CN113456588B - Abiraterone acetate solid self-microemulsion and preparation method thereof - Google Patents
Abiraterone acetate solid self-microemulsion and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a solid self-microemulsion containing abiraterone acetate. The abiraterone acetate solid self-microemulsion consists of the following components in percentage by mass: 0.25-1.5% of abiraterone acetate, 5-10% of oil phase, 25-30% of surfactant, 12.5-15% of cosurfactant and 45-55% of solid carrier. The invention realizes the solidification of the liquid medicine, obtains the self-microemulsion which does not need preservative, is easy to store, is easy to transport and is more stable by screening and optimizing the prescription through the single-factor test, and has simple and controllable preparation method and good repeatability. The transmission electron microscope image display period of the emulsion of the abiraterone acetate solid self-microemulsion is regular spherical, the particles are uniformly distributed, and the particle size is less than 100nm.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a solid self-microemulsion containing abiraterone acetate.
Background
Abiraterone Acetate (AA) is an androgen synthase CYP17A1 inhibitor, is clinically used for treating metastatic castration-resistant prostate cancer (mCRPC), belongs to a fat-soluble medicament, is mostly discharged as a prototype or a precipitate after being taken, and causes a plurality of expensive medicaments to be discharged as crystals, precipitates or prototypes after failing to exert the medicinal effect. Meanwhile, the abiraterone acetate belongs to the IV class medicament in a biological pharmaceutical classification system (BCS), and has the characteristics of low permeability and low solubility. The octanol-water partition coefficient is 5.12 (LogP), the pKa of aromatic nitrogen is 5.19, the compound is almost insoluble in water (less than 0.01 mg/ml), the permeability is poor, the compound is a BCS four-class drug, and the bioavailability is extremely low when the compound is orally absorbed.
The lipid preparation drug-loading system enters the pharmaceutical field in a simple oil solution form in 1981, and then products of the lipid preparation drug-loading system on the market mostly mainly comprise self-emulsifying preparations which can be used as an effective means for improving the bioavailability of insoluble drugs, and the self-emulsifying formula highlights the importance of lipid in the aspect of improving the oral absorption of lipophilic drugs. Patent document CN 110538150 relates to an abiraterone acetate self-microemulsion, which comprises: active ingredients: abiraterone acetate; auxiliary materials: at least one oil phase, at least one emulsifier, and at least one co-emulsifier. Although the invention improves the bioavailability, the liquid form of the invention limits the effects of transportation, preservation and quantitative taking, and the liquid preparation is heavy and easy to leak, the moist condition is easy to be bacteria, a measuring cup is needed when the medicine is taken, and patients are mostly old men with inconvenient actions, so that the accurate reaching of the scale mark is difficult to ensure, and the medicine is inconvenient to carry. In addition, the composition may contain preservatives and antioxidants for long-term storage.
Disclosure of Invention
Aiming at the defects in the prior art, the invention realizes the solidification of the liquid medicine, and further solves the problems of inconvenient transportation, storage and taking of the liquid preparation. Meanwhile, the solid abiraterone acetate can reduce the precipitation of the medicine in the stomach, thereby improving the bioavailability. Thus providing the abiraterone acetate solid self-microemulsion and the preparation method thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
an abiraterone acetate solid self-microemulsion is composed of the following components in percentage by mass:
the solid support is Aerosil200 and/or cross-linked PVP.
The oil phase is any one or more of glycerol monooleate, tween 80, ethyl oleate and Labrafil M1944 CS.
The emulsifier is Labrasol or Tween 80.
The auxiliary emulsifier is ethanol.
Furthermore, the feed consists of the following raw materials in parts by weight:
the particle size of the abiraterone acetate solid self-microemulsion emulsion is 81.09nm, and the drug loading is 0.97% +/-0.05%.
The preparation method of the abiraterone acetate solid self-microemulsion comprises the following steps:
1) Mixing the surfactant and the cosurfactant according to the proportion to obtain a mixed solution for later use;
2) Adding the abiraterone acetate into the mixed solution, uniformly mixing, and adding the oil phase to obtain an abiraterone acetate liquid self-microemulsion;
3) And adding the solid carrier into the abiraterone acetate liquid self-microemulsion to obtain the abiraterone acetate solid self-microemulsion.
In the step 1), the surfactant and the cosurfactant are mixed according to the mass ratio of 2.
The beneficial effects of the invention are as follows:
the solid self-microemulsion solves the problem that abiraterone acetate is not easy to absorb, simultaneously enables an active substance to fully exert the activity of the active substance and improves the defect that liquid self-microemulsion is precipitated in the stomach through a specific system, and further obtains the solid self-microemulsion to solidify the liquid, so that the problems that liquid preparation is inconvenient to transport and store and the precipitation in the stomach is reduced in bioavailability are solved, and the research on the quality of the obtained abiraterone acetate solid self-microemulsion shows that: the particle size of the abiraterone acetate solid self-microemulsion emulsion is 81.09nm, the particle size of the emulsion is 0.204, and the particle sizes are uniform. The drug loading rate is 0.97% +/-0.05%, and the content uniformity accords with the pharmacopoeia regulations. DSC, PXRD and SEM images show that the abiraterone acetate exists in an amorphous state in the abiraterone acetate solid self-microemulsion, and TEM images show that the nanoparticles in the emulsion are dispersed in water in a spherical shape. The dissolution rates of the abiraterone acetate solid self-microemulsion in the media with the pH value of 1.2 and 6.8 are 90.6% and 82.5%, respectively.
