Abiraterone acetate suppository and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to an abiraterone acetate suppository and a preparation method thereof. The abiraterone acetate suppository of the present invention comprises abiraterone acetate and a matrix. The matrix of the prescription amount is weighed, heated and melted, the abiraterone acetate of the prescription amount is added, stirred to dissolve, and filled on a suppository filling line to obtain the abiraterone acetate suppository. Compared with the prior art, the present invention greatly improves bioavailability, has a simple preparation process, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to an abiraterone acetate suppository and a preparation method thereof. Background Art

[0002] Abiraterone acetate is an orally effective irreversible inhibitor of CYP17 enzyme developed by Centocor Ortho, USA. It was approved by the US FDA for marketing in April 2011 and is clinically used in combination with prednisone to treat castration resistant prostate cancer (CRPC). This product is a selective oral inhibitor of 17α-hydroxylase-C17,20-lyase (human cytochrome P45017 enzyme), a key enzyme in testosterone synthesis. It can reduce the level of tumor marker prostate specific antigen (PSA) and can be used for prostate cancer patients who have been treated with drugs or surgically removed but whose tumors continue to grow. The chemical name of abiraterone acetate is 3β-acetoxy-17-(3-pyridyl)-androsta-5,16-diene, and its molecular formula is C 26 H 33 NO2, molecular weight 391.55, chemical structure:

[0003]

[0004] Abiraterone acetate is a white or off-white non-hygroscopic crystalline powder with an oil-water partition coefficient of 5.12 (logP), and is almost insoluble in water.

[0005] Due to the extremely poor water solubility of abiraterone acetate, the existing preparations need to add surfactants to detect the dissolution. Improving the dissolution of active ingredients in preparations is a problem that troubles people in this technical field. The bioavailability of abiraterone acetate is only 0.4%. The specifications of abiraterone acetate preparations currently listed at home and abroad are 0.25g, and 4 tablets need to be taken each time. For patients who cannot swallow or have difficulty swallowing, it is difficult to take tablets, resulting in poor compliance with patients' medication and difficulty in taking medication. In order to solve the problems of poor solubility and low bioavailability of drugs, researchers have tried to solve them through formulation technologies such as solid dispersions.

[0006] Patent CN103070828 reports a solid dispersion of abiraterone acetate and povidone, and the prepared solid dispersion is micronized to greatly improve the water solubility of abiraterone acetate, which is beneficial to the rapid dissolution of abiraterone acetate in gastrointestinal body fluids, but the bioavailability is not significantly improved, and chloroform is used as a solvent in the preparation of the solid dispersion, which is easy to cause environmental pollution during the process of reduced pressure drying.

[0007] Patent CN105267224 prepares an amorphous mixture of abiraterone acetate and anhydrous lactose by grinding. The amorphous mixture is easily crushed into microparticles. The solid oral preparation prepared with the microparticles has better dispersion performance and solubility. However, the preparation prepared by the invention has extremely low solubility under physiological conditions and cannot achieve the effect of improving bioavailability.

[0008] Patent CN105616364 provides an abiraterone acetate tablet and a preparation method thereof, which uses mannitol and microcrystalline cellulose as fillers, and adopts a wet granulation method after co-grinding the API with a surfactant, sodium dodecyl sulfate, to prepare the abiraterone acetate tablet, which has good compressibility, a solubility of more than 90%, good stability, and a small tablet weight, and is suitable for oral administration to humans. The invention adopts a relatively common process to prepare the preparation, and the obtained preparation has poor solubility under physiological conditions.

[0009] Patent CN105640906 reports an abiraterone sublingual tablet and a preparation method thereof, which can improve the absorption of abiraterone acetate and reduce adverse reactions after medication. However, the preparation uses a large amount of sodium dodecyl sulfate as a sublingual tablet, which has a poor taste and leads to poor medication compliance in patients.

[0010] Patent CN108785256 relates to a solid dispersion containing abiraterone or its derivatives and a carrier material, hydroxypropyl methylcellulose acetate succinate. The preparation made from the solid dispersion has good solubility and stability, can eliminate individual differences between patients after taking the medicine, and can eliminate the food effect caused by fasting or full stomach administration to a certain extent. However, the invention uses enteric material hydroxypropyl methylcellulose acetate succinate as a carrier material, which dissolves slowly in a physiological environment and cannot achieve the purpose of improving bioavailability.

