CN112022833B - A kind of enzalutamide pharmaceutical composition and preparation method thereof - Google Patents
A kind of enzalutamide pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention provides an enzalutamide pharmaceutical composition and a preparation method thereof, the composition comprises a capsule shell and a content, wherein the content comprises enzalutamide, PEG-60 hydrogenated castor oil, caprylic capric polyethylene glycol glyceride and vitamin E; the capsule shell comprises gelatin, glycerol, glycine, sorbitol, silicon dioxide, vitamin C and purified water. The enzalutamide preparation prepared by the invention has higher dissolution rate, smaller dissolution fluctuation and good stability, and is beneficial to improving the bioavailability; a smaller dose of solvent is used, thereby reducing the volume of the capsule and improving patient compliance; in addition, antioxidants BHT and BHA with poor safety are avoided, and the safety of medication is improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an enzalutamide pharmaceutical composition and a preparation method thereof.
Background
Enzalutamide (Enzalutamide) is a new generation of antiandrogen drug developed by the united states meditation and japan anslate (Astellas) corporation and is used to treat advanced (metastatic) male Castration-Resistant Prostate Cancer (Castration-Resistant Cancer) that has spread or recurred. The united states Food and Drug Administration (FDA) approved for marketing at 8/31/2012. The Enzalutamide capsule product is mainly provided for patients in the United states, is an androgen receptor inhibitor and is suitable for treating advanced prostate cancer patients, and the Enzalutamide chemical structure is as follows:
enzalutamide belongs to a low-dissolution and low-permeability medicament, belongs to BCSIV (bulk pharmaceutical chemicals) class, has low solubility in aqueous solution and buffer solutions with different pH values, is slow and incomplete in medicament dissolution, and has low bioavailability, so that the exertion of the curative effect of the Enzalutamide is limited. In order to ensure the bioavailability, the enzalutamide soft capsule developed by the answera company is dissolved in a high molecular material of caprylic capric polyethylene glycol glyceride, but the preparation produced by the method has low dissolution rate and low bioavailability, and is easy to separate out crystals after entering a human body. Furthermore, compositions comprising enzalutamide show poor dissolution behavior under acidic conditions, especially under simulated gastric fluid that appears incomplete. In particular, the API does not remain dissolved, but precipitates. In addition, the stability of enzalutamide and caprylic capric acid polyethylene glycol glyceride is poor, and the stability of anstala is improved by adding BHT and BHA into the compound antioxidant, but the two antioxidants are poor in clinical safety. CN104857517A discloses a formulation of enzalutamide soft capsules, but a large amount of caprylic capric acid polyethylene glycol glyceride solvent is still required, and also the less safe oxidant BHT and BHA is used.
The recommended FDA-approved dose for oral liquid-filled soft gelatin capsules containing enzalutamide is 160 mg, wherein each capsule contains 40 mg of the active pharmaceutical ingredient, that is, four capsules are required for a patient to take at a time per oral administration. In addition, these capsules are very large due to the large amount of caprylic capric polyethylene glycol glyceride required to maintain the active pharmaceutical ingredient in solution. Therefore, due to its large size (size 12 capsule) and the large number of capsules that must be taken, it is difficult for patients to swallow, especially for elderly men, resulting in poor patient compliance.
Therefore, there is still a need to develop an enzalutamide pharmaceutical composition with high dissolution rate, high stability, good bioavailability, small capsule volume and improved patient compliance.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an enzalutamide preparation which has high dissolution rate, high stability and good bioavailability, reduces the using amount of a solvent, reduces the volume of a capsule and improves the compliance of a patient and a preparation method thereof.
In one aspect, the invention provides an enzalutamide pharmaceutical composition, which comprises a capsule shell and contents, wherein the contents comprise enzalutamide, PEG-60 hydrogenated castor oil, caprylic capric polyethylene glycol glyceride and vitamin E.
In a further preferred embodiment of the present invention, wherein the capsule shell comprises gelatin, glycerin, glycine, sorbitol, silica, vitamin C and purified water.
