CN112353759B - Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition and preparation method thereof - Google Patents
Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition and preparation method thereof Download PDFInfo
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- CN112353759B CN112353759B CN201910673840.7A CN201910673840A CN112353759B CN 112353759 B CN112353759 B CN 112353759B CN 201910673840 A CN201910673840 A CN 201910673840A CN 112353759 B CN112353759 B CN 112353759B
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- emulsifying composition
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Abstract
The invention discloses a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition and a preparation method thereof, the self-emulsifying composition has the functions of increasing biological absorption and drug effect and reducing toxic and side effects of oral brain targeting, and the composition consists of an oil phase, an emulsifier and an auxiliary emulsifier, can be directly used, and can also be diluted into a nano-emulsion by adding water for use. The composition can form a nanoemulsion to wrap a phenanthroindolizidine alkaloid derivative prodrug after administration; meanwhile, the composition can increase intestinal mucosa epithelial cell uptake, improve biological membrane permeability, obtain higher plasma bioavailability, improve brain exposure and increase the treatment effect on brain glioma; meanwhile, the encapsulation effect can avoid direct contact and metabolism of gastrointestinal tracts, reduce lipolysis of the prodrug in plasma, reduce exposure of active metabolites in the plasma, reduce toxicity and widen the clinical treatment window of resisting brain glioma. The invention has simple and easy process and good popularization and application prospect.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition, and a preparation method and application thereof.
Background
Phenanthroindolizidine alkaloid derivativesIs one or more compounds with new structure and antitumor activity separated from plants of Tylophora ovata or Anisodus acutangulus of Asclepiadaceae. It can inhibit the Hedgehog pathway over-expressed in tumor cells to achieve antitumor effect [1] . However, the compounds belong to BCS IV, and have poor solubility and weak membrane permeability, so that the oral bioavailability is low and the blood concentration fluctuation is large. The long-term application of large dose can cause gastrointestinal side effects such as diarrhea and the like, and the clinical application of the preparation is limited.
The drug effect and toxicity are important indexes for evaluating the clinical application possibility of the compound, and the drug absorption and toxicity are two important factors. The increased absorption of the drug in vivo is helpful for the exertion of the drug effect, and the reduction of toxicity can improve the therapeutic window. The pharmaceutical research of increasing the oral absorption and the drug effect of the medicine and simultaneously reducing the toxic and side effect of the medicine is an important means for increasing the drug property of the compound.
Many studies have been reported on the use of Drug Delivery Systems (DDS) to increase the oral bioabsorption of drugs, such as micelles, solid lipid nanoparticles, and liquid lipid nanoparticle delivery systems [2] . However, the increase in bioabsorption and the inconsistency of the target site of drug action may cause the increase in toxic or side effects [3] 。
Some reports have been made on reducing the toxicity of drugs after oral administration, such as Leptospira japonica nano vesicles [4] 。
However, there are few reports of increased drug absorption and efficacy, and concomitant reduction in toxicity, via a delivery vehicle [5-7] And the different carriers are polymers, vesicles or solid lipid nanoparticles, so that it is often unpredictable to achieve the goal by using DDS as a means.
Self-microemulsion (SME) with effect of increasing oral absorption of medicine [8] However, reports of reduced toxicity are rare.
In order to promote the biological absorption of the phenanthroindolizidine alkaloid derivative, reduce the fluctuation of blood concentration, prolong the in vivo retention time, increase the treatment effect on tumors, reduce gastrointestinal toxicity and widen the treatment dosage range, the drug delivery system of the phenanthroindolizidine alkaloid derivative needs to be deeply researched.
Some formulations have been reported in the literature to have toxicity-reducing effects, but not for every compound.
The subject group has explored the compound in various preparation forms, and the results show that the pharmaceutical characteristics, the anti-tumor effect and the toxicity of the constructed nano micelle composed of polyethylene glycol 15 hydroxystearate (Solutol HS 15) and propylene glycol after oral administration are not obviously different from those of common raw material medicines; in addition, the constructed compound is glyceryl behenate: (
888 ATO), soybean phospholipid (PC S75), poloxamer188 (Poloxamer 188) and Tween 80, compared with the raw material medicines, the pharmacokinetics characteristics of the oral Solid Lipid Nanoparticles (SLN) are obviously higher than the metabolites generated in blood, thus causing more obvious gastrointestinal toxicity and simultaneously leading to the reduction of the anti-tumor effect. Therefore, it is difficult to predict which formulation form can achieve the effect of reducing gastrointestinal toxicity while promoting absorption to increase the drug efficacy for oral administration of the phenanthroindolizidine alkaloid derivative. />
Disclosure of Invention
The invention aims to solve the technical problems that the oral bioavailability of the phenanthroindolizidine alkaloid derivative is low, the blood concentration fluctuation is large, and the in-vivo retention time is short. Meanwhile, the irritation to the gastrointestinal tract is reduced, and the gastrointestinal toxicity is reduced. The invention aims to provide a novel nano self-emulsifying composition of phenanthroindolizidine alkaloid derivatives.