[0011] The prior art has not been able to provide an abiraterone acetate preparation with good absorption and high bioavailability. Summary of the invention

[0012] In view of the defects of the prior art, the present invention provides an abiraterone acetate preparation with high bioavailability.

[0013] Specifically, the present invention is achieved through the following technical solutions:

[0014] A suppository of abiraterone acetate comprises an active ingredient of abiraterone acetate and a base.

[0015] The weight ratio of abiraterone acetate to matrix in the abiraterone acetate suppository is 1:10-20.

[0016] Preferably, the weight ratio of abiraterone acetate to matrix is ​​1:12-18.

[0017] The base of the abiraterone acetate suppository is an oily base or a water-soluble base.

[0018] In some embodiments, the base of the abiraterone acetate suppository is a water-soluble base.

[0019] Specifically, the oily matrix includes cocoa butter, semi-synthetic fatty acid glyceride, litsea cubeba oil ester, palmitic acid ester, propylene glycol stearate, fully synthetic fatty acid glyceride, hydrogenated vegetable oil or balsam pear butter.

[0020] The water-soluble base includes glycerin gelatin, polyethylene glycol, polyoxyethylene stearate, poloxamer, polysorbate or polyoxyl stearate.

[0021] In some embodiments, the base of the abiraterone acetate suppository is selected from one or more of glycerin gelatin, polyethylene glycol, polyoxyethylene stearate, poloxamer, polysorbate or polyoxyl stearate.

[0022] Preferably, the base of the abiraterone acetate suppository is one or a combination of polyoxyl stearate or poloxamer.

[0023] Further preferably, the base of the abiraterone acetate suppository is polyoxyl stearate.

[0024] The invention provides a method for preparing an abiraterone acetate suppository, comprising the following steps: weighing a prescribed amount of a matrix, heating and melting it, adding a prescribed amount of abiraterone acetate, stirring to dissolve it, and filling it on a suppository filling line to obtain the abiraterone acetate suppository.

[0025] It should be noted that the present invention has no particular limitation on the heating and dissolving step, and conventional heating and dissolving methods in the art or heating and dissolving methods disclosed in the prior art can be used in the present invention.

[0026] Compared with the existing technology, it has the following advantages:

[0027] (1) The preparation process is simple;

[0028] (2) The bioavailability is significantly improved and the individual differences are small. DETAILED DESCRIPTION

[0029] The following examples further describe the beneficial effects of the present invention. The examples are for illustrative purposes only and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0030] Example 1

[0031] Component content

[0032] Abiraterone acetate 100g

[0033] Polyoxyl stearate 1500g

[0034] Preparation process:

[0035] Weigh the prescribed amount of polyoxyl stearate, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0036] Example 2

[0037] Component content

[0038] Abiraterone acetate 100g

[0039] Polyoxyl stearate 1000g

[0040] Preparation process:

[0041] Weigh the prescribed amount of polyoxyl stearate, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0042] Example 3

[0043] Component content

[0044] Abiraterone acetate 100g

[0045] Polyoxyl stearate 2000g

[0046] Preparation process:

[0047] Weigh the prescribed amount of polyoxyl stearate, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0048] Example 4

[0049] Component content

[0050] Abiraterone acetate 100g

[0051] Polyoxyl stearate 1200g

[0052] Preparation process:

[0053] Weigh the prescribed amount of polyoxyl stearate, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0054] Example 5

[0055] Component content

[0056] Abiraterone acetate 100g

[0057] Polyoxyl stearate 1800g

[0058] Preparation process:

[0059] Weigh the prescribed amount of polyoxyl stearate, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0060] Example 6

[0061] Component content

[0062] Abiraterone acetate 100g

[0063] Poloxamer 1500g

[0064] Preparation process:

[0065] Weigh the prescribed amount of poloxamer, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0066] Example 7

[0067] Component content

[0068] Abiraterone acetate 100g

[0069] Glycerin gelatin 1400g

[0070] Preparation process:

[0071] Weigh the prescribed amount of glycerin gelatin, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0072] Example 8

[0073] Component content

[0074] Abiraterone acetate 100g

[0075] Polyoxyl stearate 900g

[0076] Preparation process:

[0077] Weigh the prescribed amount of polyoxyl stearate, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0078] Example 9

[0079] Component content

[0080] Abiraterone acetate 100g

[0081] Polyoxyl stearate 2100g

[0082] Preparation process:

[0083] Weigh the prescribed amount of polyoxyl stearate, heat to melt, add the prescribed amount of abiraterone acetate, stir to dissolve, and fill on the suppository filling line.

