Crystalline forms of bicalutavir sodium
阅读说明：本技术 比卡格韦钠的晶形 (Crystalline forms of bicalutavir sodium ) 是由 H·伦加尔 A·皮希勒 R·玛格雷特尔 于 2019-01-25 设计创作，主要内容包括：本发明涉及比卡格韦钠的晶形及其制备方法。此外,本发明涉及药物组合物,其优选以预定和/或有效量包含所述比卡格韦钠晶形、至少一种药学上可接受的赋形剂、以及任选的一种或多种其他抗病毒物质。本发明的药物组合物可用作药物,特别是用于治疗和/或预防HIV-1感染。(The present invention relates to crystalline forms of bicalutavir sodium and processes for their preparation. Furthermore, the present invention relates to a pharmaceutical composition comprising said crystalline form of bicalutavir sodium, at least one pharmaceutically acceptable excipient, and optionally one or more other antiviral substances, preferably in a predetermined and/or effective amount. The pharmaceutical compositions of the invention are useful as medicaments, in particular for the treatment and/or prevention of HIV-1 infections.)
1. A crystalline form of bicalutavir sodium (form II) characterized by having a powder X-ray diffraction pattern when using Cu-K α having a wavelength of 0.15419nm1,2The diffractogram comprises reflections at 2-theta angles (6.5 + -0.2) °, (7.5 + -0.2) ° and (18.8 + -0.2) ° when measured at a temperature of 20-30 ℃.
2. The crystalline form of claim 1, characterized by having a powder X-ray diffraction pattern when using Cu-K α with a wavelength of 0.15419nm1,2The diffractogram comprises further reflections at 2-theta angles (19.4 + -0.2) ° and (20.9 + -0.2) ° when measured at a temperature of 20-30 ℃.
3. The crystalline form of claim 1 or 2, characterized by having a powder X-ray diffraction pattern when using Cu-K α with a wavelength of 0.15419nm1,2The diffractogram contains no reflections at 2-theta angles (5.5 + -0.2) ° when measured at a temperature of 20-30 ℃.
4. The crystalline form according to any one of the preceding claims, which is characterized in thatCharacterized by having a Fourier transform infrared spectrum comprising wavenumbers (3055 + -2) cm when measured with a diamond attenuated total reflectance cell at a temperature of 20-30 deg.C-1、(2964±2)cm-1And (1614. + -. 2) cm-1The peak at (c).
5. The crystalline form according to any one of the preceding claims, characterized by a Raman spectrum comprising wavenumbers (1641 ± 4) cm when measured at a temperature of 20 to 30 ℃ and a wavelength of 785nm-1、(1436±4)cm-1And (680 +/-4) cm-1The peak at (c).
6. A composition comprising the crystalline form of any of the preceding claims, and up to 5% by weight of any other physical form of bicalutavir sodium, based on the weight of the composition.
7. The composition of claim 6, wherein the other physical form of bicalutavir sodium is form I, characterized by when Cu-K α with a wavelength of 0.15419nm is used1,2A powder X-ray diffraction pattern including reflections at 2-theta angles (5.5 + -0.3) °, (16.1 + -0.3) °, (22.1 + -0.3) °, (23.3 + -0.3) °, and (28.5 + -0.3) ° when measured at a temperature of 20 to 30 ℃.
8. Composition according to claim 6 or 7, characterized in that it is obtained when using Cu-K α with a wavelength of 0.15419nm1,2A powder X-ray diffraction pattern which contains no reflections at 2-theta angles (5.5 + -0.2) ° when measured at a temperature of 20 to 30 ℃.
9. Use of a crystalline form as defined in any one of claims 1 to 5 or a composition as defined in any one of claims 6 to 8 for the preparation of a pharmaceutical composition.
10. A pharmaceutical composition comprising the crystalline form as defined in any one of claims 1 to 5 or the composition as defined in any one of claims 6 to 8, and at least one pharmaceutically acceptable excipient.
11. The pharmaceutical composition of claim 10, further comprising one or more additional pharmaceutically active ingredients.
12. The pharmaceutical composition of claim 11 wherein the other pharmaceutically active ingredients are emtricitabine and tenofovir alafenamide hemifumarate.
13. The pharmaceutical composition according to claims 10 to 12 for use in the treatment and/or prevention of HIV-1 infection.
14. Bicagavir sodium solvate characterized by having a Fourier transform infrared spectrum comprising (3069 + -2) cm when measured at a temperature of 20 to 30 ℃ using a diamond attenuated total reflectance cell-1、(2933±2)cm-1And (1526. + -. 2) cm-1The peak at (c).
15. The solvate of claim 14 which is a 2,2, 2-trifluoroethanol solvate.
Technical Field
The present invention relates to crystalline forms of bicalutavir sodium and processes for their preparation. Furthermore, the present invention relates to a pharmaceutical composition comprising said crystalline form of bicalutavir sodium, at least one pharmaceutically acceptable excipient and optionally one or more other antiviral substances, preferably in a predetermined and/or effective amount. The pharmaceutical compositions of the invention are useful as medicaments, in particular for the treatment and/or prevention of HIV-1 infections.
Background
Bicagvir is a human immunodeficiency virus type 1 (HIV-1) integrase chain transfer inhibitor (INSTI). It is suitable for the treatment of HIV-1 infection in combination with Nucleoside Reverse Transcriptase Inhibitors (NRTIs) tenofovir alafenamide (tenofovir alafenamide) and emtricitabine (emtricitabine). Bicagvir can be chemically represented as (2R,5S,13aR) -7, 9-dioxo-10- ((2,4, 6-trifluorobenzyl) carbamoyl) -2,3,4,5,7,9,13,13 a-octahydro-2, 5-methanopyrido [1 ', 2': 4,5 ]]Pyrazino [2,1-b ] s][1,3]Oxazazem
the preparation of bicalutavir is disclosed in example 42 of WO 2014/100323a 1. WO2015/196116a1 discloses a crystalline form of bicalutavir sodium, referred to as "form I". Although this application mentions that the use of certain solvents, such as methanol, ethanol, water, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, and any mixture thereof, results in different polymorphs, form I is the only crystalline form disclosed therein.
Different solid state forms of an active pharmaceutical ingredient generally have different properties. The difference in physicochemical properties of the solid state forms may be important for improving the pharmaceutical composition, e.g. due to the improvement of the solid state form of the active pharmaceutical ingredient, pharmaceutical formulations with improved dissolution properties or improved stability or shelf life may become readily available. It also improves the processing or handling of the active pharmaceutical ingredient during the formulation process. Thus, new solid state forms of the active pharmaceutical ingredient may have desirable processing properties. They may be easier to handle, more suitable for storage and/or allow better purification than previously known solid state forms.