The phenanthroindolizidine alkaloid derivative is as follows: (13 aS) -3-pivaloyloxy-6,7-dimethoxy-9-phenanthro [9,10-b ] -indolizidine (CAT 3), (13 aS) -3-hydroxy-6,7-dimethoxy-9-phenanthro [9,10-b ] -indolizidine (PF 430) or dexdeoxytylosin (CAT).
IC of CAT and CAT3 in cells 50 Are all 10 -7 -10 -8 mol/L. The two can be regarded as prodrugs, and the main metabolite is PF403 in vivo, so that the prodrug has higher biological activity and IC for tumor cells of various tissue sources 50 Is 10 -10 -10 -12 mol/L. The exposure of PF403 in plasma or gastrointestinal tract may be an important cause of severe gastrointestinal toxicity of this class of compounds.
The invention aims to improve the solubility of phenanthroindolizidine alkaloid derivatives through a self-emulsifying composition, and the self-emulsifying composition can be constructed into O/W type emulsion which can spontaneously form a large number of nano-scale emulsion drops with water or body fluid under slight stirring or peristalsis.
Another object of the present invention is to reduce the contact of phenanthroindolizidine alkaloid derivatives with the gastrointestinal wall and reduce the gastrointestinal toxicity by forming a nanoemulsion by encapsulating the derivatives in oil droplets.
The invention also aims to improve the surface hydrophobic property of the phenanthroindolizidine alkaloid derivative, increase the specific surface area, increase the intestinal mucosa permeation and improve the bioavailability by forming the nano-emulsion.
It is another object of the present invention to enhance the therapeutic effect of tumors through the improvement of bioavailability.
It is another object of the present invention to reduce the fluctuation of plasma concentration of active substances in blood, to prolong the mean residence time of the drug in blood, and to reduce the side effects caused by the fluctuation of plasma concentration by designing a drug delivery system.
In order to solve the technical problems and achieve the above object, the present invention provides the following technical solutions:
the first aspect of the technical scheme of the invention provides a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition which is characterized by containing a phenanthroindolizidine alkaloid derivative, an oil phase, an emulsifier and an auxiliary emulsifier;
phenanthroindolizidine-containing alkaloid derivatives: 0.1-50mg/g,
the oil phase, the emulsifier and the co-emulsifier are calculated according to 100 percent, and the weight ratio of each component is as follows:
oil phase: 5 to 50 percent of the total weight of the mixture,
emulsifier: 30 to 90 percent of the total weight of the mixture,
auxiliary emulsifier: 5 to 30 percent.
Wherein, the phenanthroindolizidine alkaloid derivative comprises (13 aS) -3-pivaloyloxy-6,7-dimethoxy-9-phenanthro [9,10-b ] -indolizidine, (13 aS) -3-hydroxy-6,7-dimethoxy-9-phenanthro [9,10-b ] -indolizidine or dextro-deoxytylosin, and the structural formula is shown aS follows:
(13 aS) -3-pivaloyloxy-6,7-dimethoxy-9-phenanthro [9,10-b ] -indolizidine
(13 aS) -3-hydroxy-6,7-dimethoxy-9-phenanthro [9,10-b ] -indolizidine
Dextrorotation deoxidation tylophorinine.
The oil phase comprises soybean oil, medium-chain oil, olive oil, coconut oil, peanut oil, camellia oil, castor oil, isopropyl myristate, ethyl myristate, isopropyl palmitate, caprylic/capric triglyceride, ethyl laurate, glyceryl oleate, glyceryl linoleate, and polyethylene glycol glyceryl oleate (R)
1944 cs), maisine35-1, sorbitol oleate, ethyl linoleate, corn oil or acyl-transferred corn oil C8/C10 monoglyceride, coconut oil C8/C10 diglyceride, coconut oil C8/C10 triglyceride, caprylic diglyceride, caprylic monoglyceride, capric diglyceride, capric triglyceride, caprylic capric monoglyceride, caprylic capric triglyceride, linoleic acid macrogolglyceride (| ion |)>
M2125 CS), gelucire and Capryol 90, or a mixture of more than one of the above in any proportion.
The emulsifier comprises polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, tween 80, soybean phospholipid, lecithin, caprylic/capric polyethylene glycol glyceride (labrasol), and oleic acid polyethylene glycol glyceride (LABRASOL)
1944cs)、
M2125CS is mixed in any ratio.