Meanwhile, the solid self-microemulsion has stable property under the conditions of high temperature and strong light irradiation, and the accelerated stability test result shows that the properties of 3 batches of abiraterone acetate self-microemulsion samples are changed and the drug content is reduced by 7-8% when the samples are placed for 6 months under the accelerated test condition, but all investigation indexes of the abiraterone acetate solid self-microemulsion are not obviously changed under the same condition, the stability of the solid self-microemulsion is obviously superior to that of the abiraterone acetate self-microemulsion, and the solid self-microemulsion system can be selected to achieve high entrapment rate.
Drawings
FIG. 1 is a graph showing the effect of the solubility of abiraterone acetate in oil phase and emulsifier.
FIG. 2 is a graph showing the effect of the ratio of surfactant to co-surfactant on the self-emulsifying ability of a formulation according to an embodiment of the present invention.
FIG. 3 is a graph showing the effect of a drug on the properties of a formulation provided by an embodiment of the present invention.
Fig. 4 is a particle size distribution diagram of the abiraterone acetate solid self-microemulsion provided by the embodiment of the present invention.
FIG. 5 is a DSC of four samples provided in an example of the present invention.
Figure 6 is an XRD scan of four samples provided by an embodiment of the present invention.
Fig. 7 is a scanning electron microscope image of four samples provided by the embodiment of the present invention.
Fig. 8 is a transmission electron microscope image of the abiraterone acetate solid self-microemulsion emulsion provided by the embodiment of the present invention.
FIG. 9 is a graph of dissolution profiles in media having a pH of 1.2 provided by examples of the present invention.
FIG. 10 is a graph showing the dissolution profile in a medium of pH6.8 according to an example of the present invention.
Detailed Description
The following examples are presented to further illustrate embodiments of the present invention, and it should be understood that the embodiments described herein are for purposes of illustration and explanation only and are not intended to limit the invention.
Instrument and reagent
The instrument comprises:
reagent
Example 1 selection of ingredients of Abiraterone acetate solid self-microemulsions
1.1. Solubility test
Taking a plurality of 10mL EP tubes, adding 1g of abiraterone acetate standard substance into each EP tube, adding 5mL of different oils, emulsifiers and coemulsifiers into different EP tubes, and sealing. The EP tube is fixed in a constant temperature water bath oscillator, is oscillated for 48h under the conditions of 37 ℃ of water temperature and 60rpm, and is then placed in a centrifuge for centrifugation for 10min, and the rotating speed is set to be 5000rpm. The centrifugate is taken out and filtered by a 0.45 mu m microporous filter membrane, the volume of the centrifugate is diluted by 5 times by acetonitrile, and the liquid phase is used for detecting the solubility of the abiraterone acetate in different oils and surfactants (see figure 1).
Wherein, the chromatographic conditions are as follows:
a chromatographic column: promosil C18 (4.6 mm. Times.250mm, 5 μm)
A detector: UV 254nm
Flow rate: 1.2mL/min
Mobile phase: phosphate buffer (0.01M KH2PO4, pH = 3) -acetonitrile (25: 75, v/v)
Sample injection amount: 10 μ L
Column temperature: 35 deg.C
The different oils are glyceryl oleate, caprylic capric glyceride, soybean ethyl oleate, isopropyl myristate, labrafac Lipophile 1349, labrafil M1944 CS, labrafil M2125 CS; different emulsifiers are tween and Labrasol; different co-emulsifiers ethanol, PEG400 and 1, 2-propylene glycol.
As shown in figure 1, the solubility of the abiraterone acetate of the oil phase, such as glyceryl monooleate, ethyl oleate and Labrafil M2125 CS is higher, and the solubility is respectively 46.25mg/mL, 45.63mg/mL and 48.02 mg/mL; the solubility of abiraterone acetate in the emulsifier Labrasol (40.36 mg/mL) was not significantly different from that in Tween 80 (35.54 mg/mL); while the solubility in ethanol (43.02 mg/mL) was the largest among the co-emulsifiers. The larger solubility of the drug in the auxiliary materials is beneficial to the stability of the self-microemulsion preparation, and simultaneously, the unit drug loading of the preparation can be improved. Therefore, the oil phase in the formula is determined to be glycerol monooleate, ethyl oleate and Labrafil M1944 CS through preliminary screening of the experiment, the emulsifying agents are Labrasol and Tween 80, and the auxiliary emulsifying agent is ethanol.
1.2. Phase separation experiment
The oil phase, the emulsifier and the co-emulsifier with high drug solubility obtained by screening also need to be subjected to compatibility research.
