Pharmaceutical formulation comprising apalutamide

Abstract

The present invention relates to a pharmaceutical composition comprising a solid dispersion of apalutamide and hydroxypropyl methylcellulose phthalate, wherein the solid dispersion is obtained by the spray-drying process. The invention further relates to the use of said pharmaceutical composition as a medicament in the treatment of non-metastatic castration-resistant prostate cancer and hormone-sensitive prostate cancer.

Description

[0001] P1820PC00

[0002] PHARMACEUTICAL FORMULATION COMPRISING APALUTAMIDE

[0003] BACKGROUND OF THE PRESENT INVENTION

[0004] Apalutamide, chemically 4-[7-[6-Cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6- thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide of formula (1), is an androgen receptor antagonist, that is useful for treatment of non-metastatic castrationresistant prostate cancer and metastatic hormone-sensitive prostate cancer. Apalutamide is a BSC class II compound exhibiting low solubility and high permeability.

[0005] Apalutamide is marketed by Janssen under brand name Erleada® and was first disclosed in WO2007126765. Film-coated immediate release tablets are available in two nonproportional strengths of 60 mg and 240 mg.

[0006] The Erleada® tablet formulation comprises a solid dispersion of apalutamide and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The formulation is disclosed in W02016090098.

[0007] W02016090101 discloses formulations comprising a solid dispersion of apalutamide and a poly(meth)acrylate copolymer.

[0008] WO20 16090105 discloses pharmaceutical formulations comprising a solid dispersion of apalutamide, a poly(meth)acrylate copolymer and HPMCAS. The solid dispersions described in the aforementioned patent application are obtained by melt-extrusion of a mixture comprising apalutamide and a polymeric carrier(s) or by spray-drying a mixture comprising apalutamide and a polymeric carrier(s) in a suitable solvent. The process of hot melt extrusion has the advantage of being a continuous manufacturing process that does not require the use of solvents and that yields a product with high density. However, hot melt extrusion process has also some serious drawback - the high temperatures applied might increase levels of impurities. When it comes to solid dispersions prepared by spray-drying, all examples given use large quantities of solvents, which increases the environmental footprint.

[0009] WO2015118015 discloses solid pharmaceutical composition comprising apalutamide or enzalutamide (alternative androgen receptor antagonist), a carrier and a surfactant. Apalutamide and the carrier are combined in the form of a solid adsorbate or in the form of a solid dispersion. The carrier in the solid dispersion is a polymer selected from the group consisting of hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylic acid, poly(ethylene glycol), poly(ethylene oxide), copovidone, HPMCAS, polyacrylates and mixtures thereof. However, the examples described are solely compositions comprising solid adsorbates of apalutamide, not solid dispersions.

[0010] WO20 19016747 discloses amorphous solid dispersion of apalutamide with a pharmaceutically acceptable excipient selected from hydroxypropyl methylcellulose phthalate (HPMCP), copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, prosolv, hydroxypropyl methylcellulose or mixtures thereof. The application does not disclose the tablet composition comprising the aforementioned solid dispersion.

[0011] EP3811932 discloses solid dosage form comprising a solid dispersion comprising apalutamide and hydroxypropyl methylcellulose phthalate (HPMCP) grade HP-55. The solid dosage forms disclosed show faster dissolution profile when compared to Erleada® resulting in better bioavailability. In view of the prior art cited above, there is still a need for pharmaceutical tablet compositions comprising apalutamide in amorphous form, which are suitable for production on commercial scale by applying techniques and equipment commonly used in industry in an efficient and cost-effective process; the tablet compositions which exhibit excellent long term stability and are bioequivalent to Erleada®.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention provides a pharmaceutical composition comprising a solid dispersion of apalutamide and grade HP-50 of hydroxypropyl methylcellulose phthalate.

[0014] The solid dispersion according to the present invention is prepared by spray-drying technique.

[0015] The present invention further provides a process for preparing said pharmaceutical composition comprising dry granulation step.

[0016] Said pharmaceutical composition may be used as a medicament, particularly in the treatment of non-metastatic castration-resistant prostate cancer and metastatic hormonesensitive prostate cancer.