The auxiliary emulsifier comprises glycerol, polyethylene glycol, propylene glycol, ethylene glycol monoethyl ether, ethanol, propylene carbonate, glycerol furfural, dimethyl isosorbide and diethylene glycol monoethyl ether (ethylene glycol monoethyl ether)
HP), labrasol and benzyl alcohol in any proportion.
Preferably, the phenanthroindolizidine-containing alkaloid derivative: 0.1-50mg/g,
the oil phase, the emulsifier and the co-emulsifier are calculated according to 100 percent, and the weight ratio of each component is as follows:
oil phase: 10 to 45 percent of the total weight of the mixture,
emulsifier: 40 to 80 percent of the total weight of the mixture,
auxiliary emulsifier: 10 to 25 percent.
More preferably, the phenanthroindolizidine-containing alkaloid derivative: 0.1-50mg/g,
the oil phase, the emulsifier and the co-emulsifier are calculated according to 100 percent, and the weight ratio of each component is as follows:
oil phase: 15 to 35 percent of the total weight of the mixture,
emulsifier: 45 to 70 percent of the total weight of the mixture,
auxiliary emulsifier: 10 to 25 percent.
The self-emulsifying composition may also contain an adsorbent; the adsorbent comprises one or a mixture of two of micropowder silica gel and polyvinylpyrrolidone.
The nano self-emulsifying composition can be further prepared into capsules, soft capsules, injections, enemas, nasal drops, transdermal patches or mucosal patches.
The phenanthroindolizidine alkaloid derivative nano self-emulsifying composition can be directly encapsulated in soft capsules for use. In addition, the solid preparation can be further prepared by adsorbing the extract with a suitable solid adsorbent to prepare a solid or semisolid substance.
The second aspect of the technical scheme of the invention provides a preparation method of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition in the first aspect, which is characterized in that an oil phase, an emulsifier and an auxiliary emulsifier are mixed and stirred to obtain a clear solution which is used as a blank self-emulsifying composition; adding phenanthroindolizidine alkaloid derivative, and heating, ultrasonic treating or stirring to dissolve completely to obtain the final product.
The second aspect of the technical scheme of the invention also provides a second preparation method of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition in the first aspect, which is characterized in that the phenanthroindolizidine alkaloid derivative is firstly dissolved in an oil phase, an emulsifier or an auxiliary emulsifier, or three mixtures or any two mixtures, and then stirred to obtain a clear solution, thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition.
The second aspect of the technical scheme of the invention also provides a third preparation method of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition in the first aspect, which is characterized in that the phenanthroindolizidine alkaloid derivative, an oil phase, an emulsifier and an auxiliary emulsifier are mixed, and the mixture is heated, ultrasonically treated or stirred to be completely dissolved, so that the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition is obtained.
The third aspect of the technical scheme of the invention provides application of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition in preparation of a medicament for preventing and/or treating cancer and/or inflammatory diseases. The cancer is selected from glioma, bone marrow neuroblastoma, colon cancer, gastric cancer, ovarian cancer, cervical cancer, liver cancer, lung cancer and pancreatic cancer.
Through the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition, the following beneficial effects can be realized:
the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition can be diluted and spontaneously emulsified into a nano O/W type emulsion with the particle size of less than 200nm with water, artificial gastrointestinal fluid or physiological body fluid in any proportion under the action of slight stirring or esophageal peristalsis and the like.
The nano O/W type microemulsion improves the solubility of the phenanthroindolizidine alkaloid derivative.
After emulsification, the emulsion droplets with the nano-particle size can have a large specific surface area, the surfaces of the emulsion droplets are hydrophilic and electropositive, and the absorption and transportation of gastrointestinal mucosa can be promoted.
The emulsion droplets physically wrap the phenanthroindolizidine alkaloid derivative, so that the stability of the phenanthroindolizidine alkaloid derivative in gastrointestinal fluid can be improved.
By combining the characteristics, the nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative can improve the bioavailability of the medicament by one or more characteristics of increasing the solubility of the phenanthroindolizidine alkaloid derivative, the gastrointestinal mucosa uptake and transportation, and increasing the medicament stability in the gastrointestinal tract and carrying charges opposite to the intestinal mucosa. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative improves the concentration and the residence time of the medicine in the brain and is beneficial to the treatment effect of the tumor.
In addition, the nano-scale emulsion drop can isolate the direct contact of the medicine and gastrointestinal mucosa or blood, reduce the exposure of active metabolites in plasma and reduce the toxic and side effects of the gastrointestinal tract and the whole body.
The increase of the drug effect and the reduction of toxic and side effects are beneficial to improving the clinical application range and dosage of the phenanthroindolizidine alkaloid derivative.