The solubility test is carried out to obtain 3 oil phases (namely, monooleic acid, glyceride and ethyl oleate), 2 emulsifiers (namely, labrasol and Tween 80) and 1 auxiliary emulsifier (namely ethanol), and the screened oil phases, emulsifiers and auxiliary emulsifiers are combined one by one according to the proportion of 10: 80: 10 (w/w). 6 different combinations can be obtained after one combination (see table 1). 1mL of the formulated self-emulsified concentrate was diluted with 10mL of distilled water, and the mixture was allowed to stand for 2 hours and then observed (see Table 1). The combination of obvious phase separation phenomena such as a large amount of floating oil drops, layering and the like in the diluent is discarded, and a stable compatibility combination is reserved for the subsequent research of a pseudo-ternary phase diagram.
TABLE 1 compatibility test results
As shown in Table 1, in 6 combinations, the compatible liquid consisting of glycerol monooleate, labrasol and ethanol can form clear and transparent light blue emulsion after being diluted by water, and can still keep a stable state after being placed at room temperature for 24 hours. The other compatible combinations have the phenomena of poor stability, turbidity, oil drops on the liquid surface and the like within 2 hours. Therefore, glyceryl monooleate, labrasol and ethanol are selected as a self-microemulsion formula for optimization.
2.3 drawing of pseudo-ternary phase diagram
A pseudo-ternary phase diagram of oil, water and mixed surfactant was constructed using the water titration method. The dosage of the oil phase and the mixed surfactant is configured according to the proportion (v/v) of 1: 9, 2: 8, 3: 7, 4: 6, 5: 5, 6: 4, 7: 3, 8: 2 and 9: 1, the oil phase and the mixed surfactant are uniformly mixed, then deionized water is added dropwise, stirring is carried out while dropwise adding, and meanwhile, the conductivity of the liquid is monitored in real time by a conductivity meter. The water-in-oil (W/O) type nano-emulsion is formed initially, and at the moment, the viscosity of the liquid is low, and the conductivity is minimum; along with the increasing of the added water quantity, the viscosity of the liquid begins to increase, and the conductivity value also increases; and (3) continuously dropwise adding deionized water into the system, finding that the liquid is changed from viscous to thin, the conductivity is increased to the maximum value, the critical point is formed by the oil-in-water (O/W) type nano emulsion, and recording the water adding amount of the critical point. Collecting data of each point to draw a pseudo-ternary phase diagram, and connecting each point into a line to obtain two areas: a self-emulsifying zone and a non-emulsifying zone.
2.4 selection of solid support
In the experiment, 5 materials are selected as alternative carriers, namely Aerosil200, cross-linked PVP, micro-powder silica gel, cross-linked CMC-Na and corn starch. The adsorption carrier is mainly used for investigating the adsorption capacity and desorption capacity of the L-SEDDS.
Weighing the five carrier materials, placing 1g of each carrier material in five small beakers, dropwise adding the prepared liquid self-microemulsion into the carrier powder while stirring, and continuing the operation until the powder has poor flowability. A certain amount of powder is taken out and placed on white A4 paper, and if oil marks appear on the powder paper by light pressing, the adsorption capacity is saturated. Recording the liquid dropping amount of each carrier material in a saturated state, and judging the liquid adsorption capacity of the material by the method, wherein the specific method comprises the following steps:
placing a certain amount of carrier material with saturated adsorption in a beaker, adding deionized water with the volume 10 times of the volume of the adsorption liquid, uniformly stirring, standing for 30min, and observing the appearance change of the diluent. And then taking a small amount of diluent to detect the content of the abiraterone acetate according to a liquid phase method. The desorption capacity of each carrier material was calculated and expressed as the desorption rate (see table 2).
Adsorption and desorption capacities of carrier materials as can be seen from table 2, the liquid adsorption performance of Aerosil200 is optimal, 1g of Aerosil200 can absorb 2.956g of self-microemulsion; the second adsorbed amount was crospovidone, 1g was able to absorb 1.262g of self-microemulsion, which is far from Aerosil200, and the remaining material had poor adsorption capacity, 1g of material only adsorbed 0.3-0.4 g of self-microemulsion on average. Aerosil200 is also very excellent in desorption capacity, with a desorption rate of 92.6% being comparable to that of crospovidone (93.4%). The saturated Aerosil200 powder diluted by adding water can form clear and bright light blue emulsion within 30min, which shows that the self-microemulsion absorbed in the Aerosil200 forms microemulsion with smaller particle size when meeting water. Aerosil200 is a polymer having a specific surface area of 200m 2 The silicon dioxide powder is prepared by gas phase method, and can be diluted with water to form colloidal solution with particle diameter of 10-100nm [48] . In view of the better adsorption and desorption capacity of Aerosil200, it is selected as a solid phase carrier of the solid self-microemulsion.
TABLE 2 Performance testing of the support materials
Example 2 optimization of the proportion of each component in the abiraterone acetate solid self-microemulsion system
The experiment screens the oil phase dosage, the ratio/Km of the surfactant and the cosurfactant, the drug addition and the like, and obtains an optimal system by taking the particle size, the appearance and the stability as indexes.
