukemia cell line NB
4The inhibition of cell is bred and is induced differentiation activity, has filtered out the chemical compound 4-amino-2-trifluoromethyl-phenyl retinate (4-amino-2-trifluoromethyl-phenyl retinate, ATPR) of inducing differentiation activity the strongest, and this chemical compound is to NB
4Cell has stronger induction of differentiation, and the NBT positive cell rate is 48.2%, and oily sem observation shows NB
4The cell trend is ripe breaks up, and the feature of mature cell occurs, cell surface differentiation antigen CD
11bExpression increases, CD
13Express then and reduce, by the analysis of cell cycle, find G
0/ G
1Phase cellular expression amount increases, and is G
1The phase retardance.Simultaneously, we only are hydrolyzed under the catalysis of life entity lactonase by the new derivatives of design, just can slowly release RA, can greatly reduce the rate of metabolism of RA, therefore can reduce because the too fast caused side effect of accretion rate and have preferably stability, to become treatment malignant tumor and leukemic new medicinal products with exploitation after further research, open the new piece of writing of induction-differential therapy tumor.
But we find by early-stage Study, this type of novel retinoic acid derivative hydrophilic is relatively poor, dissolubility lower (the early-stage Study data show is about 0.11mg/ml) in the water, when the dissolubility of chemical compound is lower than 1mg/ml, the low inferior problem of bioavailability be will occur after oral, later development and the clinical practice of this type of new compound directly had influence on.
In recent years, researcher is paid special attention to the bioavailability that adopts lipid to improve fat-soluble medicine for the preparation on basis, such as dosage forms such as the molten surface active agent solubilization of oil, liposome, nano-emulsions (claiming again microemulsion), especially receive much concern from nano-emulsion (self-microemulsion) preparation.From nanoemulsion medicine transmission system (self-nanoemulsified Drug Delivery System, SNEDDS) Thermodynamically stable that is formed by medicine, oil phase, surfactant and co-emulsifier, homogeneous, transparent solution, oral rear under the condition of ambient temperature and gentle agitation, the emulsion droplet of spontaneous formation particle diameter 10-100nm.The characteristics of SNEDDS are that medicine is present in the tiny oil droplet, can be distributed in fast whole gastrointestinal tract; Medicine distributes between oil/water is biphase, and the stripping that relies on the huge specific surface area of tiny oil droplet greatly to improve poorly water soluble drugs has improved the bioavailability of medicine; Owing to having used a large amount of surfactants, increase the penetrance of intestinal epithelial cell simultaneously, can promote drug absorption; Can avoid the hydrolysis of water unstable medicine.It stability, size etc. various aspect performance all be better than emulsion.
And traditional nano-emulsion oral administration generally is that the nano-emulsion concentrated solution is made soft capsule, ciclosporin A (Ciclosporin A such as Switzerland's Sandoz pharmaceutical factory exploitation, cyA) nano-emulsion concentrated solution (sandimmun neoral) soft capsule, or directly take with the form of liquid.But, studying when nanorize improves bioavailability, researcher has often been ignored the problems such as stability that this liquid dosage form may exist: can migrate in the nanoemulsions such as the moisture in the soft capsule shell, thereby changed the composition of each phase of nano-emulsion, and caused capsule shells dehydration expansion deliquescing; There are the probability that reacts with the capsule shells component in surfactant in the nanoemulsions and cosurfactant simultaneously; Storage temperature changes may be on the impact of preparation stability etc.In view of the problems that above nano-emulsion tradition administering mode exists, develop its new administering mode necessary.
Summary of the invention
Technical problem to be solved by this invention is to overcome the prior art deficiency, and a kind of stable in properties, stripping is fast, bioavailability is high ATPR self-emulsifiable preparation are provided.
For this reason, the invention provides following technical solution.
A kind of ATPR self-microemulsion, its particular point part is: be comprised of following percentage by weight and make:
ATPR self-microemulsion of the present invention, its preferred scheme is: the weight percent content of described ATPR is 0.1%-20%, more preferably 0.1%-5%.
Described oil phase can be one or more the combination in the following oil: Oleum Arachidis hypogaeae semen, Oleum Glycines, Oleum Sesami, olive oil, Oleum Brassicae campestris, Labrafac, oleic acid, ethyl oleate, hot certain herbaceous plants with big flowers acid glycerine ester and isopropyl myristate, preferred oleic acid, ethyl oleate, hot certain herbaceous plants with big flowers acid glycerine ester and lima bean model isopropyl propionate, most preferably ethyl oleate.
