WO2025051851A1

WO2025051851A1 - Pharmaceutical dosage forms comprising 2-(2-chlorophenyl)-n-[4-(4-cyano-1h-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

Info

Publication number: WO2025051851A1
Application number: PCT/EP2024/074820
Authority: WO
Inventors: Yasmin Isabelle SUESSENBACH; Susanne MERKEL; Julia FREUNDLIEB; Uwe Münster; Corinna BODE; Gabriele Winter
Original assignee: Bayer Aktiengesellschaft
Priority date: 2023-09-05
Filing date: 2024-09-05
Publication date: 2025-03-13

Abstract

A solid pharmaceutical dosage form for oral administration comprising 2-(2-Chlorophenyl)- N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) in amorphous form and hydroxypropyl methyl cellulose acetate succinate (HPMCAS) in a ratio of not less than 1 to 0.05 of HPMCAS, methods for the preparation thereof, use thereof as medicaments, and also use thereof for the treatment and/or prophylaxis of diseases, in particular for the treatment or prophylaxis of diseases.

Description

PHARMACEUTICAL DOSAGE FORMS COMPRISING 2-(2-CHLOROPHENYL)-N-[4-(4- CYANO-1H-PYRAZOL-1-YL)-3-SULFAMOYLPHENYL]ACETAMIDE

The present invention relates to amorphous solid dispersions (ASD) and solid pharmaceutical dosage forms for oral administration comprising 2-(2-chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3- sulfamoylphenyl] acetamide (active ingredient (I)), in which the active ingredient (I) is in amorphous form, methods for the preparation thereof, use thereof as medicaments, and also use thereof for the treatment and/or prophylaxis of diseases.

BACKGROUND

The compound 2-(2-chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), is known from W02017191000 and has the following structural formula:

The active ingredient (I) acts as a P2X4 inhibitor and, owing to this specific mechanism of action, is, after oral administration, useful in the treatment and/or prophylaxis of several diseases and disorders.

Standard formulation approaches of active ingredient (I) did not reach the desired bioavailability.

Amorphous solid dispersions (ASD) and manufacturing processes thereof as such are known as one of the possible alternatives for improving dissolution rate and bioavailability.

Immediately upon contact with aqueous medium, amorphous drug usually dissolves rapidly due to the absence of crystal lattice. The solution drug concentration usually reaches various supersaturations depending on the physiochemical properties of the drug and the ASD formulation design. The initial drug dissolution is vividly termed as “spring”. After supersaturation is achieved, drug concentration typically descends due to precipitation of the drug substance, for example liquid-liquid phase separation or drug crystallization, and the prolonged drug supersaturation attained by drug-polymer interaction is analogous to the “parachute”.

In ASD formulation, the “spring” and “parachute” are the two essential steps that need to be rigorously optimized, so that a proper level of drug supersaturation could be obtained (an optimal “spring”) and can be maintained over a prolonged period of time (an effective “parachute”) in order to obtain a maximal in vivo bioavailability by a balance between the “spring” and “parachute”.

Therefore, it is critical to stabilize the amorphous drug in the solid state but it is of equal importance to prevent precipitation during dissolution of the ASD. To achieve an appropriate “spring” and “parachute” profile is the biggest challenge in the design of an ASD formulation. Such a profile is not predictable and depends very much on the physicochemical characteristics of the active ingredient and the excipients used.

Fundamental processes underlying the concentration-time profiles attained during dissolution are poorly understood and very much dependent again on the active ingredient.

Various methods used for preparation of solid dispersion systems are known: melting method, solvent method, melting solvent method (melt evaporation), melt extrusion methods, lyophilization techniques, melt agglomeration process, the use of surfactant, electrospinning, Super Critical Fluid (Scf) technology. [S. Singh, R. S. Baghel, L. Yadav, A review on solid dispersion, Int. J. of Pharm. & Life Sci. (IJPLS), Vol. 2, Issue 9: Sep: 2011, 1078-1095 1087]

C. Leuner and J. Dressman, Eur. J. Pharm. Biopharm., 50 (2000) 47 to 60, divide the methods for preparing solid dispersions roughly in hot melt methods and solvent methods. According to C. Leuner and J. Dressman application of hot melt extrusion to the production of solid dispersions is regarded as method for choice for preparing solid dispersions. The authors favor hot melt extrusion as non-solvent method because small variations in the conditions used to remove the solvent can lead to quite large changes in product performance.

J. Breitenbach, Eur. J. Pharm. and Biopharm., 54 (2002) 107-117, classifies the most relevant technologies for the manufacturing of solid dispersions in hot spin mixing, embeddings by means of spray-drying, co-evaporation, co-precipitation, freeze-drying and roll-mixing or co-milling. In general, methods based on solvent evaporation known are e.g. freeze drying, spray drying, vacuum drying, layering of powders, granulates or pellets and fluidized bed granulation. J. Breitenbach states that solid dispersions show different and mostly unpredictable behavior with regard to e.g. chemical and physical stability.

Baghel et al., J. Pharm. Sci., 105 (2016), 2527-2544 (Tab. 3) give an overview of different factors affecting the stability of amorphous solid dispersions and state that different preparation methods induce different thermal histories and mechanical stresses leading to different degrees of drug-polymer mixing and drug mobility in the dispersion.

R. J. Chokshi et al., J. Pharm. Sci., 97(6) (2008) 2286-2298 and G.P. Andrews et al., J. Pharm. Pharmacol. 62 (2010) 1580-1590, state that solid dispersions are inherently unstable. Solid-dispersion approaches to drug dissolution enhancement involve the generation of a glass solution in which the drug is present in a metastable amorphous state possessing high internal energy and specific volume. This results in a system with a tendency for crystallization during storage.

The choice of the manufacturing process and the parameters applied for as well as the identification of suitable excipients to avoid crystallization is also not obvious for a person skilled in art. According to N. Shah et al., 2014, page 130 (Fig.4.2), a variety of potential excipients can be considered for composing amorphous solid dispersions. Not all these excipients are equally suited to prepare an amorphous solid dispersion.

Excipients/Polymers used for preparation of ASDs can be classified on the basis of their origin as natural (e.g., starch, cellulose, and proteins), semisynthetic (e.g., hydroxypropyl methylcellulose [HPMC]), or synthetic polymers (e.g., polyvinylpyrrolidone [PVP]). From the monomer perspective, they can be classified as homopolymers ( 1 type of monomer) such as methylcellulose or a copolymer (>2 monomers) such as crospovidone. Polymers can be amorphous (polyacrylic acid), semicrystalline (poly 1-lactic acid), or crystalline (polyethylene glycol).

So called multicomponent solid dispersions in which one or more drugs are dispersed in a (carrier) matrix composed by at least two compounds possessing properties capable to modify or to enhance the drug delivery system in terms of drug release, drug permeability, thermodynamic stability and thus affecting bioavailability are described in L. M. De Mohac, et al., Journal of Drug Delivery Science and Technology, 57 (2020) 101750.

K. Six et al., J. Pharm. Sic., 93 (2004) 124-131 investigated solid dispersions of itraconazole in a combination of two polymers (PVPVA64, a copolymer of N-vinylpyrrolidone and vinyl acetate, and Eudragit El 00, an amino methacrylate copolymer) and found that the stability and dissolution rate of solid dispersions comprising combined polymers were superior to those which could be achieved by using one single polymer only.

However, in Y. Huang et al., Acta Pharmaceutica Sinica B, 4(1) (2014) 18-25 emphasized that the intermolecular drug-polymer interaction has always been and still is the determining factor in the design and performance of solid dispersions. Stability of solid dispersions will also be influenced by moisture absorption during storage.

In dependence of the drug-carrier combination the release characteristics of the solid solution vary and therefore they are one of the main influences on the performance of a solid dispersion. C. Leuner and J. Dressman, Eur. J. Pharm. Biopharm., 50 (2000) 47 to 60 emphasized that the drug-carrier ratio has to be identified very thoroughly to find an optimal ratio for the formulation. Release rates might become slower with increased carrier amount. Depending on the carrier or carrier mixture incorporated even gel-formation can occur which results in fall-off of the release rate.

