CN113209034B - Camptothecine colon-specific drug-release pellet and preparation method thereof - Google Patents
Camptothecine colon-specific drug-release pellet and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal preparations, and particularly relates to a camptothecin colon-specific drug release pellet and a preparation method thereof. The invention provides a camptothecin nano-emulsion/micro-pill with colon-specific drug release, camptothecin is prepared into nano-emulsion, the solubility of camptothecin can be improved, the drug-loading rate of the nano-emulsion/micro-pill can be doubled, the drug-loading nano-emulsion can be released in the colon in a specific way, camptothecin can be directly absorbed in the form of nano-emulsion, the problem of opening of an inner ester ring of the nano-emulsion is avoided, the solubility of camptothecin is increased, the camptothecin can smoothly cross an aqueous barrier on the surface of the colon and can be taken by colon cancer tissues, the curative effect is enhanced, the toxicity is reduced, and the application value is great.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a camptothecin colon-specific drug release pellet and a preparation method thereof.
Background
Camptothecin is a water-insoluble pentacyclic pyrroloquinoline alkaloid separated from camptotheca acuminata of davidiaceae, is also a natural topoisomerase I inhibitor, and has good effect on treating various tumor diseases including colon cancer. However, camptothecin has poor water solubility, has irritation to gastrointestinal mucosa, is easy to open loop in an alkaline environment, has reduced curative effect and enhanced toxicity, and greatly reduces the pharmaceutical property.
Micro/nano-carriers have many advantages such as increased volume/surface area ratio, resulting in higher contact area of the drug at the same dose and more effective delivery, selective release by selecting physiologically environmentally responsive medicinal polymer materials as the capsule or matrix, and reduction of side effects and toxicity of the drug; meanwhile, the medicine is wrapped in the inner core, so that the medicine is protected from being damaged by the physiological environment. The nano-carrier can also increase the solubility of the drug and has an easily modified surface, thereby designing targeting nano-carriers with different selective distributions. Compared with the nano-emulsion, the micro-pill loaded with the nano-emulsion is more stable; the micro-pill releases concentrated nano-emulsion at specific position, and can be self-emulsified when meeting water, and the medicine can be taken by tissue in the form of nano-emulsion. By selecting different medicinal high molecular materials, the pellet can respond to different physiological environments to release medicines. The nano-emulsion and the micro-pill technology are combined, so that the stability of the preparation and the medicament can be improved, the medicament can be selectively released, the medicament can be efficiently absorbed in a nano-particle form, and the nano-emulsion and the micro-pill technology gradually become one of the main research directions of complex preparations.
Although the camptothecin known by the technicians in the field has the problems of poor water solubility, gastrointestinal mucosa irritation, easy ring opening in an alkaline environment, reduced curative effect, enhanced toxicity and the like, the camptothecin preparation which can simultaneously increase the solubility of the camptothecin, reduce the gastrointestinal mucosa irritation and realize stable drug release at the colon part so as to improve the curative effect and reduce the toxicity is not successfully prepared at present.
Sodium alginate as anionic polysaccharide has flora/pH sensitivity, is less released in stomach environment with lower pH, has better release effect in intestinal section with higher pH, and can play a role in colon-specific release under certain conditions; carbomer is a high molecular polymer of acrylic acid bonded allyl sucrose or pentaerythritol allyl ether, and has certain acidity due to the fact that the molecular structure of carbomer contains 56-68% of carboxylic acid groups. The solubility is increased in a weak alkaline environment, and the adhesion is greatly enhanced, so that the colon-specific sustained-release tablet can be adhered in a long time, and the directional sustained-release effect is further enhanced.
