Patent Description:
The present invention relates to a pharmaceutical composition comprising a stabilized solid amorphous dispersion, having high drug load, such as <NUM>%-<NUM>%, of an extremely low-solubility compound (Compound A) which resulted in significantly enhanced dissolution and bioavailability over the crystalline form of said compound. The compound <NUM>-{[(2R,<NUM>,4R,<NUM>)-<NUM>-(<NUM>-Chloro-<NUM>-fluoro-phenyl)-<NUM>-(<NUM>-chloro-<NUM>-fluoro-phenyl)-<NUM>-cyano-<NUM>-(<NUM>,<NUM>-dimethyl-propyl)-pyrrolidine-<NUM>-carbonyl]-amino}-<NUM>-methoxy-benzoic acid (Compound A), as well as methods for making it, is disclosed in <CIT> and <CIT>.

<NUM>-{[(2R,<NUM>,4R,<NUM>)-<NUM>-(<NUM>-Chloro-<NUM>-fluoro-phenyl)-<NUM>-(<NUM>-chloro-<NUM>-fluoro-phenyl)-<NUM>-cyano-<NUM>-(<NUM>,<NUM>-dimethyl-propyl)-pyrrolidine-<NUM>-carbonyl]-amino}-<NUM>-methoxy-benzoic acid (C<NUM>H<NUM>Cl<NUM>F<NUM>N<NUM>O<NUM>) (Compound A) is a potent and selective inhibitor of the p53-MDM2 interaction that activates the p53 pathway and induces cell cycle arrest and/or apoptosis in a variety of tumor types expressing wild-type p53 in vitro and in vivo. Compound A belongs to a novel class of MDM2 inhibitors having potent anti-cancer therapeutic activity, in particular in leukemia such as AML and solid tumors such as for example non-small cell lung, breast and colorectal cancers.

The above-identified international patent application and US Patent describe Compound A in crystalline form. The crystalline form of the compound has an on-set melting point of approximately <NUM>. The crystalline forms have relatively low aqueous solubility (<<NUM>µg/mL in water) at physiological pHs (which range from pH1. <NUM>-<NUM>) and consequently less than optimal bioavailability (high variability). It is thus desirable to obtain a form of the compound which has improved solubility/dissolution rate and bioavailability.

The present invention provides an amorphous form of Compound A which is substantially free of crystalline compound. The compound is present in a compound/polymer complex in an amount equal to or greater than <NUM>% of the complex, by weight.

Another aspect of the invention is a pharmaceutical composition comprising the complexes of the invention wherein Compound A is present in a therapeutically effective amount.

Another aspect of the invention is that the complex of the amorphous drug substance with the polymer is stable at high drug load.

Another aspect of the invention is a process for making the complexes of the invention that contains pharmaceutically active compounds in stabilized amorphous form.

The bioavailability of a therapeutically active compound is generally determined by (i) the solubility/dissolution rate of the compound, and (ii) the partition coefficient/permeability of the compound through a subject's gastrointestinal membrane. The major cause of poor bioavailability of a therapeutically active compound is usually the poor solubility/dissolution rate of said compound. Poor bioavailability is also often accompanied by high variable patient blood levels and unpredictable dose/therapeutic effects due to erratic absorption of the drug by the patient.

As used herein, the term "poorly soluble" when referring to a chemical compound in relation to its solubility in water or an oil, can be defined as in U. Pharmacopeia and National Formulary (USP-NF). According to this definition, solubility is stated in terms of the parts of the solvent needed to dissolve one part of the solute. A compound that is sparingly soluble in a particular solvent, such as water, requires <NUM>-<NUM> parts of the solvent to dissolve one part of the compound. A compound that is slightly soluble requires <NUM>-<NUM> parts of the solvent. A compound that is very slightly soluble requires <NUM>-<NUM>,<NUM> parts of the solvent. A compound that is insoluble (such as Compound A) requires more than <NUM>,<NUM> parts of the solvent to dissolve one part of the solute.

The lack of solubility of such drugs, and the inability to obtain sufficiently high concentrations of drugs in solution in pharmaceutically acceptable carriers, is a serious problem for formulating these drugs and thereof limit the therapeutic benefit that can be achieved for such compounds. Lack of solubility is additionally a concern in the formulation of compounds for various different targets which need significantly high doses and need to establish very high safety margin over the therapeutic effective dose. Accordingly, a significant need existed for a method to increase the solubility of these drugs.

