CN115444817A - Nanometer abiraterone acetate composition and preparation method and application thereof - Google Patents
Nanometer abiraterone acetate composition and preparation method and application thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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Abstract
The invention discloses a nanometer abiraterone acetate composition and a preparation method thereof, wherein the nanometer abiraterone acetate composition comprises the following components in percentage by weight: (0.1-0.5): (0.05-0.5): (5-25): (5-25): (0-1) abiraterone acetate, a suspending agent, a surfactant, an antioxidant, a solvent and a diluent; the D90 of the abiraterone acetate is less than or equal to 1000nm. The nanometer abiraterone acetate composition has small abiraterone acetate particle size, can obviously improve the bioavailability of the abiraterone acetate, and promotes the rapid absorption of the medicine in the body; the preparation method has simple process and high success rate. The invention also discloses a medicine containing the nano abiraterone acetate composition, which can improve the bioavailability of the abiraterone acetate. The nano abiraterone acetate composition disclosed by the invention can be applied to treating prostate cancer, reduce dosage, reduce adverse reactions and improve individual difference when the abiraterone acetate is taken.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a nano abiraterone acetate composition and a preparation method and application thereof.
Background
Abiraterone acetate, available under the name abiraterone acetate and under the nameThe Chinese name "zeke" is American vitality (Johnson)&Johnson) pharmaceutical company. The structural formula is shown as a formula I.
Abiraterone acetate reduces androgen levels by inhibiting the key enzyme in androgen synthesis, CYP450C17, which can be used in combination with prednisone (prednisone) for the treatment of patients with metastatic potential prostate tumors. Abiraterone acetate was first approved for marketing in 2011 by the Food and Drug Administration (FDA) and then marketed in various countries and regions throughout the world including china, the european union, japan, and so on.
The abiraterone acetate is converted into the abiraterone with biological activity through deacetylation after entering a human body. Abiraterone acetate is a lipophilic compound, which is highly soluble in organic solvents but hardly soluble in water and poorly permeable, belonging to BCS class 4, with a bioavailability of less than 10%, and is therefore administered at a dose of 1000mg (250 mg/tablet x 4 tablets). At the same time, abiraterone acetate also has obvious food effect: the patients were asked to take the medication in the fasting state and to maintain the fasting state not only for 2 hours before the medication was taken but also for 1 hour after the medication was taken. These above problems all indicate that the product is at a safety risk: the improvement of bioavailability and individuality of the medicine by means of preparation is the direction pursued by pharmaceutical people at present, such as hepatotoxicity, food effect, individuality difference, large daily dose (1000 mg), etc.
According to the current literature reports, there are 2 methods for improving the oral bioavailability of abiraterone acetate, namely changing the physicochemical property of the drug, improving the membrane permeability or improving the dissolution property of the drug, such as micronization technology, solid dispersion technology, inclusion technology and the like.
Patent CN103446069A discloses an abiraterone oral solid composition and a preparation method thereof, wherein abiraterone acetate raw material medicine is subjected to micronization treatment, the particle size is controlled within a range of 0-20 μm to improve the dissolution rate of tablets, but after research, the raw material medicine is independently micronized and can not obviously improve the dissolution rate, and special equipment is required for crushing to the particle size range.
Patent CN102743393A discloses a medicinal composition containing abiraterone acetate and a preparation process thereof, wherein the abiraterone acetate and hydrophilic auxiliary materials are crushed according to a proportion, and the particle size of the raw material medicine is 10-30 μm, so that the dissolution rate and the bioavailability of the medicine are improved. However, even if the particle size of the raw material drug is micronized to 10-30um, the improvement of the drug dissolution rate is still limited, the dissolution rate is only 60% in a medium with pH4.5 and added with a surfactant for 15min, and the bioavailability is still very low.