2.1 oil phase amount
Fixing the ratio of the surfactant to the cosurfactant to be 2:1 (v/v), adding 10%, 15%, 20%, 25% and 30% of oil phase of the total mass of the blank liquid self-microemulsion preparation (oil phase, emulsifier and cosurfactant), and uniformly mixing the three to prepare the blank self-microemulsion preparation. 1g of the blank preparation is diluted by adding 10mL of deionized water, the stability of the diluent is observed within 48h, and a small amount of the diluent is taken to determine the particle size and the distribution thereof (see Table 3).
TABLE 3 Effect of oil phase usage on formulation Properties
The increase of the oil phase dosage in the blank liquid self-microemulsion preparation leads to the increase of the particle size of the self-emulsified diluent, and simultaneously, the appearance of the emulsion is gradually changed from clear and transparent light blue to turbid milky white, and the stability at room temperature is reduced. Which leads to a decrease in the self-emulsifying capacity of the solution due to an increase in the specific gravity of the oil phase and a decrease in the specific gravity of the emulsifier. As can be seen from Table 3, when the oil phase consumption is increased from 10% to 20%, the particle size of the emulsion is slowly increased, and the polydispersity PDI is not obviously changed; when the oil phase consumption is increased to 30%, the particle size is sharply increased to 250.83nm, the dispersion degree is also obviously increased, and the emulsion stabilization time is reduced to be less than 12 h. The oil phase in the blank liquid self-microemulsion preparation is heavier, and the proportion of the emulsifier is correspondingly reduced, so that the stimulation and toxicity of a large amount of surfactant to the gastrointestinal tract can be avoided, and the safety of the preparation is improved. In combination, 20% of the oil phase is selected as a better formula, so as to obtain a preparation with smaller particle size, longer stabilization time and higher safety.
2.2 surfactant to co-surfactant ratio/Km
The optimal fixed oil phase dosage is X% of the blank liquid self-microemulsion preparation in the solid self-microemulsion system, and the dosage of the mixed surfactant is 1-X%. The self-emulsifying capacity of the preparation with Km of 1, 1.5, 2 and 3 is examined by the ternary phase diagram method described in 1.3. In the pseudo-ternary phase diagram, the larger self-emulsifying area indicates the stronger emulsifying capacity of the preparation, and the Km value with stronger emulsifying capacity should be selected as the optimized solid self-microemulsion system (see FIG. 2).
The self-emulsifying ability of the self-microemulsion preparations having Km of 1, 1.5, 2 and 3, respectively, is shown in FIG. 2 (the area of the gray shaded portion indicates the area of the microemulsion). When Km is 1, the area of the micro-emulsion area is minimum, and the self-emulsifying capacity is worst; when Km is increased to 1.5, the micro-emulsion area is enlarged; as Km continues to increase to 2, the microemulsion region is substantially maximized, with an area that differs less from that at Km of 3. And selecting an optimized solid self-microemulsion system with Km of 2 as a preparation.
2.3 amount of drug added
The test result is used as an optimal auxiliary material composition of a blank solid self-microemulsion system, and 0.5%, 1%, 1.5%, 2% and 3% of abiraterone acetate of the blank liquid self-microemulsion preparation is added to prepare the drug-carrying preparation. The method comprises the following specific steps: firstly, uniformly mixing a certain amount of abiraterone acetate and a surfactant mixed solution, accelerating the dissolution of the medicine by ultrasonic assistance, then adding an oil phase, and shaking up. 1g of the drug-loaded preparation is added into 10mL of deionized water for dilution, and a small amount of diluent is taken for determining the particle size. The content of the drug is detected by taking 1mL of diluent, and the drug encapsulation efficiency (EE%) of the drug-loaded preparation with different doses can be obtained through calculation, and the specific calculation formula is as follows:
the effect of the drug loading on the properties of the drug loaded formulation is shown in figure 3. Similar to some of the relevant findings, it was observed that increasing the amount of drug resulted in a gradual increase in the particle size of the diluent and a decrease in encapsulation efficiency began to appear. In fact, the particle size increased only from 75.4nm to 84.7nm during the increase of drug addition from 0.5% to 2.0%, while the encapsulation efficiency decreased from 99.3% to 96.8%, with no significant difference. When the drug loading was increased to 3.0%, the diluent particle size sharply increased and the encapsulation efficiency suddenly decreased, a change indicating 2.0% -3.0% as the critical region of the loading. Considering that the lower bioavailability of abiraterone acetate results in a high dose for clinical application, a formulation with a larger dosage and a better loading effect should be selected, so 2.0% can be considered as the optimal drug dosage.