[0084] Comparative Example 1

[0085] Component content

[0086] Abiraterone acetate 10g

[0087] Oleic acid macrogol glyceride 150g

[0088] Preparation process

[0089] Weigh abiraterone acetate and oleic acid macrogol glyceride in the prescribed amount, stir to dissolve into a uniform clear solution, and fill the solution into soft capsules.

[0090] Comparative Example 2

[0091]

[0092]

[0093] Preparation process:

[0094] (1) mixing abiraterone acetate and copovidone uniformly to prepare a physical mixture;

[0095] (2) setting the extrusion temperature of the twin-screw hot melt extruder to 100° C., starting the screw when the preset temperature is reached, adding the physical mixture in step (1) into the extruder, and extruding a strip through the screw;

[0096] (3) crushing the strips obtained in step (2) and passing through a 40-mesh sieve to obtain a solid dispersion having a uniform particle size distribution;

[0097] (4) uniformly mixing the solid dispersion obtained in step (3) with a diluent, a binder, a disintegrant, and a lubricant according to the weight percentage in the prescription;

[0098] (5) Compressing the mixture from step (4) into tablets.

[0099] Comparative Example 3

[0100]

[0101] Preparation process:

[0102] Prescribe the amount of abiraterone acetate, glutathione and L-malic acid and dry them at 60°C in advance and then pass them through an 80-mesh sieve in sequence; fully mix the raw and auxiliary materials and determine the content, determine the tablet weight according to the specification, put them on a tablet machine, inspect and package them to obtain the product.

[0103] Comparative Example 4

[0104]

[0105] Preparation process:

[0106] (a) Abiraterone acetate, soybean lecithin, and cholesterol were dissolved in 10 mL of ethanol to obtain solution A. Solution A was subjected to rotary evaporation in a water bath at 50° C. to form a film to obtain film B.

[0107] (b) Dissolve fatty acid glyceride in 5 mL of phosphate buffer at pH 6.8 to obtain solution C.

[0108] (c) Solution C was added to membrane B, and the mixture was refrigerated at below 5° C. for 40 minutes to allow the membrane to be fully hydrated, and then vortexed for 60 minutes to prepare abiraterone acetate flexible liposomes.

[0109] Verification Example

[0110] Bioequivalence study

[0111] The preparations prepared in the examples of the present invention and the comparative examples were used for pharmacokinetic experiments, and the commercially available abiraterone acetate tablets (trade name: Zeke@) were used as the reference preparation, and a single-dose, two-period crossover test was performed. 8 male Beagle dogs were divided into two groups, and after fasting for 12 hours, they were given the example preparation, the comparative example preparation and the "Zeke@" tablets (the dosage of the example and the comparative example preparation was 100 mg / dog, and the dosage of the "Zeke@" tablets was 250 mg / dog). After the elution period of 10 days, the crossover test was carried out, and the abiraterone concentration in plasma was determined by high performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated by Win Nonlin 6.4 software according to the non-compartmental model. The results are shown in Table 1.

[0112] Table 1 Results of bioequivalence determination of abiraterone acetate preparations

[0113]

[0114] Note: Relative bioavailability F = (AUC 实施例制剂 *250) / (AUC 原研制剂 *100)*100%

[0115] As can be seen from the table, the bioavailability of the embodiment is more than 20 times that of the commercially available abiraterone acetate, which greatly improves the bioavailability of the preparation.

Claims

1. An abiraterone acetate suppository, characterized in that: The abiraterone acetate suppository is composed of an active ingredient, abiraterone acetate, and a matrix; the weight ratio of the abiraterone acetate to the matrix is ​​1:12-18; and the matrix is ​​one or a combination of polyoxyl stearate or poloxamer.

2. The abiraterone acetate suppository according to claim 1, characterized in that The matrix is ​​polyoxyl stearate.

3. A method for preparing the abiraterone acetate suppository according to any one of claims 1 or 2, characterized in that: The specific steps are: weighing a prescribed amount of matrix, heating to melt, then adding a prescribed amount of abiraterone acetate, stirring to dissolve, and filling on a suppository filling line to obtain abiraterone acetate suppositories.

Images