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : Manufacturing process of the tablets.

[0019] Figure 2: Dissolution profiles of the tablet compositions prepared according to Example 1.

[0020] Figure 3: Dissolution profiles of the tablet compositions prepared according to Example 2.

[0021] Figure 4: Dissolution profiles of the tablet compositions prepared according to Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0022] The solubility of Active Pharmaceutical Ingredients (APIs) in an amorphous form is higher compared to the solubility of crystalline forms. However, drugs that can exist in either amorphous or crystalline form tend to crystallize over time when present in amorphous state because the crystalline form of the drug is a lower-energy state than the amorphous form. One of the most successful and potent strategies to improve the solubility and dissolution of poorly soluble drugs is the preparation of a solid dispersion. The term solid dispersion has been defined as a dispersion of one or more APIs in an inert carrier or matrix at the solid state, prepared by a solvent or melting process or a combination of the two. A kneading method may also be applied to obtain a solid dispersion. Depending on the physical state of the carrier, which is crystalline or amorphous, the solid dispersions are divided into crystalline solid dispersions and amorphous solid dispersions respectively. Amorphous carriers used are mostly polymers. In amorphous solid dispersions, the API is dispersed in very small size and exists in supersaturated state in amorphous carriers because of forced solubilization. The amorphous carriers can increase the wettability and dispersability of drugs as well as inhibit the precipitation process of drugs when amorphous solid dispersions are dissolved in water. These properties along with the fast dissolution rate of amorphous carriers enhance the drug solubility and release rate.

[0023] It is not self-evident that a given drug will form an amorphous solid dispersion with just any polymer, and that, even if the solid dispersion is formed, that it will be stable over time. The stability of an amorphous solid dispersion is imparted through high glass transition temperature (Tg) of a polymeric carrier, homogenous mixing and intermolecular adhesive interactions or combination thereof. In other words, the polymer must be compatible with the drug and promote drug-polymer interactions for effective stabilization of the produced system. There is no single mechanism responsible for the stability of prepared dispersions and the same applies to the obtained dissolution improvement. Other factors playing a role herein are the ratio of API to polymer used and the technique used to prepare the solid dispersion. Techniques to prepare solid dispersions often require very specific conditions for each combination of API and polymer.

[0024] We have found that the formulation that is bioequivalent to Erleada® that exhibits excellent long term stability can be prepared with the use of specific grade of hydroxypropyl methylcellulose phthalate (HPMCP), that is grade HP-50.

[0025] Cellulosic derivatives are widely used as stabilizers for amorphous solid dispersions due to their benign nature at physiological conditions, strong drug-polymer interactions and high glass transition temperatures. Cellulose derivatives can be classified based on their water solubility, chemical substituents, and pH responsiveness.

[0026] Both polymers, hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are anionic polymers that exhibit pH- dependent solubility due to deprotonation of acidic functional groups at intestinal pH, where the drug is released.

[0027] HPMCAS, the polymer used to stabilize amorphous apalutamide in Erleada®, possesses acetyl and succinoyl moieties which are substituted on the hydroxyl groups. The pH-dependent solubility can be attributed to the ratio of succinate and acetyl groups. Thus, different substitution grades of HPMCAS have different pH-dependent solubility (the L, M, and H grades dissolve at pH > 5.5, 6.0 and 6.5, respectively). According to W02016090098, Erleada® comprises grade L of HPMCAS that dissolves at pH > 5.5.

[0028] Hydroxypropyl methylcellulose phthalate (HPMCP) is the phthalic acid ester of hydroxypropyl methylcellulose. HPMCP is available in three grades, differentiated by the degree of substitution, pH solubility in buffer solution, and viscosity: HP-50, HP-55 and HP- 55 S . HPMCP grade HP-50 dissolves at pH > 5 while HPMCP grade HP-55 dissolves at pH > 5.5.

[0029] Although the employment of HPMCP in the solid dispersion of apalutamide is suggested in prior art, the present inventors have surprisingly found that for the formulation to be bioequivalent to Erleada®, HPMCP grade HP-50 has to be used in the specific ratio of apalutamide to the polymer. The weight ratio of apalutamide and HPMCP HP-50 in the solid dispersion according to the invention is between 1 :3.5 and 1 :5, more preferably from 1 :4 to 1 :5. Most preferably the ratio is 1 :4:5.