Patent CN103070828a discloses a solid dispersion and tablet containing abiraterone acetate and a preparation method thereof, wherein the solid dispersion is prepared by mixing 1: dissolving 0.5-4 of abiraterone acetate and povidone in chloroform, drying under reduced pressure, adding into water, grinding, granulating, and drying. Although the dissolution rate is improved, the process needs to prepare a solid dispersion, uses chloroform as a solvent, does not utilize workshop safety production and labor protection of workers, has limited dissolution improvement, and has lower bioavailability because 64 percent of the solution is dissolved in a medium with pH4.5 and added with a surfactant for 10 min.
CN102961358A discloses an abiraterone acetate liquid capsule, the content comprises abiraterone acetate, solvent, antioxidant and fatty acid monoglyceride. The prescription components and the preparation process of the patent are complex, the preparation process needs further heating, the stability of the medicine is reduced, the medication safety is affected, and the problem of the bioavailability of the medicine cannot be solved.
CN110354094A discloses a CYP17 inhibitor soft capsule and a preparation method thereof, wherein abiraterone acetate is dissolved in fatty glyceride, and then the solution is filled into the soft capsule. Although some improvement in vivo dissolution and solubility was seen in the beagle in vivo data, prolonged gastrointestinal residence time, stimulated lymphatic transport, and reduced metabolic effects. However, since the soft capsule contains a large amount of fatty acid glyceride, the individual difference cannot be eliminated and the stability is poor.
In addition, the method for providing bioavailability is to reduce the particle size of the abiraterone acetate to a nanometer level, and when the particle size of the bulk drug reaches the nanometer level, the solubility and the membrane permeability are greatly improved due to the extremely large specific surface area of the bulk drug.
For example, patent WO2014009436 reports a nanosuspension containing abiraterone acetate or a derivative thereof, which increases the solubility of abiraterone acetate and improves the transmembrane capacity.
For another example, patent CN111617258a reports a method for preparing abiraterone or its derivative pharmaceutical composition, which comprises preparing abiraterone acetate and absorption enhancer into a nanosuspension, then adding excipient, granulating with fluidized bed to prepare abiraterone acetate nanoparticles, tabletting into micro-tablets, and encapsulating, to improve dissolution and bioavailability of the product, but still needs to reach 300mg per day, and fails to eliminate the effect of food on the product.
In conclusion, the existing abiraterone acetate medicinal preparation has the following defects: the dissolution rate is low, and the bioavailability is not high; the daily dose is large, with the risk of food effect and individualization differences.
Disclosure of Invention
In order to overcome the defects of the prior art, one of the purposes of the invention is to provide a nano abiraterone acetate composition, wherein the abiraterone acetate has a small particle size, and can remarkably improve the bioavailability of the abiraterone acetate and promote the rapid absorption of a medicine in a body.
The invention also aims to provide a preparation method of the nanometer abiraterone acetate composition, which is simple and convenient in process and high in success rate.
The invention also aims to provide a medicament containing the nano abiraterone acetate composition, which can obviously improve the bioavailability of the abiraterone acetate and promote the rapid absorption of the medicament in vivo.
The fourth purpose of the invention is to apply the nanometer abiraterone acetate composition to a medicine for treating prostatic cancer, so that the dosage can be reduced, and the individual difference of patients taking the medicine can be improved.
One of the purposes of the invention is realized by adopting the following technical scheme:
a nanometer abiraterone acetate composition comprises the following components in percentage by weight: (0.1-0.5): (0.05-0.5): (5-25): (5-25): (0-1) abiraterone acetate, a suspending agent, a surfactant, an antioxidant, a solvent and a diluent; in the composition, the D90 of the abiraterone acetate is less than or equal to 1000nm.
Further, the weight percentages of the abiraterone acetate, the suspending agent, the surfactant, the antioxidant, the solvent and the diluent are 1: (0.2-0.3): 0.1: (10-15): (10-15): (0-0.33).
Further, in the composition, the D90 of the abiraterone acetate is less than or equal to 1000nm, and can be one of the following values: 973nm, 793nm, 506nm, 950nm, 900nm, 850nm, 800nm, 750nm, 700nm, 650nm, 600nm, 550nm, 500nm; more preferably, the Abiraterone acetate has a D90 ≦ 400nm, which may be, for example, one of the following values: 400nm, 380nm, 343nm, 350nm and 300nm.