The most thermodynamically stable polymorph of the active pharmaceutical ingredient is commonly used in the preparation of pharmaceutical products because phase changes in pharmaceutical standard processes such as tableting, milling and wet granulation can be minimized. However, one of the great drawbacks associated with the most thermodynamically stable drug form is that it is the least soluble form, which means reduced bioavailability. This is especially important for low soluble compounds (e.g. bigovir). Thus, the use of metastable polymorphs of a drug may be desirable due to the particular properties of the drug, particularly higher solubility and bioavailability, as well as better performance during milling and tableting or lower hygroscopicity. However, since solid form transformations may have a great impact on the safety and effectiveness of pharmaceutical products, it is important to avoid any possible solid form transformation during pharmaceutical processing or storage, which may occur for metastable polymorphic forms. Thus, not every metastable polymorph of an active pharmaceutical ingredient may be used in the manufacture of a pharmaceutical composition.
It is an object of the present invention to provide an improved polymorph of bicalutavir sodium which is kinetically stable, e.g. does not undergo phase changes during standard pharmaceutical processing and storage, and which exhibits both high solubility and dissolution rate.
Brief description of the invention
The present invention solves the above problems by providing a metastable polymorph (hereinafter also referred to as "form II") of bixavir sodium. Form II of the present invention was found to be associated with the known form I of WO2015/196116a1, which is a higher melting form, being a unidirectional transition. The transition temperature of form II of the present invention to form I of WO2015/196116A1 was found to be well above 300 ℃ when measured by DSC at a heating rate of 10K/min. This exceptionally high transition temperature reflects the high kinetic stability of form II of the present invention and indicates a very low probability of solid form change during standard pharmaceutical processing and storage. Form II, on the other hand, has a higher solubility than form I. Thus, the bicalutavir sodium form II of the present invention combines the advantageous properties of high physical stability and high solubility and is therefore the preferred solid form of bicalutavir sodium for the preparation of pharmaceutical compositions. Other advantageous properties over form II of cargovir sodium are low hygroscopicity, and good behaviour during grinding and compression, which makes it particularly suitable for the preparation of pharmaceutical compositions.
For short
PXRD powder X-ray diffraction pattern
FTIR Fourier transform Infrared
ATR attenuated total reflection
DSC differential scanning calorimetry
TGA thermogravimetric analysis
Definition of
The term "bikagovir" as used herein refers to (2R,5S,13aR) -7, 9-dioxo-10- ((2,4, 6-trifluorobenzyl) carbamoyl) -2,3,4,5,7,9,13,13 a-octahydro-2, 5-methanopyrido [1 ', 2': 4,5 ] according to formula I disclosed above]Pyrazino [2,1-b ] s][1,3]Oxazazem-8-alcoholate (IUPAC nomenclature) or (2R,5S,13aR) -8-hydroxy-7, 9-dioxo-N- (2,4, 6-trifluorobenzyl) -2,3,4,5,7,9,13,13 a-octahydro-2, 5-methanopyrido [1 ', 2': 4,5]Pyrazino [2,1-b ] s][1,3]Oxazazem
The term "bicalutavir sodium" as used herein refers to the sodium salt of bicalutavir having bicalutavir and Na wherein about 1 mole ratio of the bicalutavir to 1 mole of the sodium is deprotonated+Associated with a chemical structure. Bicalutavir sodium can be represented by the chemical structure according to formula (II) below.
Bicagravir sodium form I, as used herein, refers to the crystalline form of bicaravir sodium disclosed in WO 2015/196116A. Bicagravir sodium form I can be characterized by the following powder X-ray diffraction pattern when using Cu-K α having a wavelength of 0.15419nm1,2The diffractogram comprises diffraction at 2-theta angles (5.5 + -0.3) °, (16.1 + -0.3) °, (22.1 + -0.3) °, (23.3 + -0.3) ° and (28.5 + -0.3) ° when measured at a temperature of 20-30 ℃.
As used herein, the term "measuring at a temperature of 20 to 30 ℃ refers to measuring under standard conditions. Generally, the standard conditions mean a temperature of 20 to 30 ℃, i.e., room temperature. Standard conditions may mean a temperature of about 22 ℃. Generally, standard conditions may additionally mean that the measurement is performed at a relative humidity of 20-80%, preferably 30-70%, more preferably 40-60% and most preferably 50%.
As used herein, the term "reflection" with respect to powder X-ray diffraction means a peak in an X-ray diffraction pattern that is caused at certain diffraction angles (bragg angles) by constructive interference of X-rays scattered from atom-parallel planes in a solid material, which are distributed in an ordered and repetitive manner in long range order. The solid materials are classified as crystalline materials, whereas amorphous materials are defined as solid materials, which lack long-range order and show only short-range order, thus leading to broad scattering. According to the literature, long-range order extends, for example, approximately 100 to 1000 atoms, whereas short programs only go through a few atoms (see "Fundamentals of Powder differentiation and structural charateristic of Materials", Kluwer Academic Publishers, 2003, page 3, of vitaij k. pecharsky and Peter y. zavalij).
As used herein, the term "amorphous" refers to a solid form of an amorphous compound. Amorphous compounds do not have long range order and do not exhibit a deterministic X-ray diffraction pattern with reflections.
With respect to powder X-ray diffraction, the term "substantially the same" means that variations in the location of the reflection and the relative intensity of the reflection are to be taken into account. For example, the representative accuracy of the 2-theta values is within the range of + -0.2 deg. 2-theta, preferably within the range of + -0.1 deg. 2-theta. Thus, on most X-ray diffractometers, under standard conditions, reflections that normally occur at, for example, 6.5 ° 2-theta, may occur, for example, at 6.3 ° to 6.7 ° 2-theta, preferably 6.4 ° to 6.6 ° 2-theta. Furthermore, those skilled in the art will understand that: the relative reflection intensities will show device-to-device variability as well as variability due to crystallinity, preferred orientation, sample preparation, and other factors known to those skilled in the art, and should be considered only qualitative measures.
With respect to fourier transform infrared spectroscopy, the term "substantially the same" means that changes in peak position and relative intensity of the peaks are to be considered. For example, typical accuracy of wave values is within 2cm-1Within the range. Therefore, on most infrared spectrometers, 3055cm under standard conditions-1The peak at (A) can appear at 3053-3057 cm-1Within the range of (1). The difference in relative intensities is typically small compared to X-ray diffraction. However, those skilled in the art will understand that: subtle differences in peak intensity due to crystallinity, sample preparation, and other factors can also occur in infrared spectroscopy. Therefore, the relative peak intensities should only be taken as qualitative measures.