[0030] The process selected to prepare the pharmaceutical compositions of the present invention is the spray drying method, because in this method problems related to decomposition, as generally observed when applying the melting method, are prevented. The tablet composition in accordance with the present invention is prepared by dissolving APM and the HPMCP polymer in an organic solvent system comprising a mixture di chloromethane and methanol, or a mixture of acetone and water. The solution is then spray-dried executed with a spray dryer equipment. The obtained solid dispersion is blended with intragranular excipients and the blend is dry granulated with equipment commonly used in pharmaceutical industry. Preferably a roller compactor is used. The obtained granulate is blended with extragranular excipients.

[0031] According to the preferred embodiment of the invention, the concentration of solids (apalutamide and HPMCP) dissolved in a mixture of solvents is between 5 and 15% by weight. Preferably, the concentration of solids is between 10% and 12% by weight.

[0032] The solid dispersion prepared is characterized by particle size distribution (PSD) D90 between 20 and 100 pm, as measured by laser diffraction method, more preferably PSD D90 is between 30 and 60 pm. D90 is a value of the volume-based particle size distribution, such that 90% by volume of the particles have a size of this value or less. The amount of solid dispersion of apalutamide and polymer is between 35 and 55% by weight, preferably between 40 and 52% by weight, even more preferably between 44 and 50% by weight, based on the total weight of the composition.

[0033] The excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art in pharmaceutical compositions. The excipients are selected from one or more diluents, disintegrants, glidants or lubricants. Optionally, a surfactant is added to the final blend. The surfactant may be added to improve the wettability of the drug particles and its addition results in faster dissolution behavior of the tablet composition.

[0034] The diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art. Particularly, the diluent to be used in accordance with the present invention can be selected from an inorganic diluent, polysaccharide, mono- or disaccharide and / or sugar alcohol. Microcrystalline cellulose and microcrystalline cellulose silicified are particularly preferred diluents. The diluents are preferably added both intra- and extragranularly.

[0035] The amount of diluent in the pharmaceutical composition according to present invention is between 38 and 55% by weight, preferably between 40 and 52% by weight, even more preferably between 42 and 50% by weight based on the total weight of the composition.

[0036] The disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of croscarmellose sodium, crospovidone or sodium starch glycolate. Croscarmellose sodium is a particularly preferred disintegrant. The disintegrant is preferably added both intra- and extragranularly. The amount of disintegrant in the pharmaceutical composition according to the invention is between 2 and 10% by weight, more preferably between 3 and 8% by weight based on the total weight of the composition.

[0037] The glidant to be used in accordance with the present invention may be any glidant known to a person of ordinary skill in the art. Colloidal silicon dioxide is a particularly preferred glidant.

[0038] The amount of glidant in the pharmaceutical composition is between 0,5 to 2,5% by weight, more preferably between 0,8 - 2% by weight, even more preferably between 1 and 1,5% by weight based on the total weight of the composition. Glidant is preferably added both intra- and extragranularly.

[0039] The lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant. The amount of lubricant in the pharmaceutical composition according to the invention is between 0,1 - 2% by weight, preferably between 0,2 and 1% by weight, more preferably between 0,2 and 0,8% by weight based on the total weight of the composition. The lubricant is added to extragranular phase.

[0040] The surfactant to be used in accordance with the present invention may be any surfactant known to a person of ordinary skill in the art, but is preferably an anionic surfactant. A particularly preferred anionic surfactant to be used in accordance with the present invention is sodium lauryl sulfate. The surfactant is preferably added extragranularly. The amount of added surfactant might be between 0,3 and 2%, preferably between 0,5 and 1,5 %.

[0041] After the granulate is blended with extragranular excipients, the final blend is compressed into tablets, which may optionally be coated by a film-coat. The coating serves generally cosmetic purposes. The coating material typically has no influence on the release rate, except of an inherent short initial delay in dissolution due to the time necessary to dissolve the coating. The coating may be selected from amongst one or more of those suitable coating materials known in the art.