In a further preferred embodiment of the invention, the ratio of enzalutamide: PEG-60 hydrogenated castor oil/caprylic capric acid polyethylene glycol glycerides: the weight ratio of the vitamin E is 1: 6-8: 0.02-0.04, preferably 1:6: 0.02. Wherein PEG-60 hydrogenated castor oil/caprylic capric acid polyethylene glycol glyceride means that two components of PEG-60 hydrogenated castor oil and caprylic capric acid polyethylene glycol glyceride exist simultaneously.
In a further preferred embodiment of the invention, PEG-60 hydrogenated castor oil: the weight ratio of the caprylic/capric polyethylene glycol glyceride is 1: 2-2: 1.
In a further preferred embodiment of the invention, PEG-60 hydrogenated castor oil: the weight ratio of the caprylic capric acid polyethylene glycol glyceride is 1: 2.
In a further preferred embodiment of the invention, the ratio of enzalutamide: PEG-60 hydrogenated castor oil: caprylic capric acid polyethylene glycol glyceride: the weight ratio of the vitamin E is 1:2:4: 0.02.
In a further preferred embodiment of the invention, the ratio gelatin: glycerol: glycine: sorbitol: silicon dioxide: vitamin C: the weight ratio of the purified water is 1: 0.1-0.3: 0.02-0.04: 0.2-0.4: 0.005-0.01: 1.5.
In a further preferred embodiment of the invention, the ratio gelatin: glycerol: glycine: sorbitol: silicon dioxide: vitamin C: the weight ratio of the purified water is 1:0.2:0.02:0.25:0.005:0.005: 1.5.
In a further preferred embodiment of the invention, the ratio of enzalutamide: PEG-60 hydrogenated castor oil/caprylic capric acid polyethylene glycol glycerides: vitamin E: gelatin: glycerol: glycine: sorbitol: silicon dioxide: vitamin C: the weight ratio of the purified water is 1: 6-8: 0.02-0.04: 6: 0.6-1.8: 0.12-0.24: 1.2-2.4: 0.03-0.06: 9, preferably 1:6:0.02:6:1.2:0.12:1.5:0.03:0.03: 9. Wherein PEG-60 hydrogenated castor oil/caprylic capric acid polyethylene glycol glyceride means that two components of PEG-60 hydrogenated castor oil and caprylic capric acid polyethylene glycol glyceride exist simultaneously.
In a further preferred embodiment of the invention, the ratio of enzalutamide: PEG-60 hydrogenated castor oil: caprylic capric acid polyethylene glycol glyceride: vitamin E: gelatin: glycerol: glycine: sorbitol: silicon dioxide: vitamin C: the weight ratio of the purified water is 1: 2-4: 4-2: 0.02-0.04: 6: 0.6-1.8: 0.12-0.24: 1.2-2.4: 0.03-0.06: 9, preferably 1:2:4:0.02:6:1.2:0.12:1.5:0.03:0.03: 9. Wherein PEG-60 hydrogenated castor oil/caprylic capric acid polyethylene glycol glyceride means that two components of PEG-60 hydrogenated castor oil and caprylic capric acid polyethylene glycol glyceride exist simultaneously.
In another aspect, the present invention provides a method for preparing an enzalutamide pharmaceutical composition, which comprises the following steps:
preparation of the contents:
(1) mixing enzalutamide, PEG-60 hydrogenated castor oil, caprylic capric acid polyethylene glycol glyceride and vitamin E, and stirring until the enzalutamide, the PEG-60 hydrogenated castor oil, the caprylic capric acid polyethylene glycol glyceride and the vitamin E are dissolved;
preparing a capsule shell:
(2) adding purified water, glycerol, glycine, vitamin C and sorbitol solution into a gelatin melting tank and stirring;
(3) taking part of the solution in the step (2), adding silicon dioxide, dispersing and then adding the solution into a glue dissolving tank;
(4) adding gelatin into a gelatin melting tank, and dispersing to be viscous;
preparing the soft capsule:
(5) and (3) taking the prepared content and the capsule shell, preparing the soft capsule by adopting a pressing method, shaping and drying to obtain the capsule.