To improve the desired properties of poorly soluble drugs, many technologies have been developed, including but not limited to the following:.

While some of these techniques are well known, most of them provide a number of unique challenges and can't be applicable to the brick dust like compounds i.e. with very high melting point and practically no solubility in any of the organic solvents.

Furthermore, the amorphous solid dispersions are high energy formulations which present additional challenges since they are, by nature, thermodynamically unstable. Consequently, their successful development depends in good measure on the understanding of the specific interactions responsible for their stabilization (<NPL>; <NPL>. However, there is no universal or reliable method to select neither a technology nor a polymer to have guaranteed amorphous stability and improved bioavailability. Solubility parameters have been reported to aid the selection of the polymers. However, as shown in Table <NUM> below, the solubility parameters and the rank of them between different polymers are not consistent between different calculations and therefore, different polymers could be selected based on different calculations. Therefore, calculations do not predict any benefit of using one particular polymer over another in terms of providing stable amorphous dispersion.

For solid dispersion formulations, if the amorphous re-crystalize, one can speculate that the bioavailability is impacted due to the loss of the advantage from the improved solubility of the amorphous form. However, it is not clear how the drug loading or the polymer plays a role in bioavailability when the amorphous stability is maintained in a wide range of drug loads.

Compound A, methods of synthesizing it as well as conventional pharmaceutical formulations containing the compound has been described in <CIT>. This patent application describes a method for making the thermodynamically stable form of the compound and the mechanism of action for the molecule.

<CIT> discloses pharmaceutical compositions comprising of amorphous dispersion of various different compounds i.e. Tolcapone, Accutane, Saquinavir and several others, obtained by using micro precipitated bulk Powder (MBP) technology. The MBP technology was found to be widely applicable and several different polymers i.e. Eudragit® L100-<NUM>, Eudragit® L100, Hydroxypropylmethylcellulose phthalate (HP-<NUM>) or Eudragit® S100 were found to be successful in generating stable amorphous dispersion for these drugs.

US Patent Application No. <CIT> describes pharmaceutical composition of Propane-<NUM>-sulfonic acid {<NUM>-[<NUM>-(<NUM>-chloro-phenyl)-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridine-<NUM>-carbonyl]-<NUM>,<NUM>-difluoro-phenyl }-amide with HPMC-AS using MBP technology.

US Patent Application No. <CIT> discloses an amorphous composition of Propane-<NUM>-sulfonic acid {<NUM>-[<NUM>-(<NUM>-chloro-phenyl)-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridine-<NUM>-carbonyl]-<NUM>,<NUM>-difluorophenyl }-amide with co-povidone polymer via hot melt extrusion process.

US Patent Application No. <CIT> specifies a pharmaceutical composition of low melting drug HEP with HPMC-AS using MBP and HME technology, where amorphous dispersion via HME process showed slightly improved pharmacokinetic behavior over MBP formulation.

In <CIT>, solid dispersions using water-insoluble ionic polymers with a molecular weight greater than <NUM>,<NUM> D are disclosed to provide a stable amorphous formulation.

<CIT> describes the use of ionic polymers, including hypromellose acetate succinate (HPMCAS), to prepare solid dispersions for improved solubility and better bioavailability.

<CIT> discloses spray dried compositions comprising a drug and, among many other polymers, PVP or PVP-VA.

HPMCAS is a polymer that has been used for the manufacture of solid dispersions of drugs (for example, <NPL>). Other polymers as used herein, in particular Povidone (PVP) and Copovidone (PVP VA <NUM>) are commercially available, for example from BASF SE (<NUM> Ludwigshafen, Germany).

The polymer used in this preparation was hypromellose phthalate and the co-precipitates were prepared by solvent evaporation method followed by drying at <NUM>. Based on dissolution data, such co-precipitates systems solubilized by co solvents or solid dispersion approaches, may revert back to crystalline form, resulting in loss of bioavailability at higher dose.

While micro co-precipitation has been utilized for the stabilization of several drug substances in the solid state, it may not be necessary to satisfactorily tailor the pharmacokinetic profile of such poorly soluble compounds, particularly the dose dependent exposure, which is very important to manage the safety and efficacy of the compound. These supersaturated formulations may revert back to crystalline form upon storage or under stress conditions, resulting in loss of bioavailability. The polymer and process selection for amorphous dispersion found to play critical role in stabilizing those dispersions. However, there is no absolute method to a priori judge whether a given polymer or process will provide adequate stability of the amorphous dispersion.