Aiming at solving the problems of the stimulation of camptothecin on gastrointestinal mucosa and the systemic side effect caused by absorption of the camptothecin into blood, the invention aims at the application of the camptothecin in the treatment of colon cancer, and the camptothecin is prepared into colon-specific drug-release pellets. The invention has the following unexpected findings: dissolving camptothecin in a mixed oil phase of propylene glycol monocaprylate and oleic acid, and adding polyoxyethylene 40 hydrogenated castor oil and diethylene glycol monoethyl ether mixed emulsifier to prepare camptothecin nanoemulsion; and then adding the camptothecin nanoemulsion into a mixed gel liquid of sodium alginate and carbomer, and slowly dripping a calcium chloride aqueous solution to form a gel pellet to entrap the camptothecin in a nanoemulsion core, so that the problem of lactone ring opening is solved, the camptothecin solubility is increased, the camptothecin can smoothly cross an aqueous barrier on the surface of a colon and is taken by colon cancer tissues, the colon-specific release of the camptothecin is realized, the curative effect is enhanced, the toxicity is reduced, and the application value is high.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a camptothecine colon-specific drug-release pellet with improved curative effect, reduced toxicity and gastrointestinal irritation and a preparation method thereof, which specifically comprises the following contents:
in a first aspect, the invention provides a camptothecin colon-specific drug release gel pellet, which comprises the following components in parts by weight: 0.1-0.2% of camptothecin, 15-20% of propylene glycol monocaprylate, 1-2% of oleic acid, 30-42% of mixed emulsifier, 1-3% of sodium alginate, 1-3% of carbomer and 10-20% of calcium chloride; the mixed emulsifier comprises polyoxyethylene 40 hydrogenated castor oil and diethylene glycol monoethyl ether.
Preferably, the weight ratio of polyoxyethylene 40 hydrogenated castor oil to diethylene glycol monoethyl ether is 1: 1.
In a second aspect, the invention provides a method for preparing camptothecin colon-specific drug-release gel pellets, which comprises the following steps:
(1) preparing camptothecin nanoemulsion;
(2) preparing mixed gel liquid: preparing a sodium alginate gel solution and a carbomer gel solution, and mixing the sodium alginate gel solution and the carbomer gel solution according to the volume ratio of 2:1-1:2 to obtain a mixed gel solution;
(3) Ion crosslinking method: dropwise adding the camptothecin nanoemulsion prepared in the step (1) into the mixed gel liquid prepared in the step (2) to obtain a nanoemulsion/gel compound; slowly dripping the nanoemulsion/gel compound into a calcium chloride aqueous solution to form a gel pellet; filtering, and oven drying to obtain camptothecine gel pellet for colon-specific drug release.
Preferably, the step (1) is: mixing propylene glycol monocaprylate and oleic acid, and adding camptothecin to obtain a mixed oil phase; mixing the melted polyoxyethylene 40 hydrogenated castor oil and diethylene glycol monoethyl ether according to the weight ratio of 1:1 to obtain a mixed emulsifier; mixing the mixed oil phase and the mixed emulsifier; distilled water is added dropwise under continuous stirring to prepare the camptothecin nanoemulsion.
Preferably, the camptothecin nanoemulsion comprises the following components: 0.1-0.2% of camptothecin, 15-20% of propylene glycol monocaprylate, 30-42% of mixed emulsifier and 1-2% of oleic acid.
Preferably, the step (2) is: adding sodium alginate into distilled water, standing at normal temperature, and stirring to obtain sodium alginate gel solution; adding carbomer into distilled water, standing at normal temperature, and stirring to obtain carbomer gel solution; mixing the sodium alginate gel solution and the carbomer gel solution, and uniformly stirring to obtain a mixed gel solution;
Preferably, the concentration of the sodium alginate gel liquid and the carbomer gel liquid is 1-3% m/v.
Preferably, in the step (2), the carbomer is carbomer 934P.
Preferably, in the step (3), the nanoemulsion/gel complex comprises a camptothecin nanoemulsion and a mixed gel solution in a weight ratio of 2:1-1: 2.
Preferably, in the step (3), the concentration of the calcium chloride solution is 10-20% m/v.
In a third aspect, the invention provides a camptothecin colon-specific delivery gel pellet prepared according to the method of the second aspect.
In a fourth aspect, the invention provides an application of the camptothecin colon site-specific drug-release gel pellet in the first aspect or the third aspect as a drug for treating colon cancer.
The invention has the beneficial effects that: firstly, the invention provides a camptothecin nano-emulsion/micro-pill with colon-specific drug release, the camptothecin is prepared into the nano-emulsion which can improve the solubility of camptothecin, and the nano-emulsion/micro-pill is further prepared into a concentration-loaded nano-emulsion/micro-pill, so that the volume/specific surface area is obviously increased, and the drug-loading amount of the camptothecin is doubled; secondly, the camptothecin nanoemulsion is added into the mixed gel liquid of sodium alginate and carbomer, and then the calcium chloride aqueous solution is slowly dripped, so that the formed gel pellet entraps the camptothecin in the nanoemulsion core, thereby not only solving the problem of lactone ring opening, but also increasing the solubility of the camptothecin, enabling the camptothecin to smoothly cross the water-based barrier on the surface of the colon and be absorbed by colon cancer tissues, realizing colon-specific release of the camptothecin, avoiding drug waste and systemic side effects caused by large-scale release and absorption of the camptothecin in the stomach and small intestine, simultaneously enhancing the curative effect and having great application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention.