In a preferred embodiment of the invention, the steps are as follows:
preparation of the contents:
(1) mixing 1 part by weight of enzalutamide, 6-8 parts by weight of PEG-60 hydrogenated castor oil/caprylic capric acid polyethylene glycol glyceride and 0.02-0.04 part by weight of vitamin E, and stirring at 85-100 ℃ until the mixture is dissolved;
preparing a capsule shell:
(2) adding 9 parts by weight of purified water, 0.6-1.8 parts by weight of glycerol, 0.12-0.24 part by weight of glycine, 0.03-0.06 part by weight of vitamin C and 1.2-2.4 parts by weight of sorbitol solution into a gelatin melting tank and stirring;
(3) taking part of the solution in the step (2), adding 0.03-0.06 part by weight of silicon dioxide into the solution, dispersing, and adding the solution into a glue dissolving tank;
(4) adding 6 parts by weight of gelatin into a gelatin melting tank, and dispersing to be viscous;
preparing the soft capsule:
(5) and (3) taking the prepared content and the capsule shell, preparing the soft capsule by adopting a pressing method, shaping and drying to obtain the capsule.
In a further preferred embodiment of the invention, the steps are as follows:
preparation of the contents:
(1) under the protection of nitrogen, mixing 1 part by weight of enzalutamide, 2 parts by weight of PEG-60 hydrogenated castor oil, 4 parts by weight of caprylic capric polyethylene glycol glyceride and 0.02 part by weight of vitamin E, stirring at 85-100 ℃ until the mixture is dissolved, vacuumizing, and replacing with nitrogen to obtain the composition;
preparing a capsule shell:
(2) heating a gelatin melting tank to 70 ℃, adding 9 parts by weight of purified water, 1.2 parts by weight of glycerol, 0.12 part by weight of glycine, 0.03 part by weight of vitamin C and 1.5 parts by weight of sorbitol solution into the gelatin melting tank, and stirring;
(3) taking part of the solution in the step (2), adding 0.03 weight part of silicon dioxide, dispersing by using a high-speed shearing machine, and adding the uniformly dispersed solution into a glue melting tank;
(4) adding 6 parts by weight of gelatin into a gelatin melting tank, and dispersing to be viscous; sealing the glue melting tank, degassing in vacuum, maintaining the vacuum degree of-0.06 to-0.1 MPa, stirring for 1 hour, keeping the temperature at 50-60 ℃, and keeping the temperature overnight in a non-vacuum state;
preparing the soft capsule:
(5) taking the prepared content and capsule shell, controlling the thickness of the rubber to be 0.8mm-1.10mm under the protection of nitrogen, and preparing the soft capsule by adopting a pressing method; and after the capsule is pressed, blowing the capsule into a roller by cold air, shaping, adding oil absorption cotton for wiping pills, and drying at the temperature of 25.0-30.0 ℃ and the humidity less than or equal to 25.0% until the moisture of the content is less than 5.0% to obtain the capsule.
The invention has the advantages that 1, the enzalutamide preparation prepared by the invention has higher dissolution rate, smaller dissolution fluctuation, good stability and higher bioavailability; 2. the enzalutamide preparation prepared by the invention greatly reduces the using amount of solvent, thereby reducing the volume of the capsule, being beneficial to swallowing of patients and improving the compliance of the patients. 3. The enzalutamide medicine composition prepared by the invention avoids using BHT and BHA composite antioxidant, and is beneficial to improving the safety of clinical medication.
Drawings
FIG. 1 is a dissolution profile of examples 1-5.
Detailed Description
To further illustrate the present invention, the present invention will be specifically described with reference to specific examples, but the scope of the present invention is not limited to the specific examples.
