A kind of preparation method of hydroxy camptothecin@hydrotalcite-like compounds nano hybrid
Technical field:
The invention belongs to technical field of nanometer material preparation, relate to the preparation technology of a kind of nano material, particularly a kind of pH value
The preparation method of the hydroxy camptothecin@hydrotalcite-like compounds nano hybrid of response.
Background technology:
Hydroxy camptothecin (HCPT) is a kind of nonionic slightly water-soluble cancer therapy drug, and active anticancer is strong, but toxic and side effects is also big,
Develop Targeting delivery dosage form significant to its clinical practice.It addition, HCPT molecule has bioactive lactone structure not
Stable, the most easily change into inactive carboxylate structure, this is a problem that should solve in dosage form research.
Houghite (HTlc), also known as layered double-hydroxide (LDHs), is a class inorganic lamellar material, and laminate band structure is just
Electric charge, there is tradable anion in interlayer.Houghite interlayer can be as cell reservoirs, and drug molecule inserts to be formed therebetween and receives
Rice hybrid (is called for short medicine-HTlc nano hybrid), due to the interaction between sterically hindered effect and drug molecule and laminate
And there is good sustained drug release effect, thus be considered as the medicament slow release novel form of great application prospect, novel as a class
Carrier, the application in pharmaceutical dosage form field receives much concern nearly ten years.
Common method prepared by medicine-HTlc nano hybrid has coprecipitation, ion exchange and a structural remodeling method etc., but these
Traditional method is suitable for anionic water soluble drug, and nonionic slightly water-soluble (hydrophobicity) medicine is difficult to intercalation
Load.It is proposed to this end that secondary intercalation method and drug modification-ion exchange etc., the effective intercalation that can realize hydrophobic drug is born
Carry, but drug loading is low.It addition, houghite prepared by coprecipitation be prone to after lamellar, with medicine effect to be gathered into random
The bulky grain of shape, cause its dispersibility poor, application is restricted.
Along with going deep into of acrylic/hydrotalcite-like nano piece preparation method research, utilize ultrathin nanometer sheet as construction unit, as playing with building blocks one
Sample is constructed the nano material of required pattern and is increasingly becomed possibility.Compared to the method for traditional medicament intercalated houghite, peel off-
Construction from part has preparation method simply altogether, and experiment condition is gentle, drug loading high, and this will become undoubtedly prepares medicine-class water
The method that Talcum hybrid is even more important.The most first houghite is peeled off into ultrathin nanometer sheet, then assembles shape with drug molecule altogether
Become nano hybrid, because avoiding intercalation resistance and the interior space of houghite can be made full use of, the height of hydrophobic drug can be realized
Drug loading, but use the bigger Methanamide of toxicity to do medium when peeling off houghite, actual application be restricted (Wu X.W.,
Wang S.,Du N.,et al,Facile synthesis of deoxycholate intercalated layered double hydroxide
nanohybrids via a coassembly process,J.Solid State Chem.,2013,203:181-186.)。
In order to solve this problem, this seminar successfully have developed and utilizes T-shaped microreactor, adds without any Organic substance in aqueous medium
Under the conditions of adding, prepared technology (Hou Wanguo, Pang Xiujiang, Sun Meiyu, of ultra-thin acrylic/hydrotalcite-like nano sheet by a step coprecipitation
Plant the preparation method of Monodispersed acrylic/hydrotalcite-like nano monolithic, Chinese invention patent, the patent No.: ZL201210556149.9).Made
Standby nanometer sheet is made up of 1~2 layer of class shepardite synusia, and clean surface (loads without Organic substance), can be used as constructing houghite base
The assembling primitive of functional material, can prepare free of contamination medicine-HTlc hybrid with medicine by common assembling.
Although medicine-houghite hybrid that the medicine that present stage is reported is formed after inserting houghite interlayer carries at medicine
During there is certain sustained release performance, but medicine had discharged a part before arriving diseased region, caused the poison of cancer therapy drug
Side effect is unavoidable and reduces the medicine effect to diseased region.It is therefore desirable to base when exploitation medicine circulates in blood
This does not discharges, the drug-loading system of quickly release in arriving tumor tissue cell.Owing to being sour environment in cancerous cell, and class water
Talcum can decompose in sour environment, so, the hydroxy camptothecin-hydrotalcite-like compounds nano hybrid preparing pH value response is favourable
In reducing the toxic and side effects of hydroxy camptothecin, improving the utilization rate of medicine.And existing houghite grinding as pharmaceutical carrier
In studying carefully, there is not been reported for the medicine-HTlc nano hybrid of similar " stimulating-response " formula.
Summary of the invention:
It is an object of the invention to the shortcoming overcoming prior art to exist, seeking design provides a kind of cancerous cell acyclic acidic at human body
The preparation method of the hydroxy camptothecin@hydrotalcite-like compounds nano hybrid of pH value response can be produced under border.The inventive method first with
Micro passage reaction prepares ultra-thin acrylic/hydrotalcite-like nano sheet by coprecipitation, then carries out with the surfactant being enclosed with medicine
Assembling, obtain being rolled in pharmaceutical pack the hybrid of inside, type houghite drug-loading system provides one " to stimulate-response " for preparation
Effective method.