Further, in the composition, the D50 of the abiraterone acetate is less than or equal to 800nm, and can be one of the following values: 702nm, 564nm, 213nm, 206nm, 262nm, 800nm, 750nm, 650nm, 600nm, 550nm, 500nm, 450nm, 400nm, 350nm, 300nm, 250nm.
Further, in the composition, the D10 of the abiraterone acetate is less than or equal to 600nm, and can be one of the following values: 508nm, 409nm, 122nm, 127nm, 154nm, 600nm, 550nm, 450nm, 350nm, 300nm, 250nm, 200nm, 150nm.
In the present invention, D90 represents the particle size corresponding to the cumulative number of particle size distributions of the samples up to 90%; when D90 is not more than 1000nm, it means that 90% of particles having a particle size of 1000nm or less are present.
D50 represents the particle size corresponding to the cumulative percent particle size distribution of the sample at 50%. When D50 is less than or equal to 800nm, it means that 50% of the particles having a particle size of 800nm or less are present and 50% of the particles having a particle size of 800nm or more are present.
D10 represents the particle size corresponding to the cumulative number of particle size distributions of the samples reaching 10%. When D10 is less than or equal to 600nm, it means that 10% of the particles having a particle size of 600nm or less are present.
Further, in the composition, the polymer dispersity index PDI of the abiraterone acetate is less than or equal to 0.5, and can be 0.444, 0.372, 0.154, 0.146, 0.25, 0.35 and the like.
Further, the suspending agent is povidone, more preferably povidone K30 (PVP K30); the surfactant is sodium dodecyl sulfate (SLS) and/or docusate sodium; the antioxidant is any combination of Butylated Hydroxyanisole (BHA) and 2,6-ditertbutyl-p-cresol (BHT), more preferably, the antioxidant is equal mixture of BHA and BHT; the solvent is pure water; the diluent is lactose monohydrate.
The second purpose of the invention is realized by adopting the following technical scheme:
a preparation method of a nanometer abiraterone acetate composition comprises the following steps:
the preparation steps of the suspension are as follows: dividing the solvent with the formula amount into at least two parts, wherein one part is marked as a first solvent; adding the suspending agent and the surfactant according to the formula ratio into the first solvent, and stirring until the suspending agent and the surfactant are completely dissolved; then adding the abiraterone acetate with the formula amount, and uniformly stirring; adding the antioxidant with the formula amount under the stirring state, and uniformly stirring to obtain a suspension;
grinding: and transferring the suspension into a grinding machine for grinding to obtain an abiraterone acetate nano mixed solution. When the grinding is performed, the type of the grinding mill may be a bead mill, a planetary mill, a roll mill, or the like. The abrasive bodies are preferably zirconia grinding beads which may have a diameter of 0.5-10mm, preferably 0.5-1mm, more preferably YTZ zirconia grinding beads having a diameter of 0.65 mm. The grinding time and speed need to be preset to ensure that the abiraterone acetate nano mixed solution is obtained. The grinding speed is preferably 1500 to 3500rpm, more preferably 2000 to 3000rpm; the milling time is preferably from 5 minutes to 30 hours and may be selected from the following time periods: 5 minutes to 30 minutes, 10 minutes to 30 minutes, 1 hour to 5 hours, 8 hours to 15 hours, 9 hours to 24 hours.
Further, the method also comprises a dilution step, and the abiraterone acetate nanometer mixed solution is obtained and then diluted to obtain a diluted mixed solution. Upon dilution, one or more of a solvent, a stabilizer and a diluent may be added.
Further, a drying step is included, and after the diluted mixed solution is obtained, decompression freeze drying is carried out, so as to obtain the final product.
The third purpose of the invention is realized by adopting the following technical scheme:
a medicine containing a nano abiraterone acetate composition comprises the nano abiraterone acetate composition. In a specific implementation, a drug can be prepared from only the nano abiraterone acetate composition; or, in addition to the nanometer abiraterone acetate composition, pharmaceutically acceptable auxiliary materials are added to prepare the final medicine, and the auxiliary materials can be selected from one or more of excipient, flavoring agent, coloring agent, disintegrating agent and the like.