The phenanthroindolizidine alkaloid derivative nano self-emulsifying composition can be further prepared into various corresponding dosage forms such as capsules, soft capsules, injections, enemas, nasal drops, transdermal patches or mucosa patches and the like.
The phenanthroindolizidine alkaloid derivative nano self-emulsifying composition can be used for treating cancers and/or inflammatory diseases, and particularly can be applied to cancers such as human glioma, human marrow neuroblastoma, human colon cancer, human gastric cancer, human ovarian cancer, cervical cancer, liver cancer, lung cancer, pancreatic cancer and the like.
Drawings
Fig. 1 shows the particle size distribution of nanoemulsion droplets formed by the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition and an aqueous medium.
Fig. 2 shows the stabilization of CAT3 by nanoemulsion droplets formed by a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition and an aqueous medium.
FIG. 3 is a graph showing the increase in CAT3 intestinal mucosa permeability coefficient of a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition.
Fig. 4 is a graph of the improvement in plasma bioavailability of an API (Active pharmaceutical ingredient) prototype form (CAT 3) of a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition.
Figure 5 is a graph of the reduction in plasma exposure of phenanthroindolizidine alkaloid derivative nano self-emulsifying compositions to the API metabolite form (PF 403).
Fig. 6 is a graph of enhancement of API prototype form (CAT 3) brain tissue distribution by a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition.
Figure 7 is an improvement in brain tissue distribution of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition on API metabolite form (PF 403).
Fig. 8 shows the increase of inhibition effect of phenanthroindolizidine alkaloid derivative nano self-emulsifying composition on rat protoencephaloglioma.
Figure 9 is a graph of the reduction in animal body weight of a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition.
Figure 10 is a graph of the reduction of gastrointestinal irritation of a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition.
Examples
Example 1: nano self-emulsifying composition of phenanthroindolizidine alkaloid derivatives with different oil components
CAT3 is used as a model drug to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when different oil components exist. The composition consists of the following components in percentage by weight:
TABLE 1 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or carrying out ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The self-emulsifying composition is diluted with 1: 100 times of water under slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with particle size less than 200nm.
The self-emulsifying efficiency is an index for representing the mutual self-emulsifying speed of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition and water or digestive juice, and the measuring method comprises the following steps: the self-emulsifying composition is diluted by water with the volume of 1: 100 times of that of the water in a water bath at 37 ℃ under slight stirring, and if complete emulsification can be realized within 1 minute, the self-emulsifying composition is considered to have better self-emulsifying effect.
The size of the emulsion droplets formed by the nano self-emulsifying composition after emulsification is an important physical index of the dosage form, and the biological properties of the nano self-emulsifying composition can be different when the nano self-emulsifying composition has different particle sizes, so that the nano self-emulsifying composition needs to be further characterized. The formed nano-sized emulsion can be characterized by the following method:
taking a proper amount of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition, slowly dispersing the composition in water or artificial gastric juice in a water bath at 37 ℃ according to the proportion of 1: 100, and observing the time for completing emulsification and whether the solution is transparent or not, wherein if the transparent solution can be obtained, the particle size of the formed emulsion is less than 200nm. The specific value of the particle diameter can also be measured by a laser dynamic light scattering method.
Example 2: nano self-emulsifying composition of phenanthroindolizidine alkaloid derivatives with different oil phase proportions
CAT3 is used as a model drug to investigate the formation of the nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivatives at different oil component ratios. The composition consists of the following components in percentage by weight:
TABLE 2 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or carrying out ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 3: phenanthroindolizidine alkaloid derivative nano self-emulsifying composition used when different oil phases are combined and different preparation methods thereof
CAT3 is used as a model drug, and the formation of the nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative when different oils are used in combination is examined. The composition consists of the following components in percentage by weight:
TABLE 3 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) dissolving CAT3 in the oil phase according to the formula 9, adding the emulsifier and the auxiliary emulsifier, stirring, heating or performing ultrasonic treatment until the medicine is completely dissolved, thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. Mixing CAT3, the oil phase, the emulsifier and the auxiliary emulsifier according to the formula 10, and heating, ultrasonically treating or stirring to completely dissolve to obtain the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the volume of 1: 100 times under slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 4: self-emulsifying compositions of different emulsifier components
CAT3 is used as a model drug to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when different emulsifiers are composed. The composition consists of the following components in percentage by weight:
TABLE 4 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or performing ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 5: nano self-emulsifying composition of phenanthroindolizidine alkaloid derivative with different emulsifier ratios