FIG. 1 is a transmission electron microscope image of the camptothecin colon site-specific drug-release gel pellet released in simulated digestive juice;
FIG. 2 shows the release profile of the camptothecine colon specific drug release pellet in simulated digestive juice;
FIG. 3 shows the adhesion rate of the camptothecine colon-specific drug-release pellet of the present invention on isolated gastrointestinal mucosa of mouse;
FIG. 4 shows fluorescence images of the Cy 7-loaded nanoemulsion/pellet in SD rats, wherein A is an image of the SD rats at different times; b is a 12h rat anatomical in vivo imaging chart.
Detailed Description
The present invention will be explained in further detail with reference to specific examples. The experimental methods in the examples, in which specific conditions are not specified, are generally performed under the conditions described in the manual and the conventional conditions, or under the conditions recommended by the manufacturer; general equipment, materials, reagents and the like used are commercially available unless otherwise specified.
EXAMPLE 1 preparation of Camptothecine pellet with colon Targeted drug Release 1
(1) Preparing camptothecin nanoemulsion: precisely weighing 0.05g of camptothecin, adding 7.5g of oil phase propylene glycol monocaprylate (Capryol90), and dissolving by ultrasonic treatment for about 30min after vortex oscillation; heating 7.5g of emulsifier polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH 40) in an oven at 60 ℃ in advance, adding 7.5g of equivalent auxiliary emulsifier diethylene glycol monoethyl ether (transcutol HP) according to a Km value of 1:1 after the emulsifier is completely melted, and stirring by using a magnetic stirrer at a constant temperature of 30 ℃ to obtain a mixed emulsifier; adding 0.5g of oleic acid into an oil phase containing camptothecin, stirring and mixing for 5min, adding a mixed emulsifier with a constant temperature of 30 ℃, continuously stirring for about 20min, performing ultrasonic treatment for 30min, then placing on a magnetic stirrer with a constant temperature of 30 ℃, slowly dropwise adding distilled water, and then continuously stirring for 10min to obtain the camptothecin nanoemulsion, wherein the camptothecin nanoemulsion contains 0.1% m/v of camptothecin, 15% m/v of propylene glycol monocaprylate, 30% m/v of the mixed emulsifier and 1% m/v of oleic acid.
(2) Preparing mixed gel liquid: adding sodium alginate into distilled water, standing at normal temperature, and stirring to obtain sodium alginate gel solution with concentration of 1% m/v; adding carbomer 934P into distilled water, standing at normal temperature, and stirring to obtain carbomer gel solution with concentration of 1% m/v; the mass ratio of the two is 1:1, mixing and uniformly stirring to obtain mixed gel liquid.
(3) Ion crosslinking method: dropwise adding the camptothecin nanoemulsion prepared in the step (1) into the mixed gel liquid prepared in the step (2), wherein the mass ratio of the camptothecin nanoemulsion to the mixed gel liquid is 2: 1, obtaining the nano emulsion/gel compound. After fully stirring, slowly dripping the nano-emulsion/gel compound into a calcium chloride aqueous solution with the concentration of 10% m/v to form the gel pellet. Filtering, washing, and drying with 40 deg.C hot air at normal pressure for 24 hr to obtain camptothecine gel pellet for colon-specific drug release.