The combination of one or more in can be following of described surfactant: polyoxyethylene fatty acid ester class, polyoxyethylene fatty acid ethers, poloxamer, sodium lauryl sulphate, Cremophor RH, lecithin, Labrasol (PEG-8-glycerol sad/certain herbaceous plants with big flowers acid esters), HS15, emulsifying agent op, tween 80 and Cremophor EL, preferred Labrasol, emulsifying agent op, tween 80 and Cremophor EL, most preferably HS15.
Described co-emulsifier can be one or more the combination in following: ethanol, isopropyl alcohol, n-octyl alcohol, 1,2-PD or Polyethylene Glycol, preferred PEG400.
The preparation method of ATPR self-microemulsion of the present invention comprises the steps: surfactant, cosurfactant mix homogeneously, with oil phase mixing 30-40min, adds an amount of ATPR again, is stirred to medicine and dissolves fully, has both got self-microemulsion.Add adsorbent, stir, incapsulate shell, both got the ATPR Solid Self-microemulsion.
The Solid Self-microemulsion capsule of the present invention's preparation is for orally using.
Self-microemulsion provided by the invention adds that water stirs or microemulsion that can spontaneous formation 10-200nm under the dilution of gastrointestinal motility and body fluid.
Beneficial effect of the present invention:
1.ATPR self-microemulsifying drug delivery system improved the dissolubility of medicine, medicine is dissolved in the oil droplet and is protected, and has improved the stability in the body;
2. surfactant can change the flowability of cell membrane, improves the membrane permeability of medicine, has increased interior absorption of body of medicine, has improved the relative bioavailability of medicine.
3. Solid Self-microemulsion can improve the phenomenon of softening, the leakage of oil of traditional soft capsule, has increased the stability of preparation.
Description of drawings
Figure 1A TPR self-microemulsion and conventional tablet stripping are relatively
Fig. 2 ATPR self-micro emulsifying medicament delivery system In Vitro Dissolution result
The specific embodiment
Embodiment 1
The ATPR self-microemulsion is comprised of following components by weight percent:
Table 1ATPR self-microemulsion prescription
With surfactant, cosurfactant mix homogeneously, again with oil phase mixing 30-40min, add the ATPR of recipe quantity by above-mentioned prescription, be stirred to medicine and dissolve fully, both got self-microemulsion.With 100 times of distilled water dilutings, 1min namely finishes the self emulsifying process, measures the emulsion droplet mean diameter for all between 10-200nm with Ma Erwen nano particle size instrument after the emulsifying.
Embodiment 2
By prescription 3 preparation self-microemulsion, with 100 times of distilled water dilutings, 1min namely finishes the self emulsifying process, and measuring the emulsion droplet mean diameter with Ma Erwen nano particle size instrument after the emulsifying is 30.86nm; Carry out the dissolution in vitro inspection, self-microemulsion can Fast Stripping in dissolution medium, and 5min is leachable about 90%, and only stripping about 10% of conventional tablet 5min.Measurement result is seen Fig. 1.
Embodiment 3
Take by weighing raw material by prescription 3, mixed 40 minutes, it is fully dissolved, make the liquid self-microemulsion.Add the adsorbent such as following table 2 prescriptions, stir the hard capsule of packing into.0 month, in March, study on the stability had no capsule shell obvious oil impregnate and ruckbildung was arranged June.
Get 6 capsules of respectively writing out a prescription and carry out dissolution test, dissolution medium is the 0.5% sodium dodecyl sulfate solution 1000ml that 25% isopropyl alcohol is made, and rotating speed is 100rpm, temperature: (37 ± 0.5) ℃.Respectively 5,10,20,30,45, the 60min 5ml that takes a sample.Adopt high performance liquid chromatogram to detect the ATPR dissolution after processing.The HPLC chromatographic condition is: chromatographic column: Dalian Yi Lite Hypersil ODS post (4.6mm * 250mm, 5 μ m); Mobile phase: methanol-water (92: 8); Flow velocity: 1.0ml/min; Detect wavelength: 367nm; Column temperature: 30 ℃; Sample size: 20 μ 1.Measurement result is seen Fig. 2.
