Patent Application
20240226103
The present invention relates to a solid dispersion of N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide.
N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide, also herein referred to as compound (1) or zongertinib, is a HER2 (ErbB2) inhibitor described in WO 2021/213800. Zongertinib is a potent and selective tyrosine kinase inhibitor of wild type and mutant HER2 that spares wild type epithelial growth factor receptor (EGFR). Therefore, it is useful for the treatment and/or prevention of diseases and/or conditions wherein the inhibition of wild type and/or mutant HER2 is of therapeutic benefit, especially oncological and/or hyperproliferative diseases, such as cancer.
The solubility of compound (1) in aqueous media was found to be limited and strongly pH dependent with increased solubility at acidic conditions. Specifically, about 105-fold decrease in solubility was observed between pH 1.2 and pH 6.8. Consequently, the in vivo absorption of compound (1) is affected by gastric pH. In particular, low gastric pH is associated with an increase in absorption of compound (1), whereas an increased gastric pH leads to lower blood serum levels of compound (1). This pH dependency is undesirable because it may decrease bioavailability and/or bioaccessibility of compound (1). Such a decrease may occur to different extents in different patients due to inter-patient stomach pH variability.
Moreover, the gastric pH of cancer patients may be altered due to a therapeutic agent in their treatment plan, such as protein pump inhibitors (PPIs), antacids or antihistamines, which are acid-reducing agents known to increase gastric pH. These therapeutic agents are often administered to cancer patients, for instance to mediate gastrointestinal side effects brought about by medicaments, in particular those that lower gastric pH, but also to manage effects of a tumor in the gastric area. A co-administration of acid reducing agents and compound (1) may thus reduce absorption and systemic exposure of compound (1).
Therefore, there remains a need to decrease the pH dependency of compound (1) to improve its bioavailability and/or bioaccessibility.
According to a first aspect is provided a solid dispersion comprising compound (1) as defined below or a pharmaceutically acceptable salt thereof
and a pharmaceutically acceptable dispersion carrier.
Another aspect relates to a pharmaceutical composition comprising the solid dispersion as described herein and one or more pharmaceutically acceptable excipients.
Another aspect relates to the solid dispersion as described herein or the pharmaceutical composition as described herein, for use as a medicament.
Another aspect relates to the solid dispersion as described herein or the pharmaceutical composition as described herein, for use in the treatment and/or prevention of an oncological and/or hyperproliferative disease.
In an embodiment of all aspects disclosed herein, the oncological and/or hyperproliferative disease is cancer.
Another aspect relates to a process of preparing the solid dispersion as described herein, the process comprising the steps of:
Another aspect relates to a use of the solid dispersion as described herein for the preparation of a pharmaceutical composition as described herein.
Another aspect relates to a kit comprising:
It is a purpose of the present invention to decrease the pH dependency of compound (1) to improve its bioavailability and/or bioaccessibility.
It was surprisingly discovered that a formulation of compound (1) as a solid dispersion has the potential to achieve consistent bioavailability and/or bioaccessibility and to overcome inter-patient stomach pH variability compared to the administration of formulations comprising compound (1) in crystalline form.
Specifically, the administration of a solid dispersion of compound (1) provides a high up-take not only when administered to a subject with a normally low gastric pH but as well when administered in combination with a medicament that increases gastric pH such as a proton pump inhibitor, an antacid or an antihistamine. The surprising results shown in the examples described herein, in particular the superior in-vitro and in-vivo performance of the solid dispersions of the present invention compared to formulations comprising crystalline compound (1) demonstrated in Examples 5.1, 5.2 and 7.1 to 7.4 herein, indicate that the formulation of compound (1) as a solid dispersion provides a consistently high up-take unaffected by pH variations e.g. initiated by co-medication that causes a rise in stomach pH level and thus results in the possibility of including patient groups under co-medication such as under proton pump inhibitors, antacids or antihistamines in treatment with compound (1).
It was also surprising to find that compound (1) could be kept in the amorphous state such as in the solid dispersion, even when subjected to extended temperature and moisture stress as demonstrated in Example 4 herein.
As used herein, the term “compound (1)” refers to the compound as defined below or a pharmaceutically acceptable salt thereof:
The IUPAC name of compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. In case of discrepancy between IUPAC name and depicted formula, the formula shall prevail. Compound (1) is also known as zongertinib. Compound (1) is disclosed in WO 2021/213800 as example compound I-01. WO 2021/213800 describes [1,3]diazino[5,4-d]pyrimidines such as compound (1) as HER2 inhibitors and provides a synthesis procedure for compound (1). Properties of compound (1) and evidence for inhibitory effect on HER2 wild-type and YVMA kinase activity, while sparing EGFR, are also disclosed in WO 2021/213800, which is herein incorporated by reference.
The term “compound (1)” as used herein also encompasses any tautomers and pharmaceutically acceptable salts and all solid state forms of the compound, as well as solvates, including hydrates and solvates of pharmaceutically acceptable salts thereof.
In embodiments, compound (1) is a free base. Therefore, in any aspect or embodiment, the expression “compound (1) or a pharmaceutically acceptable salt thereof” can be replaced by “compound (1)”, without a reference to the pharmaceutically acceptable salt thereof. In embodiments, pharmaceutically acceptable salts of compound (1) are used. The term “pharmaceutically acceptable” used herein refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein “pharmaceutically acceptable salts” of compound (1) refers to compound (1) wherein the compound is modified by making acid or base salts thereof. The term pharmaceutically acceptable salts as used herein generally includes both acid and base addition salts. Pharmaceutically acceptable acid addition salts refer to those salts which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable, formed with inorganic acids or organic acids. Pharmaceutically acceptable base addition salts include salts derived from inorganic bases or organic nontoxic bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethane sulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. In embodiments, pharmaceutically acceptable salts are selected from chloride and fumarate salts.
Pharmaceutically acceptable salts can be synthesized from compound (1) by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of compound (1) with a sufficient amount of the appropriate acid or base in water or in an organic diluent or solvent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
The term “solvate” as used herein refers to an association or complex of one or more solvent molecules and compound (1). Examples of solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, tert-butyl methyl ether, tetrahydrofuran, methylethyl ketone, N-methylpyrrolidone and ethanolamine. The term “hydrate” refers to a complex where the solvent molecule is water.
Provided herein is a solid dispersion comprising compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier. Also provided herein is a solid dispersion consisting essentially of compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier. As used herein, the expressions “consists essentially of” and “consisting essentially of” have the meaning attributed to them in the art. In particular, they indicate that further components may be present, especially those further components that do not have a material effect on the characteristics of the respective dispersion, composition or formulation. Such further components may for example be residual solvents.
Also provided herein is a solid dispersion consisting of compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier. As used herein, the term “solid dispersion” refers to a system in a solid state comprising at least two components, wherein one component, such as compound (1) or generally an active pharmaceutical ingredient (API), preferably in amorphous state, is dispersed throughout another component such as a pharmaceutically acceptable solid dispersion carrier, particularly a dispersion polymer.
As used herein, the term “dispersion carrier” refers to a carrier component that allows for an API such as compound (1) to be dispersed throughout such that a solid dispersion may form. In embodiments, compound (1) is dispersed at the molecular level in the pharmaceutically acceptable dispersion carrier.
In embodiments, the pharmaceutically acceptable dispersion carrier is a polymer. Therefore, the present invention provides a solid dispersion comprising compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a polymer. Polymeric dispersion carriers also are denoted “dispersion polymers”. Polymers are widely used in solid dispersion formulations. Different polymeric carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug release rate and extent. Due to the complex nature solid dispersion formulation carrier best suited for a given API need to be tested. The pharmaceutically acceptable dispersion polymer preferably is a neutral or acidic polymer.
In other embodiments, the pharmaceutically acceptable dispersion carrier is a polymer that is enteric or non-enteric, preferably enteric. In other embodiments, the polymer is enteric or non-enteric, preferably enteric. The term “enteric polymer” refers to a pH-dependent acidic polymer that is insoluble or only slightly soluble at a low pH (e.g. about pH 1 up to but less than pH 3) but becomes soluble at a higher pH (e.g. pH 5 and above). In certain embodiments a pH-dependent polymer may become soluble at a pH range from about pH 5 and above, e.g. from about pH 6 to about pH 9, from about pH 6 to about pH 8, from about pH 5 to about pH 7, or from about pH 5 to about pH 6, which is generally less acidic than the gastric environment and roughly corresponds to pH values in the small intestine. Examples of enteric polymers include but are not limited to methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate, HPMCAS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers (Eudragit© L100), shellac, cellulose acetate trimellitate, sodium alginate and zein. The term “non-enteric polymer” refers to a neutral polymer that does not show pH-dependent solubility characteristics. Examples of non-enteric polymers include but are not limited to cellulose derivatives such as Methylcellulose (MC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), poly-vinyl-pyrrolidone (PVP), copovidone such as polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), poly (ethylene glycol) PEGs, starch derivatives like cyclodextrin, Soluplus® which is an amphiphilic copolymer consisting of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate.
In embodiments, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply the polymer is, selected from the group consisting of hydroxypropyl methylcelluloses and esters thereof, polyvinylpyrrolidones and copolymers thereof, and polymethacrylates and copolymers thereof. The pharmaceutically acceptable dispersion carrier may contain a mixture of two or more polymers.
In an embodiment, the hydroxypropyl methylcelluloses and esters thereof are selected from the group consisting of hydroxypropyl methyl cellulose acetate (HPMCA), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and carboxymethylcellulose acetate butyrate (CMCAB). In an embodiment, the hydroxypropyl methylcelluloses and esters thereof are selected from the group consisting of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, in particular hot melt extrusion-grade hydroxypropyl methylcellulose.
In an embodiment, the polyvinylpyrrolidones and copolymers thereof are selected from the group consisting of polyvinylpyrrolidone vinyl acetate copolymer (PVP-VA), polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers and polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone (PVP) also is commonly denoted polyvidone or povidone. In embodiments, the polyvinylpyrrolidones and copolymers thereof are a polyvinylpyrrolidone vinyl acetate copolymer (PVP-VA).
In an embodiment, the polymethacrylates and copolymers thereof are selected from the group consisting of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methyl methacrylate and methacrylic acid copolymer. Polymethacrylates and copolymers thereof are, for example, available under the brand name Eudragit© from Evonik Industries AG. Methacrylic acid-methyl methacrylate copolymer is, for example, available under the brand name Eudragit© L100. In certain embodiments, the polymethacrylates and copolymers thereof are a methylacrylic acid methyl methacrylate copolymer.
In embodiments, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply the polymer is, selected from the group of hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone vinyl acetate copolymer (PVP-VA), methylacrylic acid methyl methacrylate copolymer (such as Eudragit© L100), and hot melt extrusion-grade hydroxypropyl methylcellulose (HPMC HME).
In certain embodiments, the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS also is known as hypromellose acetate succinate. Hypromellose acetate succinate (HPMCAS) can be obtained by introducing acetyl and succinoyl groups to the hydroxyl groups of the backbone of hydroxypropyl methylcellulose (HPMC) also known as hypromellose. This procedure can be carried out by known methods, for instance by treating HPMC with acetic anhydride and/or with succinic anhydride. Acetic anhydride and succinic anhydride can be reacted with hydroxypropyl methylcellulose (HPMC) under specifically controlled conditions to produce HPMCAS with varying extent of substitution of acetyl and succinoyl groups.
HPMCAS is available in several grades (L, M and H) varying in extent of substitution of acetyl and succinoyl groups, based on the content of acetyl and succinoyl groups (wt %) in the HPMCAS molecule. Any grade of HPMCAS is usable in the solid dispersion of the invention. Preferably, HPMCAS of grade L, M or H is used. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade L. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade M. HPMCAS grade M may comprise an acetyl content of 7-11 wt %; a succinoyl content of 10-14 wt %; methoxyl content of 21-25 wt %; and a hydroxypropoxy content of 5-9 wt %. Preferably, HPMCAS grade M (HPMCAS-M) is soluble at pH ≥6. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade H. Preferably, granular HPMCAS (HPMCAS-G) is used. HPMCAS-G can be used for any grade of HPMCAS, in particular for grade G, such that HPMCAS-MG is used.