EXAMPLE 2 preparation of Camptothecine pellet with colon Targeted drug Release 2
(1) Preparing camptothecin nanoemulsion: precisely weighing 0.10g of camptothecin, adding 10g of oil phase propylene glycol monocaprylate (Capryol90), and dissolving by ultrasonic treatment for about 30min after vortex oscillation; heating 10.5g of emulsifier polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH 40) in an oven at 60 ℃ in advance, adding 10.5g of equivalent auxiliary emulsifier diethylene glycol monoethyl ether (transcutol HP) according to a Km value of 1:1 after the emulsifier is completely melted, and stirring by using a magnetic stirrer at a constant temperature of 30 ℃ to obtain a mixed emulsifier; adding 1.0g of oleic acid into an oil phase containing camptothecin, stirring and mixing for 5min, adding a mixed emulsifier with a constant temperature of 30 ℃, continuously stirring for about 20min, performing ultrasonic treatment for 30min, slowly dropwise adding distilled water on a magnetic stirrer with a constant temperature of 30 ℃, and continuously stirring for 10min to obtain camptothecin nanoemulsion; the camptothecin nanoemulsion contains 0.2% m/v of camptothecin, 20% m/v of propylene glycol monocaprylate, 42% m/v of mixed emulsifier and 2% m/v of oleic acid.
(2) Preparing mixed gel liquid: adding sodium alginate into distilled water, standing at normal temperature, and stirring to obtain sodium alginate gel solution with concentration of 3% m/v; adding carbomer 934P into distilled water, standing at normal temperature, and stirring to obtain carbomer gel solution with concentration of 3% m/v; the mass ratio of the two is 1:1, mixing and uniformly stirring to obtain mixed gel liquid.
(3) Ion crosslinking method: dropwise adding the camptothecin nanoemulsion prepared in the step (1) into the mixed gel liquid prepared in the step (2), wherein the mass ratio of the camptothecin nanoemulsion to the mixed gel liquid is 1: 2, obtaining the nano-emulsion/gel compound. After fully stirring, slowly dripping the nano-emulsion/gel compound into a calcium chloride aqueous solution with the concentration of 20% m/v to form the gel pellet. Filtering, washing, and drying with 40 deg.C hot air at normal pressure for 24 hr to obtain camptothecine gel pellet for colon-specific drug release.
EXAMPLE 3 preparation of Camptothecine pellet with colon Targeted drug Release 3
(1) Preparing camptothecin nanoemulsion: precisely weighing 0.05g of camptothecin, adding 9.0g of oil phase propylene glycol monocaprylate (Capryol90), and dissolving by ultrasonic treatment for about 30min after vortex oscillation; heating 10.0g of emulsifier polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH 40) in an oven at 60 ℃ in advance, adding 10.0g of equivalent auxiliary emulsifier diethylene glycol monoethyl ether (transcutol HP) according to a Km value of 1:1 after the emulsifier is completely melted, and stirring by using a magnetic stirrer at a constant temperature of 30 ℃ to obtain a mixed emulsifier; adding 1.0g of oleic acid into an oil phase containing camptothecin, stirring and mixing for 5min, adding a mixed emulsifier with a constant temperature of 30 ℃, continuously stirring for about 20min, performing ultrasonic treatment for 30min, slowly dropwise adding distilled water on a magnetic stirrer with a constant temperature of 30 ℃, and continuously stirring for 10min to obtain camptothecin nanoemulsion; the camptothecin nanoemulsion contains 0.2% m/v of camptothecin, 18% m/v of propylene glycol monocaprylate, 42% m/v of mixed emulsifier and 2% m/v of oleic acid.
(2) Preparing mixed gel liquid: adding sodium alginate into distilled water, standing at normal temperature, and stirring to obtain sodium alginate gel solution with concentration of 2.18% m/v; adding carbomer 934P into distilled water, standing at normal temperature, and stirring to obtain carbomer gel solution with concentration of 1.92% m/v; the mass ratio of the two is 1: 1, mixing and uniformly stirring to obtain mixed gel liquid.
(3) Ion crosslinking method: dropwise adding the camptothecin nanoemulsion prepared in the step (1) into the mixed gel liquid prepared in the step (2), wherein the mass ratio of the camptothecin nanoemulsion to the mixed gel liquid is 1: 1, obtaining the nano-emulsion/gel compound. After fully stirring, slowly dripping the nano-emulsion/gel compound into a calcium chloride aqueous solution with the concentration of 15% m/v to form the gel pellet. Filtering, washing, and drying with 40 deg.C hot air at normal pressure for 24 hr to obtain camptothecine gel pellet for colon-specific drug release.