To achieve these goals, the inventive method concrete technology step is:
(1) by solubility bivalent inorganic salt M2+Y and trivalent inorganic salt M3+Y is dissolved in deionized water and is configured to metal ion
Total concentration is the mixing salt solution of 0.01-1mol/l;Wherein, solubility bivalent inorganic salt M2+M in Y2+For Mg2+、Fe2+、
Or Zn2+Any one of;Trivalent inorganic salt M3+M in Y3+For Al3+Or Fe3+;Y is NO3 -、Cl-, F-or Br-
In any one;
(2) preparation percentage by weight is weak ammonia or the sodium hydroxide solution of 0.1-0.5mol/l of 3%-7%;
(3) T-shaped micro passage reaction is utilized to make saline solution and aqueous slkali be sufficiently mixed and react to obtain houghite precipitate,
The flow velocity of two kinds of reactants is 5-30ml/min;Reaction temperature is 25-80 DEG C;Microchannel width in micro passage reaction is 0.2-1
Mm, the degree of depth is 0.2-1mm, a length of 5-50mm;
(4) it is well dispersed in after centrifugal for precipitate, washing in water, is obtained ultra-thin acrylic/hydrotalcite-like nano sheet dispersion liquid,
Its concentration is 0.01-5g/L;
(5) prepare hydroxy camptothecin saturated solution in chloroform, it is dropwise instilled and is passed through under surfactant solution, stirring
Nitrogen, evicts from chloroform;Surfactant is dodecylamino Sodium L-alaninate, lauroyl Glycine sodium, N, N-dimethyl
Dodecyl hydroxyethyl ammonium phosphate ester, N-dodecyl hydroxyethyl ammonium phosphate ester, N, N-dibutyl dodecyl hydroxyethyl ammonium phosphoric acid
Ester, lauryl amine dimethyl sulfonic sodium, cocoamidoethyl ethoxy acid methyl Glycine sodium, cocos nucifera oil aminopropyl glycine betaine, lauryl amine
One or both in two methanesulfonic sodiums, the concentration of surfactant is 0.1-10 times of its critical micelle concentration;
(6) surfactant solution being enclosed with hydroxy camptothecin is dropwise instilled in ultra-thin acrylic/hydrotalcite-like nano sheet aqueous dispersions,
Being sufficiently stirred for 2-12 hour, reaction temperature is 25-85 DEG C;
(7) the hybrid centrifuge washing that will prepare, lyophilization obtains hydroxy camptothecin@hydrotalcite-like compounds nano hybrid.
Hydroxy camptothecin prepared by the inventive method-hydrotalcite-like compounds nano hybrid pattern is spherical, and particle diameter is 20-100nm, medicine
Thing discharges slowly in the buffer solution of pH7.2, and during drug release 80%, the time was more than 24 hours;And in the buffering of pH4.8
In solution, in 0.5 hour, medicine discharges rapidly completely.
The inventive method compared with prior art, utilizes the ultra-thin acrylic/hydrotalcite-like nano sheet of clean surface and the surface being enclosed with medicine
Activator solution self assembly in aqueous medium is prepared for hydroxy camptothecin-hydrotalcite-like compounds nano hybrid, and the hybrid pattern of preparation is
Spherical, cancer therapy drug is wrapped in the inside of ball, and this technical method is simple, mild condition, prepared hybrid particle diameter is little, point
Dissipate property good, there is pH value response, the beneficially clinical practice of houghite base drug-loading system.
Accompanying drawing illustrates:
Fig. 1 is the SEM picture of the HCPT@MgAl-HTlc that embodiment 1 prepares.
Fig. 2 is the TEM picture of the HCPT@ZnAl-HTlc that embodiment 2 prepares.
Fig. 3 is the SEM picture of the HCPT/MgAl-HTlc that embodiment 3 prepares.
Detailed description of the invention:
Below by specific embodiment and combine accompanying drawing the inventive method is further elaborated.
Embodiment 1,
(1) 2.250g Al (NO is first weighed3)3·9H2O and 3.078g Mg (NO3)2·6H2O is dissolved in 20ml water, is mixed
Saline solution;
(2) compound concentration is the dilute ammonia solution of 7wt%;
(3) at reaction temperature is 25 DEG C, the flow velocity of mixing salt solution and dilute ammonia solution is 20ml/min, T-shaped micro-
In channel reactor, hybrid reaction is precipitated thing, and the microchannel width in micro passage reaction is 0.2-1mm, and the degree of depth is 0.2-1
Mm, a length of 5-50mm;
(4) after centrifugal for precipitate, use distilled water wash, in triplicate, the jelly obtained is dispersed in distilled water, obtains
Ultrathin nanometer sheet concentration is the dispersion liquid of 0.05g/L;
(5) excess of hydroxyl camptothecine is dissolved in chloroform, after being filtered by precipitate therein after being sufficiently stirred for, obtains saturated solution
10mL;It dropwise instills 100mL concentration is 6.46 × 10-3In the lauroyl sodium glycinate solution of mol/L, it is passed through nitrogen
And be sufficiently stirred for 12 hours, the lauroyl Glycine sodium micelle being enclosed with hydroxy camptothecin obtaining clear after sucking filtration is molten
Liquid;
Instilled in 722mL ultra-thin acrylic/hydrotalcite-like nano sheet aqueous dispersions at (6) 80 DEG C, centrifugal after being sufficiently stirred for 2 hours,
Rotating speed is 12000r/min, is precipitated thing lyophilization, obtains HCPT@MgAl-HTlc nano hybrid.