The drug loading in solid amorphous formulation has been found to be critical. It is usually the lower the drug load, the better the stability. Above certain drug loading, the amorphous solid dispersion poses high risk in re-crystallization during shelf life and therefore diminishes the benefit of the improved solubility and bioavailability. Lin and Cham ( <NPL>) showed that solid dispersions of naproxen in PEG <NUM> released drug faster when a <NUM> or <NUM>% naproxen loading was used than when a <NUM>, <NUM> or <NUM>% loading was used. These results could be explained on the basis of X-ray diffraction results, which indicated that dispersions with low loading levels of naproxen were amorphous whereas those with high loadings were partly crystalline (<NPL>). An obstacle of solid dispersion technology in pharmaceutical product development is that a large amount of carrier, i.e. more than <NUM>% to <NUM>% wt/wt, was required to achieve the desired dissolution. This high percentage of carrier warrants consistency of product performance at the time of manufacturing and during shelf storage.

The present invention relates to stabilized solid dispersions of Compound A which are characterized by an enhanced dissolution rate and significantly improved bioavailability.

In one embodiment, the present solid dispersions are prepared by micro-precipitation, leading to said solid dispersion as micro-precipitated bulk powder (MBP). In another embodiment, the present solid dispersions are prepared by spray-drying (SD) processes. Depending on the process, different polymers may be used to effectively immobilize Compound A in said solid dispersion.

A polymer screening has been carried out using the following polymers:.

The following weight ratios of Compound A : Polymer were tested: <NUM>% A : <NUM>% Polymer; <NUM>% A : <NUM>% Polymer; <NUM>% A : <NUM>% Polymer; and <NUM>% A : <NUM>% Polymer : <NUM>% DOSS (Dioctyl sodium sulfosuccinate or docusate sodium).

In addition, the following polymers were tested in a weight ratio <NUM>% A:<NUM>% Polymer; and <NUM>% A:<NUM>% Polymer:.

It has been demonstrated that among the various polymers tested, HPMCAS, Povidone (PVP) and Copovidone (PVP VA <NUM>) show improved dissolution profiles for Compound A. Improved dissolution profiles mean an improved release of Compound A from the solid dispersion formed by that compound and the respective polymer. Additionally, the use of Povidone or Copovidone can lead to dissolution profiles which are independent from the pH-value in the dissolution environment. Therefore, dissolution and thus release of Compound A from a solid dispersion formed with Povidone or Copovidone may already take place early after oral administration of such solid dispersion, for example in the stomach. This early dissolution/release of Compound A may therefore significantly improve the bioavailability of Compound A.

As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient (for example Compound A); preferably dispersed among at least one other component, for example a polymer. In certain embodiments, a solid dispersion as disclosed herein is a pharmaceutical dispersion that includes at least one pharmaceutically or biologically active ingredient (for example Compound A). In some embodiments, a solid dispersion includes Compound A molecularly dispersed with a polymer. Preferably the solid dispersion is a one phase system. An especially preferred solid dispersion according to the present invention is microprecipitated bulk powder (MBP) comprising Compound A. In another embodiment, the solid dispersion is obtained by spray-drying and comprises Compound A and, as polymer, Copovidone (PVP VA <NUM>).

The term "molecularly dispersed", as used herein, refers to the random distribution of a compound (e.g., Compound A) with a polymer. In certain embodiments the compound is present in the polymer in a final state of subdivision. See, e.g., <NPL>) and <NPL>). In some embodiments, a compound (for example, Compound A) may be dispersed within a matrix formed by the polymer in its solid state such that the compound is immobilized in its amorphous form. Whether a compound is molecularly dispersed in a polymer may be evidenced in a variety of ways, e.g., by the resulting solid molecular complex having a single glass transition temperature, or the absence of signals indicating any crystalline amounts of said compound (e.g. Compound A) in X-ray diffraction curves.

The term "solid molecular complex" as used herein means a solid dispersion that includes Compound A molecularly dispersed within a polymer matrix.

The term "immobilize", as used herein with reference to the immobilization of the active compound in the polymer matrix, means that molecules of the compound interact with molecules of the polymer in such a way that the molecules of the compound are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility. In some embodiments the polymer may prevent intermolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of Compound A. See, for example, <NPL>.

Percentages (%) as used herein are expressed in weight percent (weight %, wt/wt), unless explicitly otherwise stated.