In certain embodiments, the pharmaceutically acceptable dispersion carrier is polyvinylpyrrolidone vinyl acetate copolymer (PVP-VA). Polyvinylpyrrolidone vinyl acetate copolymers are linear, random copolymers that are available by free-radical polymerization of the monomers in ratios varying from 70/30 to 30/70 vinyl acetate to vinylpyrrolidone.
In certain embodiments, the pharmaceutically acceptable dispersion carrier is methylacrylic acid methyl methacrylate copolymer, such as Eudragit© L100. As used herein, “methylacrylic acid methyl methacrylate copolymer” is used interchangeably with “methacrylic acid methyl methacrylate copolymer”.
In certain embodiments, the pharmaceutically acceptable dispersion carrier is a hot melt extrusion-grade hydroxypropyl methylcellulose (HPMC HME). HPMC HME refers to a modified grade of hydroxypropyl methylcellulose having low glass transition temperature and melt viscosity, which can be used for making a solid dispersion via hot melt extrusion. HPMC HME is a water soluble amorphous polymer, usually provided as a white to off-white powder, available in three grades, HPMC HME 15 LV, HPMC HME 100 LV and HPMC HME 4M, differing in regard to their molecular weight. Preferably, HPMC HME 15LV having a molecular weight (Mw) below 100 kDa is used. Further preferred, HPMC HME 100LV having a molecular weight (Mw) below 200 kDa is used.
By dispersing compound (1), preferably on a molecular level, in a, for example polymeric, pharmaceutically acceptable dispersion carrier, an amorphous state can be maintained, even when exposed to elevated temperature and/or humidity conditions, and the solid dispersion can reliably provide compound (1) in amorphous form. In embodiments, compound (1) is amorphous. The preferred feature of compound (1) being amorphous can be applied to any embodiment disclosed herein to provide further embodiments according to the invention, in particular, it can be applied to any embodiment of the solid dispersion (including embodiments about the identity of the pharmaceutically acceptable dispersion carrier, the amounts of the components of the solid dispersion, etc), the pharmaceutical composition, the kits, the uses and the processes described herein.
The term “amorphous” as used herein refers to a condensed phase where molecules are randomly orientated and characterized by the absence of any microscopic order, with no diffraction peaks by XRPD; an amorphous solid system may be composed of a single chemical entity or may be a multi-component system containing, e.g., an API, polymer and other excipients, without stoichiometric composition. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as found in crystalline solids. The solid state form of a solid may be determined e.g. by x-ray powder diffraction (“XRPD”) or modulated differential scanning calorimetry (“mDSC”).
In embodiments, the solid dispersion comprises, consists essentially of or consists of amorphous compound (1) and a pharmaceutically acceptable dispersion carrier, wherein compound (1) is substantially in amorphous solid state form. In certain embodiments, the substantially amorphous solid state form refers to the solid dispersion comprising at least 80 wt % amorphous compound (1) based on a total weight of 100 wt % of compound (1). In certain embodiments, the substantially amorphous solid state form refers to the solid dispersion comprising at least 85 wt % amorphous compound (1) based on a total weight of 100 wt % of compound (1). In certain embodiments, the substantially amorphous solid state form refers to the solid dispersion comprising at least 90 wt % amorphous compound (1) based on a total weight of 100 wt % of compound (1). In certain embodiments, the substantially amorphous solid state form refers to the solid dispersion comprising at least 95 wt % amorphous compound (1) based on a total weight of 100 wt % of compound (1). In certain embodiments, the substantially amorphous solid-state form refers to the solid dispersion comprising at least 96, 97, 98 or 99 wt % amorphous compound (1) based on a total weight of 100 wt % of compound (1). Thus, the solid dispersion can provide compound (1) in amorphous or essentially amorphous state. Such a solid dispersion can thus be referred to as an amorphous solid dispersion. In embodiments, the solid dispersion thus is an amorphous solid dispersion.
In one embodiment, the solid dispersion comprises a predetermined amount of compound (1) or a pharmaceutically acceptable salt thereof. In this context, a predetermined amount refers to the initial amount of compound (1), or a pharmaceutically acceptable salt thereof used for the preparation of the solid dispersion.
In another embodiment, the solid dispersion comprises a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.
In embodiments, compound (1) is present in an amount in a range of from 5 wt % to 95 wt %, based on a total weight of 100 wt % of the solid dispersion. In embodiments, compound (1) is present in an amount in a range of from 25 wt % to 75% wt %, based on a total weight of 100 wt % of the solid dispersion. In embodiments, the pharmaceutically acceptable dispersion carrier is present in an amount in a range of from 5 wt % to 95 wt %, based on a total weight of 100 wt % of the solid dispersion. In embodiments, the pharmaceutically acceptable dispersion carrier is present in an amount in a range of from 25 wt % to 75 wt %, based on a total weight of 100 wt % of the solid dispersion.
In embodiments, compound (1) is present in an amount in a range of from 20 wt % to 50 wt %, based on a total weight of 100 wt % of the solid dispersion. In embodiments, compound (1) is present in an amount in a range of from 25 wt % to 50 wt %, based on a total weight of 100 wt % of the solid dispersion. In embodiments, the pharmaceutically acceptable dispersion carrier is present in an amount in a range of from 50 wt % to 80 wt %, based on a total weight of 100 wt % of the solid dispersion. In embodiments, the pharmaceutically acceptable dispersion carrier is present in an amount in a range of from 50 wt % to 75 wt %, based on a total weight of 100 wt % of the solid dispersion.
The solid dispersion may comprise compound (1) and the pharmaceutically acceptable dispersion carrier in approximately equal weight amounts. In embodiments, the solid dispersion, based on a total weight of 100 wt %, comprises, consists of or consists essentially of approximately 50 wt % of compound (1) and approximately 50 wt % of the pharmaceutically acceptable dispersion carrier.
In embodiments, the solid dispersion, based on a total weight of 100 wt %, comprises, consists of or consists essentially of approximately 25 wt % or 50 wt % of compound (1) and approximately 75 wt % or 50 wt % of the pharmaceutically acceptable dispersion carrier.
In embodiments, the weight ratio of compound (1): the pharmaceutically acceptable dispersion carrier in the solid dispersion is of approximately 1:4 to 4:1, preferably 1:3 to 3:1, such as 1:1 to 1:3. In embodiments, the weight ratio of compound (1): the pharmaceutically acceptable dispersion carrier in the solid dispersion is of 1:1 to 1:3 In embodiments, the weight ratio of compound (1): the pharmaceutically acceptable dispersion carrier in the solid dispersion is of approximately 1:1.
As used herein, the terms “approximately” and “about” mean within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
In embodiments, the solid dispersion comprises a weight ratio of compound (1): the pharmaceutically acceptable dispersion carrier of approximately 1:4 to 4:1, preferably 1:3 to 3:1, such as 1:1 to 1:3. In embodiments, the solid dispersion comprises a weight ratio of compound (1):the pharmaceutically acceptable dispersion carrier of 1:1 to 1:3 In embodiments, the solid dispersion comprises a weight ratio of compound (1):the pharmaceutically acceptable dispersion carrier of approximately 1:1.
In an embodiment, the solid dispersion is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak at 2-theta angles equal or below 40.0°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å. “Cu-Kα radiation” as used in the present invention includes Cu-Kα1 radiation and Cu-Kα1,2 radiation, wherein Cu-Kα1 radiation has a wavelength of 1.54056 Å and Cu-Kα1,2 radiation has an average wavelength of 1.54184 Å.
In another embodiment, the solid dispersion is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak in the range of from 2.0 to 40.0°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In still another embodiment, the solid dispersion is characterized by having an x-ray powder diffractogram (XRPD) essentially the same as shown in
In yet another embodiment, the solid dispersion is characterized by having a differential scanning calorimetry curve comprising a single glass transition temperature (Tg) signal, when measured with modulated differential scanning calorimetry (mDSC) with a modulation amplitude of 1° C./min and a heating rate of 3.0° C./min. Preferably, the single glass transition temperature (Tg) signal is in the range of from 90 to 190° C., preferably of from 110 to 120° C. In yet other embodiments, the solid dispersion comprises particles characterized by a particle size distribution determined by laser diffraction having
In still other embodiments, the solid dispersion comprises particles characterized by a particle size distribution determined by laser diffraction having
The term “particle size distribution” as used herein refers to a list of values or a mathematical function that defines the relative amount, typically in mass or volume, of particles present in a sample according to size. Particle size distribution can be characterized by one or more values, such as D90, D50 or D10. The particle size distribution may be determined by means well known to the skilled artisan e.g. by laser diffraction.
A further aspect relates to the use of the solid dispersion as described herein for the preparation of a pharmaceutical composition, wherein the pharmaceutical composition preferably is as defined below.
Another aspect provides a pharmaceutical composition comprising the solid dispersion as described herein and one or more pharmaceutically acceptable excipients. Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion as described herein and one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention is a pharmaceutical composition comprising a predetermined amount of the solid dispersion as described herein and one or more pharmaceutically acceptable excipients. In this context, a predetermined amount refers to the initial amount of the solid dispersion used for the preparation of the pharmaceutical composition.
The term “pharmaceutically acceptable excipient” refers to a non-toxic component that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients that may be used in the compositions of this invention include fillers, disintegrants, glidants, lubricants, and coating agents. The compositions may comprise further pharmaceutically acceptable excipients selected from buffers, binders, dispersion agents, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives usable in the manufacturing of a pharmaceutical product.
The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients. In embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, lubricants, and coating agents. In embodiments, the pharmaceutical composition comprises a filler, a disintegrant, a glidant and a lubricant. In embodiments, the pharmaceutical composition comprises a filler, a disintegrant, a glidant, a lubricant and a coating agent. It is to be understood that the pharmaceutical composition may comprise one or more excipients of each function, e.g. one or more filler, one or more disintegrants, one or more glidants, one or more lubricants, one or more coating agents.
In embodiments, the filler(s) is(are) selected from the group consisting of microcrystalline cellulose, mannitol and mixtures thereof. In embodiments, the disintegrant(s) is(are) selected from the group consisting of crosslinked sodium carboxymethyl cellulose, also denoted croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate and mixtures thereof. In certain embodiments, the disintegrant is croscarmellose sodium. In embodiments, the glidant is colloidal silicon dioxide. In embodiments, the lubricant(s) is(are) selected from the group consisting of stearyl fumarate, magnesium stearate and mixtures thereof. In certain embodiments, the lubricant is sodium stearyl fumarate.
In embodiments, the one or more pharmaceutically acceptable excipients comprise mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and sodium stearyl fumarate.
In embodiments, the pharmaceutical composition comprises, consists of or consists essentially of: a solid dispersion comprising compound (1) as defined herein or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and sodium stearyl fumarate.
In certain embodiments, the pharmaceutical composition comprises a coating agent, such as when formulated as a film-coated tablet. In embodiments, the coating agent comprises film-forming agents such as polyvinyl alcohol that may be partially hydrolysed, anti-tacking agents such as talc, pigments such as titanium dioxide, glyceryl mono and dicaprylocaprate (GMDCC) and iron oxides such as iron oxide yellow, and lubricants such as sodium lauryl sulphate.
Coating agents are commercially available such as under the tradename Opadry® e.g. Opadry® AMB II yellow. In a preferred embodiment, the coating agent does not contain titanium dioxide e.g. is free of titanium dioxide.
In embodiments, the pharmaceutical composition comprises:
In embodiments, the pharmaceutical composition consists of or consists essentially of:
In certain embodiments, the film coating is a non-functional film coat. In one embodiment, the film-coating does not contain titanium dioxide.
In embodiments, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, comprises the solid dispersion as described herein in a range of from 25 wt % to 65 wt %, preferably of from 35 wt % to 60 wt % or of from 25 wt % to 35 wt % or of from 27 wt % to 31 wt %, still preferably of approximately 30 wt %.
In embodiments, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, comprises:
In the present and any of the following embodiments referring to wt % of components of the pharmaceutical composition, it is to be understood that the sum of the ranges or amounts of all components does not exceed 100 wt %.
In further embodiments, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, comprises:
In still further embodiments, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, comprises:
In an embodiment, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, comprises:
In this embodiment, preferably, the lower limit of the range of solid dispersion, fillers, disintegrant, glidant and lubricant refers to the pharmaceutical composition with coating agent, while the higher limit of the same range refers to the pharmaceutical composition without coating agent.