2.4 amount of solid support
The flowability of the solid self-microemulsion powder particles depends on the addition ratio of the solid carrier to the unit preparation. Sequentially inspecting that the adding ratio (v/v) of the liquid self-microemulsion to the solid carrier is 1: 2, and the adding ratio (v/v) is 1: flowability of powder at 1.5, 1:1, 1.5: 1, 2:1, which can be evaluated by measuring its angle of repose and degree of compaction (see Table 5), specifically:
the angle of repose of the powder can be determined using an angle of repose tester: 100g of solid powder is loaded in a funnel, a valve of the funnel is opened to enable the powder to naturally flow out and fall on a plane of a receiver, and an included angle between the plane of the receiver and a generatrix of a cone of the powder is an angle of repose theta. It is considered that the powder flow property is good when θ is 30 degrees or less, and the fluidity is better as the value of θ is smaller.
The degree of compaction of the powder can be determined using a tap density tester: 50g of solid powder are weighed and placed in a 100mL measuring cylinder to measure its bulk volume V0, and the vibration is carried out at a frequency and amplitude until the powder volume in the measuring cylinder is substantially constant, this value is expressed as the tap volume VF, V0/VF is expressed as the Hawsan ratio, and the flowability of the powder is inversely proportional to the value of V0/VF.
The measured changes in flowability of the abiraterone acetate solid powder at different vehicle addition ratios are shown in table 5. The flowability of the powder gradually worsens with decreasing amount of carrier added. When the ratio of the added amount of the liquid self-microemulsion to the added amount of the carrier isAt a ratio of 1:1, the angle of repose is 29.3 degrees, V 0 /V F The value is 1.14, the powder still shows better fluidity, and the preparation also has higher drug loading, so that the carrier addition amount is 40 to 60 percent and is used as a solid self-microemulsion system.
Table 5 solid self-microemulsion powder flowability test results (n = 3)
The abiraterone acetate solid self-microemulsion component system is obtained by the method.
Example 3
At room temperature, 0.263g of ethanol and 0.534g of caprylic/capric macrogol glyceride (Labrasol) are weighed and mixed in a small beaker to obtain a surfactant mixed solution.
And then adding 10.2mg of abiraterone acetate into the obtained surfactant mixed solution, uniformly mixing, accelerating the dissolution of the medicament by ultrasonic assistance, adding 0.207g of glycerol monooleate after the medicament is completely dissolved, and uniformly shaking to obtain the abiraterone acetate liquid self-microemulsion.
And (3) uniformly mixing 1.5g of abiraterone acetate liquid self-microemulsion with 1.5g of cross-linked PVP, and adsorbing to obtain 3g of abiraterone acetate solid self-microemulsion.
Example 4
0.265g of ethanol and 0.536g of Labrasol were weighed into a small beaker and mixed at room temperature to obtain a surfactant mixture.
And adding 15.3mg of abiraterone acetate into the mixed liquid of the mixed surfactants, uniformly mixing, accelerating the dissolution of the medicine by ultrasonic assistance, adding 0.217g of glycerol monooleate after the medicine is completely dissolved, and shaking uniformly to obtain the abiraterone acetate liquid self-microemulsion.
And uniformly mixing 1.5g of abiraterone acetate liquid self-microemulsion with 1.5g of cross-linked Aerosil200, and adsorbing to obtain 3g of abiraterone acetate solid self-microemulsion.
Example 5 quality evaluation of abiraterone acetate solid self-microemulsion
1) Particle size and polydispersity
1g of S-SEDDS abiraterone acetate solid self-microemulsion powder (which comprises 1% of abiraterone acetate, 9.8% of oil-phase caprylic capric glyceride, 26.15% of surfactant Labrasol, 13.05% of cosurfactant ethanol and 50% of solid carrier Aerosil by mass percent) is diluted and emulsified completely by 20 times of water, then the mixture is kept stand for 10min, a small amount of upper-layer emulsion is absorbed by a dropper, the average particle diameter and the dispersion degree of particles in the abiraterone acetate solid self-microemulsion emulsion are analyzed by a dynamic laser scattering particle size analyzer, and the average particle diameter and the dispersion degree of the particles are measured in parallel for three times (see figure 4).
As shown in FIG. 4, the mean value of the particle size was 81.09nm, and the polydispersity index (PDI) was 0.204, indicating that the degree of dispersion of the fine particles was small and the particle size was uniform.
2) Determination of drug loading and content uniformity
The abiraterone acetate solid self-microemulsion powder of the embodiment 3 with the mass of M (about 1 g) is weighed, deionized water with the volume of V (20 ml) is added for uniform mixing, the mixture is stirred gently to be emulsified and then is placed for a period of time, supernatant is absorbed after insoluble carriers are deposited, and the concentration C of abiraterone acetate is detected. The formula for calculating the drug loading (W%) of the preparation is as follows:
W％＝(C×V)/0.01M×100％
the content uniformity of the abit acetate solid self-microemulsion powder was measured according to the method specified in the chinese pharmacopoeia of 2015 edition (general rule 0941). Samples of 3 batches (with the batch numbers of 20190405, 20190501 and 20190603) of the solid self-microemulsion prepared in example 4 were taken, and 10 samples of 100mg of each batch were taken as test samples. The relative AA content x in each sample is measured, and the marked amount of the medicine is counted as 100. The mean value X and standard deviation S of the test articles X in the same batch and the absolute value A of X-100 are calculated. If 2.2S + A ≦ L (L = 15) is measured, the batch may be considered as being in compliance (see Table 6).