Example 4 self-emulsification of camptothecine colon site-specific drug-release gel pellets in water
0.1-0.5g of the camptothecin gel pellets prepared in the examples 1-3 are respectively put into a 10mL centrifuge tube, 10mL of phosphate buffer solution with pH7.4 is added, the mixture is shaken for 24h in a shaking table at 37 ℃ at the rotating speed of 100rpm, release liquid is diluted by distilled water, the mixture is filtered by a microporous filter membrane, and the average particle size and the polydispersity index (PDI) of the continuous filtrate are measured by a particle size analyzer. The results show that the supernatant of the camptothecin gel pellet release medium prepared in examples 1-3 of the invention has an average particle size of 125.27 +/-4.84 nm and a PDI value of 0.487 +/-0.007, which is consistent with the particle size of the nano-preparation, and show that after the camptothecin gel pellet disclosed by the invention is softened in the release medium, at least part of the drug exists in the release medium in the form of nano-emulsion.
The continuous filtration was dropped on a copper mesh coated with a carbon film and dyed with a 0.5% aqueous solution of phosphotungstic acid, the coated mesh was dried at room temperature, and the microscopic morphology of the emulsion droplets was observed with a TECNAI G2 field emission Transmission Electron Microscope (TEM). The results are shown in fig. 1, and the gel pellets loaded with camptothecin are spherical in the release liquid and are uniformly distributed. The particle size observed in the TEM image is about 100nm in part and about 50nm in part, the emulsion droplets have good uniformity and dispersibility, no impurities exist among particles, the background is clear, and the particle size is basically uniform with the particle size detected by a laser particle sizer.
EXAMPLE 5 in vitro delivery of Camptothecin Colon site-directed delivery pellets
0.25-0.75g of the camptothecin gel pellets prepared in examples 1-3 were placed in a jar containing 30mL of release medium and shaken constantly at 37.0 + -0.5 deg.C and 100 rpm. After releasing in hydrochloric acid solution at pH1.2 for 2h, samples were immediately taken out and transferred to phosphate buffer at pH6.8 for 3h and then transferred to phosphate buffer at pH7.4 for 19h, and 0.7mL of release medium was collected at each time period while supplementing an equal volume of release medium at the same temperature. Adding methanol with the same volume into the released medium, mixing well, centrifuging at 12000rpm for 10min in a centrifuge, filtering the supernatant with 0.45 μm organic microporous membrane, placing the filtrate into a brown sample bottle, and measuring the camptothecin concentration in the released medium by high performance liquid chromatography.
The release curve of the camptothecin colon-specific drug release pellet prepared in the embodiment 1-3 of the invention in simulated digestive juice is shown in figure 2, the camptothecin release in the camptothecin gel pellet follows an abnormal transport mechanism, which shows that the drug release mechanism is the combination of diffusion and swelling/erosion, 20% is released in vitro in 2h, about 45% is released in 5h, and more than 80% is released in 24h, thus achieving the requirements of most of the camptothecin colon release.
Example 6 evaluation of adhesion to mucous Membrane of isolated mouse organ
20-22g of Kunming mouse, fasting for 12h (free drinking water), immediately dissecting and separating the stomach after cervical vertebra death, removing stomach contents, washing with normal saline, and soaking in normal saline for 2 h. Dissected mice were mounted on a glass slide marked in advance with the inside facing up after stomach dissection. 20 camptothecin gel pellets prepared in examples 1 to 3 were counted, respectively, and uniformly placed on the gastric mucosa, the entire slide was put on the upper layer of the dryer, the dryer was sealed for 30min, the slide was taken out, placed at 45 ° slant, and the gastric mucosa was washed with an artificial gastric juice (hydrochloric acid solution at ph 1.2) at a constant flow rate of 20mL/min for 5 min. The camptothecin gel pellets adhering to the gastric mucosa were counted visually, the adhesion rate (MR) of the camptothecin gel pellets was calculated, and three groups were run in parallel. The measurement of the adhesion rates of the small intestine and colon mucosa was performed in accordance with the procedure of the stomach mucosa, except that the small intestine mucosa was washed with a simulated small intestine solution (phosphate buffer solution at pH 6.8) and the colon mucosa was washed with a simulated colon solution (phosphate buffer solution at pH 7.4).
The adhesion rate of the camptothecin colon-specific drug release pellet prepared in the embodiment 1-3 of the invention on the isolated mouse gastrointestinal mucosa is shown in figure 3, the average adhesion rate of the camptothecin pellet on the gastric mucosa is 11.67%, the adhesion rate of the small intestine mucosa is 88.33%, and the adhesion rate of the colon mucosa is 98.33%. The results show that the camptothecine colon-specific drug-release pellets prepared by the invention have small adhesion on gastric mucosa, and the pellets are retained less in vivo when passing through the stomach and are retained in a large amount at the tail end of the small intestine and the colon part, thereby achieving better effect of specific release.