In embodiments, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, consists essentially of or consists of:
In further embodiments, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, consists essentially of or consists of:
In still further embodiments, the pharmaceutical composition, based on a total weight of 100 wt % of the pharmaceutical composition, consists essentially of or consists of:
In embodiments, the pharmaceutical composition comprises compound (1) in a range of from 10 to 20 wt % based on a total weight of 100 wt % of the pharmaceutical composition. In embodiments, the pharmaceutical composition comprises compound (1) in an amount of approximately 15 wt % based on a total weight of 100 wt % of the pharmaceutical composition. In a particular embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 15 wt % compound (1), approximately 15 wt % hypromellose acetate succinate, approximately 36 wt % microcrystalline cellulose, approximately 24 wt % mannitol, approximately 7 wt % croscarmellose sodium, approximately 1.5 wt % colloidal silicone dioxide and approximately 1.5 wt % sodium stearyl fumarate, based on a total weight of 100 wt % of the pharmaceutical composition.
In a particular embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 15 wt % compound (1), approximately 15 wt % hypromellose acetate succinate, approximately 20 wt % microcrystalline cellulose, approximately 42 wt % mannitol, approximately 5 wt % croscarmellose sodium, approximately 1.5 wt % colloidal silicone dioxide and approximately 1.5 wt % sodium stearyl fumarate, based on a total weight of 100 wt % of the pharmaceutical composition.
In a particular embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 14 wt % compound (1), approximately 43 wt % hypromellose acetate succinate, approximately 19 wt % microcrystalline cellulose, approximately 24 wt % mannitol, approximately 7 wt % croscarmellose sodium, approximately 1.5 wt % colloidal silicone dioxide and approximately 1.5 wt % sodium stearyl fumarate, based on a total weight of 100 wt % of the pharmaceutical composition.
In a particular embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 17.5 wt % compound (1), approximately 17.5 wt % hypromellose acetate succinate, approximately 30 wt % microcrystalline cellulose, approximately 25 wt % mannitol, approximately 7 wt % croscarmellose sodium, approximately 1.5 wt % colloidal silicone dioxide and approximately 1.5 wt % sodium stearyl fumarate, based on a total weight of 100 wt % of the pharmaceutical composition.
In a particular embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 15 wt % compound (1), approximately 47 wt % hypromellose acetate succinate, approximately 15 wt % microcrystalline cellulose, approximately 15 wt % mannitol, approximately 5 wt % croscarmellose sodium, approximately 1 wt % colloidal silicone dioxide and approximately 1 wt % sodium stearyl fumarate, based on a total weight of 100 wt % of the pharmaceutical composition.
In one embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 15 mg compound (1), approximately 15 mg hypromellose acetate succinate, approximately 36 mg microcrystalline cellulose, approximately 24 mg mannitol, approximately 7 mg croscarmellose sodium, approximately 1.5 mg colloidal silicone dioxide and approximately 1.5 mg sodium stearyl fumarate.
In one embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 15 mg compound (1), approximately 15 mg hypromellose acetate succinate, approximately 20 mg microcrystalline cellulose, approximately 42 mg mannitol, approximately 5 mg croscarmellose sodium, approximately 1.5 mg colloidal silicone dioxide and approximately 1.5 mg sodium stearyl fumarate.
In one embodiment, the pharmaceutical composition comprises, consists essentially of or consists of: approximately 60 mg compound (1), approximately 60 mg hypromellose acetate succinate, approximately 80 mg microcrystalline cellulose, approximately 168 mg mannitol, approximately 20 mg croscarmellose sodium, approximately 6 mg colloidal silicone dioxide and approximately 6 mg sodium stearyl fumarate.
In an embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak at 2-theta angles equal or below 10.0°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In another embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak at 2-theta angles equal or below 9.0°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In yet another embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak at 2-theta angles equal or below 6.5°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Ku radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In another embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak in the range of from 2.0 to 10.0°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In still another embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak in the range of from 2.0 to 9.0°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In one embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak in the range of from 2.0 to 6.50, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å In another embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak in the range of from 2.0 to 10.0°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In yet another embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak at a 2-Theta angle of (5.9±0.2)°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In a further embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) comprising no diffraction peak at a 2-Theta angle of (6.2±0.2)°, when measured at a temperature in the range of from 20 to 30° C. and with Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å.
In another embodiment, the pharmaceutical composition is characterized by having an x-ray powder diffractogram (XRPD) essentially the same as shown in
To be used for treatment, the solid dispersion or the pharmaceutical composition may be included or formulated into appropriate dosage units to facilitate administration. The solid dispersion or the pharmaceutical composition thus may be formulated in suitable dosage unit formulations appropriate for each route of administration. Typical pharmaceutical unit formulations include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions particularly solutions for infusion, elixirs, syrups, sachets, emulsions, or dispersible powders. Dosage forms and formulations of active ingredients are known in the art and dosage units may generally be prepared in any conventional manner.
The solid dispersion or the pharmaceutical composition preferably may be administered by oral routes of administration and may be formulated in suitable dosage unit formulations. The pharmaceutical composition may be administered as a tablet, hard or soft gelatin capsule, pill, granules or a suspension. In embodiments, the pharmaceutical composition is in the form of a tablet, of granules or of a capsule. In preferred embodiments, the pharmaceutical composition is in the form of a film-coated tablet. Suitable tablets may be obtained, for example, by mixing the solid dispersion with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. Tablets may be compressed from the solid dispersion or a mixture of the solid dispersion with excipients or from pellets thereof. In other embodiments, the solid dispersion, a mixture of the solid dispersion with excipients or pellets thereof may be packed into capsules.
Although oral administration may be preferred in view of compliance, routes of administration are not limited to oral administration, but the solid dispersion or the pharmaceutical composition may be administered parenterally, e.g. intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or by implant, or enterically, nasal, vaginal, rectal, or topical administration.
The solid dispersion or the pharmaceutical composition may be administered at therapeutically effective amounts or be included in a dosage form in a therapeutically effective amount. A therapeutically effective amount refers to an amount effective at dosages and for periods of time necessary to achieve a desired therapeutic result and is the minimum amount necessary to prevent, ameliorate, or treat a disease or disorder, or which any toxic or detrimental effects of the compound is outweighed by the therapeutically beneficial effects. As used herein, the terms “active ingredient”, “active pharmaceutical ingredient”, “active substance” and “API” refer to a component that is intended to furnish pharmacological activity or other direct effect, such as compound (1).
The pharmaceutical composition preferably contains a therapeutically effective amount of compound (1). In embodiments, a therapeutically effective amount of compound (1) may be portioned in one or more individual dosage unit formulations, and thus several individual dosage unit formulations may contain a portion of a therapeutically effective amount of compound (1). In embodiments, a tablet, a portion of granules or a capsule may contain between 5 mg and 100 mg of compound (1). In embodiments, a tablet, a portion of granules or a capsule may contain between 15 mg and 80 mg of compound (1). In embodiments, a tablet, a portion of granules or a capsule may contain between 15 mg and 30 mg of compound (1). In embodiments, a tablet, a portion of granules or a capsule may contain approximately 15, 30 or 60 mg of compound (1).
For storage, the solid dispersion or the pharmaceutical composition may be packaged in appropriate containments (i.e. a means to contain the solid dispersion or pharmaceutical composition). Such containments may be selected from bags, blisters, bottles, ampoules, and vials. The containments may be made of suitable packaging materials.
Typical packaging materials are selected from glass, polyethylene, polypropylene, polystyrene, polymethyl methacrylate, low-density polyethylene (LDPE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cyclic olefin copolymers (COC), cyclic olefin polymers (COP), polyethylene terephthalate (PET), glycol-modified polyethylene terephthalate (PETg), aluminum, polyamide, and any combinations thereof. In a particular embodiment, the solid dispersion is packaged into double low-density polyethylene (LDPE) bags. In still another embodiment, the pharmaceutical composition is packaged into high-density polyethylene (HDPE) bottles. Preferably, the HDPE bottles further contain a desiccant. Typical desiccants may be selected from activated alumina, aerogel, benzophenone (as anion), bentonite clay, calcium chloride, calcium oxide, calcium sulfate, cobalt(II) chloride, copper(II) sulfate, lithium chloride, lithium bromide, magnesium chloride hexahydrate, magnesium sulfate, magnesium perchlorate, molecular sieve, phosphorous pentoxide, potassium carbonate, potassium hydroxide, rice, silica gel, sodium chlorate, sodium chloride, sodium hydroxide, sodium sulfate, sucrose and sulfuric acid. In a preferred embodiment the desiccant is silica gel.
A further embodiment of the present invention refers to a kit comprising:
The solid dispersion and pharmaceutical compositions as described herein can be used as medicaments. Particularly, the solid dispersion and pharmaceutical compositions as described herein can be used for the treatment and/or prevention of oncological and/or hyperproliferative disorders, in particular in anti-cancer therapy.
According to an aspect is provided the solid dispersion, as described herein, for use as a medicament. According to another aspect is provided the pharmaceutical composition, as described herein, for use as a medicament. Another embodiment of the present invention is the solid dispersion or the pharmaceutical composition for treating or preventing a disease.
According to an aspect is provided the solid dispersion, as described herein, for use as an anti-cancer medicament. According to another aspect is provided the pharmaceutical composition, as described herein, for use as an anti-cancer medicament.
In an embodiment is provided the solid dispersion as described herein for use in the treatment and/or prevention of a disease or a disorder modulated by HER2, particularly an oncological and/or hyperproliferative disease. A further embodiment provides the pharmaceutical composition as described herein for use in the treatment and/or prevention of a disease or disorder modulated by HER2, particularly an oncological and/or hyperproliferative disease. Another aspect refers to the solid dispersion described herein or the pharmaceutical composition described herein for use in a method of treating and/or preventing a disease or disorder modulated by HER2, particularly an oncological or hyperproliferative disease.
A further aspect relates to a method of treating and/or preventing a disease or disorder modulated by HER2, particularly an oncological and/or hyperproliferative disease, wherein the method comprises the step of administering the solid dispersion described herein or the pharmaceutical composition described herein to a patient. In an embodiment, such method comprises administering to a human in need of such treatment a therapeutically effective amount of the solid dispersion or pharmaceutical composition described herein.
A related aspect relates to the use of the solid dispersion described herein or the pharmaceutical composition described herein in the manufacture of a medicament. An embodiment relates to the use of the solid dispersion described herein or the pharmaceutical composition described herein in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder modulated by HER2, particularly an oncological and/or hyperproliferative disease.
In one aspect, is provided the solid dispersion or the pharmaceutical composition as described herein for use in the treatment and/or prevention of a disease and/or condition, wherein the inhibition of wild type and/or mutant HER2 is of therapeutic benefit, particularly for the treatment and/or prevention of a disease and/or condition, wherein the inhibition of HER2 exon 20 mutant protein is of therapeutic benefit. Examples of such diseases and/or conditions include, but are not limited to, oncological and/or hyperproliferative diseases such as cancer.
One aspect relates to the solid dispersion described herein for use in the treatment and/or prevention of an oncological and/or hyperproliferative disease. A further aspect relates to the pharmaceutical composition as described herein for use in the treatment and/or prevention of an oncological and/or hyperproliferative disease.
As used herein, the term “hyperproliferative disease” refers to conditions wherein cell growth is increased over normal levels. Hyperproliferative diseases include malignant diseases, such as cancers, and non-malignant diseases. In preferred embodiments, the hyperproliferative disorder is cancer. As used herein, the term “oncological disease” refers to a disease or medical condition associated with cancer or cancer indication. Cancers can be classified by the type of tissue in which the cancer originates (histological type) and by primary site, or the location in the body, where the cancer first developed.
In an embodiment, the oncological and/or hyperproliferative disease is cancer.
In an embodiment is provided the solid dispersion as described herein for use in the treatment and/or prevention of cancer. A further embodiment provides the pharmaceutical composition as described herein for use in the treatment and/or prevention of cancer. Another aspect refers to the solid dispersion described herein or the pharmaceutical composition described herein for use in a method of treating and/or preventing cancer.