Table 6 content uniformity measurement results (n = 3)
The drug loading of the abiraterone acetate solid self-microemulsion is 0.97% +/-0.05% calculated by a formula.
The A +2.2S values of the three batches of samples are respectively 3.95, 5.89 and 6.12, and are all less than 15. The content uniformity of the three batches of samples was considered to be acceptable.
3) Study and morphological evaluation of molecular states of drugs
In order to observe the influence of the adsorption of the liquid self-microemulsion on the solid phase carrier on the crystal structure of the medicine, differential Scanning Calorimetry (DSC) analysis and powder X-ray diffraction (PXRD) analysis (see 5-8) are carried out on the bulk drug Abiraterone Acetate (AA), the solid phase carrier Aerosil200, the Physical Mixture (PM) and the solid self-microemulsion of abiraterone acetate in the examples in the experiment.
A differential scanning calorimeter was used to obtain a DSC plot for each sample, and approximately 5mg of the sample was placed in an aluminum pan with a lid, referenced to a blank aluminum pan without sample. Under the blowing protection of 20mL/min of nitrogen flow, the aluminum pot is heated from 35 ℃ to 200 ℃ at a constant heating rate of 10 ℃/min. Powder diffraction analysis is carried out by using an X-ray diffractometer, cu is used as a target element, the scanning range 2 theta is 5-60 degrees, the scanning speed is 5 DEG/min, and the scanning step length is 0.02 degrees.
In order to realize visualization of the microscopic morphology of the preparation, the bulk drug abiraterone acetate, the solid phase carrier Aerosil200, the Physical Mixture (PM) and the abiraterone acetate solid self-microemulsion (S-SEDDS) are respectively subjected to Scanning Electron Microscope (SEM) analysis, and meanwhile, the abiraterone acetate solid self-microemulsion emulsion is subjected to Transmission Electron Microscope (TEM) analysis.
The morphological characteristics of each sample were observed using a scanning electron microscope: and uniformly coating the sample powder on the conductive adhesive of the carrying plate, removing residual sample powder, spraying gold for about 2min, and scanning and observing under the voltage of 15 KV. And (3) observing the morphological characteristics of the particles in the emulsion by using a transmission electron microscope: diluting S-SEDDS powder by a certain time with water until the liquid presents light blue opalescence, dripping a small amount of emulsion on a copper net coated with a carbon film, removing residual liquid on the edge of the copper net, then carrying out negative dyeing on a sample by using a 2% phosphotungstic acid solution, and carrying out transmission observation on the copper net under the condition that the pressurizing voltage is 200KV after the sample is dried.
Thermal analysis can provide information about melting, recrystallization, decomposition, and changes in specific heat capacity, which determine the physicochemical properties of the compound. The thermal analysis result is shown in fig. 5, a DSC curve of abiraterone acetate shows a sharp endothermic peak at a temperature of 146.44 ℃, which indicates that the bulk drug powder is in a crystalline state, and the peak is substantially consistent with a melting point (146 ℃) reported in the literature. The solid phase carrier Aerosil200 has no specific endothermic peak near the melting point of the drug substance. The physical mixture shows a relatively smooth peak between 140 ℃ and 150 ℃, which indicates that the crystals of the raw material medicine still exist. The endothermic peak of the abiraterone acetate solid self-microemulsion at the melting point of the raw material drug is completely disappeared, which shows that the abiraterone acetate is completely dissolved in the abiraterone acetate liquid self-microemulsion and is absorbed into the solid carrier, and exists in an amorphous state. Meanwhile, in order to further study the crystallinity of abiraterone acetate in the preparation, PXRD analysis was performed on the above samples, and the spectrum is shown in fig. 6. The diffraction pattern of the abiraterone acetate crude drug has stronger crystal diffraction characteristic peaks at multiple positions. The crystal diffraction characteristic peaks at two positions in the diffraction pattern of the physical mixture still exist, the peak intensity is reduced, and the existence of abiraterone acetate crystals in the physical mixture is further verified. In contrast, in a diffraction pattern of the abiraterone acetate solid self-microemulsion prepared by adopting a solid phase carrier adsorption method, no obvious crystal diffraction peak exists, which also indicates that the abiraterone acetate solid self-microemulsion prepared by the crystalline bulk drug is converted into an amorphous state.
In this study, the surface microstructures of the four samples were observed using a scanning electron microscope. Figure 7 shows the morphology of various solid samples. The abiraterone acetate as a raw material medicine has an irregular crystal structure; the solid support Aerosil200 consists of a loose assembly of very fine particles, with a particle size of around 50 μm, while the assembly can be observed to have a rough porous surface; the presence of abiraterone acetate crystals can still be seen in the scans of the Gute mixture; however, no significant crystallization was observed in the abiraterone acetate solid self-microemulsion, indicating that the abiraterone acetate was adsorbed on the solid support after dissolving in the liquid lipid.