The nature of ASDs and the inherent risk of recrystallization require in-depth characterization of these formulations. No single characterization technique can give the full picture, and a suite of complementary methods is often required. For assessment of amorphous solid dispersions several analytical methods are known. Dissolution testing will be the primary in vitro method based on the large amount of literature directly related to dissolution of amorphous solid dispersions. One reason for collecting in vitro dissolution data for amorphous solid dispersions is to try to predict the in vivo biological performance. [A. Newman et al., J. Pharm. Sci, 101 (4) (2012) 1355-377] Biorelevant dissolution testing has made it possible to predict, at least on a rank-order basis, in vivo formulation behavior. Biorelevant dissolution media like FaSSIF and FeSSIF (Fasted- and Fed State Simulated Intestinal Fluid) attempt to simulate the most relevant parameters including pH, osmolality, surface tension, and the solubilization capacity for drugs. Comparative dissolution data generated by biorelevant dissolution testing may be combined with data received by e.g. solid-state characterization techniques such as X-ray powder diffraction (XRPD) as described in S. Dedroog et al., J. Pharm Biopharm Analysis, 178 (2020) 1-13, to complement the assessment of performance of amorphous solid dispersions.

Therefore, it is neither obvious for a person skilled in the art which excipient(s) to use nor which manufacturing process to apply for preparation of an amorphous solid dispersions containing an active ingredient in a stable amorphous form.

The aim of the development was, therefore, to provide solid pharmaceutical dosage forms for oral administration comprising active ingredient (I), where the oral solid dosage form shows a good dissolution behaviour and a bioavailability and in which the active ingredient (I) is used as amorphous form and which shows a satisfying long-term stability.

DESCRIPTION of the INVENTION

The present invention relates to a solid pharmaceutical dosage form for oral administration comprising 2-(2-Chlorophenyl)-N-[4-(4-cyano-lH-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) in amorphous form and hydroxypropyl methyl cellulose acetate succinate (HPMCAS) in a ratio of not less than 1 to 0.05 of HPMCAS (not less than 1:0.05 ratio), methods for the preparation thereof, use thereof as medicaments, and also use thereof for the treatment and/or prophylaxis of diseases, in particular for the treatment or prophylaxis of diseases.

According to the invention, the amount of active ingredient (I) in amorphous form is always to be intended as the reference in the given ratio, as far it is not differently stated. Said ratio is intended as weight ratio, for example a ratio of not less than 1 to 0.05 of HPMCAS (1:0.05 ratio) means 1:0.05, 1:0,5, 1: 1, 1: 10, 1 :20 or for each milligram of active ingredient (I) in amorphous form not less than 0.05 mg of HPMCAS.

The present invention further relates to in a pharmaceutically acceptable matrix comprising active ingredient (I) in amorphous form in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 to solid dispersion base, methods for the preparation thereof, use thereof as medicaments, and the use thereof for the treatment and/or prophylaxis of diseases, in particular for the treatment or prophylaxis of diseases. A solid pharmaceutical dosage form comprising the active ingredient (I) in an amorphous form according to the invention have shown good dissolution behaviour and bioavailability. The amorphous form of the active ingredient (I) was stabilized by excipients in the amorphous solid dispersion (ASD).

Amorphous solid dispersion (ASP):

The present invention provides an amorphous solid dispersion (ASD) comprising 2-(2-chlorophenyl)- n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) in amorphous form, in a pharmaceutically acceptable matrix, in a weight ratio of 1 : 0.5 to 1 :20, preferably 1 : 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 to the solid dispersion base.

The present invention provides an amorphous solid dispersion (ASD) comprising 2-(2-chlorophenyl)- n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) in amorphous form, in a pharmaceutically acceptable matrix, in a weight ratio of 1 : 0.5 to 1 :20, preferably 1 : 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 to the base and in which said solid dispersion comprises hydroxypropyl methyl cellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone (PVP), preferably HPMCAS.

The present invention also provides an amorphous solid dispersion (ASD) comprising active ingredient (I) in amorphous form, in a pharmaceutically acceptable matrix, optionally sweeteners, flavoring agents and colorants, and comprising HPMCAS in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 of active ingredient (I) to HPMCAS.

The present invention also provides an amorphous solid dispersion (ASD) comprising active ingredient (I) in amorphous form, in a pharmaceutically acceptable matrix, optionally sweeteners, flavoring agents, and colorants and comprising PVP in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 of active ingredient (I) to PVP.

The present invention also provides an amorphous solid dispersion (ASD) wherein the active ingredient (I) is present in amorphous form.

In the context of the present invention, the term amorphous solid dispersion (ASD) is used whereas in the literature some authors use the term solid solution which has the same meaning as solid dispersion in the context of the present invention.

In the following, the different types of solid dispersions (solid solutions, glass solutions, glass suspensions, amorphous precipitations in a crystalline carrier, eutectics or monotectics, compound or complex formation and combinations thereof) are collectively referred to as solid dispersion.

An amorphous solid dispersion (ASD) according to the present invention comprising active ingredient (I) with superior dissolution behaviour and a good bioavailability of the active ingredient (I) is dependent on a) the matrix used, b) the solvent used in the manufacturing process and c) the manufacturing process. According to the present invention the amorphous solid dispersion (ASD) comprising active ingredient (I) in amorphous form, in a pharmaceutically acceptable matrix, in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 to solid dispersion base is preferably a granulate. a) the matrix

A “matrix” according to the present invention are polymeric excipients, non-polymeric excipients, and combinations thereof, capable of dissolving or dispersing the active ingredient (I). In the context of the present invention the “matrix” consists of the combination of the “solid dispersion base” and the “carrier” used during the manufacturing process of the amorphous solid dispersion (ASD). Thus the “matrix” becomes an integral part of the amorphous solid dispersion (ASD). In the prior art some authors use the term carrier instead of matrix or instead of a matrix agent. In case a carrier is used, the carrier is defined as an excipient on which the liquid comprising the active pharmaceutical ingredient (I) is applied.

In the context of the present invention the pharmaceutically acceptable matrix consists of the combination of the solid dispersion base and optionally a carrier.

In the context of the present invention the solid dispersion base is a pharmaceutically acceptable polymer, selected from the group consisting of polyethylene oxide, polyvinylpyrrolidone (PVP), vinylpyrrolidone/vinylacetate copolymer (copovidone) (e.g. Kollidon VA64), polyalkylene glycol (e.g. polyethylene glycol), hydroxyalkyl cellulose (e.g. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (e.g. hydroxypropyl methyl cellulose), carboxymethyl cellulose, sodium carboxymethyl cellulose, polymethacrylates (e.g. Eudragit® types), polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, and combinations thereof. Preferred the solid dispersion base is selected from the group consisting of polyvinylpyrrolidone (PVP), vinylpyrrolidone/vinylacetate copolymer (copovidone), hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyethylene glycol and polyethylene oxide. The solid dispersion base is preferably made of the polymer hydroxypropyl methyl cellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone (PVP), most preferably of HPMCAS in the different forms and qualities regarding e.g. their particle size distribution or substitution grade of succinate and acetate groups ( like HPMCAS MG and/or HPMCAS LG).

In the context of the present invention the carrier is selected from the groups of fillers, lubricants, disintegration promoters, surfactants, sweeteners, flavoring agents and/or colorants or a combination thereof. Preferred carrier according to the invention is Croscarmellose sodium.

It was found according to the invention that the amorphous form of active ingredient (I) comprised in an amorphous solid dispersion could be stabilized by applying polymer as solid dispersion base, more particularly by a solid dispersion base which is based on hydroxypropyl methyl cellulose acetate succinate (HPMCAS) or by a solid dispersion base which is based on a different polymer, particularly polyvinylpyrrolidone (PVP) and in which HPMCAS is not part of the solid dispersion base.