A further aspect relates to a method of treating and/or preventing cancer, wherein the method comprises the step of administering the solid dispersion described herein or the pharmaceutical composition described herein to a patient. In an embodiment, such method comprises administering to a human in need of such treatment a therapeutically effective amount of the solid dispersion or pharmaceutical composition described herein.
An embodiment relates to the use of the solid dispersion described herein or the pharmaceutical composition described herein in the manufacture of a medicament for the treatment and/or prevention of cancer.
In embodiments, the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant. In embodiments, the cancer is HER2 exon 20 mutant cancer. In embodiments, the oncological and/or hyperproliferative disease is a HER2 overexpressed, HER2 amplified and/or HER2 mutant cancer.
“HER2 overexpressed” as used herein refers to a cancer, where the cells of the cancer or tumor express HER2 at levels detectable by immunohistochemistry (e.g. IHC 2+ or IHC 3+) and/or methods assaying ERBB2 messenger RNA.
“HER2 amplified” as used herein refers to a cancer where the cancer or tumor cells exhibit more than 2, in particular more than 3, 4, 5, 6, 7, 8, 9 or 10, preferably more than 6, copies of the HER2 gene ERBB2.
HER2 expression, gene copy number and amplification can be measured, for example, by determining nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), ELISAs, and RNA quantification using techniques such as RT-PCR, microarray analysis and Next Generation Sequencing (NGS). HER2 expression in or on the cancer sample cells can be compared to a reference cell. The reference cell can be a non-cancer cell obtained from the same subject as the sample cell. The reference cell can be a non-cancer cell obtained from a different subject or a population of subjects.
When the cancer is HER2 overexpressed and/or HER2 amplified in or on a cell, the cancer can be referred to as being “HER2 positive”.
“HER2 mutant” as used herein refers to a cancer harbouring at least one mutation, i.e. an alteration in the nucleic acid sequence of the HER2 gene and/or an alteration in the amino acid sequence of the HER2 protein, including but not limited to those listed below. Mutations can be found with any method known to the skilled person, such as molecular diagnostic methods including but not limited to Polymerase Chain Reaction (PCR), Single Strand Conformational Polymorphism (SSCP), Denaturing Gradient Gel Electrophoresis (DGGE), Heteroduplex analysis, Restriction fragment length polymorphism (RFLP), Next Generation Sequencing (NGS) and Whole Exome Sequencing.
“Cancer with HER2 exon 20 mutation” or “HER2 exon 20 mutant cancer” as used herein refers to a cancer where the cancer or tumor cells harbour at least one HER2 exon 20 mutation including but not limited to the mutations listed below.
ERBB2 (HER2) exon 20 encodes for a part of the kinase domain and ranges from amino acids 769 to 835. Every mutation, insertion, duplication or deletion within this region is defined as an exon 20 mutation including the following mutations: p.A772_G773insMMAY; p.Y772_A775_dup (YVMA); p.A775_G776insYVMA; p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insSVMA; p.A775_G776insVVMA; p.A775_G776insYVMS; p.A775_G776insC; p.A776_delinsVC; p.A776_delinsLC; p.A776_delinsVV; p.A776_delinsAVGC; p.A776_delinsIC; p.A776_V777delinsCVC; p.V777_insE; p.G778_P780dup (GSP); p.G776_delinsVC (“p.” is referring to the HER2 protein).
In addition oncogenic HER2 mutations exist outside of exon 20 including the following mutations: p.S310F; p.R678Q; p.L755S; p.L755A; p.L755P; p.S310Y; p.S310A; p.V842I; p.D769Y; p.D769H; p.R103Q; p.G1056S; p.I767M; p.L869R; p.L869R; p.T733I; p.T862A; p.V697L; p.V777L; p.V777M; p.R929W; p.D277H; p.D277Y; p.G660D (“p.” is referring to the HER2 protein).
In embodiments, the oncological and/or hyperproliferative disease or the cancer is one of the following cancers, tumors or other proliferative diseases, without being restricted thereto: Cancers/tumors/carcinomas of the head and neck: e.g. tumors/carcinomas/cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands);
All cancers/tumors/carcinomas mentioned above which are characterized by their specific location/origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom. Preferably, the cancer as defined herein (including in any embodiment referring to e.g. cancer types) is metastatic, advanced, and/or unresectable.
All cancers/tumors/carcinomas mentioned above may be further differentiated by their histopathological classification:
In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecologic cancer, head and neck tumor, lung cancer, nervous system cancer, and skin cancer.
Preferably, said brain cancer is a glioblastoma or a glioma.
Preferably, said breast cancer is lobular breast cancer. In addition or in alternative, said breast cancer is preferably metastatic.
Preferably, said endocrine cancer is nerve sheath tumor, more preferably HER2 mutant nerve sheath tumor.
Preferably, said gastrointestinal cancer is selected from the group consisting of anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophagus tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer and small bowel cancer. In addition or in alternative, said gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably HER2 mutant. Still preferably, said gastrointestinal cancer is selected from the group consisting of gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and esophageal adenocarcinoma, in particular metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma and metastatic esophageal adenocarcinoma.
Preferably, said gynecologic cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer and ovarian cancer.
Preferably, said head and neck tumor is a salivary gland cancer or tumor.
Preferably, said lung cancer is non-small cell lung cancer (NSCLC).
Preferably, said nervous system cancer is peripheral nervous system cancer, more preferably HER2 amplified peripheral nervous system cancer.
Preferably, said skin cancer is not a melanoma, i.e. non-melanoma skin cancer.
In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophagus tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer and non-melanoma skin cancer.
In some embodiments, the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophagus tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer and non-melanoma skin cancer.
In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophagus tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
In some embodiments, the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophagus tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophagus tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
In embodiments, the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer selected from brain cancer, breast cancer, biliary cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophagus tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
In other embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer or lung cancer. In further embodiments, the cancer is selected from cancers/tumors/carcinomas of the lung: e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer). In still further embodiments, the cancer is NSCLC. In still further embodiments, the cancer is HER2 exon 20 mutant NSCLC.
In an embodiment, the cancer is advanced, unresectable or metastatic NSCLC harbouring a HER2 mutation, wherein said HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, the solid dispersion or the pharmaceutical composition as described herein is administered as first line of therapy. Still preferably, in this embodiment, the solid dispersion or the pharmaceutical composition as described herein is administered as second or further line of therapy.
In embodiments, the cancer is HER2 positive metastatic breast cancer. Preferably, in this embodiment, the solid dispersion or the pharmaceutical composition as described herein is administered as first line of therapy. Still preferably, in this embodiment, the solid dispersion or the pharmaceutical composition as described herein is administered as second or further line of therapy.
In embodiments, the cancer is HER2 positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, the solid dispersion or the pharmaceutical composition as described herein is administered as first line of therapy. Still preferably, in this embodiment, the solid dispersion or the pharmaceutical composition as described herein is administered as second or further line of therapy.
A further aspect relates to compound (1), the solid dispersion or the pharmaceutical composition for use as a medicament, particularly, for the treatment and/or prevention of oncological and/or hyperproliferative disorders, such as cancer, wherein compound (1), the solid dispersion or the pharmaceutical composition is administered:
In embodiments, the solid dispersion as described herein or the pharmaceutical composition as described herein is administered:
Another aspect relates to compound (1) as defined above for use in the treatment and/or prevention of an oncological and/or hyperproliferative disease, wherein compound (1) is administered:
In embodiments, compound (1), the solid dispersion or the pharmaceutical composition is administered to a fasted subject.
The term “subject” as used herein refers to a human, e.g. a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer.
In embodiments, compound (1), the solid dispersion or the pharmaceutical composition is administered in combination with a medicament that increases gastric pH, preferably a proton-pump inhibitor (PPI), an antacid or an antihistamine.
In embodiments, compound (1), the solid dispersion or the pharmaceutical composition is administered to a fasted subject and in combination with a medicament that increases gastric pH, preferably a proton-pump inhibitor (PPI), an antacid or an antihistamine.
In embodiments, compound (1), the solid dispersion or the pharmaceutical composition is administered to a subject having a gastric pH in the range of from about 1 to 7.
In embodiments, compound (1), the solid dispersion or the pharmaceutical composition is administered to a subject having a gastric pH in the range of from about 1 to 5.
A “fasted subject” as used herein refers to one who has not eaten for at least eight hours, preferably for at least ten hours, typically overnight, prior to administration of the solid dispersion or the pharmaceutical composition or a dosage form thereof. A fasted subject conveniently may receive compound (1), the solid dispersion, the pharmaceutical composition or a dosage form thereof with water after at least eight or 10 hours fasting. Thereafter, no food may be taken for a period of, e.g. 4 hours although small quantities of water may be taken after, e.g. 2 hours after receiving medicament.
In embodiments, a fasted subject is one who has not eaten for at least two hours prior to the administration of the solid dispersion or the pharmaceutical composition described herein and/or who does not eat for at least one hour after administration of the solid dispersion or the pharmaceutical composition described herein.
In embodiments, a fasted subject is one who has not eaten for approximately two hours prior to the administration of the solid dispersion or the pharmaceutical composition described herein and who does not eat for approximately one hour after administration of the solid dispersion or the pharmaceutical composition described herein. In these embodiments, the fasted subject may be referred to as “modified fasted subject”.
“Medicament that increase gastric pH” refers to a class of medications that neutralize stomach acidity. Medicaments that neutralize gastric acid may reduce pepsin activity. In embodiments, the medicament that increases gastric pH is a proton-pump inhibitor. The term “proton-pump inhibitor” (PPI) refers to a class of medications that cause a profound and prolonged reduction of stomach acid production. In embodiments, they are suppressors of gastric acid secretion. In embodiments, PPIs which may be administered in combination with compound (1), the solid dispersion or the pharmaceutical composition, include, without being restricted thereto, rabeprazole, omeprazole, pantoprazole, esomeprazole, lansoprazole, dexlansoprazole, and ilaprazole. Rabeprazole is a proton-pump inhibitor indicated for diseases that profit with an increased gastric pH such as reflux esophagitis.
In embodiments, the medicament that increases gastric pH is an antacid. The term “antacid” refers to a class of medications that neutralize stomach acidity. In embodiments, antacids which may be administered in combination with compound (1), the solid dispersion or the pharmaceutical composition, include, without being restricted thereto, salts of aluminium, calcium, magnesium or sodium, such as aluminium hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and sodium bicarbonate.
In embodiments, the medicament that increases gastric pH is an antihistamine, in particular a H2 receptor antagonist. The term “H2 receptor antagonist” refers to a class of medications that block the action of histamine in the stomach. In embodiments, antihistamines which may be administered in combination with compound (1), the solid dispersion or the pharmaceutical composition, include, without being restricted thereto, cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine, lavoltidine and niperotidine.
Compound (1), the solid dispersion, the pharmaceutical composition or a dosage form thereof and the medicament that increases gastric pH, can be administered simultaneously, concurrently, sequentially, or successively. The term “simultaneous” refers to the administration of both compounds/compositions at substantially the same time. The term “concurrent” refers to administration of the active ingredients within the same general time period, for example on the same day(s) but not necessarily at the same time. The term “sequential” administration includes administration of one active ingredient during a first time period, for example over the course of a few hours, days or a week, using one or more doses, followed by administration of the other active ingredient during a second time period, for example over the course of a few hours, days or a week, using one or more doses. An overlapping schedule may also be employed, which includes administration of the active ingredients on different days over the treatment period, not necessarily according to a regular sequence. The term “successive” administration, alternatively, refers to an administration where the second administration step is carried out immediately once the administration of the first compounds has been finished. Variations of these general administration forms may also be employed.
In embodiments, compound (1), the solid dispersion, the pharmaceutical composition or a dosage form thereof is administered after a medicament that increases gastric pH, preferably a proton-pump inhibitor (PPI), an antacid or an antihistamine.
In another aspect, the present invention relates to the solid dispersion or the pharmaceutical composition as described herein for use in the treatment and/or prevention of an oncological and/or hyperproliferative disease as defined herein, wherein the solid dispersion or the pharmaceutical composition is administered in combination with a cytostatic and/or cytotoxic active substance and/or in combination with radiotherapy and/or immunotherapy.