As shown in fig. 8, transmission electron microscopy images of abiraterone acetate solid self-microemulsion emulsion showed that the particles in the microemulsion were in a regular spherical shape, uniformly distributed, and the particle size was less than 100nm.
4) Dissolution determination
The in vitro dissolution is measured by the second method (slurry method) of the Chinese pharmacopoeia 2015 edition. The abiraterone acetate solid self-microemulsion prepared according to the abiraterone acetate solid self-microemulsion preparation system of the embodiment and containing 10mg of abiraterone acetate raw material drug and liquid containing 10mg of abiraterone acetate raw material drug are respectively filled into hard gelatin capsules with the size of 00 type to be used as targets for in vitro dissolution rate investigation. The two dissolution media are respectively hydrochloric acid solution with pH1.2 and phosphate buffer solution with pH6.8, and the volume of the media is 500mL. The water bath temperature is controlled to be 37 ℃ by adjusting parameters, and the stirring speed is 100rpm. Timing was started after the drug-loaded gelatin capsule was placed in the dissolution cup, and samples were taken 2, 5, 10, 20, 40, 60, 120min later, 5mL each time and supplemented with an equal amount of fresh medium. After the sampling solution is filtered, the content of abiraterone acetate is detected, and the dissolution rate of each time point is calculated, so that a dissolution rate-time curve graph (see 9 and 10) can be drawn.
The study investigated the dissolution rates of the abiraterone acetate bulk drug, the abiraterone acetate liquid self-microemulsion (L-SEDDS) and the abiraterone acetate solid self-microemulsion (S-SEDDS) in the medium with pH1.2 and pH6.8 within 2h, and the results are shown in FIG. 9 and FIG. 10. The phenomenon that the cumulative dissolution rates of abiraterone acetate raw material medicines under different pH conditions are greatly different, namely the dissolution rate is about 36.7% in pH1.2 and is close to 0 in pH6.8 shows that the dissolution rate of abiraterone acetate has certain dependence on a pH environment. After the medicament is prepared into a self-emulsifying preparation, the dissolution rate is obviously improved and can reach more than 80% in two different media, wherein the dissolution rate of the abiraterone acetate liquid self-microemulsion is the largest under the environment of pH1.2 and can reach 96.1%; secondly, the dissolution rate (90.6%) of the abiraterone acetate solid self-microemulsion in a pH1.2 environment, and the dissolution rate of the abiraterone acetate solid self-microemulsion in a pH6.8 medium can also reach 82.5%. Although the dissolution rate of the abiraterone acetate solid self-microemulsion in two media is slightly lower than that of the abiraterone acetate liquid self-microemulsion, the general behaviors of the abiraterone acetate solid self-microemulsion and the abiraterone acetate liquid self-microemulsion are similar, the dissolution rate is fast in the first 20min initially, the dissolution rate is gradually slowed down, and the abiraterone acetate solid self-microemulsion enters a stable period after about 1 h. The reason for the relative decrease in dissolution rate of abiraterone acetate solid from the microemulsion may be that a portion of the drug is adsorbed onto the solid carrier and not released into the dissolution medium. The self-microemulsion has good drug solubilization, and can improve the probability of drug absorption by gastrointestinal tract in dissolved state, thereby improving bioavailability and improving drug effect.
Example 6
1) Test for influencing factor
High-temperature test:
respectively taking 10g of liquid self-microemulsion (which comprises, by mass percent, 2% of abiraterone acetate, 19.6% of oil-phase caprylic capric glyceride, 52.3% of surfactant Labrasol and 26.1% of cosurfactant ethanol) and 10g of solid self-microemulsion (which comprises, 1% of abiraterone acetate, 9.8% of oil-phase caprylic capric glyceride, 26.15% of surfactant Labrasol, 13.05% of cosurfactant ethanol and 20050% of solid carrier) into a 30mL flat weighing bottle, transferring the weighing bottle into a constant-temperature drying oven, standing the sample at 60 ℃ for 10 days, sampling at 5 and 10 days after the beginning, checking whether the properties of the sample are changed, and determining indexes such as drug content, clarity, emulsified particle size of the abiraterone acetate self-microemulsion, drug content, dissolution rate, emulsified particle size of the abiraterone acetate solid self-microemulsion and the like according to the method in the section (see tables 7 and 8).
High humidity test:
respectively placing 10g of the liquid and solid self-emulsifying preparation into a 30mL flat weighing bottle, transferring the weighing bottle into a drug stability test box, standing for 10 days, simultaneously controlling the temperature and humidity in the test box to be kept at 25 +/-0.5 ℃ and 90 +/-3% relative humidity, sampling on the 5 th and 10 th days after the beginning, checking whether the properties of a sample are changed, and determining indexes such as drug content, clarity and emulsifying particle size of the abiraterone acetate solid self-microemulsion and drug content, dissolution and emulsifying particle size of the abiraterone acetate liquid self-microemulsion according to the method in the section.