Accordingly, in a first aspect, provided is a solid dispersion that includes Compound A and a polymer. Also provided is a solid molecular complex that includes Compound A and a polymer. The polymer may be a non-ionic polymer or an ionic polymer. In certain embodiments, the polymer is selected from the group consisting of hydroxypropylmethyl cellulose, methacrylic acid copolymers, and the like, as well as mixtures of any two or more thereof. In a preferred embodiment, the polymer is selected from Povidone (PVP, Kollidon®) or Copovidone (Kollidon® VA <NUM>; PVP VA <NUM>).

The stable solid dispersion comprises from about <NUM>% to about <NUM>%, in certain embodiments from about <NUM>% to about <NUM>%, or from about <NUM>% to about <NUM>%, or from about <NUM>% to about <NUM>%, or from about <NUM>% to about <NUM>% (wt/wt) of Compound A molecularly dispersed in a matrix formed by a polymer. In certain embodiments this polymer is Povidone (PVP), or Copovidone (PVP VA <NUM>). Most preferably the stabilized amorphous dispersion composition of Compound A of the present invention comprises no significant amounts of crystalline Compound A, as demonstrated by amorphous X-ray powder diffraction (XRPD) of said compositions.

The active ingredient (i.e. Compound A) has the chemical name of <NUM>-{[(2R, <NUM>, 4R, <NUM>)-<NUM>-(<NUM>-Chloro-<NUM>-Fluoro-Phenyl)-<NUM>-(<NUM>-Chloro-<NUM>-Fluoro-Phenyl)-<NUM>-Cyano-<NUM>-(<NUM>,<NUM>-Dimethyl-Propyl)-Pyrrolidine-<NUM>-Carbonyl]-Amino}-<NUM>- Methoxy -Benzoic Acid, (Compound A) and can be represented by the following structural formula:
<CHM>.

The crystalline form of Compound A (herein sometimes referred to as "drug", "API") has a melting point of approximately <NUM> and possess very low aqueous solubility (<<NUM>µg/ml) at physiological pHs (from pH <NUM>-<NUM>), consequently very low bioavailability. The permeability of the compound is not high as determined with the Caco-<NUM> assay value of <NUM> x <NUM>-<NUM> cm/s. The poor solubility and the targeted high doses/frequency of dosing for this series of compounds led to the categorization of Compound A as BCS class IV compound (poor solubility/poor permeability).

Compound A, as well as methods for making it, is for example disclosed in <CIT> and <CIT>. More specifically, Compound A has the potential to treat a variety of proliferative disorders, such as e.g. cancer, due to its ability to inhibit the MDM2-p53 interaction. The term "cancer" as used herein means solid - and hematological tumors, selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer (i.e. including colon cancer and rectal cancer), pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, hematological malignancies (e.g. leukemia), melanoma and sarcomas. More especially preferably the cancer is selected from the group consisting of hematological malignancies, prostate cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, melanoma and lung cancer. In an especially preferred embodiment the cancer is acute myeloid leukemia (AML), or prostate cancer.

In one embodiment, the present invention provides a physically stable solid dispersion comprising the compound <NUM>-{[(2R, <NUM>, 4R, <NUM>)-<NUM>-(<NUM>-Chloro-<NUM>-Fluoro-Phenyl)-<NUM>-(<NUM>-Chloro-<NUM>-Fluoro-Phenyl)-<NUM>-Cyano-<NUM>-(<NUM>,<NUM>-Dimethyl-Propyl)-Pyrrolidine-<NUM>-Carbonyl]-Amino}-<NUM>- Methoxy -Benzoic Acid (Compound A) together with a stabilizing polymer, wherein the stabilizing polymer is EUDRAGITR L-<NUM>, Eudragit L100-<NUM> or Copovidone (PVP VA <NUM>).

In another embodiment, the present invention provides any of the solid dispersions as disclosed above wherein the ratio of the amount by weight of the Compound A within the solid dispersion to the amount by weight of the stabilizing polymer therein is between <NUM>:<NUM> to <NUM>:<NUM>.

In another embodiment, the present invention provides any of the solid dispersions as disclosed above wherein the ratio of the amount by weight of the Compound A within the solid dispersion to the amount by weight of the stabilizing polymer therein is preferably <NUM>:<NUM> to <NUM>:<NUM>.