In another aspect, the present invention relates to a combination of the solid dispersion or the pharmaceutical composition as described herein with a cytostatic and/or cytotoxic active substance and/or in combination with radiotherapy and/or immunotherapy for use in the treatment and/or prevention of cancer.
The solid dispersion or the pharmaceutical composition as described herein may be used on their own or in combination with one or more other pharmacologically active substances such as state-of-the-art or standard-of-care compounds, such as e.g. cell proliferation inhibitors, anti-angiogenic substances, steroids or immune modulators/checkpoint inhibitors, and the like.
Pharmacologically active substances which may be administered in combination with the solid dispersion or the pharmaceutical composition as described herein, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors and/or of their corresponding receptors (growth factors such as for example platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER, e.g. HER2, HER3, HER4) and hepatocyte growth factor (HGF) and/or their corresponding receptors), inhibitors are for example (anti-)growth factor antibodies, (anti-)growth factor receptor antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, pertuzumab and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5fluorouracil (5fluorineU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (e.g. anthracyclins such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g. tasquinimod), tubuline inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g. PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORCT/2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors), protein protein interaction inhibitors (e.g. IAP activator, Mel-1, MDM2/MDMX), MEK inhibitors, ERK inhibitors, KRAS inhibitors (e.g. KRAS G12C inhibitors), signalling pathway inhibitors (e.g. SOS1 inhibitors), FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2/Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g. everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1/2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents such as immune checkpoint inhibitors (e.g. CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules/immunoglobulins, such as e.g. ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g. anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T-cell engagers (e.g. bi-specific T-cell engagers (BiTEs®) like e.g. CD3×BCMA, CD3×CD33, CD3×CD19), PSMA×CD3), tumor vaccines and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
Solid dispersions of the invention can be prepared from any process known in the art for this purpose, for example as disclosed in S. V. Bhujbal et al., Acta Pharmaceutica Sinica B 2021; 11(8):2505e2536, which is herein incorporated by reference. According to the invention, solid dispersions are generally prepared by dissolving an active substance and a pharmaceutically acceptable dispersion carrier in a solvent or mixture of solvents to form a feed solution, and then the solvent is removed from the feed solution, such as by spray-drying, to form the solid dispersion.
In an embodiment, a process of preparing the solid dispersion as described herein is provided, the process comprising the steps of:
This process may further comprise the step of drying the solid dispersion obtained in step b).
In an embodiment, a process of preparing the solid dispersion as described herein is provided, the process comprising the steps of:
The solution or suspension of step a) according to any of the above-described processes can be referred to as a feed solution.
In embodiments, the removing of the solvent in step b) of the above defined processes is carried out by spray-drying, freeze drying, rotary evaporation, distillation, drum drying and/or vacuum drying. In a preferred embodiment, the removing of the solvent in step b) is carried out by spray-drying.
The term “spray drying” as used herein is used conventionally and broadly and generally refers to any process that involves the atomization of a solution, suspension, slurry, or emulsion containing one or more components of the desired product into droplets by spraying followed by the rapid evaporation of the sprayed droplets into solid powder by hot air at a certain temperature and pressure. Spray drying is a process known to a person skilled in the art.
Spray drying is generally performed by dissolving compound (1) and the pharmaceutically acceptable dispersion carrier in a solvent to prepare a feed solution. The feed solution may be pumped through an atomizer into a drying chamber. The feed solution can be atomized by conventional means known in the art, such as a two-fluid sonicating nozzle, a pressure nozzle, a rotating nozzle and a two-fluid non-sonicating nozzle. Then, the solvent is removed in the drying chamber to form the solid dispersion. A typical drying chamber uses hot gases, such as forced air, nitrogen, nitrogen-enriched air, or argon to dry particles. The size of the drying chamber may be adjusted to achieve particle properties or throughput.
Although the solid dispersion is preferably prepared by conventional spray drying techniques, other techniques known in the art may be used, such as melt extrusion, freeze drying, rotary evaporation, co-precipitation, KinetiSol® Dispersing Technology (KSD), fluidized bed technology, drum drying, vacuum drying or other solvent removal processes.
The processes described above of preparing the solid dispersion as described herein may comprise an additional step between steps a) and b) of spraying the solution or suspension obtained in step a) onto inert excipient cores. This process belongs to fluid bed technology, in particular fluid bed granulation technology.
In an embodiment, a process of preparing the solid dispersion as described herein is provided, the process comprising the steps of:
The spraying in step (a′) may be performed in a fluidized bed coater e.g. as top spray, bottom spray, Wurster, tangential or side rotor spray.
Any solvent or mixture of solvents where compound (1) at least partially dissolves can be used. Examples of suitable solvents that can be used individually or as mixtures include water, alcohols, such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol, isopropanol and butanol such as n-butanol, 2-butanol, isobutanol and tert-butanol; ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters, such as methyl acetate, ethyl acetate and propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; and various other solvents, such as dichloromethane (DCM), chloroform, tetrahydrofuran, acetonitrile, toluene and 1,1,1-trichloroethane. In an embodiment, the solvent referred to in any of the above described processes and embodiments thereof is selected from the group consisting of water, alcohols, ketones, esters, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, 1,1,1-trichloroethane and mixtures thereof. In an embodiment, the solvent referred to in any of the above described processes and embodiments thereof is selected from the group consisting of alcohols (in particular methanol, ethanol, n-propanol, isopropanol and butanol such as n-butanol, 2-butanol, isobutanol and tert-butanol), ketones (in particular acetone, methyl ethyl ketone and methyl isobutyl ketone), esters (in particular methyl acetate, ethyl acetate and propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate), dichloromethane (DCM), tetrahydrofuran, acetonitrile, toluene and 1,1,1-trichloroethane. Mixtures of solvents with water may also be used.
In embodiments, said solvent is a mixture of dichloromethane (DCM) and methanol (MeOH). The relative amounts of DCM and MeOH in the mixture may vary. Preferably, the mixture comprises at least 25 wt % MeOH based on a total weight of 100 wt % of the mixture. In embodiments, the mixture comprises an excess of DCM. Still preferably, the weight:weight ratio of DCM:MeOH ranges from 25:75 to 95:5 (w/w). Preferably, DCM and MeOH are in a weight:weight ratio of approximately 25:75, 50:50, 70:30, 75:25, 80:20, 85:15 or 90:10. A solvent mixture of DCM:MeOH in a ratio of approximately 90:10 (w/w) was advantageously found to enable higher throughput for spray-drying.
In embodiments, the concentration of solids in the feed solution (in particular the suspension or solution as defined in step a) above) is in the range of from about 1 to 20 wt %, based on a total weight of 100 wt % of the feed solution. Preferably, the concentration of solids in the feed solution is in the range of from about 5 to 15 wt %, more preferably of from about 8 to 12 wt % based on a total weight of 100 wt % of the feed solution. For example, the concentration of solids in the feed solution is about 8 wt % or 10 wt %, based on a total weight of 100 wt % of the feed solution.
After removal of the solvent by spray drying, the obtained solid dispersion is optionally subjected to a drying process in order to reduce residual solvent content. In embodiments, drying is performed at a temperature in the range of from about room temperature to 100° C., preferably of from about 30 to 60° C., more preferably of from about 35 to 45° C. For example, the drying is performed at a temperature of about 40° C. In other embodiments, the drying is performed at ambient pressure and/or under reduced pressure. For example, the drying is performed at ambient pressure or at a pressure of about 900 mbar or less, more preferably of about 100 mbar or less and most preferably of about 50 mbar or less, such as about 20 mbar or less. In still other embodiments, the drying is performed for a period in the range of from about 6 to 72 hours, preferably of from about 12 to 48 hours.
Another aspect relates to a solid dispersion obtainable by a process comprising the steps of:
Another aspect relates to a solid dispersion obtainable by a process comprising the steps of:
Another aspect relates to a solid dispersion obtainable by a process comprising the steps of:
In these aspects relating to a solid dispersion obtainable by a process, the process steps can be performed as described above with reference to the processes of preparing the solid dispersion. Pharmaceutical compositions, such as tablets, preferably film-coated tablets, can be manufactured according to conventional methods known to a skilled person. In embodiments, the manufacturing process can comprise the steps of 1) manufacturing a solid dispersion such as by spray-drying as described herein, 2) dry granulating of the solid dispersion with one or more suitable excipient(s), 3) blending the granules with suitable disintegrant(s) and/or lubricant(s) and/or glidants, 4) compressing the blend into tablet cores, and 5) optionally film-coating the tablet cores.
In the present invention, any aspect or embodiment referring to a feature (e.g. compound (1) being amorphous in the solid dispersion) can be combined to any one or more aspect(s) or embodiment(s) referring to (an)other feature(s) (e.g. the weight ratio of compound (1): the pharmaceutically acceptable dispersion carrier in the solid dispersion being 1:1 and/or the pharmaceutically acceptable dispersion carrier being HPMCAS), to provide further aspects or embodiments of the invention, e.g.
The expressions “as defined herein”, “as disclosed herein”, “as described herein”, “as used herein” and variants thereof at each instance they occur include all aspects, embodiments, subaspects, subembodiments, etc. of the feature or term they refer to.
In some embodiments, numerical values are cited, sometimes as part of a range. Said numerical values should be taken as approximate values, even when the terms “approximately” or “about” are not explicitly cited.
Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The examples which follow serve to illustrate the invention in more detail but do not constitute a limitation thereof.
In this Example, solid dispersions were prepared containing 25 wt % or 50 wt % compound (1) and 75 wt % or 50 wt %, respectively, of dispersion carriers HPMCAS-M (Shin-Etsu AQOAT), PVP-VA, Eudragit© L100 or HPMC HME 15LV.
The solid dispersions of this Example can be prepared according to the following protocol: the solid dispersion is spray dried from a spray solution composition comprising compound (1), the dispersion carrier and a DCM:MeOH (1:1 (w/w)) solvent system with a solids content of 8 wt % total solids. Solid dispersions are manufactured using a Procept 4M8TRX spray drier with 2-fluid nozzle type and 1.0 mm/1.0 mm nozzle cap/tip dimension, an inlet temperature of 85-90° C., an outlet temperature of 45-50° C., atomization at 3.0 bar, drying gas air flow rate of 0.50 m3/min, and a solution feed rate of approx. 15 g/min. Secondary drying of the dispersion is done in a vacuum dryer of tray dryer type in collection vessels, at 40° C. for 22.5 hours.
The spray drying yield results obtained following the protocol from the previous paragraph are summarized in Table 1, where gA stands for gram API (active pharmaceutical ingredient, i.e. compound (1)).
XRPDs can be obtained according to the following protocol: XRPD analysis is done with a Rigaku Miniflexx 600 diffractometer. An amount of approx. 10 mg of samples of the solid dispersions of compound (1) with dispersion carriers, e.g. with HPMCAS-M, PVP-VA, Eudragit® L100 or HPMC HME 15LV as in Example 1, is placed onto a zero-background sample disk and placed into the auto sampler of the Rigaku Miniflex 600. Samples are analyzed using the instrument parameters described in Table 2 below.
The XRPDs obtained following the protocol from the previous paragraph with the various solid dispersions prepared under Example 1 are displayed in
2.2 Modulated Differential Scanning Calorimetry (mDSC)
The solid dispersions of compound (1) with dispersion carriers HPMCAS-M, PVP-VA, Eudragit® L100 or HPMC HME 15LV of Example 1 were characterized by mDSC to determine the glass transition temperature (Tg).
mDSC can be performed according to the following protocol: mDSC analysis is done on a Thermal Analysis DSC 2500 with a Thermal Analysis Refrigerated Cooling System 90. An amount of 2-5 mg of samples is placed into a non-hermetic pan. A Tzero non-hermetic lid is affixed onto the pan and samples are analyzed in modulated mode in a scan range of 20 to 250° C. (unless otherwise specified) with a modulation amplitude of 1° C./min and a ramp rate (heating rate) of 3.0° C./min.
A summary of the glass transition temperatures (Tg) obtained following the protocol from the previous paragraph is presented in Table 3.