According to the present invention the amount of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) in the matrix is in a weight ratio of 1:0.5 to 1 :20, preferably 1 : 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 of the active ingredient (I) to HPMCAS. b) the solvent used in the manufacturing process

Surprisingly, acetone alone or in combination with ethanol were found to be the solvent most suited in the manufacturing process to obtain an ASD with optimal stability and desired dissolution profile. The solvent in the granulation process allows, that active ingredient (I) can be introduced in the process for preparing an amorphous solid dispersion (ASD). The relevant solvents used in the manufacturing process for the production of the ASD according to the invention are discussed below under the paragraph “Manufacturing process of the amorphous solid dispersion (ASD)” and “Manufacturing process of the solid pharmaceutical dosage forms based on an amorphous solid dispersion (ASD)” c) the manufacturing process

For manufacturing of the ASDs, various manufacturing processes are known for a skilled person (solvent based and non-solvent based manufacturing processes). The amorphous solid dispersion (ASD) according to the present invention comprising active ingredient (I) was preferably manufactured by solvent-based processes (e.g. wet granulation processes such as fluidized-bed granulation, or spray drying).

Active ingredient (I) and the solid dispersion base are present in the amorphous solid dispersion (ASD) in a ratio of active ingredient (I) to solid dispersion base of 1 to 0.5 up to 1 to 20. Preferred is a ratio of active ingredient (I) to solid dispersion base of 1 to 0.5 up to 1 to 10, more preferred is a ratio of active ingredient (I) to solid dispersion base of 1 to 0.5 up to 1 to 5 and very preferred is a ratio of active ingredient (I) to solid dispersion base of 1 to 2, 1 to 3.

Active ingredient (I) and the solid dispersion base are present in the amorphous solid dispersion (ASD) in a ratio of active ingredient (I) to HPMCAS and/or PVP, preferably HPMCAS, of 1 to 0.5 up to 1 to 20. Preferred is a ratio of active ingredient (I) to solid dispersion base of 1 to 0.5 up to 1 to 10, more preferred is a ratio of active ingredient (I) to solid dispersion base of 1 to 0.5 up to 1 to 5 and very preferred is a ratio of active ingredient (I) to solid dispersion base of 1 to 2, 1 to 3.

Solid pharmaceutical dosage forms based on an Amorphous solid dispersion (ASD):

The present invention provides solid pharmaceutical dosage forms for oral administration comprising 2-(2-chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) in amorphous form and not less than 1:0.05 ratio to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1 :20, preferably 1 : 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 to HPMCAS.

The present invention provides solid pharmaceutical dosage forms for oral administration comprising active ingredient (I) in amorphous form in a pharmaceutically acceptable matrix, optionally sweeteners, flavoring agents, colorants and not less than 1:0.05 ratio to HPMCAS.

The present invention provides solid pharmaceutical dosage forms for oral administration comprising the active ingredient (I) in amorphous form in, a pharmaceutically acceptable matrix, further pharmaceutical acceptable excipients, with the active ingredient (I) in a weight ratio of not less than 1:0.05 to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1:10, most preferably 1:5, especially preferred 1:3 and 1:2 to HPMCAS.

The present invention provides solid pharmaceutical dosage forms for oral administration comprising active ingredient (I) in amorphous form, further pharmaceutical acceptable excipients, and with the active ingredient (I) in a weight ratio of not less than 1:0.05 to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1 :20, preferably 1 : 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 to HPMCAS.

The present invention also provides solid pharmaceutical dosage forms for oral administration comprising active ingredient (I) in amorphous form in a weight ratio of 1 : 1 to 1 : 10 to HPMCAS, at least one lubricant, at least one disintegration promoter, and optionally one or more fillers, and optionally one or more surfactants.

The present invention also provides a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in amorphous form in a weight ratio of 1 : 1 to 1 : 10 to HPMCAS, Croscarmellose sodium, and Magnesium stearate.

Furthermore, the present invention also provides a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in amorphous form, and with the active ingredient (I) in a weight ratio of not less than 1:0.05, preferably 1:0.5 to 1: 1 to HPMCAS and in a weight ratio of 1:0.5 to 1:20, preferably 1:1 to 1:10, most preferably 1:5, especially preferred 1:3 and 1:2 of active ingredient (I) to a combination of PVP and HPMCAS.

Furthermore, the present invention also provides a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in amorphous form, with the active ingredient (I) in a weight ratio of 1 : 0.05 to HPMCAS and in a weight ratio of 1 : 1 to 1 :5 of active ingredient (I) to a combination of PVP and HPMCAS.

Furthermore, the present invention also provides a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in amorphous form, with the active ingredient (I) in a weight ratio of 1 : 0.5 to 1 : 1 to HPMCAS and in a weight ratio of 1 : 1 to 1 :5 of active ingredient (I) to a combination of PVP and HPMCAS. For oral administration, the amorphous solid dispersion comprising the active ingredient (I) can be formulated into solid preparations such as powder, granulates, pellets, tablets, sachets, capsules, dragees, chewable tablets, effervescent tablets, dispersible tablets, troches, lozenges, melts, suspensions, and may be prepared according to the methods known to the art of the manufacture of pharmaceutical compositions. The above identified solid preparations are particular forms of embodiment of the pharmaceutical dosage form for oral administration according to the invention.

The pharmaceutical dosage form according to the present invention is a granulate.

The pharmaceutical dosage form according to the present invention is a tablet.

The pharmaceutical dosage form according to the present invention is an immediate release tablet.

The pharmaceutical dosage form according to the present invention is a tablet optionally covered with a coating, preferably the tablet is covered with a coating.

The pharmaceutical dosage form according to the present invention is also an amorphous solid dispersion (ASD), containing active ingredient (I) in a matrix and optionally sweeteners, flavoring agents and colorants, formulated into sachets.

Dosages:

2-(2-chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) is present in the pharmaceutical dosage form according to the invention in an amount between 2 and 200 mg preferably between 10 and 150 mg. The amount of active ingredient (I) in the pharmaceutical dosage form according to the invention is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, most preferably 20 and 100 mg.

Therefore, the present invention provides a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in amorphous form in an amount between 2 and 200 mg preferably between 10 and 150 mg and not less than 1:0.05 ratio to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10.

Furthermore, the present invention provides a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in amorphous form in an amount between 10 and 150 mg and not less than 1:0.05 ratio to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1:20.

According to a further particular form of embodiment of the present invention the solid pharmaceutical dosage form for oral administration is comprising active ingredient (I) in amorphous form in an amount between 2 and 200 mg preferably between 10 and 150 mg and with the active ingredient (I) in a weight ratio of not less than 1 :0.05, preferably 1 :0.5 to 1 : 1 to HPMCAS and in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 of active ingredient (I) to a combination of PVP and HPMCAS.

Another form of embodiment according to the present invention comprises a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in amorphous form between 10 and 150 mg, with the active ingredient (I) in a weight ratio of 1:0.05 to HPMCAS and in a weight ratio of 1 : 1 to 1 :5 of active ingredient (I) to a combination of PVP and HPMCAS.

Dissolution profile:

In the context of the present invention, solid pharmaceutical dosage forms for oral administration, particularly immediate release tablets as previously described, are those wherein at least 75% of active ingredient (I) are released into the release medium after 45 minutes, according to the quality control method of the European Pharmacopoeia using apparatus 2 (paddle).

Furthermore, the present invention provides a solid pharmaceutical dosage form for oral administration comprising active ingredient (I) in a pharmaceutically acceptable matrix 1: 1 to 1: 10 to HPMCAS, at least one lubricant, at least one disintegration promoter, and wherein at least 75% of active ingredient (I) is released into the release medium after 45 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).

According to a further embodiment of the present invention, a solid pharmaceutical dosage form for oral administration is comprising the active ingredient (I) in amorphous form in an amount between 2 and 200 mg preferably between 10 and 150 mg and not less than 1:0.05 ratio to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1 :20, preferably 1 : 1 to 1: 10, and wherein at least 80% of active ingredient (I) is released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).

According to a further embodiment of the present invention, a solid pharmaceutical dosage form for oral administration is comprising the active ingredient (I) in amorphous form in an amount between 2 and 200 mg preferably between 10 and 150 mg and with the active ingredient (I) in a weight ratio of not less than 1:0.05, preferably 1:0.5 to 1: 1 to HPMCAS and in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10, to a combination of PVP and HPMCAS, and wherein at least 75% of active ingredient (I) is released into the release medium after 45 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).