Further, the medicament is a tablet or a capsule.
Further, for a unit dose of the drug, 100mg to 280mg of nano abiraterone acetate is contained. For example, a unit dose of a drug comprising 280mg, 260mg, 240mg, 220mg, 200mg, 180mg, 160mg, 140mg, 120mg, 115mg, 105mg, 100mg of nano abiraterone acetate.
The fourth purpose of the invention is realized by adopting the following technical scheme:
the application of the nanometer abiraterone acetate composition in preparation of medicines for treating prostate cancer can improve individual difference of patients taking the medicines.
Compared with the prior art, the invention has the beneficial effects that:
(1) Compared with the existing abiraterone acetate on the market, the nanometer abiraterone acetate composition provided by the invention has the advantages that the particle size D90 of the abiraterone acetate is controlled within 1000nm, the bioavailability of the abiraterone acetate can be obviously improved, the rapid absorption of the medicine in the body is promoted, and the risks of large daily dose, food influence effect and individual difference of the existing abiraterone acetate tablets are solved. In addition, the composition also comprises auxiliary materials of a suspending agent, a surfactant, an antioxidant, a solvent and a diluent, and the components in the formula are reasonably matched, so that the dissolution rate and the stability of the abiraterone acetate can be ensured, and the bioavailability of the abiraterone acetate is improved.
(2) The preparation method of the nanometer abiraterone acetate composition provided by the invention is simple and convenient in process and high in success rate, and can solve the agglomeration problem of the abiraterone acetate nanometer suspension in the preparation process.
Drawings
FIG. 1 is a particle polarization microscope (PLM) map of a currently marketed abiraterone acetate drug substance;
fig. 2 is a particle polarization microscope (PLM) map of the milled abiraterone acetate nanosuspension in example 4 of the invention.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and the detailed description, and it should be noted that any combination of the embodiments or technical features described below can be used to form a new embodiment without conflict. The raw materials, equipments and the like used in the following examples are commercially available unless otherwise specified.
A nanometer abiraterone acetate composition comprises the following components in percentage by weight of 1: (0.1-0.5): (0.05-0.5): (5-25): (5-25): (0-1) abiraterone acetate, a suspending agent, a surfactant, an antioxidant, a solvent and a diluent; in the composition, the D90 of the abiraterone acetate is less than or equal to 1000nm.
Example 1
A nanometer abiraterone acetate composition has a formula shown in the following table 1.
Table 1 examples formulation table of nano abiraterone acetate composition
The nano abiraterone acetate composition of example 1 was prepared as follows:
155g of purified water is accurately measured at room temperature, placed in a beaker, added with 4g of PVP K30 and 2g of SLS under magnetic stirring, and stirred until the materials are completely dissolved to obtain an auxiliary material solution. Adding 20g of abiraterone acetate raw material medicine under stirring, dispersing the raw material medicine in the auxiliary material solution, and stirring uniformly. 100mg of BHA and 100mg of BHT were added while stirring, and the mixture was further stirred to obtain a suspension before grinding. The pre-mill suspension prepared was transferred to the circulation cylinder of a mill (already loaded with YTZ zirconia milling beads of diameter 0.65 mm). The inner wall of the beaker is washed with the remaining purified water in several times, and the washing solution is poured into a circulation cylinder. Starting grinding, adjusting the rotating speed to 3000rpm, grinding for 4 hours, stopping grinding, and discharging. Weighing, calculating the addition amount of lactose monohydrate according to the weight, adding 6.6g of lactose monohydrate under stirring, stirring for 10min to obtain a liquid medicine mother solution, diluting the liquid medicine mother solution by 1 time, and quickly freeze-drying under stirring to obtain the final product.
The final product of example 1 was reconstituted with a diluent and tested for particle size, the results of which are shown in table 2 below.
Table 2 example 1 particle size test results table
Example 2
A nanometer abiraterone acetate composition has a formula shown in the following table 3.