CAT3 is used as a model drug to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition at different emulsifier ratios. The composition consists of the following components in percentage by weight:
TABLE 5 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or carrying out ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 6: phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when different emulsifiers are used in combination
CAT3 is used as a model drug, and the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when different emulsifiers are used in combination is investigated. The composition consists of the following components in percentage by weight:
TABLE 6 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or carrying out ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 7: nano self-emulsifying composition of phenanthroindolizidine alkaloid derivative with different auxiliary emulsifier components
CAT3 is used as a model drug to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when different co-emulsifiers are composed. The composition consists of the following components in percentage by weight:
TABLE 7 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or carrying out ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 8: phenanthroindolizidine alkaloid derivative nano self-emulsifying composition with different coemulsifier ratios
CAT3 is used as a model drug to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when the co-emulsifier is in different proportions. The composition consists of the following components in percentage by weight:
TABLE 8 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or performing ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 9: nano self-emulsifying composition of phenanthroindolizidine alkaloid derivatives when different co-emulsifiers are used in combination
CAT3 is used as a model drug to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when different co-emulsifiers are composed. The composition consists of the following components in percentage by weight:
TABLE 9 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or carrying out ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Example 10: nano self-emulsifying composition of phenanthroindolizidine alkaloid derivative with different drug-loading rates of phenanthroindolizidine alkaloid derivative
CAT3 is used as a model drug to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition at different drug-loading rates. The composition consists of the following components in percentage by weight:
TABLE 10 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3 according to the formula amount, stirring, heating or carrying out ultrasonic treatment until the medicine is completely dissolved, and thus obtaining the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. As a result, it was found that the API was completely dissolved at a drug loading of the phenanthroindolizidine alkaloid derivative of less than 50 mg/g. At 100mg/g, the API was not completely soluble, even with heat, sonication, etc.
The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative with the drug loading of less than 50mg/g is diluted by water with the volume of 1: 100 times under slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm. The phenanthroindolizidine alkaloid derivative nano self-emulsifying composition with the drug loading capacity of more than 50mg/g is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and the formed emulsion contains a large amount of crystalline substances.
Example 11: nano self-emulsifying composition of different phenanthroindolizidine alkaloid derivatives
CAT3, PF403 and CAT are respectively used as model drugs to investigate the formation of the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition when different compounds are used. The composition consists of the following components in percentage by weight:
TABLE 11 Phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula
The preparation method comprises the following steps: and (3) uniformly mixing the oil phase, the emulsifier and the co-emulsifier according to the formula, adding CAT3, PF403 and CAT according to the formula amount, and stirring, heating or performing ultrasonic treatment until the medicine is completely dissolved to obtain the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition. The nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative is diluted by water with the proportion of 1: 100 times under the condition of slight stirring, and can be completely emulsified within 1 minute to form transparent emulsion with the particle size of less than 200nm.
Experimental example 1: characterization of Nano self-emulsifying composition of phenanthroindolizidine alkaloid derivative
In this example, a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula 1 (abbreviated as CAT 3-SMEDDS) prepared by CAT3 is characterized by the following method:
the particle size and distribution of the CAT3 self-emulsifying composition after the self-emulsifying and the aqueous medium are emulsified: a suitable amount of CAT3-SMEDDS was slowly dispersed in water at 37 ℃ in a water bath at a ratio of 1: 100, and the particle size was measured by laser dynamic light scattering, as shown in FIG. 1.
Stabilization of CAT3: about 1g of CAT3-SMEDDS is precisely weighed, placed in a 500mL beaker, diluted by 250mL of artificial gastric juice and artificial intestinal juice at 37 ℃, slowly stirred in a thermostatic water bath, sampled by 5mL at different times within 8h, filtered by a 0.22 mu m microporous filter membrane, the subsequent filtrate is placed in an ultraviolet spectrophotometer, the absorbance is measured at 262nm, the CAT3 content is calculated by an external standard method, and a stability curve is drawn, as shown in figure 2.
The results show that: the CAT3 self-emulsifying composition and the aqueous medium are spontaneously emulsified and then have uniform particle size and distribution, and the particle size is less than 200nm; the stability in artificial gastrointestinal fluid is more than 80 percent in 8 hours. Compared with the CAT3 bulk drug incubated in the artificial gastric juice at 37 ℃, 59 percent of the raw drug is degraded and converted into PF403 in 15 minutes, and the stability of the nano self-emulsifying composition is obviously improved.