Strong light irradiation test:
respectively placing 10g of the liquid and solid self-emulsifying preparation into 30mL flat weighing bottles, transferring the weighing bottles into a drug stability test box, standing for 10 days, simultaneously controlling the illumination in the test box to be kept at 4500lx +/-300 lx, sampling 5 and 10 days after the beginning, checking whether the properties of a sample are changed, and determining the indexes such as the content, the clarity and the emulsified particle size of the abiraterone acetate liquid self-microemulsion medicine, the content, the dissolution and the emulsified particle size of the abiraterone acetate solid self-microemulsion medicine according to the method in the section.
The experimental results are as follows:
the test results of the sample under high temperature, high humidity and strong light irradiation are shown in the table. The result shows that the abiraterone acetate self-microemulsion is placed for 10 days under various influence factors, the investigation items such as sample properties, drug content, solution clarity, emulsion particle size and the like are not obviously changed, and the sample property is stable. The abiraterone acetate solid self-microemulsion is placed for 10 days under the same condition, the investigation items such as sample properties, content, dissolution rate and emulsified particle size do not change obviously, the investigation item of weight increase and loss under the high-humidity condition is enlarged by 5.74%, and the sample is easy to absorb moisture and should be stored in a sealed manner.
Table 7 abiraterone acetate liquid self-microemulsion influence factor test results
TABLE 8 Abiraterone acetate solid self-microemulsion influencing factor test results
2) Accelerated stability test
About 10g of 3 groups of liquid self-emulsifying preparations (comprising 2% of abiraterone acetate, 19.6% of oil phase, 52.3% of surfactant and 26.1% of cosurfactant) prepared at different times and about 10g of solid self-emulsifying preparations (comprising 1% of abiraterone acetate, 9.8% of glyceryl caprylate, 26.15% of surfactant Labrasol, 13.05% of cosurfactant ethanol and 200% of solid carrier Aerosil) prepared at different times are respectively transferred into 30mL flat stopper weighing bottles (the time batch numbers of the liquid and the solid self-emulsifying preparations are respectively 20190513, 20190515 and 20190517). Transferring the weighing bottle with the sample into a drug stability test box, standing for 6 months, controlling the temperature and humidity conditions in the test box to be 40 +/-0.5 ℃ and 75% +/-3 RH, sampling at the bottom of 1 st, 2 th, 3 th and 6 th months, checking whether the properties of the test sample change, and determining indexes such as abiraterone acetate liquid self-microemulsion drug content, clarity, emulsion particle size, abiraterone solid self-microemulsion drug content, dissolution rate, emulsion particle size and the like according to the method in the section (see table 9).
TABLE 9 Abiraterone liquid self-microemulsion accelerated stability test results
TABLE 10 Abiraterone solid self-microemulsion accelerated stability test results
Test results show that when the abiraterone liquid self-microemulsion is placed for 6 months under accelerated test conditions, the properties of 3 batches of samples are changed from light yellow viscous liquid to yellow viscous liquid, which is probably caused by lipid denaturation, the drug content in the 3 batches of samples is reduced by 7-8%, and the clarity and the emulsified particle size are not obviously changed. The abiraterone solid self-microemulsion is placed for 6 months under the same condition, and each investigation item of 3 batches of samples has no obvious change, which shows that the stability of the abiraterone solid self-microemulsion is stronger than that of the abiraterone liquid self-microemulsion under the condition.
The abiraterone acetate solid self-microemulsion obtained by the invention has the advantages of good emulsifying capacity of liquid self-microemulsion and good stability of solid preparations, preservatives are not required to be added, long-term storage can be realized only under a drying condition, the cost is saved, the obtained solid self-microemulsion can be further prepared into preparations such as tablets, capsules and granules, and more choices are provided for self-microemulsion oral administration dosage forms.
Claims (3)
1. The abiraterone acetate solid self-microemulsion is characterized by comprising the following components in percentage by mass:
0.25 to 1.5 percent of abiraterone acetate
5 to 10 percent of oil phase
25 to 30 percent of surfactant
Cosurfactant 12.5-15%
45-55% of a solid carrier;
the oil phase is glycerol monooleate;
the surfactant is Labrasol;
the cosurfactant is ethanol;
the solid carrier is Aerosil200 and/or cross-linked PVP;
the mass ratio of the surfactant to the cosurfactant is 2.
2. The preparation method of the abiraterone acetate solid self-microemulsion according to claim 1, which is characterized in that:
1) Mixing the surfactant and the cosurfactant according to the proportion to obtain a mixed solution for later use;
2) Adding the abiraterone acetate into the mixed solution, uniformly mixing, and adding the oil phase to obtain an abiraterone acetate liquid self-microemulsion;
3) And adding a solid carrier into the abiraterone acetate liquid self-microemulsion to obtain the abiraterone acetate solid self-microemulsion.
3. The preparation method of the abiraterone acetate solid self-microemulsion according to claim 2, which is characterized in that: in the step 1), the surfactant and the cosurfactant are mixed according to the mass ratio of 2.
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