In the context of the present invention, the solid pharmaceutical dosage form for oral administration, is in particular a tablet, comprising active ingredient (I) in amorphous form and not less than 1:0.05 ratio to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1 :20, preferably 1 : 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1:2 to HPMCAS or to combination of PVP and HPMCAS, have a release of about 30% to 60% of active ingredient (I) into the release medium in about from 30 to about minute 90, using a dissolution method with FaSSGF/FaSSIF as dissolution media under the conditions: FaSSGF pH 1.6 (250mL) 30 minutes / buffering to FaSSIF Vl(total volume 500mL), 50rpm, 37°C, and/or FaSSGF/FeSSIF under the conditions: FaSSGF pH 1.6 (250mL) 30 minutes / buffering to FeSSIF Vl(total volume 500mL), 50rpm, 37°C.

According to a further embodiment of the present invention, the solid pharmaceutical dosage form for oral administration, is in particular a tablet, comprising active ingredient (I) in amorphous form in an amount between 2 and 200 mg preferably between 10 and 150 mg, and not less than 1:0.05 ratio to HPMCAS, preferably with the active ingredient (I) in a weight ratio of 1:0.5 to 1:20, preferably 1: 1 to 1: 10, most preferably 1:5, especially preferred 1:3 and 1 :2 to HPMCAS or to a combination of PVP and HPMCAS, have a release of about 30% to 60% of active ingredient (I) into the release medium in about from 30 to about minute 90, using a dissolution method with FaSSGF/FaSSIF as dissolution media under the conditions: FaSSGF pH 1.6 (250mL) 30 minutes / buffering to FaSSIF Vl(total volume 500mL), 50rpm, 37°C, and/or FaSSGF/FeSSIF under the conditions: FaSSGF pH 1.6 (250mL) 30 minutes / buffering to FeSSIF Vl(total volume 500mL), 50rpm, 37°C.

Manufacturing process:

The present invention further relates to the use of active ingredient (I) for preparing a solid pharmaceutical dosage form for oral administration according to the invention.

The active ingredient (I) is present in the pharmaceutical dosage forms according to the invention in amorphous form.

In the context of the present invention, “excipients” are fillers, lubricants, disintegration promoters, surfactants, sweeteners, flavoring agents and colorants. It may therefore come to happen that a person skilled in the art assigns similar or even identical substances to be member of more than one of the above-mentioned groups of substances. Within the context of the present invention, the functional descriptions of the substances are however intentionally filled with specific substances to clarify their respective property assigned to them.

The expression ‘pharmaceutically acceptable’ refers to those excipients, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

Fillers that can be used in the formulation according to the present invention are those selected from the list consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose or maltodextrins. Preferred as filler is microcrystalline cellulose or lactose or a combination thereof. Lubricants prevent ingredients from sticking, e.g. to production equipment. Lubricants that can be used in the formulation according to the present invention are those selected from the list consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydogenated vegetable fat or oil, polyethylenglycol and talc. Preferred lubricants according to the present invention are those selected from the list consisting of magnesium stearate, stearic acid and talc. Very preferred as lubricant is magnesium stearate.

Disintegration promoters expand and dissolve when wet. They can be used to break the dosage form apart in the digestive tract, releasing the active ingredients. Disintegration promoters suitable in the context of the present invention are those selected from the list consisting of alginic acid, cross-linked polyvinylpyrrolidone, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium) or microcrystalline cellulose or a combination of croscarmellose sodium and microcrystalline cellulose. Preferred as a disintegration promoter is croscarmellose sodium or cross-linked polyvinylpyrrolidone. Very preferred as a disintegration promoter is croscarmellose sodium.

Surfactants are usually organic compounds that are amphiphilic, meaning they contain both hydrophobic groups (their tails) and hydrophilic groups (their heads). Therefore, a surfactant contains both a water-insoluble (or oil-soluble) component and a water-soluble component and help to solubilize certain chemical compounds. Surfactants according to the present invention are complexing agents such as cyclodextrines and sodium ethylene diamintetraacetic acid (EDTA), cosolvents such as ethanol, propylene glycol and dimethyl acetamide, tensides such as fatty alcohols (e.g. cetylalcohol), phospholipids (e.g. lecithine), bile acids, polyoxyethylene stearate fat esters (e.g. polyoxyethylene), polyoxyethylene sorbitan fat esters, polyoxypropylene-polyoxyethylene-block copolymers (e.g. Poloxamer), alkylsulfates (e.g. sodium lauryl sulfate, sodium cetylstearyl sulfate), alkyl soaps (e.g. sodium palmitate, sodium stearate) and saccharose fatty acid esters.

Preferred as sweetener is a pharmaceutically acceptable excipients that has a similar taste to sugar. Sweeteners suitable in the context of the present invention are those selected from the list consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin orthaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol. In the context of the present invention sweeteners are added in amounts known for persons skilled in the art.

In the context of the present invention flavoring agents are pharmaceutically acceptable excipients appropriate to improve or give an agreeable taste of a pharmaceutical dosage form to complement its effect and also to increase its elegance. In the context of the present invention flavoring agents are natural flavoring substances obtained from plant or animal raw materials, nature-identical flavoring substances obtained by synthesis or isolated through chemical processes, which are chemically and organoleptically identical to flavoring substances naturally present in products intended for human consumption and artificial flavoring substances. In the context of the present invention flavoring agents are added in amounts known for persons skilled in the art. Flavoring agents suitable in the context of the present invention are those selected from the list consisting of synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart. In the context of the present invention flavoring agents are added in amounts known for persons skilled in the art.

In the context of the present invention colorants are pharmaceutically acceptable excipients appropriate to color an uncolored pharmaceutical dosage form or to enhance its color, to minimize batch-to-batch variations or to replace a color already present to complement its effect and also to increase its elegance. It can be any dyes, lakes or pigment such as indigo carmine, riboflavine and titanium dioxide. In the context of the present invention colorants are added in amounts known for persons skilled in the art.

In the context of the present invention the optional coating is carried out with addition of customary coating and film -forming agents familiar to the person skilled in the art, such as hydroxypropyl cellulose, hydroxypropylmethylcellulose (Hypromellose), ethylcellulose, polyvinyl-pyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (e.g. polyethylene glycol 3350), glycerol triacetate or triethyl citrate, and/or colorants/pigments such as, for example, titanium dioxide, iron oxide (e.g. red iron oxide, yellow iron oxide), indigotin or suitable colour lakes, and/or antitacking agents such as talc, and/or opacifiers such as titanium dioxide. As optional coating and film-forming agents according to the present invention.

A mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available under the trade name Opadry®. Opadry 14F94373® is a mixture of about 60 wt.% hydroxypropylmethylcellulose, about 19.4 wt.% titanium dioxide, about 0.6 wt.% ferric oxide red and about 20 wt.% polyethylene glycol.

Preferably the coating is about 0.5% to 10% by weight of the coated tablet formulation, preferably 0.5% to 4.5% by weight of the coated tablet formulation, more preferably about 1.5% to 4.5% by weight of the coated tablet formulation. HPMCAS can be considered according to the present invention also as part of the coating. Binders are used in the comparison formulations according to the invention. Binders that can be used are cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins or hypromellose (e.g. hypromellose 3 cP)..

Manufacturing process of the amorphous solid dispersion (ASP):

The present invention provides a process for preparing an amorphous solid dispersion (ASD) containing 2-(2-chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), characterized in that the amorphous solid dispersion (ASD) is prepared by a solvent based process.

The solvent based process can be carried out as a wet granulation or a spray-drying process, in a spray dryer or in a fluidized bed granulator. The wet granulation in a fluidized bed granulator (= fluidized bed granulation) is preferred.

In the wet granulation the active ingredient (I) is dissolved in the granulation fluid and introduced into the fluidized bed granulator. Most preferably, the granulating fluid containing the active ingredient (I) is sprayed onto a carrier via fluidized bed granulation.

In the context of the present invention the granulating fluid consists of the solid dispersion base, the active ingredient (I) and solvents.