Experimental example 2: permeability of phenanthroindolizidine alkaloid derivative nano self-emulsifying composition in single-layer cell membrane
In this example, the effect of increasing the intestinal mucosa permeability coefficient was measured by using a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula 1 (CAT 3-SMEDDS for short) prepared from CAT3 according to the following method:
MDCK-MDR1 monolayer cells which meet the transport conditions and have good cell growth and are grown on a Transwell culture plate are taken to determine the two-way permeability coefficient. The method comprises the following specific steps: before the test, the cell surface was washed three times with HBSS solution at 37 ℃ to remove the cell surface attachments, and incubated at 37 ℃ for 30min to remove HBSS solution. Transport from the AP-BL side: 0.5mL of HBSS solution containing CAT3 at a concentration of 100ng/mL, prepared by diluting HBSS solution of formulation 1, was added to the AP side as a supply solution, and 1.5mL of blank HBSS solution was added to the BL side as a receiving solution. Transport from BL-AP side: 1.5mL of HBSS solution containing CAT3 at a concentration of 100ng/mL prepared by diluting HBSS solution of formulation 1 was added to the BL side as a feed solution, and 0.5mL of blank HBSS solution was added to the AP side as a receiving solution. The same method is used for the operation of CAT3 bulk drug suspension (called CAT3-API for short).
Each sample was assayed in parallel with three wells. The Transwell plate was placed in a 37 ℃ incubator set at 50rpm, and 50. Mu.L of the receiving solution was aspirated from the receiving cell at 0.5, 1, 1.5 and 2 hours, respectively, to measure the concentration of the transporter by HPLC-MS/MS method, and simultaneously, an equal amount of blank HBSS solution was added.
The apparent permeability coefficients (Papp) of CAT3 on the AP-BL side and BL-AP side were measured and calculated from the received solutions at different time points, as shown in FIG. 3.
The results show that: the nano-scale emulsion droplets formed after the CAT3 self-emulsifying composition is spontaneously emulsified with an aqueous medium greatly increase the membrane permeability. Papp (AP-BL) and Papp (BL-AP) were increased by 3.91 times and 2.36 times, respectively, relative to the drug substance.
Experimental example 3: relative bioavailability of phenanthroindolizidine alkaloid derivative nano self-emulsifying composition
In this example, the relative plasma bioavailability of CAT3 and the exposure of its metabolite PF403 in plasma were determined by using a nano self-emulsifying composition formula 1 (CAT 3-SMEDDS) prepared from CAT3 and using the following methods:
SD rats were taken and fasted for 12h before administration, and were randomly divided into two groups. Separately perfusing 10mg/kg doses of CAT3-API and CAT3-SMEDDS, collecting blood from eye orbit at 5, 10, 15, 30min, l, 2h, 4, 6, 8, 12, 24h after administration, placing in BNPP (lipase inhibitor) -treated EP tube, storing on ice after heparin anticoagulation, centrifuging, and separating plasma for use.
The amounts of CAT3 and PF403 were measured by HPLC-MS/MS method. The method comprises the following steps:
HPLC：C 18 column of type (50 mm. Times.2.1mm, 1.8 μm), column temperature: 25 ℃, mobile phase: acetonitrile (0.1% fa: water = 80: 20, flow rate: 0.2mL/min, sample size: 5 mu L of the solution;
and (2) MS: the mass spectrum detection conditions of CAT3, PF403 and ISTD (CAT) are as follows: CAT3: ESI + ion model, MRM detected ion pair 434.3 → 70.2, fragment 135, CE 25; the metabolite of CAT3 PF403: ESI + ion model, MRM detected ion pair 350.2 → 70.2, fragment 135, CE 20; ISTD (CAT): ESI + ion model, MRM detected ion pair 364.2 → 70.2, fragment 135, CE 20.
Plasma samples were measured according to the established HPLC-MS/MS method and substituted into the running standard curve to calculate the concentration of CAT3 and PF 403. Unless otherwise indicated, experimental data are presented as mean ± standard deviation (n = 3). The results are shown in Table 12, the main pharmacokinetic parameters are shown in Table 13, and the bioavailability changes are shown in Table 14. The drug-time curves after oral administration of CAT3-API or CAT3-SMEDDS were plotted on the time scale of the abscissa and the concentration of CAT3 in plasma on the ordinate, as shown in FIG. 4. The time-course curve after oral administration of CAT3-API or CAT3-SMEDDS was plotted on the abscissa as time and on the ordinate as the concentration of the in vivo metabolite PF403 of CAT3 in plasma, as shown in FIG. 5.
The results show that: the nano-scale emulsion droplets formed after the CAT3 self-emulsifying composition is spontaneously emulsified with an aqueous medium greatly increase the membrane permeability. Papp (AP-BL) and Papp (BL-AP) were increased by 3.91 times and 2.36 times, respectively, relative to the drug substance.