With respect to raman spectroscopy, the term "substantially the same" means that variations in peak position and relative intensity of the peaks are to be considered. For example, typical accuracy of wave values is within 4cm-1Within the range of (1). Thus, on most Raman spectrometers, under standard conditions, e.g., 1641cm-1The peak of (A) can appear in 1637-1645 cm-1Within the range. The difference in relative intensities is typically small compared to X-ray diffraction. However, those skilled in the art will understand that: due to crystallizationSmall differences in intensity of peaks, sample preparation and other factors may also occur in raman spectra. Therefore, the relative peak intensities should only be taken as qualitative measures.
As used herein, for a composition comprising a particular physical form of bigevir sodium, the term "substantially free of any other physical form" means that the composition includes at most 20% by weight, preferably at most 10% by weight, more preferably at most 5% by weight, even more preferably at most 2% by weight, and most preferably at most 1% by weight of any other physical form of bigevir sodium, based on the weight of the composition.
As used herein, the term "physical form" refers to any crystalline and/or amorphous phase of a compound.
As used herein, the term "solvate" refers to a crystalline form of molecules, atoms, and/or ions that further comprises one or more solvent molecules incorporated into the lattice structure.
The crystalline form of bicalutavir sodium may be characterized herein by the "as shown" in the powder X-ray diffraction pattern, FTIR spectrum or raman spectrum. Those skilled in the art understand that: factors such as changes in instrument type, response, and sample directionality, sample concentration, sample purity, sample history, and sample preparation can cause changes, such as changes related to the exact reflectance and peak location, and their intensity. However, it is well known to those skilled in the art to compare the graphical data in the figures herein with graphical data generated for unknown physical forms, and to confirm that the two sets of graphical data relate to the same crystalline form.
As used herein, the term "mother liquor" refers to the solution remaining after the crystallization of a solid from solution.
As used herein with respect to bicalutavir sodium, "predetermined amount" refers to the starting amount of bicalutavir sodium used to prepare a pharmaceutical composition of bicalutavir having the desired dosage strength.
With respect to bicalutavir sodium, the term "effective amount" as used herein includes an amount of bicalutavir sodium that produces the desired therapeutic and/or prophylactic effect.
As used herein, the term "about" is intended to mean within a statistically significant range of values. The range can be within an order of magnitude of the value or range indicated, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1%. Sometimes, the range can be within experimental error, which is generally a standard method for measuring and/or determining a given value or range.
As used herein, the term "pharmaceutically acceptable excipient" means a substance that does not exhibit significant pharmacological activity at a given dose and is added to a pharmaceutical composition in addition to an active pharmaceutical ingredient.
Brief Description of Drawings
FIG. 1: a representative PXRD for bicalutavir sodium form II of the present invention is illustrated. The X-axis represents the scattering angle in degrees 2-theta and the y-axis represents the intensity of the scattered X-ray beam in detected photon counts.
FIG. 2: representative PXRD of the
FIG. 3: a graphical representation of a representative PXRD of bicalutavir sodium form II of the present invention (bottom) compared to a representative PXRD of bicalutavir sodium form I of WO2015/196116a1 (top) prepared according to reference example 1 herein is illustrated. The x-axis represents the scattering angle in units of 2-theta. For clarity, form I PXRD is shifted along the y-axis to separate the diffraction patterns.
FIG. 4: a comparison of representative PXRD of bicalutavir sodium form II of the present invention (bottom) to representative PXRD of
FIG. 5: a representative FTIR spectrum of bicafovir sodium form II of the present invention is illustrated. x-axis shows in cm-1The y-axis shows the relative intensity in percent transmittance as a unit of wavenumber.
FIG. 6: illustration of the drawingsRepresentative FTIR spectra of the
FIG. 7: a representative raman spectrum of form II bicalutavir sodium of the present invention is illustrated. x-axis shows in cm-1The y-axis shows the raman intensity in units of wavenumbers.
FIG. 8: representative raman spectra of the
FIG. 9: a representative DSC curve for bicalutavir sodium form II of the present invention is illustrated. The x-axis shows temperature in degrees Celsius (C.) and the y-axis shows heat flow rate in watts/gram (W/g), with the endothermic peak rising.
FIG. 10: representative DSC curves for the
FIG. 11: a representative TGA profile of bicalutavir sodium form II of the present invention is illustrated. The x-axis shows temperature in degrees celsius (° c) and the y-axis shows sample mass (loss) in weight percent (wt%).
FIG. 12: a representative TGA profile of the
Detailed Description
The present invention provides metastable polymorphs of bixavir sodium, also referred to herein as "form II".
Although a metastable polymorph, the present invention has a higher physical stability than form II of cabravir sodium, e.g. it only converts to the thermodynamically more stable form I of WO2015/196116a1 at temperatures well above 300 ℃, when measured by DSC at a heating rate of 10K/min. The fact that form II of the present invention shows higher solubility means higher bioequivalence than the low soluble drug like canavir. Thus, form II of the present invention combines the advantageous properties of high physical stability and high solubility, and is thus an ideal solid form of bigevir sodium for the preparation of improved pharmaceutical compositions, e.g. having improved bioavailability, which are safe and effective throughout the shelf life.
Bicalutavir sodium can be represented by the chemical structure according to formula (II) below:
the bicalutavir sodium may be characterized by a molar ratio of bicalutavir to sodium, preferably in the range of 1.0:0.7 to 1.0:1.3, more preferably in the range of 1.0:0.8 to 1.0:1.2, even more preferably in the range of 1.0:0.9 to 1.0:1.1, and in particular a molar ratio of 1.0: 1.0.
Bicalutavir sodium form II of the present invention may be characterized by any one of or a combination of two or more of the following embodiments.
Accordingly, in a first aspect, the present invention relates to a crystalline form of bicalutavir sodium (form II) which may be characterized by a powder X-ray diffraction pattern comprising reflections at the following 2 Θ angles:
(6.5 + -0.2) °, (7.5 + -0.2) ° and (18.8 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (18.8 + -0.2) °, and (20.9 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) ° and (20.9 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, and (20.9 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, (20.9 + -0.2) ° and (26.5 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (18.1 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, (20.9 + -0.2) °, and (26.5 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (16.8 + -0.2) °, (18.1 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, (20.9 + -0.2) °, and (26.5 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (14.6 + -0.2) °, (16.8 + -0.2) °, (18.1 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, (20.9 + -0.2) °, and (26.5 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (14.6 + -0.2) °, (16.8 + -0.2) °, (18.1 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, (20.9 + -0.2) °, (24.2 + -0.2) °, and (26.5 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (14.6 + -0.2) °, (16.8 + -0.2) °, (18.1 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, (20.9 + -0.2) °, (24.2 + -0.2) °, (24.7 + -0.2) °, and (26.5 + -0.2) °; or
(6.5 + -0.2) °, (7.5 + -0.2) °, (13.0 + -0.2) °, (14.6 + -0.2) °, (16.8 + -0.2) °, (18.1 + -0.2) °, (18.8 + -0.2) °, (19.4 + -0.2) °, (20.9 + -0.2) °, (23.5 + -0.2) °, (24.2 + -0.2) °, (24.7 + -0.2) ° and (26.5 + -0.2) °,
when using Cu-K α with the wavelength of 0.15419nm1,2When the radiation is measured at a temperature of 20-30 ℃.
