Abiraterone acetate solid self-microemulsion and preparation method thereof

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 is prepared from the following components in percentage by mass: 0.25%-1.5% of abiraterone acetate, 5%-10% of an oil phase, 25%-30% of a surfactant, 12.5%-15% of a cosurfactant and 45%-55% of a solid carrier. According to the invention, solidification of the liquid medicine is realized, prescription screening and optimization are carried out through a single factor test to obtain the self-microemulsion which is free of preservatives, easy to store, easy to transport and more stable, and the preparation method is simple, controllable and good in repeatability. Particles in the transmission electron microscope image display period of the emulsion of the abiraterone acetate solid self-microemulsion are regularly spherical and are uniformly distributed, and the particle size is less than 100nm.

Description

technical field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a solid self-microemulsion containing abiraterone acetate. Background technique

[0002] Abiraterone acetate (AA) is an inhibitor of androgen synthase CYP17A1, which is clinically used to treat metastatic castration-resistant prostate cancer (mCRPC). Or precipitate discharge, so that many expensive drugs are discharged as crystals, precipitates or prototypes without being effective. At the same time, abiraterone acetate belongs to the IV class drug in the biopharmaceutical classification system (BCS), and has the characteristics of low permeability and low solubility. Its octanol-water partition coefficient is 5.12 (LogP), the pKa of aromatic nitrogen is 5.19, it is almost insoluble in water (less than 0.01mg / ml), and has poor permeability. extremely low.

[0003] Lipid preparation drug delivery system entered the pharmaceutical field in the form of a simpl...

Examples

Embodiment 1

[0040] The selection of each composition of embodiment 1 abiraterone acetate solid self-microemulsion

[0041] 1.1. Solubility test

[0042] Take multiple 10mL EP tubes, add 1g of abiraterone acetate standard to each EP tube, add 5mL of different oils, emulsifiers and co-emulsifiers to different EP tubes and seal them. Fix the EP tube in a constant temperature water bath shaker, shake it for 48 hours at a water temperature of 37°C and 60 rpm, and then place it in a centrifuge for 10 minutes at a speed of 5000 rpm. Take out the centrifugate and filter it with a 0.45 μm microporous membrane, then dilute its volume 5 times with acetonitrile, and enter the liquid phase to detect the solubility of abiraterone acetate in different oils and surfactants (see figure 1 ).

[0043] Among them, the chromatographic conditions are:

[0044] Chromatographic column: Promosil C18 (4.6mm×250mm, 5μm)

[0045] Detector: UV 254nm

[0046] Flow rate: 1.2mL / min

[0047] Mobile phase: phosphate...

Embodiment 2

[0068] The ratio optimization of each component in the Abiraterone acetate solid self-microemulsion system of embodiment 2

[0069] In this experiment, the amount of oil phase, the ratio of surfactant to co-surfactant / Km, and the amount of drug added were screened, and the optimal system was obtained based on particle size, appearance and stability.

[0070] 2.1 Amount of oil phase

[0071] The ratio of fixed surfactant and co-surfactant is 2: 1 (v / v), adding blank liquid self-microemulsion preparation (oil phase, emulsifier and co-emulsifier) ​​total mass 10%, 15%, 20%, 25%, 30% oil phase, the three are mixed evenly to make a blank self-microemulsion preparation. Take 1 g of the blank preparation and add 10 mL of deionized water to dilute, observe the stability of the diluent within 48 hours, and take a small amount of the diluent to measure the particle size and its distribution (see Table 3).

[0072] The influence of table 3 oil phase dosage on preparation properties

...

Embodiment 3

[0091] At room temperature, weigh 0.263 g of ethanol and 0.534 g of caprylic capric acid polyethylene glycol glyceride (Labrasol) and mix them in a small beaker to obtain a surfactant mixture.