TABLE 12-1 results of determination of CAT3 concentration in plasma after oral administration of CAT3-API to rats
TABLE 12-2 CAT3 concentration measurement results in plasma after oral administration of CAT3-SMEDDS to rats
TABLE 12-3 measurement results of PF403 concentration in plasma after CAT3-API oral administration to rats
TABLE 12-4 determination of PF403 concentration in plasma following CAT3-SMEDDS oral administration to rats
TABLE 13-1 major pharmacokinetic parameters of CAT3 in plasma following oral administration of CAT3-API or CAT3-SMEDDS in rats
TABLE 13-2 major pharmacokinetic parameters PF403 in plasma following CAT3-API or CAT3-SMEDDS oral administration to rats
TABLE 14-1 relative bioavailability of CAT3 in plasma following oral administration of CAT3-API or CAT3-SMEDDS to rats
** P＜0.01 vs.CAT3-API
TABLE 14-2 relative bioavailability of PF403 in plasma following oral administration of CAT3-API or CAT3-SMEDDS to rats
** P＜0.01 vs.CAT3-API
Experimental example 4: improvement of brain tissue distribution of phenanthroindolizidine alkaloid derivative nano self-emulsifying composition
In this example, the exposure concentration of CAT3 and its metabolite PF403 in rat brain tissue after administration was determined by taking the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula 1 (CAT 3-SMEDDS for short) prepared by CAT3 and using the same dose of raw material drug as a control according to the following method.
SD rats are taken and fasted for 12h before administration, and are randomly divided into six groups A-F. A group A to a group C are subjected to intragastric administration and CAT3-API with a dose of 10mg/kg, a group D to a group F are subjected to CAT3-SMEDDS with the same dose, and the groups A/D, B/E, C/F are respectively subjected to animal sacrifice after 1, 4 and 8 hours of administration, whole brains are separated by operation on ice, rinsed twice with 4 ℃ physiological saline and frozen for later use.
Brain tissue samples were measured according to the HPLC-MS/MS method of Experimental example 3, and substituted into the associated standard curve to calculate the concentrations of CAT3 and PF403, respectively. Unless otherwise indicated, experimental data are presented as mean ± SD (n = 3). The concentrations of CAT3 in the whole rat brain were compared at different times and the concentration of the metabolite PF403 was also compared.
Experimental data are presented as mean ± standard deviation (n = 3) and results were tested for variability using the two-sided T-test method, as shown in fig. 7.
Experimental example 5: pharmacodynamic test of nano self-emulsifying composition of phenanthroindolizidine alkaloid derivatives
In this example, a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula 1 (abbreviated as CAT 3-SMEDDS) prepared by CAT3 was used for a pharmacodynamic test according to the following method:
pharmacodynamic tests were performed in a mouse orthotopic brain jelly model. ICR mice were cranially operated, C6 brain glioma cells with luc luciferase marker injected, the cranium sealed with bone wax, and the animals carefully cared for. Taking in-situ C6-luc glioma tumor-bearing mice on the 3 rd day after molding, injecting a luciferase substrate into the abdominal cavity by 150mg/kg, carrying out IVIS chemiluminescence detection by using a small animal living body imaging system 15-20 min after injecting the luciferase substrate by using isoflurane gas anesthesia, and taking mice with medium luminous intensity according to light intensity sequencing, wherein the mice are randomly divided into 5 groups, and each group comprises 5 mice. Normal saline control group (NS); the positive medicine TMZ 50mg/kg control treatment group, 5mg/kg, 10mg/kg CAT3-API treatment group and 10mg/kg CAT3-SMEDDS treatment group are orally administered by gastric lavage for 5 days continuously 1 time per day. The primary administration time is counted by 0 day, 150mg/kg of luciferase substrate is injected into the abdominal cavity on the 6 th day, isoflurane is used for performing IVIS chemiluminescence detection by using a living body imaging system of the small animals 15-20 min after the luciferase substrate is injected, and the brain tumor luminescence intensity of each mouse is recorded respectively. The results are expressed as mean ± sd, and the comparisons between the two groups were analyzed using Student's t-test, and the comparisons between the groups were analyzed using Fisher LSD test, and statistically analyzed, as shown in fig. 8.
The results show that: the CAT3 self-emulsifying composition has obvious effect of inhibiting in-situ brain glioma. Compared with a positive drug control group and the same dose of raw material drugs, the drug effect is obviously better than the two, and the P value is less than 0.05.
Experimental example 6: initial toxicity test of phenanthroindolizidine alkaloid derivative nano self-emulsifying composition
In this example, a phenanthroindolizidine alkaloid derivative nano self-emulsifying composition formula 1 (abbreviated as CAT 3-SMEDDS) prepared by CAT3 was subjected to a preliminary toxicity test in the following manner:
ICR mice were randomly divided into 5 groups of 10 mice each, each group having male and female halves, a normal saline control group, a blank SMEDDS control group (SME blank), 15 and 25mg/kg/d CAT3-API control groups, and 25mg/kg CAT3-SMEDDS preparation groups, each group being administered 7 times in a row. Initial dosing time was measured as 0 days, and animal body weights were weighed every other day, as in fig. 9. Skin tone and fecal status were recorded. At the end of the observation period, all animals were euthanized and gross anatomical observations were performed, as shown in fig. 10.