In another embodiment, the present invention relates to a crystalline form of bicalutavir sodium (form II) that may be characterized by a powder X-ray diffraction pattern comprising reflections at the following 2 Θ angles:
(6.5 + -0.1) °, (7.5 + -0.1) ° and (18.8 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (18.8 + -0.1) °, and (20.9 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) ° and (20.9 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, and (20.9 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, (20.9 + -0.1) ° and (26.5 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (18.1 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, (20.9 + -0.1) °, and (26.5 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (16.8 + -0.1) °, (18.1 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, (20.9 + -0.1) °, and (26.5 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (14.6 + -0.1) °, (16.8 + -0.1) °, (18.1 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, (20.9 + -0.1) °, and (26.5 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (14.6 + -0.1) °, (16.8 + -0.1) °, (18.1 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, (20.9 + -0.1) °, (24.2 + -0.1) °, and (26.5 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (14.6 + -0.1) °, (16.8 + -0.1) °, (18.1 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, (20.9 + -0.1) °, (24.2 + -0.1) °, (24.7 + -0.1) °, and (26.5 + -0.1) °; or
(6.5 + -0.1) °, (7.5 + -0.1) °, (13.0 + -0.1) °, (14.6 + -0.1) °, (16.8 + -0.1) °, (18.1 + -0.1) °, (18.8 + -0.1) °, (19.4 + -0.1) °, (20.9 + -0.1) °, (23.5 + -0.1) °, (24.2 + -0.1) °, (24.7 + -0.1) ° and (26.5 + -0.1) °,
when using Cu-K α with the wavelength of 0.15419nm1,2When the radiation is measured at a temperature of 20-30 ℃.
The powder X-ray diffraction pattern of bicalutavir sodium form II of the present invention can be readily distinguished from the known form I of WO2015/196116a1 (for this reason, see also the overlay shown in fig. 3 herein.) form II shows reflections, for example at 2-theta angles of (6.5 ± 0.2) °, (7.5 ± 0.2) ° and (18.8 ± 0.2) ° whereas form I shows no reflections within these ranges1,2Irradiating, at a temperature of 20-30 ℃, the powderThe X-ray diffraction pattern includes reflections at the 2-theta angles described above, but not the 2-theta angles of (5.5 ± 0.2) °.
In yet another embodiment, the present invention relates to a crystalline form of bicalutavir sodium (form II) characterized by when Cu-K α having a wavelength of 0.15419nm is used1,2Radiation, when measured at a temperature of 20 to 30 ℃, has a powder X-ray diffraction pattern substantially the same as that shown in figure 1 of the present invention.
In another embodiment, the present invention relates to a crystalline form of bicalutavir sodium (form II) characterized by an FTIR spectrum comprising peaks at the following wavenumbers:
(3055±2)cm-1、(2964±2)cm-1and (1614. + -. 2) cm-1(ii) a Or
(3055±2)cm-1、(2964±2)cm-1、(1614±2)cm-1And (1525. + -. 2) cm-1(ii) a Or
(3055±2)cm-1、(2964±2)cm-1、(1614±2)cm-1、(1525±2)cm-1And (1435. + -. 2) cm-1(ii) a Or
(3055±2)cm-1、(2964±2)cm-1、(1614±2)cm-1、(1525±2)cm-1、(1435±2)cm-1And (1315. + -. 2) cm-1(ii) a Or
(3055±2)cm-1、(2964±2)cm-1、(1614±2)cm-1、(1525±2)cm-1、(1435±2)cm-1、(1315±2)cm-1And (1290. + -. 2) cm-1(ii) a Or
(3055±2)cm-1、(2964±2)cm-1、(1614±2)cm-1、(1525±2)cm-1、(1435±2)cm-1、(1315±2)cm-1、(1290±2)cm-1And (1252. + -. 2) cm-1(ii) a Or
(3055±2)cm-1、(2964±2)cm-1、(1614±2)cm-1、(1525±2)cm-1、(1435±2)cm-1、(1315±2)cm-1、(1290±2)cm-1、(1252±2)cm-1And (1069. + -. 2) cm-1(ii) a Or
(3055±2)cm-1、(2964±2)cm-1、(1614±2)cm-1、(1525±2)cm-1、(1435±2)cm-1、(1315±2)cm-1、(1290±2)cm-1、(1252±2)cm-1、(1069±2)cm-1And (998. + -. 2) cm-1When measured with a diamond ATR cell at a temperature of 20-30 ℃.
In yet another embodiment, the present invention relates to a crystalline form of bicalutavir sodium (form II) characterized by having an FTIR spectrum substantially the same as shown in fig. 5 of the present invention when measured with a diamond ATR cell at a temperature of 20 to 30 ℃.
In another embodiment, the present invention relates to a crystalline form of bicalutavir sodium (form II) characterized by having a raman spectrum comprising peaks at the following wavenumbers:
(1641±4)cm-1、(1436±4)cm-1and (680 +/-4) cm-1(ii) a Or
(1641±4)cm-1、(1436±4)cm-1、(1404±4)cm-1And (680 +/-4) cm-1(ii) a Or
(1641±4)cm-1、(1436±4)cm-1、(1404±4)cm-1、(1328±4)cm-1And (680 +/-4) cm-1(ii) a Or
(1641±4)cm-1、(1436±4)cm-1、(1404±4)cm-1、(1328±4)cm-1、(1254±4)cm-1And (680 +/-4) cm-1(ii) a Or
(1641±4)cm-1、(1436±4)cm-1、(1404±4)cm-1、(1328±4)cm-1、(1254±4)cm-1、(759±4)cm-1And (680 +/-4) cm-1(ii) a Or
(1641±4)cm-1、(1474±4)cm-1、(1436±4)cm-1、(1404±4)cm-1、(1328±4)cm-1、(1254±4)cm-1、(759±4)cm-1And (680 +/-4) cm-1(ii) a Or
(1641±4)cm-1、(1517±4)cm-1、(1474±4)cm-1、(1436±4)cm-1、(1404±4)cm-1、(1328±4)cm-1、(1254±4)cm-1、(759±4)cm-1And (680 +/-4) cm-1(ii) a Or
(1641±4)cm-1、(1586±4)cm-1、(1517±4)cm-1、(1474±4)cm-1、(1436±4)cm-1、(1404±4)cm-1、(1328±4)cm-1、(1254±4)cm-1、(759±4)cm-1And (680 +/-4) cm-1When measured at a temperature of 20 to 30 ℃ and a wavelength of 785 nm.