As can be taken from Table 3, all solid dispersions exhibited a single glass transition temperature, indicating a homogenous dispersion without evidence of phase separation. Glass transition temperature values trended as expected with respect to polymer and loading with compound (1). For Eudragit® L100 with glass transition temperatures greater than amorphous compound (1), the glass transition temperature decreased with increasing drug loading. For polymers HPMCAS-M, PVP-VA, and HPMC HME 15LV with glass transition temperatures below that of compound (1), glass transition temperature increased with increasing drug loading. All solid dispersions provided a glass transition temperature that is sufficiently high.
Solid dispersions of compound (1) were tested for different spray-drying conditions, such as solvents, inlet temperature, and spray drying parameters.
The solubility of compound (1) was measured in solvent blends of dichloromethane (DCM):methanol.
To do so, the following protocol can be followed: a solution of compound (1) is prepared at a high concentration, then diluted with solvent until compound (1) dissolves or until the concentration dropped below 1 wt %. Solubility is determined by visual observation.
The solubility data of compound (1) obtained following this protocol are shown in Table 4 below.
Therefore, a solvent blend of 90:10 DCM:methanol provides high solubility of compound (1) and has the highest potential throughput due to a lower concentration of methanol in the solvent system compared to DCM:methanol solvent blends with higher methanol ratio.
Solid dispersions comprising 50 wt % compound (1) and 50 wt % HPMCAS-M or 25 wt % compound (1) and 75 wt % HPMC HME 15LV were manufactured at a larger scale using lower inlet temperature than in Example 1.
To do so, the following protocol can be followed: the solid dispersions are spray dried from a spray solution composition comprising compound (1) and HPMCAS-M or HPMC HME 15LV using a DCM:MeOH (1:1 (w/w)) solvent system with a solids content of 8 wt % total solids. Solid dispersions are manufactured using a Procept 4M8TRX spray drier with 2-fluid nozzle type and 1.0 mm/1.0 mm nozzle cap/tip dimension, an inlet temperature of 55-70° C., an outlet temperature of 45-50° C., atomization at 3.0 bar, drying gas air flow rate of 0.50 m3/min, and a solution feed rate of approx. 10-15 g/min. Secondary drying of the dispersion is done in a vacuum dryer of tray dryer type in collection vessels, at 40° C. for approx. 24 hours.
The spray drying yield results obtained following this protocol are summarized in Table 5, where gA stands for gram API (active pharmaceutical ingredient, i.e. compound (1)). mDSC results (non-hermetic pan, heating 3° C./min, modulation 1° C./min) are summarized in Table 6.
The effects of flow rate (=liquid feed rate), dryer outlet temperature, and drying environment on the spray dried solid dispersions were tested. For the tests a composition containing 50 wt % compound (1) and 50 wt % of dispersion carrier HPMCAS-M was used. The composition was spray dried from a spray solution composition comprising compound (1) and HPMCAS-M using a solvent ratio DCM:MeOH of 90:10 (w/w) with a solids content of 10 wt % total solids. Solid dispersions were manufactured using an open loop custom development spray dryer SD-90, with SK 79-16 spray systems nozzle. Liquid feed rates between 291 and 317 g/min and outlet temperatures between 35 and 45° C. were tested. The process parameters are summarized in Table 7 below.
Yield increased from the first lot sprayed (3.3-A) to the last lot sprayed (3.3-C). Yield was lower for lot A due to fixed losses, which decreased the percentage yield of smaller batch sizes relative to larger batches and increased as lots were sprayed because of carryover from previous lots and the diminishing effect of fixed losses on the later lots.
Characterization of the solid dispersions of samples 3.3-A, 3.3-B and 3.3-C was performed using X-Ray Powder Diffraction (XRPD), modulated Differential Scanning Calorimetry (mDSC) and particle size distributions (PSD). PSD was determined by laser diffraction.
XRPDs can be obtained according to the following protocol: XRPD analysis is performed using a Rigaku Miniflex 600 diffractometer. An amount of approx. 10 mg of samples 3.3-A, 3.3-B and 3.3-C is placed onto a zero-background sample disk and loaded into the auto sampler of the Rigaku Miniflex 600. Samples are analyzed using the instrument parameters as described in Table 8 below.
The XRPDs obtained following the protocol from the previous paragraph with the solid dispersions of samples 3.3-A, 3.3-B and 3.3-C are displayed in
For mDSC measurements, this protocol can be followed: an amount of 2-5 mg of samples 3.3-A, 3.3-B and 3.3-C is placed into a Tzero pan. A Tzero non-hermetic lid is affixed onto the pan and samples are analyzed in modulated mode in a scan range of 0 to 250° C. with a modulation amplitude of 1° C./min, a modulation period of 60 s and a ramp rate (heating rate) of 3° C./min. A summary of the glass transition temperatures is given in Table 9.
The thermograms obtained following the protocol from the previous paragraph of the solid dispersion of samples 3.3-A, 3.3-B and 3.3-C all showed a single glass transition around 116° C. with no obvious melt or recrystallization events. This indicates that the solid dispersions were single-phase, comprising amorphous compound (1).
The particle size distribution (PSD) for the solid dispersions of samples 3.3-A, 3.3-B and 3.3-C can be measured by laser diffraction of dry, dispersed powder using a Sympatec HELOS laser diffraction system and RODOS dry powder feed system. The system can be run at a dispersive pressure of 3 bar with an R4 lens. The results according to this method are summarized in Table 10.
Spray drying parameters were further tested for larger batch sizes. For the tests a mixture containing 50 wt % compound (1) and 50 wt % of dispersion carrier HPMCAS-M was used. The mixture was spray dried from a spray solution composition using a solvent ratio DCM:MeOH of 90:10 (w/w) with a solids loading of 10 wt %. Solid dispersions were manufactured using an open loop custom development spray dryer SD-90, with SK 79-16 spray systems nozzle. Feed rates of 300 and 325 g/min and outlet temperatures of 44° C. and 40° C. were tested. The process parameters are summarized in Table 11 below.
It is assumed that the yield for sample 3.4-A was low because of the small batch size due to fixed losses. Fixed losses are independent of batch size but represent a higher portion of smaller batches. Therefore, the larger batch size of sample 3.4-B led to a higher yield. The characterization of both samples was performed using XRPD, mDSC and PSD. PSD was determined by laser diffraction.
XRPD scans of samples 3.4-A and 3.4-B were performed as described in Example 3.3 above. The diffractograms for the solid dispersion of samples 3.4-A and 3.4-B are displayed in
For mDSC measurements, an amount of 2-5 mg of samples 3.4-A and 3.4-B was placed into a Tzero pan and measurement was performed as described in Example 3.3 above, except that a scan range of 0 to 200° C. was used for sample 3.4-B. A summary of the glass transition temperatures is given in Table 12 below.
The thermograms of the solid dispersion of samples 3.4-A and 3.4-B exhibited a single glass transition, indicating single-phase, amorphous material with no obvious peaks in the mDSC thermograms that would indicate crystalline material. The difference in glass transition temperatures compared to samples 3.3 may be attributed to different lots of compound (1) being used for the SDD manufacture and/or noise within the measurement of the instrument.
The mDSC results are consistent with the XRPD results, indicating by two orthogonal methods that the solid dispersions contained compound (1) in amorphous form.
The particle size distribution (PSD) for the solid dispersions of samples 3.4-A and 3.4-B can be measured by laser diffraction of dry, dispersed powder using a Sympatec HELOS laser diffraction system and RODOS dry powder feed system. The system can be run at a dispersive pressure of 3 bar with an R4 lens. The results according to this method are summarized in Table 13.
Physical stability of amorphous solid dispersion formulations of compound (1) equivalent to samples 3.3-A, 3.3-B and 3.3-C obtained in Example 3.3 was evaluated in an accelerated stability study. Each sample was incubated in open vials at: (i) ambient temperature/ambient humidity, (ii) ambient temperature/60% relative humidity, (iii) 40° C./ambient humidity and (iv) 40° C./75% relative humidity. Relative humidity (RH) was achieved through use of saturated salt solutions (sodium bromide for an approximate 60% RH at ambient temperature, and sodium chloride for 75% RH at 40° C.). After two and four weeks, samples were removed for analysis and characterized via XRPD to evaluate potential recrystallization.
No changes in physical properties were observed. Diffractograms of all amorphous solid dispersions remained consistent with an amorphous form of compound (1) after four weeks at all storage conditions.
An amorphous solid dispersion (50 wt %:50 wt % compound (1):HPMCAS-M, e.g. prepared according to the procedure of Example 1) was exposed in an open container to 75° C./79% relative humidity and 80° C./76% relative humidity for three weeks. The respective XRPDs are displayed in
Solubilities of an amorphous solid dispersion of compound (1) with HPMCAS-M (50 wt %:50 wt %) and of crystalline compound (1) (e.g. prepared according to Reference Example 1 and 2 hereinafter) were measured in different aqueous media at room temperature, and in biorelevant media at 37° C. The media used for solubility assays are listed in Table 14 below.
The following protocol has been used to prepare samples for solubility measurements:
Two standard calibration curves (chromatographic UV peak area vs. concentration) are established in DMSO at 254 nm or 410 nm for each solid form and for the solid dispersion, one between 0.025 or 0.050 μg/mL and 1 μg/mL (injection volume=9 μL) and another between 1 μg/mL and 500 μg/mL (injection volume=0.4 μL). The calibration curves are linear in the whole investigated concentration range.
The results of the solubility assays obtained following the protocol from the previous paragraphs are summarized in Table 15 and displayed in
Both crystalline forms of compound (1) have been found to be soluble in strong acidic media but solubility drops at pH 5. Also, in the biorelevant fasted and fed simulated intestinal fluids (FaSSIF and FeSSIF) the solubility of the crystalline forms of compound (1) is poor. It has been found that the solubility of compound (1) is significantly improved at pH 5 and in biorelevant media, when it is formulated as an amorphous solid dispersion with HPMCAS-M.
The kinetic solubilities of crystalline compound (1) and of various amorphous solid dispersions formulations prepared according to the procedures disclosed in Example 1 (25 wt %:75 wt % as well as 50 wt %:50 wt % compound (1):polymer) with polymers selected from HPMCAS-M, HPMC HME 15LV, PVP-VA, Eudragit® L100 were measured in biorelevant media in the course of a pH change non-sink dissolution test.
To do so, the following protocol can be used: samples are first delivered into simulated gastric fluid (SGF) and then transferred via a dilution step into simulated intestinal fluid (SIF). The test is conducted at 3 mg/mL in 0.01N HCl as SGF (first stage) followed by 3× dilution to target 1 mg/mL in FaSSIF, pH 6.5 (+33 mM sodium phosphate for additional buffering capacity) after 30 minutes. An evaluation of “total drug” and “dissolved drug” is made. Total drug is determined by sampling the supernatant of a non-sink (saturated) sample after bench-top centrifugation (˜19000 rcf, 3-5 min). Total drug includes free drug, bile salt micelles (in SIF), and colloidal species formed by drug-polymer interactions. Dissolved drug is determined by filtering the total drug supernatant through a 0.22 μm filter to remove large colloidal species. Dissolved drug includes free drug and bile salt micelles.
Following this protocol, it was observed that while all formulations were fully dissolved at 3 mg/mL in simulated gastric fluid (data not shown) the amorphous solid dispersion formulations demonstrated significantly more dissolved drug relative to crystalline API in simulated intestinal fluid (see
Film-coated tablets comprising a solid dispersion of compound (1) generally were prepared according to the following scheme unless otherwise specified.
Compound (1) and HPMCAS-MG (hydroxypropopyl methylcellulose acetate succinate-MG) are dissolved in a solvent mixture of dichloromethane (DCM) and methanol (MeOH) to produce a spray drying solution. Alternative dispersion carriers could be used instead of or in addition to HPMCAS-MG. The solution is spray dried using a suitable spray drying machine to produce a spray dried solid dispersion. This step of spray drying can be performed as described in detail in Examples 1 and 3. The spray dried solid dispersion is then further dried in a suitable dryer to remove residual solvents as described in detail in Examples 1 and 3.
Step 2: Dry Granulation of Solid Dispersion with Excipients
The dried solid dispersion is mixed with portions of microcrystalline cellulose, mannitol, croscarmellose sodium, and colloidal silicon dioxide, and the mixture of solid dispersion and fillers, disintegrant and glidant is then pre-blended and screened/delumped. Sodium stearyl fumarate as lubricant is added to the pre-blend. The intragranular blend is then granulated using a roller compactor, equipped with a 1.0 mm screen. The screened dry granules are collected for subsequent final blending.