Solvents suitable for manufacturing the amorphous solid dispersions by solvent based processes during which the solvents are evaporated such as fluidized bed granulation can be any solvent, wherein the active ingredient (I) can be dissolved. The polymer of the solid dispersion base has also to be sufficiently soluble to make the process practicable. Preferred solvents include alcohols (e.g. methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g. acetone, methyl ethyl ketone and methyl isobutyl ketone), esters (e.g. ethyl acetate and propyl acetate) and various other solvents such as acetonitrile, methylene chloride, chloroform, hexane, toluene, tetrahydrofuran, cyclic ethers, and 1,1,1 -trichloroethane. Lower volatility solvents, such as dimethyl acetamide or dimethyl sulfoxide can also be used. Preferred solvents for manufacturing the amorphous solid dispersions comprising the active ingredient (I) are methanol, ethanol, n-propanol, isopropanol, acetone or mixtures thereof. Also preferred for manufacturing the amorphous solid dispersions comprising the active ingredient (I) is ethanol or a mixture of 20% ethanol and 80% acetone or 50% ethanol and 50% acetone. Very preferred for manufacturing the amorphous solid dispersions comprising the active ingredient (I) is a mixture of 0- 50% ethanol and 50-100% acetone.

The amorphous solid dispersion (ASD) is preferably isolated as granulate.

The present invention provides a process for preparing an amorphous solid dispersion (ASD) containing 2-(2-chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), characterized in that a) active ingredient (I) is dissolved in a suitable solvent or solvent mixture, b) the polymer (solid dispersion base) is added to receive the granulating liquid, c) the granulating liquid is sprayed onto the carrier, d) the solvent or the solvents are evaporated to result in an ASD. e) the ASD is isolated as a granulate

In an additional step f) the from step e) resulting granulate is optionally further processed by mixing with sweeteners, flavoring agents and colorants and/or milling and/or sieving and/or compacting to result in a granulate which can be used as solid pharmaceutical dosage form.

Manufacturing process of the solid pharmaceutical dosage forms based on an amorphous solid dispersion (ASD):

The present invention provides a process for preparing solid pharmaceutical dosage forms for oral administration comprising an amorphous solid dispersion (ASD) 2-(2-chlorophenyl)-n-[4-(4-cyano- lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), in which an amorphous solid dispersion (ASD), comprising (active ingredient (I) in a pharmaceutically acceptable matrix, is initially prepared, a) and the amorphous solid dispersion (ASD), optionally with addition of pharmaceutically acceptable excipients, is then converted into the pharmaceutical dosage form.

Furthermore the present invention provides a process for preparing solid pharmaceutical dosage forms for oral administration comprising an amorphous solid dispersion (ASD) containing 2-(2- chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), characterized in that an amorphous solid dispersion (ASD), comprising active ingredient (I) in a pharmaceutically acceptable matrix, is initially prepared, a) and the amorphous solid dispersion (ASD), optionally with addition of pharmaceutically acceptable excipients, is then converted into the pharmaceutical dosage form, wherein at least 75% of active ingredient (I) are released into the release medium after 45 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle). Furthermore the present invention provides a process for preparing solid pharmaceutical dosage forms for oral administration comprising an amorphous solid dispersion (ASD) containing 2-(2- chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), characterized in that an amorphous solid dispersion (ASD), comprising (active ingredient (I) in a pharmaceutically acceptable matrix, is prepared by solvent based granulation, a) and the amorphous solid dispersion (ASD), optionally with addition of pharmaceutically acceptable excipients, is then converted into the pharmaceutical dosage form.

The solvent in the granulation process of preparing an amorphous solid dispersion (ASD) allows, that 2-(2-chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) can be introduced in the process for preparing solid pharmaceutical dosage forms in the amorphous form.

Converted into the pharmaceutical dosage form in process step (b) comprises, for example, tabletting, filling into capsules, preferably hard gelatine capsules, or filling as sachets, in each case according to customary methods familiar to the person skilled in the art, if appropriate with addition of further pharmaceutically suitable excipients.

For conversion into the solid pharmaceutical dosage form in process step (b) the amorphous solid dispersion, which is isolated as a granulate, can be roller compacted and grinded with and without further excipients to obtain roller compacted granulate. The obtained granulate with and without further excipients is compressed into the pharmaceutical dosage form such as tablets.

Furthermore the present invention provides a process for preparing solid pharmaceutical dosage forms for oral administration comprising an amorphous solid dispersion (ASD) containing 2-(2- chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), characterized in that an amorphous solid dispersion (ASD), comprising active ingredient (I) in a pharmaceutically acceptable matrix, is prepared by solvent based granulation, a) to the amorphous solid dispersion (ASD) further pharmaceutically acceptable excipients are added, b) the resulting mixture is compressed into tablets, and c) the tablets are optionally coated

Furthermore the present invention provides a process for preparing solid pharmaceutical dosage forms for oral administration comprising an amorphous solid dispersion (ASD) containing 2-(2- chlorophenyl)-n-[4-(4-cyano-lh-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)), characterized in that an amorphous solid dispersion (ASD), comprising active ingredient (I) in a pharmaceutically acceptable matrix, is prepared by wet granulation, a) to the amorphous solid dispersion (ASD) further pharmaceutically acceptable excipients are added, b) the resulting mixture is roller compacted and optionally grinded, c) optionally further pharmaceutically acceptable excipients are added, d) the resulting mixture is compressed into tablets, and e) the tablets are optionally coated to receive the pharmaceutical dosage form.

Medicaments and use:

Administration of the oral solid dosage form comprising an amorphous solid dispersion of amorphous active ingredient (I) stabilized by selected excipients and manufactured by a process according to the invention leads to high relative bioavailability to the Liquid Service Formulation (LSF) in human ranging from 85% up to even 100%.

The present invention further provides medicaments comprising a solid pharmaceutical dosage form for oral administration in accordance with the invention comprising the active ingredient (I).

The present invention further relates to the use of solid pharmaceutical dosage forms for oral administration in accordance with the invention comprising the active ingredient (I) and for preparing a medicament for the treatment and/or prophylaxis of disorders, -in particular for the treatment or prophylaxis of diseases associated with pain, pain syndromes (acute and chronic), inflammatory- induced pain, neuropathic pain, diabetic neuropathic pain, diabetic neuropathy, cancer-associated pain, chemotherapy or intoxication induced pain, pelvic pain, endometriosis-associated pain as well as endometriosis as such, bladder pain syndrome; asthma, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease (COPD), chronic cough, diseases related to goblet cells and lung fibrosis, liver fibrosis, fatty liver disorders, NASH (Non-Alcoholic Steato-Hepatitis); brain ischemia, ischemic brain injury, ischemic stroke, haemorrhagic stroke, traumatic brain injury, spinal cord injury, aneurysm;; atopic dermatitis, chronic itch, pruritus; osteoarthritis, burning mouth syndrome, migraine disorders, irritable bowel disease; urology related syndromes like, overactive urinary bladder, interstitial cystitis, bladder pain syndrome.

The present invention further relates to the use of solid pharmaceutical dosage forms for oral administration in accordance with the invention comprising the active ingredient (I) and for preparing a medicament for the treatment and/or prophylaxis of cancer and hyperproliferative disorders

The present invention further relates to the use of the solid pharmaceutical dosage forms for oral administration comprising the active ingredient (I) as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. Said combination can be considered also as “kit of parts” combination. Those combined pharmaceutical agents can be other agents having antiproliferative, antinociceptive and/or antiinflammatory effects such as for example for the treatment of haematological tumours, solid tumours and/or metastases thereof and/or agents for the treatment of different pain syndromes and/or undesired side effects. The present invention relates also to such combinations.

Below, the invention is illustrated in detail by preferred working examples; however, the invention is not limited to these examples. Unless indicated otherwise, all amounts given refer to mg of dosage form.