Example 1
Preparation of the contents:
(1) under the protection of nitrogen, mixing 1 part by weight of enzalutamide, 2 parts by weight of PEG-60 hydrogenated castor oil, 4 parts by weight of caprylic capric polyethylene glycol glyceride and 0.02 part by weight of vitamin E, stirring at 85-100 ℃ until the mixture is dissolved, vacuumizing, and replacing with nitrogen to obtain the composition;
preparing a capsule shell:
(2) heating a gelatin melting tank to 70 ℃, adding 9 parts by weight of purified water, 1.2 parts by weight of glycerol, 0.12 part by weight of glycine, 0.03 part by weight of vitamin C and 1.5 parts by weight of sorbitol solution into the gelatin melting tank, and stirring;
(3) taking part of the solution in the step (2), adding 0.03 weight part of silicon dioxide, dispersing by using a high-speed shearing machine, and adding the uniformly dispersed solution into a glue melting tank;
(4) adding 6 parts by weight of gelatin into a gelatin melting tank, and dispersing to be viscous; sealing the glue melting tank, degassing in vacuum, maintaining the vacuum degree of-0.06 to-0.1 MPa, stirring for 1 hour, keeping the temperature at 50-60 ℃, and keeping the temperature overnight in a non-vacuum state;
preparing the soft capsule:
(5) taking the prepared content and capsule shell, controlling the thickness of the rubber to be 0.8mm-1.10mm under the protection of nitrogen, and preparing the soft capsule by adopting a pressing method; and after the capsule is pressed, blowing the capsule into a roller by cold air, shaping, adding oil absorption cotton for wiping pills, and drying at the temperature of 25.0-30.0 ℃ and the humidity less than or equal to 25.0% until the moisture of the content is less than 5.0% to obtain the capsule.
Example 2
The preparation method is as in example 1.
Example 3
The preparation method is as in example 1.
Example 4
The preparation method is as in example 1.
Example 5
The preparation method is as in example 1.
EXAMPLE 6 Enzalutamide pharmaceutical compositions dissolution test
Referring to the second method of XC paddle method in the appendix of the second part of the 2010 version of the Chinese pharmacopoeia, the stirring speed is 50rpm, and 900ml of hydrochloric acid solution containing 0.2% of sodium dodecyl sulfate is used as a dissolution medium. The results of the dissolution rate and the dissolution fluctuation (RSD) in batches of the enzalutamide soft capsules prepared in the above examples 1 to 5 were as follows:
TABLE 1
Dissolution curves for examples 1-5 are shown in FIG. 1.
Example 7 Enzalutamide pharmaceutical composition stability testing
Detection by HPLC method, chromatographic column: kromasil C18(250 mm. times.4.6 mm, 5 μm); mobile phase: 0.1% trifluoroacetic acid-acetonitrile (35: 65), flow rate: 1.0 ml/min; detection wavelength: 250 nm; taking each sample, adding mobile phase to prepare 0.1mg/ml solution, filtering, taking 20 mul, injecting into a liquid chromatograph, calculating related substances according to an area normalization method, and inspecting the change condition of the related substances.
(1) Respectively placing the sample at 60 deg.C, 25 deg.C/RH 90%, and illuminating (total illumination is not less than 1.2 × 10)6Lux hr) at 5d and 10d respectively, and comparing with 0d, the test result is as follows:
TABLE 2
EXAMPLE 8 Enzalutamide pharmaceutical compositions bioavailability test
30 SD rats are divided into 5 groups, 6 rats in each group are respectively administered with the enzalutamide soft capsules of the embodiments 1 to 5 by intragastric administration, 2ml of blood is respectively taken from tail veins of 30 min, 60 min, 90 min, 120 min, 180 min, 240 min and 300min, methanol ultrasonic extraction is carried out for 10min, 20 mu l of supernatant is taken, and sample HPLC is adopted to detect the content, and the results are as follows:
TABLE 3
The experimental results show that the enzalutamide soft capsule prepared by the method has less solvent dosage, is beneficial to swallowing of patients, and improves the compliance of the patients; BHT and BHA antioxidants are avoided, and the safety of clinical medication is improved; the dissolution rate is good, the bioavailability is high, the dissolution fluctuation is small, the uniformity is good, the stability and controllability of the soft capsule release effect can be ensured, and the quality of the preparation product and the effectiveness and predictability of the administration of patients are improved.
Claims (7)
1. The enzalutamide pharmaceutical composition comprises a capsule shell and contents, wherein the contents comprise enzalutamide, PEG-60 hydrogenated castor oil, caprylic capric acid polyethylene glycol glyceride and vitamin E, the capsule shell comprises gelatin, glycerol, glycine, sorbitol, silicon dioxide, vitamin C and purified water, and the ratio of the enzalutamide: PEG-60 hydrogenated Castor oil + caprylic capric Polyglyeryl acid: the weight ratio of the vitamin E is 1: 6-8: 0.02-0.04, and the weight ratio of the PEG-60 hydrogenated castor oil: the weight ratio of the caprylic/capric acid polyethylene glycol glyceride is 1: 2-2: 1, and the weight ratio of gelatin: glycerol: glycine: sorbitol: silicon dioxide: vitamin C: the weight ratio of the purified water is 1: 0.1-0.3: 0.02-0.04: 0.2-0.4: 0.005-0.01: 1.5.