The granules are blended together with a pre-screened extragranular mixture of croscarmellose sodium and colloidal silicon dioxide in a blender. Sodium stearyl fumarate is added and blended to produce a final blend.
The final blend is then compressed into tablet cores.
Steps 1 to 4 were followed with the ingredients given in Table 16 below.
Steps 1-4 can be followed by an optional film-coating step, which can be performed as outlined below.
The film coating mixture Opadryo AMB II yellow is dispersed in water for injection using a stirrer and vessel. The tablet cores are coated with the film coating suspension in a suitable pan coater to obtain film-coated tablets comprising a solid dispersion of compound (1) and the dispersion carrier. Step 5 is optional. Alternative film coating mixtures could be used instead of Opadryo AMB II yellow.
Film-coated tablets comprising a spray-dried solid dispersion of compound (1) and HPMCAS MG (hypromellose acetate succinate where MG refers to the grade that is soluble at pH ≥6.0 and it is a granular free flowing powder) were prepared as described in Example 6.1, followed by Step 5 described above. A summary of the ingredients is given in Table 17 below.
The film-coated tablets comprised 15 mg or 60 mg of compound (1). Dichiloromethane and methanol were used as solvents and nitrogen was used as drying gas for the solid dispersion but were removed during the process, and thus did not appear in the final product. Further, as solvent for the film coating mixture water for injection was used, but also was removed during the drying and thus not analysed.
The film-coating mixture used was Opadryo AMB II yellow 88A120087. It comprises partially hydrolysed polyvinyl alcohol as film-forming agent, talc as anti-tacking agent, sodium lauryl sulphate as lubricant and titanium dioxide, glyceryl mono and dicaprylocaprate (GMDCC) and iron oxide yellow as pigments.
Non-coated tablet formulations comprising a spray-dried solid dispersion of compound (1) and HPMCAS-M in a ratio of 25:75 wt % or 50:50 wt % were prepared as described in Example 6.1 above. A summary of the ingredients is given in Tables 18 and 19 below.
It is known that solid dispersion formulations with non-enteric polymers such as HPMC are prone to gelation and, as a result, slow disintegration when formulated as tablets. Knowing this potential challenge, an initial feasibility assessment was completed for the solid dispersion comprising a spray-dried solid dispersion of 25 wt % of compound (1) and 75 wt % HPMC HME 15LV. A summary of the starting ingredients is given in Table 20 below.
The formulation described in Table 20 did not disintegrate as expected. A formulation approach that improved disintegration was a 50% dilution of the intragranular blend of Table 20 with increased amount of microcrystalline cellulose and mannitol (24 wt % each) and only 2 wt % croscarmellose sodium and a tablet architecture leveraging granulated and extragranular components. The final formulation contained 50 mg compound (1) in a 700 mg tablet.
Tablet cores (Example 6.1-C) and film-coated tablets (Example 6.2-C) were investigated by XRPD in order to confirm absence of crystalline compound (1) such as Form III and Form IV. To do so, the following protocol can be followed: samples are prepared by slightly grinding the tablet cores or film coated tablets in a mortar with a pestle followed by homogenously mixing the obtained powder with a spatula. The obtained powder is then measured by XRPD using an X'pert PRO diffractometer and applying the following settings and measurement parameters:
XRPDs of the tablet core of Example 6.1-C and the film-coated tablet of Example 6.2-C obtained following the procedure from the previous paragraph are displayed in
A dissolution test comparison was performed comparing conventional film-coated tablets comprising a total of 15 mg of the crystalline compound (1) and the film-coated tablet comprising 15 mg of compound (1) as a spray-dried solid dispersion with HPMCAS MG of Example 6.2-B.
The comparative film-coated tablets with crystalline compound (1) contained 5 mg of compound (1), 64.5 mg silicified microcrystalline cellulose comprised of colloidal silicon dioxide and microcrystalline cellulose as filler, 21 mg anhydrous lactose as filler, 3 mg type A sodium starch glycolate as disintegrant, 5 mg hydroxypropyl cellulose as binder, 0.5 mg colloidal silicon dioxide as glidant, 1 mg magnesium stearate of vegetable origin as lubricant, 4.5 mg of film-coating mixture (e.g. Opadry® yellow 03B120053). For the testing three 5 mg tablets were used.
To perform a dissolution test comparison, the following protocol can be used: dissolution testing is performed in 20 mM phosphate buffer (NaH2PO4) at a pH of 2.0, using an Agilent 708-DS Apparatus with 850-DS sampling station at 37° C. The 15 mg tablet comprising compound (1) as a solid dispersion equivalent to sample 6.2-B and three 5 mg tablets adding up to a total of 15 mg of compound (1) in crystalline form are suspended in the buffer solution. Dissolution profiles are evaluated under the following conditions: shaft rotation 50 rpm, medium volume 900 mL, sample volume 3 mL. The amount of compound (1) in the buffer is measured by HPLC at regular intervals over 60 minutes. The % dissolution is calculated by following equation (A):
The results of the in vitro dissolution comparison between the conventional tablet and the solid dispersion tablet in pH 2.0 buffer, obtained according to the protocol described in the previous paragraph, are shown in
7.2 In Vitro Dissolution Profile in Phosphate Buffer pH 6.8 with 0.1% SDS
A dissolution test comparison was performed comparing conventional film-coated tablets comprising a total of 60 mg (3×20 mg) of the crystalline compound (1), the film-coated tablet comprising a total of 60 mg (4×15 mg) of compound (1) as a spray-dried solid dispersion with HPMCAS MG of Example 6.2-A and the film-coated tablet comprising 60 mg of compound (1) as a spray-dried solid dispersion with HPMCAS MG of Example 6.2-C.
The conventional film-coated tablets with crystalline compound (1) contained 20 mg of compound (1), 49.5 mg silicified microcrystalline cellulose comprised of colloidal silicon dioxide and microcrystalline cellulose as filler, 21 mg anhydrous lactose as filler, 3 mg type A sodium starch glycolate as disintegrant, 5 mg hydroxypropyl cellulose as binder, 0.5 mg colloidal silicon dioxide as glidant, 1 mg magnesium stearate of vegetable origin as lubricant, 4.5 mg of film-coating mixture (e.g. Opadry® yellow 03B120053). For the testing three 20 mg tablets were used.
Dissolution testing was performed under the conditions outlined in Table 22.
The % dissolution (same as % dissolved) was calculated as described above in Example 7.1. The results of the in vitro dissolution comparison between the conventional tablet and the solid dispersion tablets in pH 6.8 buffer are shown in
Bioavailability in humans was evaluated using the dynamic in vitro gastrointestinal model for the simulation of the physiological processes occurring in human stomach and small intestine tiny-TIM.
A conventional tablet of crystalline compound (1) (conventional formulation) and a tablet comprising a solid dispersion of compound (1) (SDD formulation) were tested in the tiny-TIM model.
The conventional formulation included 100 mg of compound (1), 247.5 mg of silicified microcrystalline cellulose and 105 mg of anhydrous lactose as fillers, 25 mg of hydroxypropyl cellulose as a binder, 15 mg of sodium starch glycolate as a disintegrant, 2.5 mg of colloidal silicon dioxide as a glidant, and 5 mg of magnesium stearate as a lubricant.
The SDD formulation tested in the tiny-TIM model corresponds to Example 6.2-A, as shown in Table 17.
For simulation of the fasted state condition, a glass of water (240 mL) is administered to the tiny-TIM system.
The study is performed in the TNO dynamic, multi-compartmental in vitro system of the stomach and small intestine (tiny-TIM).
The tiny-TIM system consists of a gastric compartment and one small intestinal compartment (
The tiny-TIM system mimics the intraluminal pH, enzyme activity, bile salt concentrations, peristaltic movements, and gastrointestinal transit of the contents. The set-points for gastrointestinal simulation are controlled and monitored by specific computer programs. Released and dissolved drug molecules are removed from the intestinal lumen by semipermeable membrane units connected to the small intestinal compartment. This allows the assessment of the so-called bioaccessible fraction, i.e. the fraction of the drug which is available for small intestinal absorption.
The experiments in tiny-TIM are performed under simulation of the average physiological conditions in the gastrointestinal tract as described for humans in the fasted state. These conditions include especially the dynamics of gastric emptying and pH decline, intestinal transit times, housekeeper wave, the gastric and the intestinal pH values (Tables 23 and 24), and the composition and activity of the secretion products. The digested and soluble (low-molecular) compounds are removed continuously from the intestinal compartment via a special membrane system.
Prior to the performance of each experiment the secretion fluids (e.g. gastric juice with enzymes, electrolytes, bile, and pancreatic juice) are freshly prepared, the pH electrodes calibrated, and semipermeable membrane (hollow fiber) units installed.
The housekeeper wave (HKW) is simulated after 60 minutes by automated transfer of residual material from the gastric compartment to the intestinal compartment.
The experiments are performed as duplicate experiments. All runs are performed under yellow light to prevent degradation of compound (1).
Filtration of released and dissolved/solubilized drug molecules from the intestinal lumen via a semi-permeable membrane unit (Fresenius plasmaFlux® P1dry) allows the assessment of the so-called bio-accessible fraction, i.e. the fraction of the drug which is available for small intestinal absorption. Filtrate is collected in the following time intervals: 0-30, 30-60, 60-90, 90-120, 120-180, 180-240 and 240-300 minutes from the start of the experiments (
At the end of each experiment the residues in the gastric compartment and in the small intestinal compartment plus filter unit are collected, measured, and analyzed. These residue samples represent the non-bioaccessible fraction. This rinse is pooled with the residue sample of the same compartment, the volume measured and stored at 2-10° C., protected from light, until analysis.
The back-up samples are stored at <−18° C., protected from light, for 1 month after finalization of the study report, thereafter the samples are destroyed.
The collected samples are analyzed for the concentration of compound (1).
The absolute amount of the API in a sample is calculated by multiplying the analyzed concentration in the sample with the collected volume (equation 1).
The recovery of the API is determined by the sum of all amounts recovered in the filtrate fractions of the intestinal compartment and in the residue and rinse fractions of the gastric and intestinal compartments and the drug product. The total recovery is expressed as % of amount added (equation 2).
The bioaccessibility (% of intake) is calculated by expressing the amount of API recovered from the filtrate as a percentage of the intake (equation 3).
The results of the duplicate runs are presented as mean±SD. For the SD, in Microsoft® Excel® the STDEVP function is used (equation 4).
No statistical analysis is performed for this study.
The bioaccessibility profiles obtained from the tiny-TIM protocol above are presented in
A clinical study was performed to assess the relative bioavailability of compound (1) in two different oral formulations, namely as conventional tablet comprising the crystalline form of compound (1) and as a tablet comprising a solid dispersion of compound (1) according to the invention. In addition, the effects of food and multiple-doses of the protein pump inhibitor (PPI) rabeprazole on the pharmacokinetics of single-dose administration of compound (1) were investigated following oral administration of the above-mentioned solid dispersion formulation in healthy male subjects.
A number of 16 healthy male subjects, aged 18 to 45 years (inclusive) and with a body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) is included in the study. The study design is an open-label, randomized, four-way crossover trial. The primary endpoints are the area under the plasma concentration-time curve from time 0 (t0) corresponding to the timepoint of drug administration until time z (tz) corresponding to the last quantifiable timepoint (AUC0-tz) and the maximum concentration in plasma (Cmax) of compound (1). The secondary endpoint is the area under the plasma concentration-time curve from t0 extrapolated to infinity (AUC0-∞) of compound (1).
Thus, the objectives of the trial are to investigate
Test product 1: The comparative film-coated tablets with crystalline compound (1) contain 5 mg or 20 mg of compound (1) and 64.5 or 49.5 mg, respectively, silicified microcrystalline cellulose comprised of colloidal silicon dioxide and microcrystalline cellulose as filler, 21 mg anhydrous lactose as filler, 3 mg type A sodium starch glycolate as disintegrant, 5 mg hydroxypropyl cellulose as binder, 0.5 mg colloidal silicon dioxide as glidant, 1 mg magnesium stearate of vegetable origin as lubricant, 4.5 mg of film-coating mixture (e.g. Opadry® yellow 03B120053).
