CN111217757B - Enzalutamide compound and pharmaceutical composition preparation thereof - Google Patents
Enzalutamide compound and pharmaceutical composition preparation thereof Download PDFInfo
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- CN111217757B CN111217757B CN202010009858.XA CN202010009858A CN111217757B CN 111217757 B CN111217757 B CN 111217757B CN 202010009858 A CN202010009858 A CN 202010009858A CN 111217757 B CN111217757 B CN 111217757B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to an enzalutamide compound and a pharmaceutical composition preparation thereof, wherein the enzalutamide compound is enzalutamide dihydrate with the molecular formula of C21H16F4N4O2S·2H2And O. The pharmaceutical composition preparation contains, besides enzalutamide compounds, sodium tartrate and xylitol, wherein each 1000 preparation units of enzalutamide compounds (calculated by anhydrous substances) are 40g, the sodium tartrate is 100g, and the xylitol is 255 g. The enzalutamide compound prepared by the method has good solubility and stability, and the prepared pharmaceutical composition has good stability, good dissolution rate and simple preparation process, and has obvious advantages compared with the prior art.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an enzalutamide compound and a pharmaceutical composition preparation thereof.
Background
The enzalutamide (enzalutamide) compound has the chemical formula 4- [3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thione-1-imidazolidinyl ] -2-fluoro-N-methylbenzamide. Enzalutamide is an androgen receptor antagonist, and is capable of competitively inhibiting the binding of androgen to the receptor and inhibiting the nuclear transport of androgen receptor and the interaction of the receptor with DNA. Enzalutamide, developed by astela (Astellas) corporation, was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of advanced male castration-resistant prostate cancer that has spread or recurred, and is currently marketed as an oral solid dosage form, is suitable for use in patients with prostate cancer that have metastatic castration resistance who have previously received docetaxel treatment. Enzalutamide is a low-solubility and low-permeability drug, and Chinese applications: 201880028051.1 original manufacturer Anschlai company discloses Enzalutamide with solubility of only 2 μ g/ml in water, Chinese application: 201380075784.8 discloses that the solubility of amorphous enzalutamide in water is only 7.85 mug/ml, and the enzalutamide soft capsule developed by anslat adopts the technical scheme that enzalutamide is dissolved in polyethylene glycol caprylic capric acid glyceride which is a high molecular material to ensure bioavailability. However, the preparation produced by the method has low dissolution rate and low bioavailability, is easy to separate out crystals after entering a human body, has poor stability of enzalutamide and caprylic capric acid polyethylene glycol glyceride, adopts a compound antioxidant added with BHT and BHA to improve the stability of the original preparation, but has poor clinical safety of the two antioxidants, has complex preparation process and high cost, and solves the problems of low dissolution rate and low bioavailability of the enzalutamide by adopting a complex pharmaceutical preparation technology in the prior art, for example: the Chinese application 201880028051.1 uses enzalutamide and polyvinyl alcohol to prepare a solid dispersion system preparation, the Chinese application 201510251067.7 uses enzalutamide and a complex process to prepare a soft capsule, the Chinese application 201510429742.0 uses a polymer carrier to prepare an enzalutamide preparation of a dispersion system, and the like. The Enzalutamide hemihydrate prepared by Chinese application No. 201610601509.0 has improved stability and purity, but the dissolution rate is not improved compared with the prior art.
Disclosure of Invention
The invention aims to provide an enzalutamide compound and a preparation method thereof, wherein the enzalutamide compound has better stability and solubility and lower hygroscopicity, and is convenient for preparing a pharmaceutical preparation; simultaneously provides an enzalutamide preparation with good stability, high dissolution rate and simple preparation process.