[0092] Add 10.2 mg of abiraterone acetate to the surfactant mixture obtained above and mix evenly, and ultrasonically assists in accelerating the dissolution of the drug. After the drug is completely dissolved, add 0.207 g of glyceryl monooleate and shake well to obtain acetic acid Abiraterone Liquid Self Microemulsion.

[0093] Take 1.5g of abiraterone acetate liquid self-microemulsion and 1.5g of cross-linked PVP to mix and absorb, and obtain 3g of abiraterone acetate solid self-microemulsion.

technical field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a solid self-microemulsion containing abiraterone acetate. Background technique

[0002] Abiraterone acetate (AA) is an inhibitor of androgen synthase CYP17A1, which is clinically used to treat metastatic castration-resistant prostate cancer (mCRPC). Or precipitate discharge, so that many expensive drugs are discharged as crystals, precipitates or prototypes without being effective. At the same time, abiraterone acetate belongs to the IV class drug in the biopharmaceutical classification system (BCS), and has the characteristics of low permeability and low solubility. Its octanol-water partition coefficient is 5.12 (LogP), the pKa of aromatic nitrogen is 5.19, it is almost insoluble in water (less than 0.01mg / ml), and has poor permeability. extremely low.

[0003] Lipid preparation drug delivery system entered the pharmaceutical field in the form of a simpl...

Examples

Embodiment 1

[0040] The selection of each composition of embodiment 1 abiraterone acetate solid self-microemulsion

[0041] 1.1. Solubility test

[0042] Take multiple 10mL EP tubes, add 1g of abiraterone acetate standard to each EP tube, add 5mL of different oils, emulsifiers and co-emulsifiers to different EP tubes and seal them. Fix the EP tube in a constant temperature water bath shaker, shake it for 48 hours at a water temperature of 37°C and 60 rpm, and then place it in a centrifuge for 10 minutes at a speed of 5000 rpm. Take out the centrifugate and filter it with a 0.45 μm microporous membrane, then dilute its volume 5 times with acetonitrile, and enter the liquid phase to detect the solubility of abiraterone acetate in different oils and surfactants (see figure 1 ).

[0043] Among them, the chromatographic conditions are:

[0044] Chromatographic column: Promosil C18 (4.6mm×250mm, 5μm)

[0045] Detector: UV 254nm

[0046] Flow rate: 1.2mL / min

[0047] Mobile phase: phosphate...

Embodiment 2

[0068] The ratio optimization of each component in the Abiraterone acetate solid self-microemulsion system of embodiment 2

[0069] In this experiment, the amount of oil phase, the ratio of surfactant to co-surfactant / Km, and the amount of drug added were screened, and the optimal system was obtained based on particle size, appearance and stability.

[0070] 2.1 Amount of oil phase

[0071] The ratio of fixed surfactant and co-surfactant is 2: 1 (v / v), adding blank liquid self-microemulsion preparation (oil phase, emulsifier and co-emulsifier) ​​total mass 10%, 15%, 20%, 25%, 30% oil phase, the three are mixed evenly to make a blank self-microemulsion preparation. Take 1 g of the blank preparation and add 10 mL of deionized water to dilute, observe the stability of the diluent within 48 hours, and take a small amount of the diluent to measure the particle size and its distribution (see Table 3).

[0072] The influence of table 3 oil phase dosage on preparation properties

...

Embodiment 3

[0091] At room temperature, weigh 0.263 g of ethanol and 0.534 g of caprylic capric acid polyethylene glycol glyceride (Labrasol) and mix them in a small beaker to obtain a surfactant mixture.

[0092] Add 10.2 mg of abiraterone acetate to the surfactant mixture obtained above and mix evenly, and ultrasonically assists in accelerating the dissolution of the drug. After the drug is completely dissolved, add 0.207 g of glyceryl monooleate and shake well to obtain acetic acid Abiraterone Liquid Self Microemulsion.

[0093] Take 1.5g of abiraterone acetate liquid self-microemulsion and 1.5g of cross-linked PVP to mix and absorb, and obtain 3g of abiraterone acetate solid self-microemulsion.

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