The results show that: the CAT3 self-emulsifying composition can obviously reduce the weight of animals to a smaller extent than the bulk drugs with the same dosage. The gastrointestinal state of the normal control group and the blank SMEDDS group is normal; the 25mg/kg/d CAT3-API group has blackening and degeneration condition of stomach, and edema of intestine; the 25mg/kg/d CAT3-SMEDDS group has no obvious symptoms in the stomach, only has slight edema in the intestinal part, and shows that the CAT3-SMEDDS can reduce the gastrointestinal toxicity. The self-emulsifying composition was observed to have a significant toxicity-reducing effect, combining gross observations of body weight and gastrointestinal anatomy.
Reference to the literature
[1]Chen J，Lv H，Hu J，et al.CAT3，a novel agent for medulloblastoma and glioblastoma treatment，inhibits tumor growth by disrupting the Hedgehog signaling pathway[J].Cancer letters，2016，381(2)：391-403.
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Rodriguez-Gascón A，et al.Nanostructured lipid carriers：Promising drug delivery systems for future clinics[J].Nanomedicine：Nanotechnology，Biology and Medicine，2016，12(1)：143-161.
[3]Alsaggar M，Liu D.Organ-based drug delivery[J].Journal of drug targeting，2018，26(5-6)：385-397.
[4]Zhang L，Wang T，Li Q，et al.Fabrication of novel vesicles of triptolide for antirheumatoid activity with reduced toxicity in vitro and in vivo[J].International journal of nanomedicine，2016，11：2663.
[5]Yuan Q，Han J，Cong W，et al.Docetaxel-loaded solid lipid nanoparticles suppress breast cancer cells growth with reduced myelosuppression toxicity[J].International journal of nanomedicine，2014，9：4829.
[6]Han W，Wang S，Liang R，et al.Non-ionic surfactant vesicles simultaneously enhance antitumor activity and reduce the toxicity of cantharidin[J].International journal of nanomedicine，2013，8：2187.
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Claims (6)
1. The application of the nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative in preparing the medicine for preventing and/or treating glioma is characterized in that the nano self-emulsifying composition of the phenanthroindolizidine alkaloid derivative contains the phenanthroindolizidine alkaloid derivative, an oil phase, an emulsifier and a co-emulsifier;
phenanthroindolizidine-containing alkaloid derivatives: 0.1-50mg/g,
the oil phase, the emulsifier and the co-emulsifier are calculated according to 100 percent, and the weight ratio of each component is as follows:
oil phase: 15 to 35 percent of the total weight of the mixture,
emulsifier: 45 to 70 percent of the total weight of the mixture,
auxiliary emulsifier: 10 to 25 percent;
the phenanthroindolizidine alkaloid derivative is (13 aS) -3-pivaloyloxy-6,7-dimethoxy-9-phenanthro [9,10-b ] -indolizidine, and the structural formula of the derivative is aS follows:
the oil phase comprises one or more than one of soybean oil, medium-chain oil and isopropyl myristate which are mixed in any proportion;
the emulsifier comprises polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and/or tween 80;
the auxiliary emulsifier comprises one or more than one of glycerol, polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether and caprylic capric acid polyethylene glycol glyceride in any proportion.
2. Use according to claim 1, characterized in that: the self-emulsifying composition also contains an adsorbent.
3. Use according to claim 2, characterized in that: the adsorbent comprises one or a mixture of two of micropowder silica gel and polyvinylpyrrolidone.
4. Use according to any one of claims 1 to 3, characterized in that said nano self-emulsifying composition is further formulated as a capsule, injection, enema, nasal drop, transdermal patch or mucosal patch.
5. A method for preparing the phenanthroindolizidine alkaloid derivative nano self-emulsifying composition according to any one of claims 1 to 3, characterized in that an oil phase, an emulsifier and a co-emulsifier are mixed and stirred to obtain a clear solution as a blank self-emulsifying composition; adding phenanthroindolizidine alkaloid derivative, heating, and performing ultrasonic treatment or stirring to completely dissolve the phenanthroindolizidine alkaloid derivative to obtain the final product.
6. A method for preparing the nano self-emulsifying composition of phenanthroindolizidine alkaloid derivatives according to any one of claims 1 to 3, characterized in that the phenanthroindolizidine alkaloid derivatives are dissolved in the oil phase, the emulsifier or the co-emulsifier, or in the three mixtures or any two mixtures, and stirred to obtain a clear solution.
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