The scheme adopted by the invention for solving the technical problems is as follows:
an enzalutamide compound, wherein the enzalutamide compound is enzalutamide dihydrate and the molecular formula of the enzalutamide dihydrate is C21H16F4N4O2S·2H2O。
Another object of the present invention is to provide a method for preparing the enzalutamide compound, comprising the following steps:
(1) the enzalutamide is placed in a mixed solution of acetonitrile and water, heated to 45-50 ℃, and stirred to be dissolved; wherein the weight volume ratio of the enzalutamide to the mixed solution of acetonitrile and water is 1g:5ml, and the volume ratio of acetonitrile to water is 7:3, obtaining a solution;
(2) filtering the solution into a crystallizer, reducing the temperature to 8-10 ℃, slowly adding ethanol with the volume being 12-14 times of that of the mixed solution of acetonitrile and water in the step (1) at the speed of 40-60ml/min, cooling to 2-4 ℃, keeping the temperature for 4-6 hours, separating out crystals, and filtering to obtain crystals;
(3) and (3) sieving the crystals with a 60-80-mesh sieve, flattening the crystals until the thickness is not more than 2mm, placing the crystals in a constant-temperature and constant-humidity box with the temperature of 20-25 ℃ and the humidity of 75-85% for 48-60 hours, taking out the crystals, drying the crystals under a vacuum condition, adjusting the drying starting temperature to be 20 ℃, increasing the temperature by 5 ℃ per hour to 35 ℃, and drying the crystals at 35 ℃ to constant weight to obtain the enzalutamide compound.
Another object of the present invention is to provide a pharmaceutical composition preparation of enzalutamide, which contains the aforementioned enzalutamide compound.
Furthermore, the enzalutamide pharmaceutical composition preparation also contains sodium tartrate and xylitol.
Furthermore, the dosage of the enzalutamide compound (calculated by anhydrous substance) is 40g, the dosage of sodium tartrate is 100g and the dosage of xylitol is 255g in each 1000 preparation units of the enzalutamide pharmaceutical composition preparation.
Furthermore, the enzalutamide pharmaceutical composition preparation is a capsule.
Furthermore, the specification of the enzalutamide medicine combination capsule is 40 mg.
The invention also aims to provide a preparation method of the enzalutamide pharmaceutical composition preparation, which comprises the following steps:
(1) drying enzalutamide compound or enzalutamide compound, sodium tartrate and xylitol at 60 deg.C in advance, and sieving with 80 mesh sieve;
(2) taking the raw materials and auxiliary materials according to the formula amount, fully mixing, measuring the content, determining the loading amount according to the specification, loading into a capsule shell on a machine, inspecting and packaging to obtain the capsule.
In order to overcome the defects of low dissolution rate and low bioavailability, the enzalutamide dihydrate prepared by the method has better water solubility, under the general condition, the sequence of the solubility and the dissolution speed of a medicament in water is that a hydrate is less than an anhydrate and less than an organic solvate, and the enzalutamide dihydrate prepared by the method has better solubility than the enzalutamide anhydrous compound, and simultaneously has better stability and the same pharmaceutical activity as the enzalutamide.
The enzalutamide dihydrate is obtained by controlling the proportion, the temperature, the screened mesh number, the temperature and humidity of constant temperature and humidity and the heating speed of acetonitrile and water, and the factors have important influence on the formation of the dihydrate.
Sodium tartrate and xylitol are used as auxiliary materials of the enzalutamide capsule, the use of 2 auxiliary materials has unexpected effect on increasing the solubility of the enzalutamide, and the effect of the specific proportion of 100g of sodium tartrate and 255g of xylitol added in each 40g of the enzalutamide compound is optimal.
Detailed Description
The following examples are provided to further illustrate the present invention for better understanding, but the present invention is not limited to the following examples.
Example 1 preparation of enzalutamide dihydrate
(1) Putting the enzalutamide into a mixed solution of acetonitrile and water, heating to 45 ℃, and stirring for dissolving; wherein the weight volume ratio of the enzalutamide to the mixed solution of acetonitrile and water is 1g:5ml, and the volume ratio of the acetonitrile to the water is 7:3, so as to obtain a solution;
(2) filtering the solution into a crystallizer, reducing the temperature to 8 ℃, slowly (40ml/min) adding ethanol with the volume 12 times that of the mixed solution of acetonitrile and water in the step (1), cooling to 2 ℃, keeping the temperature for 4 hours, separating out crystals, and filtering to obtain crystals;
(3) and (3) sieving the crystals with a 60-mesh sieve, flattening (the thickness is not more than 2mm), placing in a constant-temperature constant-humidity box with the temperature of 20 ℃ and the humidity of 75-85% for 48 hours, taking out, drying under a vacuum condition, wherein the initial drying temperature is 20 ℃, the temperature is increased by 5 ℃ per hour to 35 ℃, and drying at 35 ℃ to constant weight to obtain the enzalutamide dihydrate.