Table 3 formula of nano abiraterone acetate composition of example
261g of purified water is accurately measured at room temperature, placed in a beaker, and added with 6g of PVP K30 and 3g of SLS under magnetic stirring to be stirred until the PVP K30 and the SLS are completely dissolved, so that an auxiliary material solution is obtained. Adding 30g of abiraterone acetate raw material medicine under stirring, dispersing the abiraterone acetate raw material medicine in the auxiliary material solution, and stirring uniformly. 150mg of BHA and 150mg of BHT were added while stirring, and the mixture was further stirred to obtain a suspension before grinding. This suspension was transferred to the circulating cylinder of a mill (already equipped with YTZ zirconia grinding beads of diameter 0.65 mm). The inner wall of the beaker is washed by the residual purified water in several times, and the washing liquid is poured into a circulating cylinder. Starting grinding, adjusting the rotating speed to 3000rpm, and grinding for 24h. Weighing, calculating the addition amount of lactose monohydrate according to the weight, adding 6.6g of lactose monohydrate under stirring, and stirring for 10min to obtain the liquid medicine mother liquor. Diluting the solute of the mother liquid of the liquid medicine by one time, and then quickly freezing and drying to obtain the final product.
The final product of example 2 was reconstituted with a diluent and tested for particle size, the results of which are shown in table 4 below.
Table 4 example 2 particle size test results table
Example 3
A nano abiraterone acetate composition, the formula of which is shown in the following table 5.
Table 5 formulation of the nano abiraterone acetate composition of the examples
155g of purified water is accurately measured at room temperature, placed in a beaker, added with 4g of PVP K30 and 2g of SLS under magnetic stirring, and stirred until the materials are completely dissolved to obtain an auxiliary material solution. Adding 20g of abiraterone acetate raw material medicine under stirring, dispersing the raw material medicine in the auxiliary material solution, and stirring uniformly. 100mg of BHA and 100mg of BHT were added while stirring, and the mixture was further stirred to obtain a suspension before grinding. The pre-mill suspension prepared was transferred to the circulation cylinder of a mill (already loaded with YTZ zirconia milling beads of diameter 0.65 mm). The inner wall of the beaker is washed by the residual purified water in several times, and the washing liquid is poured into a circulating cylinder. Grinding is started, the rotating speed is adjusted to 3000rpm, grinding is stopped after 9 hours, discharging is carried out, and stirring is carried out for 10 minutes to obtain liquid medicine mother liquor. Diluting the mother liquid by 1 time, and quickly freeze-drying under stirring to obtain the final product.
The final product of example 3 was reconstituted with a diluent and tested for particle size, the results of which are shown in table 6 below.
Table 6 example 3 particle size test results table
Example 4
A nano abiraterone acetate composition, the formula of which is shown in table 7 below.
Table 7 formulation of the nano abiraterone acetate composition of the examples
155g of purified water is accurately measured at room temperature, placed in a beaker, added with 4g of PVP K30 and 2g of SLS under magnetic stirring, and stirred until the PVP K30 and the SLS are completely dissolved to obtain an auxiliary material solution. Adding 20g of abiraterone acetate raw material medicine under stirring, dispersing the raw material medicine in the auxiliary material solution, and stirring uniformly. 100mg of BHA and 100mg of BHT were added while stirring, and the mixture was further stirred to obtain a suspension before grinding. The pre-mill suspension prepared was transferred to the circulation cylinder of a mill (already loaded with YTZ zirconia milling beads of diameter 0.65 mm). The inner wall of the beaker is washed by the residual purified water in several times, and the washing liquid is poured into a circulating cylinder. Grinding is started, the rotating speed is adjusted to 2000rpm, grinding is stopped after 0.5h, discharging is carried out, and stirring is carried out for 10min to obtain liquid medicine mother liquor. Diluting the mother liquid by 1 time, and quickly freeze-drying under stirring to obtain the final product.
The final product of example 4 was reconstituted with a diluent and tested for particle size, the results of which are shown in Table 8 below.