EXPLANATION OF THE FIGURES

Figure 1: Comparison of the dissolution profdes of example 1-3, 9-1, 10-1 and 11-5 according to Table 1. (FaSSGF-FaSSIF)

Figure 2: Comparison of the dissolution profdes of example 9-1,10-1 and 11-5 according to Table 1 (FaSSGF-FeSSIF)

Figure 3: Comparison of the dissolution profdes of example 11-2 to 11-4 according to Table 1 (FaSSGF-FaSSIF)

Figure 4: Comparison of the dissolution profdes of example 10-1 and 11-5 according to Table 1 (quality control methods)

Figure 5. 1-5.3: Diffractograms of the active ingredient (I) in a tablet according to example 9-1 (Fig. 5.1), 10-1 (Fig. 5.2), 11-5 1 (Fig. 5.3)

EXPERIMENTAL SECTION

Abbreviations:

PXRD: powder X-ray diffraction

LSF = liquid service formulation

IR tablet: immediate release tablet

ASD = Amorphous solid dispersion rel. BA: relative bioavailability

AUC/D: Area under the curve per dose

Cmax/D: maximum concentration per dose

HPMCAS MG: AquaSolve™ hydroxypropylmethylcellulose acetate succinate Typ MG

SDS: sodium dodecyl sulfate also called sodium lauryl sulfate

PEG: polyethylene glycol rh: relative humidity rpm: revolutions per minute 1. Preparation methods

1.1. Preparation of active ingredient

Active ingredient was synthesised for example in accordance with the procedures described in the international patent application W02017191000, example 39, page 253 incorporated herein.

1.2. Preparation method for liquid formulations

Examples 1-1 (comparison example)

This solution is used as LSF (liquid service formulation)-like formulation for the investigation of bioavailability of active ingredient in rats. For the preparation of the oral solution, the active ingredient is dissolved in ethanol before the PEG is added. Water is added and the solution is mixed well.

Example 1-2 (comparison example)

This suspension is used as comparative formulation for the investigation of bioavailability of active ingredient in rats. The resulting suspension is simulating a suspension derived from the disaggregation of an IR tablet. For the preparation of the suspension, tylose and water are mixed while stirring. The micronized active ingredient is added and further stirred.

Example 1-3 (comparison example) - Liquid Service Formulation (LSF) 70mg

This solution is used for administration in clinical trials in humans. For the preparation of the liquid service formulation, the active ingredient is dissolved in a PEG-based oral solution.

1.3. Preparation method for immediate release tablet

Examples 2-1 (tablets as comparison examples) - IR Tablet containing active ingredient

The binder and the surfactant are dissolved in water and the active ingredient is suspended in this solution. This suspension is sprayed as granulating fluid on the initial charge composed of fillers and parts of the disintegration promoter. After drying and sieving the resulting granules, the remaining parts of the disintegration promoter and a lubricant are added and mixed. The ready to press blend thus obtained is compressed to produce tablets. The tablets are then coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents.

1.4. Preparation method for amorphous solid dispersions

1.4.1. Granules manufactured via Vacuum Drying (VD)

Examples 3-1 Kollidon VA 64 Granules

The solid dispersion base and active ingredient are dissolved in organic solvent. In the course of a vacuum drying process, the solution is dispersed with filler and disintegration promoter (carrier) and dried under vacuum. After drying and milling, the granules are resulting. As organic solvent, acetone is used. Example 4-1 to 4-6 - HPMCAS Granules

The solid dispersion base and active ingredient are dissolved in organic solvent. In the course of a vacuum drying process, the solution is dispersed with filler and disintegration promoter (carrier) and dried under vacuum. After drying and milling, the granules are resulting. As organic solvent, acetone is used.

Example 5-1 to 5-6 - PVP Granules

The solid dispersion base and active ingredient are dissolved in organic solvent. In the course of a vacuum drying process, the solution is dispersed with filler and disintegration promoter (carrier) and dried under vacuum. After drying and milling, the granules are resulting. As organic solvents, a combination of ethanol and acetone is used.

1.4.2. Granules manufactured via Fluidized Bed Granulation (FBG)

Example 6-1 - Kollidon VA 64 Granules

The solid dispersion base, surfactant and active ingredient are dissolved in organic solvent. In the course of a fluidized bed granulation, this solution is sprayed as granulating fluid on the initial charge composed of filler or the disintegration promoter (carrier). After drying and sieving, the granules are resulting. As organic solvent, acetone is used.

Examples 7-1, 7-2 - HPMCAS Granules

Example 8-1 - PVP Granulate

The solid dispersion base and active ingredient are dissolved in organic solvent. In the course of a fluidized bed granulation, this solution is sprayed as granulating fluid on the initial charge composed of filler or the disintegration promoter (carrier). After drying and sieving, the granules are resulting. As organic solvents, a combination of ethanol and acetone is used.

1.5. Manufacturing of pharmaceutical dosage form (tablets) comprising ASD granules

Example 9-1 - tablets based on ASP comprising Kollidon VA 64

Granules resulting from example 6-1 are blended with added glidants and disintegrants. The ready-to- press blend thus obtained is compressed to produce tablets. The tablets are then coated with pigments, which are suspended in an aqueous solution composed of coating and film -forming agents.

Example 10-1 - tablets based on ASD comprising HPMCAS Granules resulting from examples 7-1 and 7-2 may be roller compacted and grinded. This is followed by the addition and blending of fdlers, glidants and disintegrants. The ready-to-press blend thus obtained is compressed to produce tablets. The tablets are then coated with pigments which are suspended in an aqueous solution composed of coating and fdm -forming agents.

Examples 11-1 -11-5 - tablets based on ASP comprising PVP

Granules resulting from example 8-1 may be roller compacted and grinded. This is followed by the addition and blending of fillers, glidants and disintegrants. The ready-to-press blend thus obtained is compressed to produce tablets. The tablets are then coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents.

2. Instrumental set-up for the XRPD measurement

X-ray powder diffraction (XRPD) data were recorded on a STOE STADI P diffractometer using monochromatized CuKal -radiation, a position sensitive detector, at generator settings of 40 kV and 40 mA. The tablets were crushed using a mortar and pestle, prepared as a layer between two foils and collected in transition mode. The scanning range was between 4° and 30° 2 theta with a 0. 1° step at 30 sec/step.

Description

The diffractograms are characterized by the halos of the amorphous API and amorphous components of the formulation, in addition the diffraction peak at 5.3° 2 theta corresponds to Magnesium stearate and the peak at 25.3° 2 theta to Titanium dioxide, respectively (Figures 5. 1-5.3).

3. Release/ Dissolution method

According to the European Pharmacopoeia, 10th Edition, last revision of monograph 01/2016, the oral solid dosage form was tested with apparatus 2 (paddle). For characterization of the ASD formulations, various dissolution settings were used. Table 1 describes different dissolution media/ dissolution setups, which were used during development and for final release testing of the dosage form.

Table 1:

As biorelevant media a FaSSGF/ FaSSIF/ FeSSIF buffer concentrate from biorelevant.com Ltd were used.

4. Composition of dosage forms

Liquid formulation and IR tablets as comparison examples (Table 2)

* Solvent is removed during the manufacturing process ** according table 1 Amorphous solid dispersion (Granulate - ASP) manufactured via VD (Table 3)

* Solvent is removed during the manufacturing process

* * according table 1

* Solvent is removed during the manufacturing process

* * according to table 1

* * according to table 1 Amorphous solid dispersion (Granulate - ASP) manufactured via FBG (Table 4)

* Solvent is removed during the manufacturing process

* * according to table 1 Solid pharmaceutical dosage forms (tablets) containing the amorphous solid dispersion (ASD);

Fluidized bed granulation preparation method (Table 5)

* Solvent is removed during the manufacturing process

* according to table 1

* Solvent is removed during the manufacturing process

* * according to table 1 5. Bioavailability, dissolution and results

5.1 Comparison of liquid service formulations and amorphous solid dispersions (in an animal model)

The liquid service formulations of reference (examples 1-1 and 1-2) and the amorphous solid dispersion of example 3-1, 4-1 and 4-2 have been tested in rats. Single doses were orally administered to male rats.

The amorphous solid dispersion granules of example 3-1, 4-1 and 4-2, were suspended in water prior to administration.

Formulations containing solid active ingredient (examples 1-2 and 3-1, 4-1 and 4-2) have been evaluated against the reference (example 1-1).