In yet another embodiment, the invention relates to a crystalline form of bicalutavir sodium (form II) characterized by having a Raman spectrum substantially the same as shown in figure 7 of the invention when measured at a temperature of 20 to 30 ℃ and a wavelength of 785 nm.
In one aspect, the invention relates to a composition comprising bicalutavir sodium form II of the invention, which is substantially free of any other physical form of bicalutavir sodium e.g. a composition comprising bicalutavir sodium form II of the invention comprises at most 20% by weight, preferably at most 10% by weight, more preferably at most 5% by weight, even more preferably at most 2% by weight, and most preferably at most 1% by weight of any other physical form of bicalutavir sodium, based on the weight of the composition preferably any other physical form of bicalutavir sodium is selected from the group consisting of form I of WO2015/196116a1, 2, 2-trifluoroethanol solvate defined below or amorphous bicalutavir sodium, thus, in another preferred embodiment, the invention relates to a composition comprising bicalutavir sodium form II defined above, characterized in that when having a Cu-K α nm wavelength of 0.15419nm1,2Radiation having a PXRD with no reflection at 2-theta angles in the range of (5.5 + -0.2) ° and/or (5.8 + -0.2) ° when measured at a temperature of 20-30 ℃.
It has been surprisingly found that by crystallizing bicalutavir sodium from 2,2, 2-trifluoroethanol and applying the conditions described below, novel crystalline forms of bicalutavir sodium can be obtained. Crystallization of cagavir sodium from 2,2, 2-trifluoroethanol under the conditions disclosed hereinafter results in the formation of a 2,2, 2-trifluoroethanol solvate which can be further desolvated under the drying conditions disclosed hereinafter to form the preferred bicalutavir sodium form II of the present invention. Thus, 2,2, 2-trifluoroethanol solvate is an intermediate for the preparation of bicalutavir sodium form II of the present invention.
The bicalutavir solvate of the present invention may be characterized in that: any one or combination of two or more of the following embodiments.
In one aspect, the present invention relates to bicalutavir sodium solvates which may be characterized as having a reflection at an angle 2-theta comprising:
(5.8 + -0.2) °, (16.8 + -0.2) ° and (21.0 + -0.2) °; or
(5.8 + -0.2) °, (16.8 + -0.2) °, (19.5 + -0.2) °, and (21.0 + -0.2) °; or
(5.8 + -0.2) °, (16.8 + -0.2) °, (17.5 + -0.2) °, (19.5 + -0.2) ° and (21.0 + -0.2) °; or
(5.8 ± 0.2) °, (15.9 ± 0.2) °, (16.8 ± 0.2) °, (17.5 ± 0.2) °, (19.5 ± 0.2) °, and (21.0 ± 0.2) °; or
(5.8 ± 0.2) °, (9.1 ± 0.2) °, (15.9 ± 0.2) °, (16.8 ± 0.2) °, (17.5 ± 0.2) °, (19.5 ± 0.2) ° and (21.0 ± 0.2) °; or
(5.8 ± 0.2) °, (9.1 ± 0.2) °, (12.5 ± 0.2) °, (15.9 ± 0.2) °, (16.8 ± 0.2) °, (17.5 ± 0.2) °, (19.5 ± 0.2) ° and (21.0 ± 0.2) ° are used; or
(5.8 ± 0.2) °, (9.1 ± 0.2) °, (12.5 ± 0.2) °, (15.9 ± 0.2) °, (16.8 ± 0.2) °, (17.5 ± 0.2) °, (19.5 ± 0.2) °, (21.0 ± 0.2) ° and (25.0 ± 0.2) °; or
(5.8 ± 0.2) °, (9.1 ± 0.2) °, (12.5 ± 0.2) °, (15.9 ± 0.2) °, (16.8 ± 0.2) °, (17.5 ± 0.2) °, (19.5 ± 0.2) °, (21.0 ± 0.2) °, (22.3 ± 0.2) °, and (25.0 ± 0.2) °;
when using Cu-K α with the wavelength of 0.15419nm1,2And (3) irradiating, and measuring at the temperature of 20-30 ℃.
In another embodiment, the present invention relates to bicalutavir sodium solvates which may be characterized as having a reflection at angles 2-theta comprising:
(5.8 + -0.1) °, (16.8 + -0.1) ° and (21.0 + -0.1) °; or
(5.8 + -0.1) °, (16.8 + -0.1) °, (19.5 + -0.1) °, and (21.0 + -0.1) °; or
(5.8 + -0.1) °, (16.8 + -0.1) °, (17.5 + -0.1) °, (19.5 + -0.1) ° and (21.0 + -0.1) °; or
(5.8 ± 0.1) °, (15.9 ± 0.1) °, (16.8 ± 0.1) °, (17.5 ± 0.1) °, (19.5 ± 0.1) °, and (21.0 ± 0.1) °; or
(5.8 ± 0.1) °, (9.1 ± 0.1) °, (15.9 ± 0.1) °, (16.8 ± 0.1) °, (17.5 ± 0.1) °, (19.5 ± 0.1) ° and (21.0 ± 0.1) °; or
(5.8 ± 0.1) °, (9.1 ± 0.1) °, (12.5 ± 0.1) °, (15.9 ± 0.1) °, (16.8 ± 0.1) °, (17.5 ± 0.1) °, (19.5 ± 0.1) ° and (21.0 ± 0.1) ° are used; or
(5.8 ± 0.1) °, (9.1 ± 0.1) °, (12.5 ± 0.1) °, (15.9 ± 0.1) °, (16.8 ± 0.1) °, (17.5 ± 0.1) °, (19.5 ± 0.1) °, (21.0 ± 0.1) ° and (25.0 ± 0.1) °; or
(5.8 ± 0.1) °, (9.1 ± 0.1) °, (12.5 ± 0.1) °, (15.9 ± 0.1) °, (16.8 ± 0.1) °, (17.5 ± 0.1) °, (19.5 ± 0.1) °, (21.0 ± 0.1) °, (22.3 ± 0.1) °, and (25.0 ± 0.1) °;
when using Cu-K α with the wavelength of 0.15419nm1,2And (3) irradiating, and measuring at the temperature of 20-30 ℃.