Table 8 example 4 particle size test results table
Example 5
A nano abiraterone acetate composition, the formula of which is shown in table 9 below.
Table 9 formulation of the nano abiraterone acetate composition of the examples
155g of purified water is accurately measured at room temperature, placed in a beaker, added with 4g of PVP K30 and 2g of SLS under magnetic stirring, and stirred until the PVP K30 and the SLS are completely dissolved to obtain an auxiliary material solution. Adding 20g of abiraterone acetate raw material medicine under stirring, dispersing the raw material medicine in the auxiliary material solution, and stirring uniformly. 100mg of BHA and 100mg of BHT were added while stirring, and the mixture was further stirred to obtain a suspension before grinding. The pre-mill suspension prepared was transferred to the circulation cylinder of a mill (already loaded with YTZ zirconia milling beads of diameter 0.65 mm). The inner wall of the beaker is washed by the residual purified water in several times, and the washing liquid is poured into a circulating cylinder. Grinding is started, the rotating speed is adjusted to 2000rpm, grinding is stopped after 10min, discharging is carried out, and stirring is carried out for 10min to obtain liquid medicine mother liquor. Diluting the mother liquid by 1 time, and quickly freeze-drying under stirring to obtain the final product.
The final product of example 5 was reconstituted with a diluent and tested for particle size, the results of which are shown in Table 10 below.
Table 10 table for particle size test results of example 5
Effect verification
1. Pharmacokinetic protocol and results
1.1 pharmacokinetic protocol
1.11 design of the Experimental protocol
16 male SD rats were taken and given a single oral gavage, with the animals in the oral group fasted overnight (10-14 hours) prior to administration. The experimental design is shown in table 11 below.
TABLE 11 Experimental design
Note: the control group is a commercial abiraterone acetate sample which is not subjected to nano grinding and is prepared according to the formula of the composition.
1.12 preparation of test article
The preparation is carried out on the day of administration (about 1 hour before intragastric administration, and the suspension is shaken up before administration). Solvent: 0.4% sodium carboxymethylcellulose (CMC) in water.
1.13 modes of administration
The weight was weighed before administration, and the amount administered was calculated from the body weight. Administration is by intragastric administration.
1.14 blood sampling time points
PO blood sampling point 0.33hr, 0.66hr, 1hr, 1.5hr, 2hr, 4hr, 8hr, 24hr.
1.15 plasma sample treatment
Blood is collected via jugular vein or other suitable means, with each sample collected at about 200 μ L/time point, anticoagulated with K2-EDTA, and placed on ice after collection. Blood samples were collected, placed on ice, and plasma was centrifuged within 1 hour (centrifugation conditions: 6800g,6 minutes, 2-8 ℃). Plasma samples were stored in a-80 ℃ freezer prior to analysis.
1.2 results of the experiment
The concentration of abiraterone in the plasma samples was determined using a validated LC-MS/MS analytical method. The main pharmacokinetic parameters of the drug were calculated from the plasma concentration data at different time points using Phoenix WinNonlin, and the main pharmacokinetic data of abiraterone in plasma are shown in Table 12.
Table 12 main pharmacokinetic parameters of abiraterone in plasma after oral administration (Mean ± SD, n = 4).
Analyzing the experimental data in table 12, fasted male rats dosed with 40mg/kg abiraterone in plasma of the test formulation (CJ-2103-03, D90=380 nm) had a Cmax of 176.76 ± 34.32ng/ml, an exposure AUC (0-t) of 963.01 ± 243.48h ng/ml, and an AUC (0- ∞) of 965.53 ± 235.00h ng/ml, which were 1.8, 2.0 and 1.96 times the dose of 40mg/kg control group (commercial abiraterone acetate drug substance), respectively. And the tested preparation CJ-2103-03 (example 3) has the advantage that the abiraterone acetate in the blood plasma has the rapid peak time, and the Tmax is 1.50 +/-1.19 h, so that the method provided by the embodiment of the invention can obviously improve the bioavailability of the abiraterone acetate by grinding the abiraterone acetate into a nano suspension, and can promote the rapid absorption of the drug in the body. Especially, when the particle size D90 of the nanosuspension is 380nm, the effect is the best, and the method is the best embodiment.