Example 2 preparation of enzalutamide dihydrate
(1) Putting enzalutamide in a mixed solution of acetonitrile and water, heating to 50 ℃, and stirring for dissolving; wherein the weight volume ratio of the enzalutamide to the mixed solution of acetonitrile and water is 1g:5ml, and the volume ratio of the acetonitrile to the water is 7:3, so as to obtain a solution;
(2) filtering the solution into a crystallizer, reducing the temperature to 10 ℃, slowly (60ml/min) adding ethanol with the volume 14 times that of the mixed solution of acetonitrile and water in the step (1), cooling to 4 ℃, keeping the temperature for 6 hours, separating out crystals, and filtering to obtain crystals;
(3) and (3) sieving the crystals with a 80-mesh sieve, flattening (the thickness is not more than 2mm), placing in a constant-temperature constant-humidity box with the temperature of 25 ℃ and the humidity of 75-85% for 60 hours, taking out, drying under a vacuum condition, wherein the initial drying temperature is 20 ℃, the temperature is increased by 5 ℃ per hour to 35 ℃, and drying at 35 ℃ to constant weight to obtain the enzalutamide dihydrate.
Example 3 preparation of enzalutamide dihydrate
(1) Putting the enzalutamide into a mixed solution of acetonitrile and water, heating to 48 ℃, and stirring for dissolving; wherein the weight volume ratio of the enzalutamide to the mixed solution of acetonitrile and water is 1g:5ml, and the volume ratio of the acetonitrile to the water is 7:3, so as to obtain a solution;
(2) filtering the solution into a crystallizer, reducing the temperature to 9 ℃, slowly (50ml/min) adding ethanol with the volume 13 times that of the mixed solution of acetonitrile and water in the step (1), cooling to 3 ℃, keeping the temperature for 5 hours, separating out crystals, and filtering to obtain crystals;
(3) and (3) sieving the crystals with a 65-mesh sieve, flattening (the thickness is not more than 2mm), placing in a constant-temperature constant-humidity box with the temperature of 22 ℃ and the humidity of 75-85% for 54 hours, taking out, drying under a vacuum condition, wherein the initial drying temperature is 20 ℃, the temperature is increased by 5 ℃ per hour to 35 ℃, and drying at 35 ℃ to constant weight to obtain the enzalutamide dihydrate.
Characterization of enzalutamide dihydrate:
1. elemental analysis
Elemental analysis was performed on the enzalutamide dihydrate obtained in example 1 of the present invention, and the results were as follows: c: 50.38%, H: 4.04%, N: 11.18%, S: 6.38%, F: 15.19% (two decimal places accurate) which is consistent with the theoretical value of enzalutamide dihydrate, the theoretical value of enzalutamide dihydrate is: c: 50.36%, H: 4.03%, N: 11.20%, S: 6.41%, F: 15.19% (to the nearest two decimal places). Consistent results were obtained with enzalutamide dihydrate prepared in other embodiments of the invention.
2. Differential thermal analysis
The enzalutamide dihydrate obtained in the embodiments 1 to 3 of the invention is subjected to differential thermal analysis, and compared with the enzalutamide dihydrate used as a raw material for preparing the enzalutamide. The results show that: the enzalutamide dihydrate has an absorption peak at 110-115 ℃, which indicates that the sample contains crystal water or a crystal solvent, and the reference substance does not have the absorption peak, which indicates that the sample does not contain the crystal water or the crystal solvent.
3. Moisture analysis
The moisture content of the enzalutamide dihydrate obtained in the examples 1 to 3 of the invention is measured according to a karl fischer moisture content measurement method, the result is 7.20 to 7.23 percent, and the theoretical moisture content of the enzalutamide dihydrate is 7.20 percent, and the two results are consistent. This indicates that the sample contained only water and no other solvents.