Test product 2: Film-coated tablets comprising 15 mg of compound (1) as a spray-dried solid dispersion with HPMCAS MG as defined in Example 6.2-A.
Test product 3: Proton pump inhibitor rabeprazole gastroresistant tablets PARIET® of a strength of 20 mg.
The reference treatment (R or TF1) consists of a total dose of 30 mg crystalline compound (1) in form of test product 1 (1 tablet a 20 mg and 2 tablets a 5 mg) administered orally with 240 Ml of water after an overnight fast of at least 10 h on day 1.
Test treatment 1 (T1 or NF1) consists of a total dose of 30 mg compound (1) in form of a solid dispersion as test product 2 (2 tablets a 15 mg) administered orally with 240 mL of water after an overnight fast of at least 10 h on day 1.
Test treatment 2 (T2) consists of a total dose of 30 mg compound (1) in form of a solid dispersion as test product 2 (2 tablets a 15 mg) on day 1 administered under fed conditions after a high-fat, high-calorie breakfast. The total caloric content of the high fat, high-calorie breakfast is supplied approximately as follows: 150 kcal as protein, 250 kcal as carbohydrate, and 500 to 600 kcal as fat; Ingredients: 2 chicken eggs (whole content) for scrambled eggs 192 kcal; 10 g butter for frying scrambled eggs 75 kcal, 35 g fried bacon 186 kcal, 2 toasted slices of wheat bread 130 kcal, 15 g butter for buttering toast slices 113 kcal, 115 g hash brown potatoes 132 kcal, 240 mL whole milk (3.5% fat) 156 kcal; Sum 984 kcal.
Test treatment 3 (T3) consists of a total dose of 30 mg compound (1) in form of a solid dispersion as test product 2 (2 tablets a 15 mg) administered under fasting conditions. Subjects in T3 further receive test product 3 in a total dose of 200 mg of rabeprazole in daily doses of 40 mg once daily (2 tablets a 20 mg) on four days prior to and on the day of administration of compound (1).
Blood sampling is performed up to 118 h post administration of compound (1) for all treatments to analyze for plasma concentrations of compound (1). Plasma concentration time profiles are evaluated by non-compartmental analysis to calculate respective PK parameters. Relative bioavailability is estimated by the ratios of the geometric means (T1/R, T2/T1 and T3/T1) for the primary and secondary endpoints. Additionally, their two-sided 90% confidence intervals (CIs) are provided. This method corresponds to the two one-sided t-test procedure, each at a 5% significance level. Since the main focus is on estimation and not on testing, a formal hypothesis test and associated acceptance range is not specified. The statistical model was analysis of variance (ANOVA) on the logarithmic scale including effects for sequence, subjects nested within sequences, period and treatment. CIs are calculated based on the residual error from the ANOVA. Descriptive statistics were calculated for all endpoints. Pharmacokinetic analyses are performed on the Pharmacokinetic parameter analysis set (PKS) and safety analyses are performed on the Treated set (TS). No formal interim analysis is planned or performed.
From the 16 subjects planned to be included in the trial, 13 subjects completed the study. For the treatment comparisons, 12 subjects were evaluable for the relative bioavailability comparison of T1 to R, 9 subjects for the food effect evaluation (comparison of T2 to T1) and 11 subjects for the evaluation of the drug-drug interaction between compound (1) and rabeprazole (comparison of T3 to T1). The relative bioavailability comparison showed a decreased variability for the tablets comprising a solid dispersion of compound (1) (T1) compared to the tablets comprising crystalline compound (1) (R). The exposure of T1 was in average increased by 3% (Cmax) and 35% (AUC0-tz) in comparison to R. The food effect evaluation showed that exposure was decreased under fed conditions (T2) in comparison to fasted (T1), in average by −46% for Cmax and −26% for AUC0-tz. Pretreatment with rabeprazole did not relevantly change the exposure of the tablets comprising a solid dispersion of compound (1) (in average −13% for Cmax and −3% for AUC0-tz) suggesting that there is no relevant DDI between compound (1) and proton pump inhibitors or other pH-increasing comedications.
Results of the trial are discussed in more detail below.
Trial subjects and compliance with the clinical trial protocol
A total of 13 subjects received trial medication and completed the planned observation time. No important protocol violations were reported. Of the 13 healthy male subjects treated in the trial, 12 subjects (92.3%) were White, 1 subject (7.7%) was Black or African American. The mean age of the subjects was 34.8 years (standard deviation [SD]=5.8 years); age ranged from 25 to 45 years. The mean BMI was 25.49 kg/m2 (SD=3.03 kg/m2); BMI ranged from 20.7 to 29.5 kg/m2. The treatment groups were similar with respect to demographic and baseline characteristics.
Twelve subjects received the reference treatment (R), twelve subjects received the test treatment 1 (T1), nine subjects received the test treatment 2 (T2) and eleven subjects received the test treatment 3 (T3) in a randomized way and separated by a washout interval of at least 14 days between the administrations of compound (1) and subsequent treatments.
Relative bioavailability of the formulations NF (T1) and TF1 (R) under fasted conditions is given in Table 25. The adjusted geometric mean ratios for the primary and secondary endpoints in subjects on treatment T1/R ranged between 129.1% and 139.3%, with 90% CIs ranging between 87.7% and 221.3% (Table 25). The variability of the pharmacokinetic (PK) parameters Cmax (geometric coefficient of variation [gCV] 93.1%), AUC0-tz (gCV 52.7%) and AUC0-∞ (gCV 52.7%) was higher for subjects on treatment R compared with subjects on treatment T1 with Cmax (gCV 37.3%), AUC0-tz (gCV 18.8%) and AUC0-∞ (gCV 19.2%). The trend towards increased bioavailability of the NF was not consistently observed in all subjects, however an overall trend towards increased oral bioavailability has been shown.
ANOVA results comparing the primary and secondary endpoints of the NF formulation when given fasted (T1) or after intake of a high-fat high-calorie meal (T2) is provided in Table 26. The adjusted gMean ratios for the primary and secondary endpoints in subjects on treatment T2/T1 ranged between 53.5% and 74.9%, with 90% CIs ranging between 40.5% and 81.7% (Table 26). The values for Cmax, AUC0-tz, and AUC0-∞ were lower in subjects receiving treatment under fed condition, indicating a negative food effect.
ANOVA results comparing the primary and secondary endpoints of the NF formulation when given fasted in the absence (T1) and presence of coadministration with the proton pump inhibitor (PPI) rabeprazole (T3) is presented in Table 27. The adjusted geometric mean (gMean) ratios of the endpoints in subjects on treatment T3/T1 ranged between 87.0% and 97.1%, with 90% CIs ranging between 66.8% and 113.2% (Table 27). The PK parameters and profiles for T1 and T3 were similar while the time from (last) dosing to the maximum measured concentration of the analyte in plasma (tmax) appeared to be delayed in the presence of rabeprazole. Taken together, the results suggest that rabeprazole does not interfere with the PK of compound (1).
Form III and IV of compound (1) referred to in Example 5.1 can be produced according to the procedures given below. It should be noted that the input form of compound (1) is not strictly consequential for the crystallization procedures if full dissolution is achieved prior to crystallization. In case of full dissolution, the compound (1) starting material can for example be produced according to the synthesis described in WO 2021/213800.
First example procedure for the preparation of form I (crystallization): 19 kg of compound (1) (any solid state form) are dissolved in a mixture of ˜54 kg THF, ˜160 kg DCM and ˜48 kg MeOH. Residual inorganic salts are removed by washing with brine (48 kg). Undissolved particulates are removed by polish filtration of the organic layer. The organic layer is then distilled to ˜160 L and the mixture is diluted with 78 kg of THF. The distillation, THF dilution, distillation sequence is repeated until levels of water and MeOH ≤1.0% w/w each. Upon completion of distillations, the obtained slurry is held at ambient temperature for not longer than 12 hrs and filtered to yield form I.
Second example procedure for the preparation of form I (crystallization): 6 g of form IV of compound (1) (e.g. prepared according to one of the Examples described herein) are dissolved in 75 g 5% w/w H2O in IPA solution at 90° C. Solution is slowly cooled to 75° C. and seeded with 60 mg of form I. Mixture is agitated at 75° C. for 2 hours followed by cooling at 0.3° C./min rate to 20° C. Upon completion of cooling, solids are filtered and dried to yield form I.
Example procedure for the preparation of form III (slurry): 17 kg of form I of compound (1) is mixed with 271 kg of IPAc. Slurry is heated to 70° C. To the slurry, 0.2 kg of seeds of form III of compound (1) (e.g. prepared according to one of the Examples described herein) are added, and mixture is agitated for ˜16 hrs. Upon completion of hold, mixture is gradually cooled to 53° C. in ˜40 mins, then, to 33° C. in ˜40 mins, then to 25° C. Obtained slurry is agitated for ˜1 hr and filtered. Solids are washed with 27 kg of IPAc and dried to yield form III.
The procedure can also be performed without addition of seeds.
First example procedure for the preparation of form IV (crystallization): 300 mg form I of compound (1) are dispersed in 3 ml of 1-BuOH. Mixture is heated to 90° C. with over-head agitation. Dissolution is observed. Solution is cooled with the rate of 0.2° C./min to 75° C. followed by quick cooling to 20° C. Obtained slurry is held for ˜12 hrs at 20° C. while agitated and filtered to yield form IV.
Second example procedure for the preparation of form IV (crystallization): Form III of compound (1) is dissolved in 10 volumes of 1-BuOH/Anisole (1:1) mixture at 110° C. Solution is subjected to distillation with slight vacuum during which most of the 1-BuOH is removed. The solution is seeded with form III seeds, held at 110° C. and a slurry is obtained. Mixture is cooled to ambient temperature while agitated and filtered to yield isolated compound (1) as form IV. This despite being seeded with form III.
Third example procedure for the preparation of form IV (slurry): A slurry of form I and IV of compound (1) is slurried in IPAc at temperatures ranging from 25-75° C. for 72-168 hrs. Mixture is brought to ambient temperature if applicable and filtered to yield compound (1) as form IV.
Crystalline forms of compound (1) were analysed by XRPD. XRPDs were measured at a temperature in the range of from 20 to 30° C. using CuKα radiation having a wavelength of 1.54184 Å.
The methodology for this analysis was as follows: the respective solid compound (approximately 0.2 g) is representatively subsampled into a stainless-steel sample holder fitted with a zero-diffraction plate (ZDP). The sample holder is then levelled off with a glass slide to create a flat sample surface level with the sample holder. The instrument used for the analysis is a Bruker D2 Phaser (system EQ-SSRD-XRD-01). A corundum reference standard is run each day to evaluate the system performance. Two peaks must be within ±0.02° 20 for system suitability to be acceptable. The instrument settings for the measurement of the solid compound samples can be seen in Table 28. Processing (Kα2 contribution stripping, peak labelling) was completed using DIFFRAC.EVA software (version 5.0).
In the following, experimental parameters for XRPD measurements are given:
Table 29 lists the peaks for each form (that are above 5% relative intensity). Table 30 lists the best characteristic peaks to use when trying to identify a given polymorphic form where another form is present. The diagnostic peaks are indicative of peak positions where the impurity has a relatively high intensity peak, and the sample dominant form has a flat baseline.
With regard to Table 29, peaks marked “#” are determined to be characteristic peaks, peaks marked “*” have a greater than 10% relative intensity, peaks marked “**” have a greater than 50% relative intensity. Further, the peaks are listed in order of peak position (°2θ), with similar peak positions on the same row.
| Number | Date | Country | Kind |
|---|---|---|---|
| 23156485.7 | Feb 2023 | EP | regional |
| 23156619.1 | Feb 2023 | EP | regional |
| 23383302.9 | Dec 2023 | EP | regional |
This application claims the benefit of U.S. Patent Application No. 63/476,715, filed Dec. 22, 2022; U.S. Patent Application No. 63/476,733, filed Dec. 22, 2022; European Patent Application No. EP 23156485.7, filed Feb. 14, 2023, European Patent Application No. EP 23156619.1, filed Feb. 14, 2023; and European Patent Application No. EP 23383302.9, filed Dec. 15, 2023; each of which is hereby incorporated by reference herein in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63476715 | Dec 2022 | US | |
| 63476733 | Dec 2022 | US |