In yet another embodiment, the invention relates to solvates of bicalutavir sodium characterized by when Cu-K α having a wavelength of 0.15419nm is used1,2Radiation, when measured at a temperature of 20 to 30 ℃, has a powder X-ray diffraction pattern substantially the same as that shown in figure 2 of the present invention.
In another embodiment, the present invention relates to a bicalutavir solvate characterized by having an FTIR spectrum comprising peaks at the following wavenumbers:
(3069±2)cm-1、(2933±2)cm-1and (1526. + -. 2) cm-1(ii) a Or
(3069±2)cm-1、(2933±2)cm-1、(1526±2)cm-1And (1290. + -. 2) cm-1(ii) a Or
(3069±2)cm-1、(2933±2)cm-1、(1623±2)cm-1、(1526±2)cm-1And (1290. + -. 2) cm-1(ii) a Or
(3069±2)cm-1、(2933±2)cm-1、(1623±2)cm-1、(1526±2)cm-1、(1434±2)cm-1And (1290. + -. 2) cm-1(ii) a Or
(3069±2)cm-1、(2933±2)cm-1、(1623±2)cm-1、(1526±2)cm-1、(1434±2)cm-1、(1290±2)cm-1And (1207. + -. 2) cm-1(ii) a Or
(3069±2)cm-1、(2933±2)cm-1、(1623±2)cm-1、(1526±2)cm-1、(1434±2)cm-1、(1290±2)cm-1、(1207±2)cm-1And (1073. + -. 2) cm-1(ii) a Or
(3069±2)cm-1、(2933±2)cm-1、(1623±2)cm-1、(1526±2)cm-1、(1434±2)cm-1、(1290±2)cm-1、(1207±2)cm-1、(1073±2)cm-1And (998. + -. 2) cm-1(ii) a Or
(3069±2)cm-1、(2933±2)cm-1、(1623±2)cm-1、(1526±2)cm-1、(1434±2)cm-1、(1290±2)cm-1、(1207±2)cm-1、(1073±2)cm-1、(998±2)cm-1And (832. + -. 2) cm-1When measured with a diamond ATR cell at a temperature of 20-30 ℃.
In yet another embodiment, the present invention relates to solvates of bicalutavir sodium characterized by having an FTIR spectrum substantially the same as shown in fig. 6 of the present invention when measured with a diamond ATR cell at a temperature of 20 to 30 ℃.
In another embodiment, the present invention relates to solvates of bicalutavir sodium characterized by having a raman spectrum comprising peaks at the following wavenumbers:
(1501±4)cm-1、(1472±4)cm-1and (1400. + -. 4) cm-1(ii) a Or
(1501±4)cm-1、(1472±4)cm-1、(1400±4)cm-1And (1328. + -. 4) cm-1(ii) a Or
(1645±4)cm-1、(1501±4)cm-1、(1472±4)cm-1、(1400±4)cm-1And (1328. + -. 4) cm-1(ii) a Or
(1645±4)cm-1、(1587±4)cm-1、(1501±4)cm-1、(1472±4)cm-1、(1400±4)cm-1And (1328. + -. 4) cm-1(ii) a Or
(1645±4)cm-1、(1587±4)cm-1、(1501±4)cm-1、(1472±4)cm-1、(1436±4)cm-1、(1400±4)cm-1And (1328. + -. 4) cm-1(ii) a Or
(1645±4)cm-1、(1587±4)cm-1、(1501±4)cm-1、(1472±4)cm-1、(1436±4)cm-1、(1400±4)cm-1、(1328±4)cm-1And (1294. + -. 4) cm-1(ii) a Or
(1645±4)cm-1、(1587±4)cm-1、(1501±4)cm-1、(1472±4)cm-1、(1436±4)cm-1、(1400±4)cm-1、(1328±4)cm-1、(1294±4)cm-1And (1211. + -. 4) cm-1(ii) a Or
(1645±4)cm-1、(1587±4)cm-1、(1501±4)cm-1、(1472±4)cm-1、(1436±4)cm-1、(1400±4)cm-1、(1328±4)cm-1、(1294±4)cm-1、(1211±4)cm-1And (681. + -. 4) cm-1When measured at a temperature of 20 to 30 ℃ and a wavelength of 785 nm.
In yet another embodiment, the present invention relates to solvates of bicalutavir sodium characterized by having a raman spectrum substantially the same as shown in figure 8 of the present invention when measured at a temperature of 20 to 30 ℃ and a wavelength of 785 nm.
The solvate described above is preferably a 2,2, 2-trifluoroethanol solvate, more preferably a 2,2, 2-trifluoroethanol mono-solvate.
In another aspect, the present invention relates to a process for preparing crystalline form II of bicalutavir sodium of the present invention or a composition comprising form II of bicalutavir sodium as defined above, the process comprising:
(i) providing a solution comprising bicalutavir sodium and 2,2, 2-trifluoroethanol;
(ii) (ii) crystallizing bigevir sodium from the solution provided in step (i);
(iii) (iii) optionally separating at least a portion of the crystals obtained in step (ii) from its mother liquor;
(iv) (iv) optionally washing the isolated crystals obtained in step (iii);
(v) (iii) drying the crystals obtained in any one of steps (ii) to (iv), wherein the drying is carried out at a temperature of 50 ℃ to 150 ℃ under an atmosphere of about 1 to 50mbar vacuum;
bicalutavir can be prepared according to the teaching of WO 2014/100323a1, in particular according to the teaching of example 42 therein. The solution in step (i) of the above process may be prepared by reacting bicalutavir with a basic sodium source, such as sodium hydroxide, which is preferably used in the form of an aqueous solution, in the presence of 2,2, 2-trifluoroethanol. Alternatively, the solution in step (i) of the above process may be prepared starting from bicalutavir sodium and dissolving bicalutavir sodium in 2,2, 2-trifluoroethanol. The bicalutavir sodium starting material is prepared by reacting bicalutavir with aqueous sodium hydroxide solution in a suitable solvent such as water, ethanol, THF or any mixture thereof. Bicalutavir sodium may be prepared, for example, according to reference example 1 herein. WO2015/196116a1, particularly the specific examples disclosed in the paragraph bridging pages 38 and 39, also provides a method of producing bicalutavir sodium.