The drug loading of the hybrid that the present embodiment obtains is 6.2%, when medicine discharges 80% in the buffer solution of pH7.2, time
It it is 26.7 hours;And in the buffer solution of pH4.8, after 15 minutes, medicine discharges rapidly completely.Use JSM-6700F field
Launching scanning electron microscope (SEM) to characterize the pattern of sample, as it is shown in figure 1, the product obtained is spherical, particle diameter is 20nm
Left and right.
Embodiment 2,
(1) 0.250g Al (NO is first weighed3)3·9H2O and 0.397g Zn (NO3)2·6H2O is dissolved in 20ml water, is mixed
Saline solution;
(2) compound concentration is the sodium hydrate aqueous solution of 0.20mol/L;
(3) at reaction temperature is 25 DEG C, the flow velocity of mixing salt solution and sodium hydrate aqueous solution is 20ml/min, at T
In type micro passage reaction, hybrid reaction is precipitated thing, and the microchannel width in micro passage reaction is 0.2-1mm, and the degree of depth is
0.2-1mm, a length of 5-50mm;
(4) after centrifugal for precipitate, use distilled water wash, in triplicate, the jelly obtained is dispersed in distilled water, obtains
Ultrathin nanometer sheet concentration is the dispersion liquid of 0.05g/L;
(5) excess of hydroxyl camptothecine is dissolved in chloroform, after being sufficiently stirred for and being filtered by precipitate therein, obtains saturated solution
10mL, it dropwise instills 17mL concentration is 38.76 × 10-3In the lauroyl sodium glycinate solution of mol/L, it is passed through nitrogen
And be sufficiently stirred for 12 hours, the lauroyl Glycine sodium micelle being enclosed with hydroxy camptothecin obtaining clear after sucking filtration is molten
Liquid;
Instilled in 722mL ultra-thin acrylic/hydrotalcite-like nano sheet aqueous dispersions at (6) 80 DEG C, centrifugal after being sufficiently stirred for 2 hours,
Rotating speed is 12000r/min, is precipitated thing lyophilization, obtains HCPT@ZnAl-HTlc nano hybrid.
The drug loading of the hybrid that the present embodiment obtains is 3.9%, when medicine discharges 80% in the buffer solution of pH7.2, time
It it is 25.1 hours;And in the buffer solution of pH4.8, after 50 minutes, medicine discharges rapidly completely.Use JEM-2100 type saturating
Penetrate ultramicroscope (TEM) pattern of sample is characterized, as in figure 2 it is shown, the product obtained is hollow ball shape, particle diameter
For about 100-200nm.
Embodiment 3,
(1) 2.250g Al (NO is first weighed3)3·9H2O and 3.078g Mg (NO3)2·6H2O is dissolved in 20ml water, is mixed
Saline solution;
(2) compound concentration is the dilute ammonia solution of 7wt%;
(3) at reaction temperature is 25 DEG C, the flow velocity of mixing salt solution and dilute ammonia solution is 20ml/min, T-shaped micro-
In channel reactor, hybrid reaction is precipitated thing, and the microchannel width in micro passage reaction is 0.2-1mm, and the degree of depth is 0.2-1
Mm, a length of 5-50mm;
(4) after centrifugal for precipitate, use distilled water wash, in triplicate, the jelly obtained is dispersed in distilled water, obtains
Ultrathin nanometer sheet concentration is the dispersion liquid of 0.05g/L;
(5) excess of hydroxyl camptothecine is dissolved in chloroform, after being filtered by precipitate therein after being sufficiently stirred for, obtains saturated solution
10mL, it dropwise instills 100mL concentration is 8.00 × 10-3In the dodecylamino Sodium L-alaninate solution of mol/L, it is passed through
Nitrogen is also sufficiently stirred for 12 hours, obtains the dodecylamino alanine being enclosed with hydroxy camptothecin of clear after sucking filtration
Sodium micellar solution;
Instilled in 500mL ultra-thin acrylic/hydrotalcite-like nano sheet aqueous dispersions at (6) 25 DEG C, centrifugal after being sufficiently stirred for 2 hours,
Rotating speed is 12000r/min, obtains product, be designated as HCPT/MgAl-HTlc after being precipitated thing lyophilization.
The drug loading of the hybrid that the present embodiment obtains is 5.0%, when medicine discharges 80% in the buffer solution of pH7.2, time
It it is 450 minutes;In the buffer solution of pH4.8, after 20 minutes, medicine discharges rapidly completely.Use JSM-6700F Flied emission
The pattern of sample is characterized by scanning electron microscope (SEM), from the figure 3, it may be seen that the granule that the product obtained is random accumulation.