The results of element analysis, differential thermal analysis and moisture analysis are integrated, so that the enzalutamide contains 2 molecules of crystal water.
4. Stability analysis
The results of the test for influencing factors of enzalutamide dihydrate and enzalutamide obtained in examples 1 to 3 of the present invention are shown in Table 1, which is obtained by standing for 10 days under the conditions of high temperature (60 ℃), high humidity (RH 92.5% +/-5%) and illumination (4500lx), sampling on the 10 th day, and examining the content and related substances (total impurities).
TABLE 1 Enzalutamide dihydrate influencing factor test results
Table 1 the test results show that: the enzalutamide dihydrate has better stability and lower hygroscopicity and impurities.
5. Solubility analysis
The enzalutamide dihydrate prepared in inventive examples 1-3 was compared with enzalutamide in terms of its solubility in water (25 ℃. + -. 2 ℃) and the results are shown in table 2: (sample 1 is enzalutamide hemihydrate prepared as per example 1 of chinese application 201610601509.0).
Table 2 solubility comparison
| Sample (I) | Solubility (. mu.g/ml) |
| Example 1 | 50.2 |
| Example 2 | 50.4 |
| Example 3 | 50.3 |
| Enzalutamide | 2.1 |
| Sample 1 | 2.2 |
Table 2 test results surface: the solubility of the enzalutamide dihydrate prepared by the method is obviously improved.
Study on auxiliary material proportion characteristics of enzalutamide capsules
In order to make the technical effect of the combined use of sodium tartrate and xylitol easier to understand, the following experiment explains the effect of the combined use of sodium tartrate and xylitol on the dissolution effect of enzalutamide capsules: dissolution tests were carried out with water as the medium, and the test results are shown in table 3:
TABLE 3 comparative test results of different prescription amounts of sodium tartrate and xylitol
As can be seen from the results of table 3: the combined use of xylitol and sodium tartrate has obvious effect on improving the dissolution rate of the enzalutamide compound, and particularly, the effect of adding 100g of sodium tartrate and 255g of xylitol into every 40g of enzalutamide in a specific ratio is optimal.
EXAMPLE 4 Enzalutamide pharmaceutical composition Capsule preparation (40mg)
Prescription:
enzalutamide compound (anhydrous): 40g of,
Sodium tartrate: 100g of,
Xylitol: 255 g.
Making into 1000 pieces
The process comprises the following steps:
(1) weighing the enzalutamide compound, sodium tartrate and xylitol according to the prescription amount, drying the enzalutamide compound at 60 ℃ in advance, and sieving the enzalutamide compound, the sodium tartrate and the xylitol with a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining loading amount according to specification, loading into capsule shell, inspecting, and packaging.
Test example 1:
the enzalutamide compound prepared in example 1 of the present invention and commercially available enzalutamide were subjected to accelerated tests, and the enzalutamide used was synthesized according to a known technique, or commercially available products were also available. The accelerated test method is as follows: the samples were placed in a stability chamber (40 ℃ C. + -2 ℃ C., RH 75% + -5%) and sampled at 1, 2, 3, and 6 months, respectively, and the results are shown in Table 4.
TABLE 4 Enzalutamide accelerated test results
As can be seen from the results in table 4, the enzalutamide compounds prepared by the present invention have good stability under accelerated conditions and have obvious advantages compared with the commercial products, and similar results were obtained by performing the same tests in other examples of the present invention.
Test example 2:
the enzalutamide capsules prepared in example 4 of the invention and the enzalutamide soft capsules marketed are subjected to accelerated tests by the following methods: the samples were placed in a stability test chamber (40 ℃. + -. 2 ℃ C., RH 75%. + -. 5%) and sampled at 1, 2, 3, 6 months, respectively, and the results are shown in the table: 5.
TABLE 5 Enzalutamide Capsule acceleration test results
As can be seen from the results of table 5, the enzalutamide capsules prepared by the present invention have good stability under accelerated conditions without complicated formulation processes, and have significant advantages compared to the marketed products.