Table 2 Solid Self-microemulsion prescription
Claims (13)
1. 4-amino-2-trifluoromethyl-phenyl retinate self-microemulsion is characterized in that: be comprised of following percentage by weight and make:
Preparation method: with surfactant, cosurfactant mix homogeneously, again with oil phase mixing 30-40min, add the 4-amino-2-trifluoromethyl-phenyl retinate of recipe quantity, be stirred to medicine and dissolve fully, both got self-microemulsion.
2. self-microemulsion according to claim 1, it is characterized in that: the content of described 4-amino-2-trifluoromethyl-phenyl retinate is 0.1%-5%.
3. self-microemulsion according to claim 1, it is characterized in that: described oil phase is long-chain fat oil or medium chain fatty oil.
4. self-microemulsion according to claim 3 is characterized in that: described oil phase can be one or more the combination in the following oil: Oleum Arachidis hypogaeae semen, Oleum Glycines, Oleum Sesami, olive oil, Oleum Brassicae campestris, Labrafac, oleic acid, ethyl oleate, hot certain herbaceous plants with big flowers acid glycerine ester and isopropyl myristate.
5. self-microemulsion according to claim 4 is characterized in that: described oil phase is oleic acid, ethyl oleate, hot certain herbaceous plants with big flowers acid glycerine ester and isopropyl myristate.
6. self-microemulsion according to claim 5, it is characterized in that: described oil phase is ethyl oleate.
7. self-microemulsion according to claim 1 is characterized in that: described surfactant can be one or more the combination in following: polyoxyethylene fatty acid ester class, polyoxyethylene fatty acid ethers, poloxamer, sodium lauryl sulphate, Cremophor RH, lecithin, Labrasol (PEG-8-glycerol sad/certain herbaceous plants with big flowers acid esters), HS15, emulsifying agent op, tween 80 and Cremophor EL.
8. self-microemulsion according to claim 7, it is characterized in that: described surfactant is one or more combination among Labrasol, emulsifying agent op, tween 80, Cremophor EL and the HS15.
9. self-microemulsion according to claim 8, it is characterized in that: described surfactant is HS15.
10. self-microemulsion according to claim 1 is characterized in that: described cosurfactant is one or more the combination in following: ethanol, isopropyl alcohol, n-octyl alcohol, 1,2-PD or Polyethylene Glycol.
11. self-microemulsion according to claim 10 is characterized in that: described cosurfactant is PEG400.
12. self-microemulsion according to claim 1 is characterized in that: described self-microemulsion also contains adsorbent.
13. self-microemulsion according to claim 12 is characterized in that: described adsorbent is a kind of in micropowder silica gel, the polyvinyl pyrrolidone or two kinds of mixture.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103976952A (en) * | 2014-06-06 | 2014-08-13 | 山东大学齐鲁医院 | Alda-1 oral self-microemulsion preparation and preparation method thereof |
| CN104706590A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Clarithromycin fat emulsion concentrate and preparation method and use thereof |
| CN104706585A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Vinorelbine bitartrate fat emulsion concentrated solution, preparation method and application thereof |
| CN111671902A (en) * | 2020-03-19 | 2020-09-18 | 中山大学孙逸仙纪念医院 | Sensitizer drug, drug composition and application |
-
2012
- 2012-04-07 CN CN2012101050742A patent/CN103356504A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104706590A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Clarithromycin fat emulsion concentrate and preparation method and use thereof |
| CN104706585A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Vinorelbine bitartrate fat emulsion concentrated solution, preparation method and application thereof |
| CN103976952A (en) * | 2014-06-06 | 2014-08-13 | 山东大学齐鲁医院 | Alda-1 oral self-microemulsion preparation and preparation method thereof |
| CN103976952B (en) * | 2014-06-06 | 2015-04-08 | 山东大学齐鲁医院 | Alda-1 oral self-microemulsion preparation and preparation method thereof |
| CN111671902A (en) * | 2020-03-19 | 2020-09-18 | 中山大学孙逸仙纪念医院 | Sensitizer drug, drug composition and application |
| CN111671902B (en) * | 2020-03-19 | 2022-08-16 | 中山大学孙逸仙纪念医院 | Sensitizer drug, drug composition and application |
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Application publication date: 20131023 |