The solution of step (i) in the above process of the present invention may be prepared at room temperature or by heating bicalutavir sodium in trifluoroethanol to a temperature in the range of about 40 ℃ to reflux temperature, for example, a temperature of about 50 to 70 ℃. The solution typically has a bicalutavir sodium concentration of about 25 to 100g/L, preferably about 40 to 60g/L, and most preferably about 50 to 55 g/L. Optionally, the solution may be filtered to remove any particles that may not be dissolved.
After a clear solution containing bicalutavir sodium and 2,2, 2-trifluoroethanol is obtained, bicalutavir sodium is crystallized in the next step (ii). (ii) initiating crystallization by reducing the temperature of the solution provided in step (i) to a temperature of-25 to 30 ℃, preferably about-10 to 10 ℃. Optionally, seeds of bigevirin form II may be added to initiate crystallization and/or to control the particle size distribution of the finally obtained material. The amount of seed crystals may be about 1 wt% to 10 wt% based on the amount of bicalutavir sodium present in the solution. Once the material crystallizes and the resulting suspension has reached the final target temperature, the resulting suspension is preferably further stirred at that temperature for a period of time that allows bulk crystallization and/or crystal maturation. Typically, the suspension is further stirred for about 1 to 48 hours, preferably about 2 to 24 hours, and most preferably about 3 to 12 hours, for example 4 to 6 hours.
Optionally, in a next step, at least a portion of the crystals are separated from their mother liquor. Preferably, the crystals are separated from their mother liquor by any conventional method, such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation, and most preferably by filtration.
In a further optional step, the isolated crystals may be washed with a suitable solvent, for example an organic solvent selected from 2,2, 2-trifluoroethanol or ethanol.
The material thus obtained was found to be 2,2, 2-trifluoromethanolic solvate of bigevir sodium, which can be desolvated by applying the conditions disclosed below.
The crystals obtained from any of steps (ii) to (iv), preferably from step (iii) or (iv), are then dried, wherein the drying is done at a temperature of about 50 to 150 ℃, e.g. at about 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃ or 150 ℃, and a vacuum of about 1 to 50mbar, e.g. about 10 to 30 mbar. Generally, drying is carried out for a period of about 6 to 72 hours, preferably 10 to 48 hours, more preferably 12 to 24 hours. Drying is carried out until most, preferably all, 2,2, 2-trifluoroethanol solvates obtained from any of steps (II) to (iv) of the above process have been desolvated to form II of bicalutavir sodium as required in the present invention. The transformation may be detected, for example, by PXRD. One indication that desolvation is complete and drying can be stopped is the disappearance of the most intense reflection at 2-theta (5.8 + -0.2) ° in PXRD of 2,2, 2-trifluoroethanol solvate, which is not seen in PXRD of phase-pure bigevir sodium form II.
As mentioned above, bicalutavir sodium form II of the present invention combines the advantageous properties of high physical stability and high solubility and is therefore the preferred solid form of bicalutavir sodium for the preparation of pharmaceutical compositions.
Despite the metastable polymorph, it was found in DSC experiments performed at a heating rate of 10K/min: the bicalutavir sodium form II of the present invention is extremely resistant to temperature stress and only changes its crystal structure when heated to temperatures well above 300 ℃ (see experimental section and figure 9 herein). The solid-solid phase transition was confirmed by hot stage microscopy and powder X-ray diffraction. For example, a sample of form II heated to just above the transition temperature and then cooled to room temperature shows a PXRD consistent with that of WO2015/196116a1 form I. From the thermal behavior, it can be concluded that, firstly, form II is highly stable to temperature stress and changes its crystal structure only at temperatures that are never experienced during processing and storage of the drug substance, and, secondly, form I and form II are unidirectionally related to form I, which is a thermodynamically stable polymorph below its melting point (see Heat-of-Transition rule ", a. burger and r. rambler," On the polymerization of Pharmaceuticals and Other Molecular crystals.i. "microchip. The fact that the present invention has higher solubility than form II of tegravir as compared to form I of WO2015/196116a1 is very appreciated, since the higher solubility of form II also translates into higher dissolution and, most importantly, higher bioavailability, which is important for low solubility materials such as tegravir. Thus, form II of bicalutavir sodium of the present invention is a preferred form to be used in pharmaceutical compositions intended for administration to patients in need of such treatment.
Thus, in another aspect, the present invention relates to the use of bicalutavir sodium form II of the invention as defined above for the preparation of a pharmaceutical composition.
In another aspect, the present invention relates to a pharmaceutical composition comprising bicalutavir sodium form II as defined above, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient. Most preferably, the pharmaceutical composition of the invention is an oral solid dosage form, such as a tablet or capsule. Preferably, the pharmaceutical composition of the invention is a tablet, most preferably a film coated tablet. In one embodiment, the tablets are film coated with a coating material comprising polyvinyl alcohol (e.g., partially hydrolyzed), iron oxide, talc, and titanium dioxide.
The at least one pharmaceutically acceptable excipient comprised in the pharmaceutical composition of the present invention is preferably selected from the group consisting of carriers, fillers, diluents, lubricants, sweeteners, stabilizers, solubilizers, antioxidants and preservatives, flavoring agents, binders, colorants, penetrants, buffers, surfactants, disintegrants, granulating agents, coating materials and combinations thereof. More preferably, the at least one pharmaceutically acceptable excipient is selected from the group consisting of fillers, diluents, lubricants, disintegrants and coating materials. In one embodiment, the pharmaceutically acceptable excipients are all included in the pharmaceutical composition of the invention.
In a preferred embodiment, the at least one pharmaceutically acceptable excipient is selected from microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In a preferred embodiment, all of these pharmaceutically acceptable excipients are included in the pharmaceutical composition of the present invention.
Preferably, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bicalutavir sodium form II is selected from the group consisting of 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg and 100mg calculated as bicalutavir. Most preferably, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bicalutavir sodium form II is 50mg calculated as bicalutavir.
In another aspect, the present invention relates to a pharmaceutical composition comprising bicalutavir sodium form II as defined above, preferably in an effective and/or predetermined amount, together with at least one pharmaceutically acceptable excipient and optionally one or more other active pharmaceutical ingredients. Most preferably, the pharmaceutical composition of the invention is an oral solid dosage form, such as a tablet or capsule. Preferably, the pharmaceutical composition of the invention is a tablet, most preferably a film coated tablet. In one embodiment, the tablets are film coated with a coating material comprising polyvinyl alcohol (e.g., partially hydrolyzed), iron oxide, talc, and titanium dioxide.