Test example 3:
the enzalutamide capsules prepared in the embodiment 4 of the invention and the enzalutamide soft capsules on the market are subjected to dissolution test according to four methods of the Chinese pharmacopoeia 2015 edition, and the determination method comprises the following steps: a paddle method, wherein the rotating speed is 50 revolutions per minute, 900ml of buffer solution with the pH value of 1.0 is used as a dissolving medium, and samples are respectively taken at 10min, 20min, 30min and 45 min; and rotating at 75 rpm, taking 250ml phosphate buffer (pH6.8) as dissolution medium, sampling at 10min, 15min, 20min, and 30min, respectively, and measuring by high performance liquid chromatography, wherein the detection wavelength is 255nm, and the results are shown in tables 6-7.
TABLE 6 dissolution results of enzalutamide capsules
TABLE 7 dissolution results of enzalutamide capsules
As can be seen from the results in tables 6 and 7, the enzalutamide capsule prepared by the invention has a dissolution rate of 90% or more in 10min without complex preparation process, has good dissolution condition, and has obvious advantages compared with the marketed product.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. The preparation method of the enzalutamide dihydrate is characterized by comprising the following steps:
(1) the enzalutamide is placed in a mixed solution of acetonitrile and water, heated to 45-50 ℃, and stirred to be dissolved; wherein the weight volume ratio of the enzalutamide to the mixed solution of acetonitrile and water is 1g:5ml, and the volume ratio of acetonitrile to water is 7:3, obtaining a solution;
(2) filtering the solution into a crystallizer, reducing the temperature to 8-10 ℃, slowly adding ethanol with the volume being 12-14 times of that of the mixed solution of acetonitrile and water in the step (1) at the speed of 40-60ml/min, cooling to 2-4 ℃, keeping the temperature for 4-6 hours, separating out crystals, and filtering to obtain crystals;
(3) sieving the crystals with a 60-80 mesh sieve, spreading to a thickness of no more than 2mm, placing in a constant temperature and humidity chamber with a temperature of 20-25 ℃ and a humidity of 75-85% for 48-60 hours, taking out, drying under vacuum condition, wherein the initial drying temperature is 20 ℃, increasing the temperature by 5 ℃ per hour to 35 ℃, and drying at 35 ℃ to constant weight to obtain the enzalutamide compound with the molecular formula of C21H16F4N4O2S·2H2O。
2. An enzalutamide compound characterized by being produced by the production method according to claim 1.
3. An enzalutamide pharmaceutical composition preparation, which is characterized in that: comprising the enzalutamide compound of claim 2.
4. The enzalutamide pharmaceutical composition formulation of claim 3, wherein: also contains sodium tartrate and xylitol.
5. The enzalutamide pharmaceutical composition formulation of claim 4, wherein: per 1000 preparation units, the dosage of the enzalutamide compound is 40g calculated by anhydrous substance, the dosage of the sodium tartrate is 100g, and the dosage of the xylitol is 255 g.
6. The enzalutamide pharmaceutical composition formulation of any one of claims 3 to 5, wherein: the enzalutamide pharmaceutical composition preparation is a capsule.
7. The enzalutamide pharmaceutical composition formulation of claim 6, wherein: the specification of the enzalutamide medicine combination capsule is 40 mg.
8. The enzalutamide pharmaceutical composition preparation as claimed in any one of claims 3 to 5 and 7, which is prepared by the following method:
(1) drying enzalutamide compound or enzalutamide compound, sodium tartrate and xylitol at 60 deg.C in advance, and sieving with 80 mesh sieve;
(2) taking the raw materials and auxiliary materials according to the formula amount, fully mixing, measuring the content, determining the loading amount according to the specification, loading into a capsule shell on a machine, inspecting and packaging to obtain the capsule.
9. The enzalutamide pharmaceutical composition formulation of claim 6, prepared by the method of:
(1) drying enzalutamide compound or enzalutamide compound, sodium tartrate and xylitol at 60 deg.C in advance, and sieving with 80 mesh sieve;
(2) taking the raw materials and auxiliary materials according to the formula amount, fully mixing, measuring the content, determining the loading amount according to the specification, loading into a capsule shell on a machine, inspecting and packaging to obtain the capsule.
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