Animals (male rats, n=4 per formulation) were orally dosed with 10.00 mg active ingredient/kg body weight. The volume of the application solution was 5.00 mL/kg body weight. Approximately 0.5 mb of whole blood were collected via an indwelling jugular catheter at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 7, 8, 24, 30, 48 and 72 h post-dose. The blood samples were centrifuged in order to obtain plasma which was then transferred to the appropriately labeled vials and stored frozen (< 15 °C) until analysis. Plasma samples were prepared by protein precipitation with acetonitrile and the supernatant was analyzed via LC/MSMS for active ingredient concentrations and pharmacokinetic parameters were calculated. The results are presented in Table 6.

Table 6: Comparison of the exposure of active ingredient in the rat for examples 1-1, 1-2, 3-1, 4-1 and 4-2

Result: The AUC and c_maxnorm data revealed significant differences for the exposure of active ingredient after oral application of the liquid formulations of examples 1-1 and 1-2 and the ASDs of examples 3-1, 4-1 and 4-2. Example 1-1 is used as a 100% reference. The exposures obtained after administration of granules based on ASD of examples 3-1, 4-1 and 4-2 are significantly higher compared to the exposure of the liquid formulation of example 1-2. AUC is increased by a factor of approximately 4.6 (example 4-1) and c_max norm is increased by a factor of approximately 7.9 for example 4-1. The active ingredient shows a low oral relative bioavailability and inferior dissolution profde. In particular example 1-2 shows a relative bioavailability of 16% only, whereas the solid dispersion comprising the active ingredient in amorphous form shows a relative bioavailability of 73% (example 4-1) when administered in rats.

This proved that oral absorption is improved significantly by formulations containing the amorphous active ingredient (examples 3-1, 4-1, 4-2).

5.2 Comparison of standard IR tablet with PEG solution (in humans)

Comparison examples 2- 1 was manufactured using aqueous fluidized bed granulation and was tested in fasted state as 70 mg dose against the PEG solution from example 1-3 in humans. The results are presented in Table 7.

Table 7: Comparison of the exposure of active ingredient in humans for examples 1-3 and 2-1

Result: Comparison example 2-1 showed a rel. BA of 27% for AUC/D and 14% for Cmax/D compared to the PEG solution from example 1-3. This proved that oral absorption is improved significantly by administering of the active ingredient solved in liquids (example 1-3). Thus, the IR tablet according to example 2-1 have shown inferior bioavailability compared to example 1-3, where active ingredient is dissolved.

5.3 Comparison of pharmaceutical dosage forms of ASP with PEG solution

5.3.1 in-vitro data of ASP granules

Kollidon VA 64 und PVP25

Examples 5-1 to 5-6 are describing ASD granules manufactured with VD. The granules were evaluated in order to identify the best formulation with regards to its dissolution behaviour and in particular with reference to the spring and parachute profile (Table 8). These granules varied regarding their amounts of polymer and additional excipients. For comparison, example 6-1 describes a granulate, where an alternative polymer was used (PVA 64) - in alignment with example 3-1, which revealed superior exposition in the rat study. Table 8: Comparison of the dissolution profiles in phosphate buffer pH 6.8 (according to Table 1) of examples 5-1 to 5-6 with example 6-1

Result: With increasing polymer content from 1:2 (active ingredient: polymer) shown in example 5-3 to 1:3 (active ingredient: polymer) shown in example 5-1, the dissolution rate increases. The addition of sole disintegrant without additional filler (example 5-4) significantly increases the dissolution rate whereas the sole binder without disintegrant (example 5-5) further decreases the dissolution rate. Examples 5-1 to 5-6 reveal still increasing amounts of active ingredients dissolved after 60 minutes. In contrast, example 6-1 shows an initial fast dissolution up to 15 minutes, followed by a short plateau up to 30 minutes. After that, decreasing amounts of active ingredient dissolved were observed, indicating precipitation from the supersaturated solution. Examples 5-1 to 5-6 have shown a superior dissolution behaviour in comparison to 6-1.

HPMCAS

Example 6-1 describes a granulate consisting of a different polymer (PVA 64, FBG) in alignment with example 3-1 (PVA 64, VD), which revealed promising exposition in the above-mentioned rat study.

Examples 4-1 to 4-2 describe ASD granules manufactured with VD, which were administered within the above-mentioned rat study. Examples 4-3 to 4-6 describe ASD granules manufactured with VD to evaluate the best formulation with regards to its dissolution behaviour (Table 9). These granules varied regarding their amounts of polymer and additional excipients.

Table 9: Comparison of the dissolution profiles in phosphate buffer pH 6.8 (according to Table 1) of examples 4-3 to 4-6 with example 6-1.

Result: ASD containing low polymer content with a ratio of 1:2 (active ingredient: polymer) and without additional disintegrant or fdler reveal a low dissolution rate with only 20% dissolved active ingredient after 60 minutes. Higher polymer content with a ratio of 1:3 (active ingredient: polymer) in addition to a filler (example 4-6) or disintegrant (example 4-5) or a combination thereof (example 4-3) improve the dissolution behaviour.

In comparison to example 6-1, no decrease in the dissolution rate over time was observed for examples 4-4 to 4-6, indicating a stable dissolution.

Examples 7-1 to 7-2 describe the ASD granules comprising different qualities of the same polymer. Granules were tested in a biorelevant dissolution setting (according to Table 1). The results are presented in Table 10.

Table 10: Comparison of the dissolution profiles in biorelevant media (according to Table 1) of examples 7-1 to 7-2

Result: The polymers utilized in examples 7-1 to 7-2 are characterized by a pH-dependent solubility. The ASD granules of both polymer qualities (examples 7-1 to 7-2) reveal a low dissolution with values below 15% at low pH-values (pH 1.6, FaSSGF). After buffering to FaSSIF, both polymer qualities show a high dissolution of more than 50% within 15 min after rebuffering. In comparison to FaSSIF, FeSSIF has a lower pH value (pH 5). The dissolution of the ASD granules of both polymers in FeSSIF reveal lower dissolution in comparison to the higher pH value of FaSSIF (pH 6.5). The utilized polymer quality of example 7-1 reveals a stable dissolution after rebuffering to FaSSIF in comparison to example 7-2, showing decreasing values of active ingredient (from 80% at 45 min to 69% at 90 min) indication a precipitation of active ingredient.

6.3.2 in-vitro data of ASD tablets

Examples 9-1, 10-1 and 11-1 to 11-5 are describing pharmaceutical dosage forms (tablets) based on ASD with a dose strength of 50 mg (for example 9-1) and lOOmg using granules manufactured in examples 6-1 and 7-1 to 7-2 and 8-1.

Comparing the dissolution profiles of the example 10-1 with example 9-1 regarding the transfer assay to FaSSIF, example 10-1 reveals a superior dissolution behaviour (Figure 1), with regards to the dissolution rate as well as the amount of released active ingredient: After 90 minutes, only 38 % (example 9-1) and 31% (example 1-3) active ingredient are dissolved, whereas example 10-1 shows a dissolution of 75% for the active ingredient. Both tablet formulations don’t show a decreasing dissolution over the investigated time period, indicating a stable ASD without precipitation of active ingredient. In comparison to example 1-3 (31% dissolved active ingredient after 90 minutes), which represents the liquid service formulation, only example 10-1 reveals a superior dissolution profile with 75% dissolved active ingredient after 90 minutes.

The results of the dissolution are displayed in Table 11.

Table 11: Comparison of the dissolution profdes in biorelevant media (according to Table 1) of examples 1-3, 9-1 and 10-1

Comparing the dissolution profdes of the example 10-1 with example 9-1 using the transfer assay to FeSSIF (Figure 2), example 10-1 reveals an inferior dissolution behaviour with 22% dissolved active ingredient after 90 minutes in comparison to 38% dissolved active ingredient for example 9-1. Both tablet formulations don’t show a decreasing dissolution over the investigated time period, indicating a stable ASD.

Dissolution testing of example 1-3, 9-1, 10-1 and 11-5 according to Table 1 (FaSSGF-FaSSIF) is reported in Figure 1.