The at least one pharmaceutically acceptable excipient comprised in the pharmaceutical composition of the present invention is preferably selected from the group consisting of carriers, fillers, diluents, lubricants, sweeteners, stabilizers, solubilizers, antioxidants and preservatives, flavoring agents, binders, colorants, penetrants, buffers, surfactants, disintegrants, granulating agents, coating materials and combinations thereof. More preferably, the at least one pharmaceutically acceptable excipient is selected from the group consisting of fillers, diluents, lubricants, disintegrants and coating materials. In one embodiment, the pharmaceutically acceptable excipients are all included in the pharmaceutical composition of the invention.
In a preferred embodiment, the at least one pharmaceutically acceptable excipient is selected from microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In a preferred embodiment, all of these pharmaceutically acceptable excipients are included in the pharmaceutical composition of the present invention.
Preferably, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bicalutavir sodium form II is selected from the group consisting of 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg and 100mg calculated as bicalutavir. Most preferably, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bicalutavir sodium form II is 50mg calculated as bicalutavir.
In another preferred embodiment, the one or more further pharmaceutically active ingredients are selected from the group consisting of entry/fusion inhibitors, Reverse Transcriptase Inhibitors (RTIs), integrase chain transfer inhibitors (intis), maturation inhibitors, Protease Inhibitors (PIs) or mixtures thereof. In another preferred embodiment, the entry/fusion inhibitor is selected from the group consisting of enfuvirtide, maraviroc (maraviroc), vicrivic, cericiviroc and fostemsvavir or mixtures thereof; the Reverse Transcriptase Inhibitors (RTIs) are selected from abacavir, didanosine (didanosine), emtricitabine, lamivudine, stavudine, zidovudine, amdoxovir (amdoxovir), aricitabine (apricitabine), censvudine, elvucitabine (elvucitabine), lacivir (racivir), stampidine, zalcitabine, tenofovir (tenofovir disoproxil), tenofovir alafenamide (tenofovir alafenamide), efavirenz (efavirenz), nevirapine, delavirdine, etravirine (etravirine), rilpivirine (rilpivirine), doravirine or mixtures thereof; the integrase chain transfer inhibitor (INSTI) is selected from the group consisting of durevir (dolutegravir), elvitegravir, raltegravir (raltegravir), and bicarvir (bictegravir) or mixtures thereof; the maturation inhibitor is Bevirima (bevirimat); and the Protease Inhibitor (PIs) is selected from amprenavir, furazanavir (fosamprenavir), indinavir (indinavir), lopinavir, nelfinavir, ritonavir (ritonavir), saquinavir, atazanavir, darunavir (dauunavir), tipranavir (tipranavir) or mixtures thereof.
In a particularly preferred embodiment, the one or more further pharmaceutically active ingredients are selected from emtricitabine (emtricitabine) or a pharmaceutically acceptable salt thereof, and tenofovir alafenamide or a pharmaceutically acceptable salt thereof, most preferably the one or more further pharmaceutically active ingredients are emtricitabine and tenofovir alafenamide hemifumarate.
In some embodiments, the pharmaceutical composition comprises 50mg bicalutavir sodium form II calculated as bicalutavir, 25mg tenofovir alafenamide or a pharmaceutically acceptable salt thereof calculated as tenofovir alafenamide, and 200mg emtricitabine or a pharmaceutically acceptable salt thereof calculated as emtricitabine. For example, in some embodiments, the pharmaceutical composition comprises 52.5mg of bifovir sodium form II, 28mg of tenofovir alafenamide hemifumarate, and 200mg of emtricitabine. In a particularly preferred embodiment, the pharmaceutical composition of the invention is a bilayer tablet comprising a first layer comprising bifovir dipivoxil sodium form II and a second layer comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof. Preferably, the present invention relates to a bilayer tablet comprising a first layer comprising bicalutamide form II and a second layer comprising tenofovir alafenamide hemifumarate and emtricitabine.
Preferably, the present invention relates to a pharmaceutical composition as described above, wherein said pharmaceutical composition should be administered once a day.
In another aspect, the present invention relates to a pharmaceutical composition as described above for use as a medicament.
In yet another aspect, the present invention relates to the pharmaceutical composition described above for use in the treatment or prevention of viral infections caused by DNA viruses, RNA viruses, herpes viruses (e.g., CMV, HSV1,
In a particular embodiment, the present invention relates to a pharmaceutical composition as described above for use in the treatment and/or prevention of HIV-1 infection.
In another embodiment, the present invention relates to a method of treating or prophylactically preventing HIV-1 infection by administering to a patient in need of such treatment and/or prevention a pharmaceutical composition as described above.
In another aspect, the present invention relates to a pharmaceutical composition as described above intended for use in the treatment of HIV-1 infection in combination with one or more other pharmaceutically active ingredients selected from the group consisting of entry/fusion inhibitors, Reverse Transcriptase Inhibitors (RTIs), integrase chain transfer inhibitors (INSTI), maturation inhibitors, Protease Inhibitors (PI) or mixtures thereof. In another preferred embodiment, the entry/fusion inhibitor is selected from the group consisting of enfuvirtide, maraviroc, vicrivic, cericiviroc, ibalizumab and fostemavir, or mixtures thereof; the Reverse Transcriptase Inhibitors (RTIs) are selected from abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine, amdoxovir, aricitabine, censvudine, elvitabine, lacivirel, stampidine, zalcitabine, tenofovir alafenamide, efavirenz, nevirapine, delavirdine, etravirine, rilpivirine, doravirine or mixtures thereof; an integrase chain transfer inhibitor (INSTI) selected from the group consisting of Durutevir, elvitegravir, Letegravir and Bicagvir or mixtures thereof; the maturation inhibitor is Bezivian; and the Protease Inhibitor (PIs) is selected from amprenavir, furanavir, indinavir, lopinavir, nelfinavir, ritonavir (ritonavir), saquinavir, atazanavir, darunavir (daronavir), tipranavir (tipranavir) or mixtures thereof.
Treatment in combination with one or more other pharmaceutically active ingredients may mean administration of a pharmaceutical dosage form comprising bicalutavir sodium form II of the invention and one or more other pharmaceutically active ingredients in the same dosage form, e.g. as a fixed dose combination product.
Alternatively, treatment in combination with one or more other pharmaceutically active ingredients may mean the administration of separate (separate) pharmaceutical dosage forms, one containing bicalutavir sodium form II of the present invention and the other containing one or more other pharmaceutically active ingredients in separate dosage forms. Pharmaceutical dosage forms comprising bicalutavir sodium form II of the present invention will generally be provided in the combination treatment instructions to be administered in combination with the individual dosage forms to effectively treat viral invention, such as HIV-1 infection.
Examples
For the purposes of this disclosure, the following non-limiting examples are illustrative and should not be construed as limiting the scope of the invention in any way.
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