2. The enzalutamide pharmaceutical composition of claim 1, wherein the ratio of PEG-60 hydrogenated castor oil: the weight ratio of the caprylic capric acid polyethylene glycol glyceride is 1: 2.
3. The enzalutamide pharmaceutical composition of claim 1, wherein the ratio of enzalutamide: PEG-60 hydrogenated castor oil: caprylic capric acid polyethylene glycol glyceride: the weight ratio of the vitamin E is 1:2:4: 0.02.
4. The enzalutamide pharmaceutical composition of claim 1, wherein the ratio of gelatin: glycerol: glycine: sorbitol: silicon dioxide: vitamin C: the weight ratio of the purified water is 1:0.2:0.02:0.25:0.005:0.005: 1.5.
5. The enzalutamide pharmaceutical composition of claim 1, wherein the ratio of enzalutamide: PEG-60 hydrogenated Castor oil + caprylic capric Polyglyeryl acid: vitamin E: gelatin: glycerol: glycine: sorbitol: silicon dioxide: vitamin C: the weight ratio of the purified water is 1: 6-8: 0.02-0.04: 6: 0.6-1.8: 0.12-0.24: 1.2-2.4: 0.03-0.06: 9.
6. A process for preparing the enzalutamide pharmaceutical composition of any one of claims 1 to 5, comprising the steps of:
preparation of the contents:
(1) mixing enzalutamide, PEG-60 hydrogenated castor oil, caprylic capric acid polyethylene glycol glyceride and vitamin E, and stirring until the enzalutamide, the PEG-60 hydrogenated castor oil, the caprylic capric acid polyethylene glycol glyceride and the vitamin E are dissolved;
preparing a capsule shell:
(2) adding purified water, glycerol, glycine, vitamin C and sorbitol into a gelatin melting tank and stirring;
(3) taking part of the solution in the step (2), adding silicon dioxide, dispersing and then adding the solution into a glue dissolving tank;
(4) adding gelatin into a gelatin melting tank, and dispersing to be viscous;
preparing the soft capsule:
(5) and (3) taking the prepared content and the capsule shell, preparing the soft capsule by adopting a pressing method, shaping and drying to obtain the capsule.
7. The process for preparing the enzalutamide pharmaceutical composition of claim 6, comprising the steps of:
preparation of the contents:
(1) mixing enzalutamide, PEG-60 hydrogenated castor oil, caprylic capric acid polyethylene glycol glyceride and vitamin E, and stirring at 85-100 ℃ until the enzalutamide, the PEG-60 hydrogenated castor oil, the caprylic capric acid polyethylene glycol glyceride and the vitamin E are dissolved;
preparing a capsule shell:
(2) adding purified water, glycerol, glycine, vitamin C and sorbitol into a gelatin melting tank and stirring;
(3) taking part of the solution in the step (2), adding silicon dioxide, dispersing and then adding the solution into a glue dissolving tank;
(4) adding gelatin into a gelatin melting tank, and dispersing to be viscous;
preparing the soft capsule:
(5) and (3) taking the prepared content and the capsule shell, preparing the soft capsule by adopting a pressing method, shaping and drying to obtain the capsule.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
| WO2015049650A1 (en) * | 2013-10-01 | 2015-04-09 | Glaxosmithkline Intellectual Property (No.2) Limited | Enzalutamide in combination with afuresertib for the treatment of cancer |
| CN104857517B (en) * | 2015-05-14 | 2018-04-27 | 南京海纳医药科技股份有限公司 | A kind of miscellaneous Shandong amine soft capsule of grace and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
| WO2015049650A1 (en) * | 2013-10-01 | 2015-04-09 | Glaxosmithkline Intellectual Property (No.2) Limited | Enzalutamide in combination with afuresertib for the treatment of cancer |
| CN104857517B (en) * | 2015-05-14 | 2018-04-27 | 南京海纳医药科技股份有限公司 | A kind of miscellaneous Shandong amine soft capsule of grace and preparation method thereof |
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