[0042] The coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution / suspension. Coating is done using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.

[0043] The pharmaceutical composition of the present invention exhibits excellent accelerated and long term stability. The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

[0044] EXAMPLES

[0045] Example 1: Pharmaceutical composition comprising a solid dispersion of apalutamide and different grades of HPMCP

[0046] The film-coated tablets comprising a solid dispersion of apalutamide and different grades of HPMCP, HP-55 and HP-50, have been prepared having composition as given in Table 1.

[0047] Table 1

[0048] The core tablets were prepared by the process as depicted in the flowchart of Figure 1

[0049] The dissolution profiles of the obtained core tablets, when tested in 900 ml phosphate buffer pH 6.8 in a USP apparatus II at 75 rpm (normal vessel) at 37°C, show that the tablets prepared with HPMCP HP-50 exhibit more similar dissolution to Erleada® (Figure 2). In both examples, XRPD and DSC analysis performed after storage of the core tablets after 6 months at 40°C / 75%RH in open dish showed no conversion of amorphous enzalutamide into any crystalline form of apalutamide. The core tablets comprising HPMCP HP-50 were coated with Opadry II 85F yellow up to weight gain of 3%. The coated tablets were packed in Al / Al blister and tested after storing for six months at 40°C / 75%RH. The result of testing is depicted in Table 2.

[0050] Table 2

[0051] Example 2: Pharmaceutical composition comprising a solid dispersion with different ratios of apalutamide to HPMCP HP-50

[0052] The tablets comprising a solid dispersion with different ratios of apalutamide to HPMCP HP-50, have the composition as given in Table 3.

[0053] Table 3 1Evaporated during the manufacturing process.

[0054] 2Extragr anular excipients

[0055] The tablets were prepared by the process as depicted in the flowchart of Figure 1. The dissolution profiles of uncoated tablets, when tested in 900 ml phosphate buffer pH

[0056] 6.8 in a USP apparatus II at 75 rpm (normal vessel) at 37°C, in comparison to the uncoated tablets of example 1.2 and Erleada® are depicted in Figure 3. The tablets of example 1.2 comprising a solid dispersion of apalutamide and HPMCP HP-50 in the ratio 1 :3 show the slowest dissolution profile. The core tablets comprising HPMCP HP-50 were coated with Opadry II 85F yellow to weight gain of 3%. The coated tablets were packed in Al / Al blister and tested after storing for six months at 40°C / 75%RH. The result of testing is depicted in Table 4.

[0057] Table 4 Example 3: Pharmaceutical composition comprising a solid dispersion of apalutamide and HPMCP HP-50 with weight ratio 1:3 and a surfactant.

[0058] To improve the dissolution of the tablets of example 1.2, following tablet formulations comprising different percentages of SLS were prepared. The tablets were prepared by the process as depicted in the flowchart of Figure 1.

[0059] Table 5

[0060] 1Evaporated during the manufacturing process.

[0061] The dissolution profiles of tablets obtained, in comparison with tablets of example 1.2, when tested in 900 ml phosphate buffer pH 6.8 in a USP apparatus II at 75 rpm (normal vessel) at 37°C, are depicted in Figure 4.

[0062] Example 4: Assessment of the bioequivalence

[0063] In a single dose pilot bioavailability study of apalutamide, coated tablets prepared according to examples 1.2, 2.3 and 3.1 were compared with that of Erleada® 60 mg in 40 subjects under fasting conditions and fed conditions. Table 6

Claims

CLAIMS1. A tablet composition comprising a solid dispersion comprising apalutamide and hydroxypropyl methylcellulose phthalate grade HP-50, wherein the weight ratio of apalutamide and hydroxypropyl methylcellulose phthalate in the solid dispersion is in the range from 1 :3.5 to 1 :5.

2. The tablet composition according to claim 1, wherein the weight ratio of apalutamide and hydroxypropyl methylcellulose phthalate in the solid dispersion is in the range from 1 :4 to 1 :5.

3. The tablet composition according to claims 1-2, wherein the tablet composition further comprises pharmaceutically acceptable excipients selected form one or more fillers, binders, disintegrants, glidants or lubricants.

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