Example 7 transportation and Release of Camptothecine Colon site-directed drug Release gel pellets in rat
Cy7 is a near-infrared fluorescent dye, and is often used for biomolecular labeling, fluorescence imaging and other fluorescence biological analysis. The excitation wavelength is 747nm, the emission wavelength is 774nm, and the appearance is green black solid powder. In this experiment, fluorescently-labeled gel pellets were prepared by substituting Cy7 for camptothecin according to the preparation method of example 3. In the experiment, polyethylene tubes with the inner diameter of 2mm are used for gastric perfusion of SD rats which are fasted for 20 hours, Cy7 marks a plurality of pellets, the rat anesthesia method is ether inhalation anesthesia, the transportation and diffusion conditions of fluorescent substances in the gastrointestinal tracts of the rats are observed through a small animal living body imaging technology, and the release conditions of the colon positioning pellets in the gastrointestinal tracts of the rats are judged.
In-vivo imaging graphs of the Cy 7-loaded nanoemulsion/pellet in SD rats are shown in FIG. 4, in the group A, as can be seen from 2h fluorescence graphs, the pellet is in an aggregation state in the stomach, rarely diffuses, the fluorescence points are concentrated, and part of the pellet begins to transfer to the small intestine; the fluorescent material can be seen to begin diffusing at 4 h; the pellets basically reach the colorectal part at 8h and 12h, and the fluorescence intensity is gradually reduced (the observation of fluorescence is influenced because of thicker fat at the position); b is a fluorescence imaging picture observed after the rat is dissected for 12h, and the fluorescent substance is found to have a larger diffusion area and is mainly dispersed in the colon part at the moment, so that most of the pellets are dissolved. The phenomenon can preliminarily prove that the pellet can basically achieve colon-specific release effect.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (6)
1. A method for preparing camptothecin colon-specific drug release gel pellets is characterized by comprising the following steps:
(1) Preparing camptothecin nano-emulsion, wherein the camptothecin nano-emulsion comprises the following components: camptothecin 0.1-0.2% m/v, propylene glycol monocaprylate 15-20% m/v, mixed emulsifier 30-42% m/v, oleic acid 1-2% m/v;
(2) preparing mixed gel liquid: respectively preparing sodium alginate gel liquid and carbomer gel liquid with the concentration of 1-3% m/v, and mixing the sodium alginate gel liquid and the carbomer gel liquid according to the volume ratio of 2:1-1:2 to obtain mixed gel liquid;
(3) ion crosslinking method: dropwise adding the camptothecin nanoemulsion prepared in the step (1) into the mixed gel liquid prepared in the step (2) to obtain a nanoemulsion/gel compound; slowly dripping the nanoemulsion/gel compound into a calcium chloride aqueous solution to form a gel pellet; filtering, and oven drying to obtain camptothecine gel pellet for colon-specific drug release.
2. The method of claim 1, wherein step (1) is: mixing propylene glycol monocaprylate, oleic acid and camptothecin to obtain a mixed oil phase; mixing the melted polyoxyethylene 40 hydrogenated castor oil and diethylene glycol monoethyl ether according to the weight ratio of 1:1 to obtain a mixed emulsifier; mixing the mixed oil phase and the mixed emulsifier; and dropwise adding distilled water under continuous stirring to prepare the camptothecin nanoemulsion.
3. The method of claim 1, wherein the nanoemulsion/gel complex of step (3) comprises a camptothecin nanoemulsion and a mixed gel solution in a weight ratio of 2:1-1: 2.
4. The method according to claim 1, wherein in the step (3), the concentration of the calcium chloride solution is 10 to 20% m/v.
5. The camptothecine colon-specific delivery gel pellet prepared according to any one of claims 1-4.
6. The use of the camptothecin colon-specific delivery gel pellet of claim 5 in the preparation of a medicament for treating colon cancer.
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| US20020150615A1 (en) * | 2001-02-12 | 2002-10-17 | Howard Sands | Injectable pharmaceutical composition comprising microdroplets of a camptothecin |
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