2. Polarizing microscope (PLM) testing
2.1A polarization microscope (PLM) test was performed on the currently available abiraterone acetate crude drug (a commercially available abiraterone acetate sample without nano-grinding, a control sample), and the test results are shown in FIG. 1.
As can be seen from fig. 1, the existing commercial abiraterone acetate bulk drug is in the form of lamellar crystals with non-uniform crystal size, and these characteristics affect the absorption and bioavailability of abiraterone acetate.
2.2 samples of example 4 were taken for polarization microscope (PLM) testing and the results are shown in FIG. 2.
As can be seen from fig. 2, compared with the existing commercial abiraterone acetate drug substance, the crystal particle size of the nanosuspension formed by grinding in example 4 is reduced from about 100 microns to below 1000nm compared with the crystal particle size of the unground abiraterone acetate drug substance. The particle size of the active ingredient abiraterone acetate was measured using a malvern laser particle size detector and the D90 was found to be 793nm. Combining the results in table 12, the exposure AUC (0-t) of abiraterone in plasma of fasting dosed male rat dose of the test formulations (example 4, cj-2103-04, D90=793 nm) was 811.59 ± 96.99h ng/ml, AUC (0- ∞) was 814.08 ± 178.08h ng/ml, which was 1.69 and 1.65 times higher than that of the unmilled control group (commercial abiraterone acetate drug substance), respectively. The embodiment of the invention shows that the bioavailability of the abiraterone acetate can be improved to different degrees by grinding the abiraterone acetate into nanosuspensions with different particle sizes.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (10)
1. The nanometer abiraterone acetate composition is characterized by comprising the following components in percentage by weight of 1: (0.1-0.5): (0.05-0.5): (5-25): (5-25): (0-1) abiraterone acetate, a suspending agent, a surfactant, an antioxidant, a solvent and a diluent; in the composition, the D90 of the abiraterone acetate is less than or equal to 1000nm.
2. The nano abiraterone acetate composition of claim 1, wherein the weight percentages of the abiraterone acetate, the suspending agent, the surfactant, the antioxidant, the solvent and the diluent are 1: (0.2-0.3): 0.1: (10-15): (10-15): (0-0.33).
3. The nano abiraterone acetate composition of claim 1, wherein the D90 of the abiraterone acetate in the composition is 400nm or less.
4. The nano abiraterone acetate composition of claim 1, wherein the D50 of the abiraterone acetate in the composition is 800nm or less.
5. The nano abiraterone acetate composition of claim 1, wherein the D10 of the abiraterone acetate in the composition is 600nm or less.
6. The nano abiraterone acetate composition of claim 1, wherein the suspending agent is povidone; the surfactant is sodium dodecyl sulfate and/or docusate sodium; the antioxidant is any combination of butyl hydroxyanisole and 2,6-ditert-butyl paracresol; the solvent is pure water; the diluent is lactose monohydrate.
7. A method for preparing a nano abiraterone acetate composition of any of claims 1-6, comprising the steps of:
the preparation steps of the suspension are as follows: dividing the solvent with the formula amount into at least two parts, wherein one part is marked as a first solvent; adding the suspending agent and the surfactant according to the formula ratio into the first solvent, and stirring until the suspending agent and the surfactant are completely dissolved; then adding the abiraterone acetate with the formula amount, and uniformly stirring; adding the antioxidant with the formula amount under the stirring state, and uniformly stirring to obtain a suspension;
grinding: and transferring the suspension to a grinder for grinding to obtain the abiraterone acetate nano mixed solution.
8. A medicament containing a nano abiraterone acetate composition, which comprises the nano abiraterone acetate composition of any one of claims 1-6.
9. The drug containing a nano abiraterone acetate composition of claim 8, wherein for a unit dose of the drug, 100mg to 280mg of nano abiraterone acetate is included.
10. Use of the nano abiraterone acetate composition of any of claims 1-6 in the preparation of a medicament for treating prostate cancer.
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