6, 3, 2, 2 Tablets based on ASD comprising PVP

Examples 11-1 and 11-2 are providing different active ingredient to polymer ratios (1:2.5 and 1:2) within the formulation. The dissolution profiles of these formulations, reveal a faster dissolution onset of example 11-1 in comparison with example 11-2. The amount of dissolved active ingredient is higher for example 11-1 (maximum of 61% after 60 minutes) than for example 11-2 (maximum of 44% after 60 minutes). However, both formulations show a similar decrease of the dissolution rate over the time indicating a precipitation of the active ingredient (Table 12). Table 12: Comparison of the dissolution profiles in biorelevant media (according to Table 1) of examples 11-1 and 11-2.

Examples 11-2, 11-3 and 11- 4 are representing tablets where the ASD is based on PVP with varying amount of HPMCAS and disintegrant in the post blend. Comparing the dissolution profiles of these formulations (Figure 3) using the transfer assay FaSSGF/FaSSIF example 11-2 revealed lowest dissolution of active ingredient (max 44% after 60 minutes) and show a decrease of amount of active ingredient with only 28% dissolved active ingredient after 90 minutes, indicating a precipitation of the active ingredient. With addition of HPMCAS (example 11-3) to the post-blend, a superior dissolution profile could be obtained without a decreasing concentration of active ingredient (59% after 90 minutes), indicating a stable dissolution. The combination of high amounts of disintegrant (150mg/tablet) with HPMCAS in the post-blend (example 11-4), revealed the dissolution profile with highest concentration of active ingredient with 78% dissolved active ingredient after 90 minutes (Table 13).

Table 13: Comparison of the dissolution profiles in biorelevant media (according to Table 1) of examples 11-2 to 11-4.

Dissolution testing (FaSSGF-FaSSIF) of example 11-2 to 11-4 according to Table 1 are reproduce in Figure 3.

Testing of the example 11-1 and 11-4 with the transfer assay from FaSSGF to FeSSIF, both tablet formulations reveal comparable dissolution profiles, despite one formulation containing a lower active ingredient- polymer ratio and HPMCAS in the post blend (example 11-4). Dissolution data are presented in Table 14. Table 14: Comparison of the dissolution profiles in biorelevant media (according to Table 1) of examples 11-1 and 11-4.

The dissolution profiles measured with the transfer-assays for example 11-5 show a fast dissolution after buffering to intestinal fluid, independent of the pH value of the dissolution medium (FaSSIF pH 5 vs. FeSSIF pH 6.5). Therefore, example 11-5 shows a fast-decreasing dissolution rate after an initial high dissolution when using the transfer assay FaSSGF-FeSSIF (Figure 2). The dissolution stays stable when using the transfer-assay FaSSGF-FaSSIF (also shown in Figure 1 and Figure 3).

Table 15: Comparison of the dissolution profiles in biorelevant media (according to Table 1) of examples 11-5.

6.3.3 in-vivo data of ASD tablets

Table 16: Comparison of the exposure of active ingredient in humans for examples 10-1 and 11-5

Result: Tablets (example 10-1) manufactured by using the ASD from example 7-1 showed high relative bioavailability in humans given with light meal (rel. BA of 94.3% for AUC/D and 95.5% for Cmax/D relating to the LSF from example 1-4). Tablets (example 11-5) manufactured by using the ASD from example 8-1 revealed lower bioavailability’s in humans given with light meal (rel. BA of 87% for AUC/D and 44% for Cmax/D relating to the LSF from example 1-4). Both ASD tablets showed a higher relative bioavailability in comparison to the ASD tablet of example 9-1 (rel. BA of 42% for AUC/D and 11% for Cmax/D relating to the LSF from example 1-4).

Claims

1. Solid pharmaceutical dosage form for oral administration comprising 2-(2-Chlorophenyl)-N- [4-(4-cyano-lH-pyrazol-l-yl)-3-sulfamoylphenyl]acetamide (active ingredient (I)) in amorphous form and HPMCAS, in a weight ratio of not less than 1 to 0.05 of HPMCAS.

2. Solid pharmaceutical dosage form according to claim 1 characterized in that the ratio of the active ingredient (I)) in amorphous form to HPMCAS is of 1:0.5 to 1:20.

3. Solid pharmaceutical dosage form according to claim 1 or 2 characterized in that the ratio of the active ingredient (I)) in amorphous form to HPMCAS is of 1 : 1 to 1: 10.

4. Solid pharmaceutical dosage form according to claim 1 comprising the active ingredient (I) in amorphous form, and with the active ingredient (I) in a weight ratio of not less than 1:0.05 of HPMCAS and of active ingredient (I) in a weight ratio of 1:0.5 to 1:20 to a combination of PVP and HPMCAS.

5. Solid pharmaceutical dosage form according to claim 4 characterized in that the ratio of the active ingredient (I)) in amorphous form to a combination of PVP and HPMCAS is of 1: 1 to 1: 10.

6. Solid pharmaceutical dosage form according to any one of the previous claims characterized in that the active ingredient (I) is in an amount between 2 and 200 mg.

7. Solid pharmaceutical dosage form according to any one of the previous claims characterized in that the active ingredient (I) is in an amount between 10 and 150 mg.

8. Solid pharmaceutical dosage form according to any one of the previous claims characterized in that the active ingredient (I) in amorphous form is between 10 and 150 mg, and in a weight ratio of 1 : 1 to 1 :5 to HPMCAS.

9. Solid pharmaceutical dosage form according to any one of the previous claims characterized in that the active ingredient (I) in amorphous form is between 10 and 150 mg, and in a weight ratio of 1:0.05 to HPMCAS and in a weight ratio of 1: 1 to 1:5 to a combination of PVP and HPMCAS.

10. A solid pharmaceutical dosage form for oral administration comprising the active ingredient (I) in amorphous form and HPMCAS in a ratio of not less than 1 to 0.05 of HPMCAS characterized in that at least 75% of active ingredient (I) is released into the release medium after 45 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).

11. A solid pharmaceutical dosage form for oral administration according to claim 10 characterized in that the active ingredient (I) in amorphous form and HPMCAS are in a ratio of 1:0.5 to 1:20.

12. A solid pharmaceutical dosage form for oral administration according to claim 10 or 11 characterized in that the active ingredient (I) in amorphous form and HPMCAS are in a ratio of 1: 1 to 1: 10.

13. A solid pharmaceutical dosage form for oral administration according to claim 10 to 12 characterized in that the active ingredient (I) in amorphous form and HPMCAS are in a ratio of not less than 1 to 0.05 and in a weight ratio of 1 : 1 to 1 :5 to a combination of PVP and HPMCAS.

14. A solid pharmaceutical dosage form for oral administration comprising the active ingredient (I) in amorphous form and HPMCAS in a ratio of not less than 1 to 0.05 of HPMCAS characterized in that have a release of about 30% to 60% of active ingredient (I) into the release medium in about from 30 to about minute 90, using a dissolution method with FaSSGF/FaSSIF as dissolution media under the conditions: FaSSGF pH 1.6 (250mL) 30 minutes / buffering to FaSSIF Vl(total volume 500mL), 50rpm, 37°C, and/or FaSSGF/FeSSIF under the conditions: FaSSGF pH 1.6 (250mL) 30 minutes / buffering to FeSSIF Vl(total volume 500mL), 50rpm, 37°C.

15. A solid pharmaceutical dosage form for oral administration according to claim 14 charachterized in that the active ingredient (I) in amorphous form and HPMCAS are in a ratio of 1:0.5 to 1:20.

16. A solid pharmaceutical dosage form for oral administration according to claim 14 or 15 charachterized in that the active ingredient (I) in amorphous form and HPMCAS are in a ratio of 1: 1 to 1: 10.

17. A solid pharmaceutical dosage form for oral administration according to claim 14 to 17 charachterized in that the active ingredient (I) in amorphous form and HPMCAS are in a ratio of not less than 1 to 0.05 and in a weight ratio of 1 : 1 to 1 :5 to a combination of PVP and HPMCAS.

18. Solid pharmaceutical dosage form for oral administration according to any one of the preceding claims, characterized in that the dosage form is a tablet.

19. Solid pharmaceutical dosage form for oral administration according to any one of the preceding claims, characterized in that the tablet has a film coating.

20. Solid pharmaceutical dosage form for oral administration according to any one of the preceding claims, characterized in that the dosage form is a granulate.