In yet another embodiment, the solid dispersion according to the present invention is obtained by spray drying a solution of Copovidone (PVP VA <NUM>) and Compound A. Any solvent wherein both, Copovidone and Compound A are soluble can be used. Preferably, <NUM>% (by weight) Copovidone and <NUM>% (by weight) Compound A are dissolved in acetone. The combined amount of Copovidone + Compound A represents <NUM>-<NUM>%, preferably <NUM>% (by weight), of the acetone solution. This solution is spray dried by conventional spray dried methods, followed by a secondary drying process. All conventional secondary drying methods can be used, preferably a tray dryer, a screw dryer or a fluid bed dryer. The so obtained spray dried powder is further characterized by a particle size distribution from about d<NUM> = <NUM> to <NUM>, d<NUM> = <NUM> to <NUM> and d<NUM> = <NUM> to <NUM> (measured by laser diffraction), and a bulk density of <NUM> to <NUM>/cm<NUM>.

The solid dispersion, in particular the MBP and/or spray-dried products obtainable according to the methods provided, can be used in a wide variety of forms for administration of drugs that are poorly water soluble, such as Compound A, and in particular for oral dosage forms. Exemplary dosage forms include powders or granules that can be taken orally either dry or reconstituted by addition of water to form a paste, slurry, suspension or solution; tablets, capsules, or pills. Various additives can be mixed, ground or granulated with the solid dispersion as described herein to form a material suitable for the above dosage forms. Potentially beneficial additives may fall generally into the following classes: other matrix materials or diluents, surface active agents, drug complexing agents or solubilizers, fillers, disintegrants, binders, lubricants, and pH modifiers (e.g., acids, bases, or buffers). Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of surface active agents include sodium lauryl sulfate and polysorbate <NUM>. Examples of drug complexing agents or solubilizers include the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins. Examples of disintegrants include sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, and croscarmellose sodium. Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and the salts of said acids. At least one function of inclusion of such pH modifiers is to control the dissolution rate of the drug, matrix polymer, or both, thereby controlling the local drug concentration during dissolution.

Additives may be incorporated into the solid amorphous dispersion during or after its formation. In addition to the above additives or excipients, use of any conventional materials and procedures for formulation and preparation of oral dosage forms using the compositions disclosed herein known by those skilled in the art are potentially useful.

Therefore, in another embodiment, there is provided a unit dose solid formulation, preferably a tablet, comprising a solid dispersion according to the present invention together with commonly used pharmaceutical ingredients selected from the group consisting of disintegrants, diluents, lubricants, glidants together with a film coat.

In another embodiment, the present invention provides a unit dose solid formulation comprising approximately <NUM>% of any of a solid dispersion according to the present invention together with about <NUM>% croscarmellose sodium, about <NUM>% mannitol, about <NUM>% crospovidone, about <NUM>% colloidal silicon dioxide and about <NUM>% of magnesium stearate which is then encapsulated or compressed and coated as tablet.

In yet another embodiment, the present invention provides a unit dose solid formulation, characterized in that a solid dispersion obtained by spray drying of the Compound A together with Copovidone (PVP VA <NUM>) representing about <NUM>% wt/wt of the kernel weight is further blended with a filler (<NUM>% up to <NUM>% of kernel weight), preferably selected from mannitol, microcrystalline cellulose, lactose monohydrate or silicon dioxide; one or two disintegrants (<NUM>% wt/wt of kernel weight) selected from croscarmellose sodium or crospovidone; a glidant (<NUM>% wt/wt of kernel weight) preferably colloidal silicon dioxide; and a lubricant (<NUM>% wt/wt of kernel weight) magnesium stearate, using a tumble mixer.

In yet another embodiment, there is provided the specific tablet formulation according to Example <NUM>.

In another embodiment, the present invention provides a method for preparing a solid dispersion of a compound having an aqueous solubility of less than <NUM>µg/ml, preferably Compound A, and an ionic polymer which comprises forming a solution of the compound and the polymer in dimethyl-acetamide, or any other suitable solvent and co-precipitating the drug with the polymer using anti-solvent.

In another embodiment, the present invention provides a method for preparing a solid dispersion of a compound having an aqueous solubility of less than <NUM>µg/ml, preferably Compound A, and an ionic polymer which comprises forming a solution of the compound and the polymer in acetone, or any other suitable solvent, and spray drying the drug with the polymer. Preferably the polymer in this embodiment is Copovidone (PVP VA <NUM>).

In another embodiment, the present invention provides a pharmaceutical preparation comprising a solid dispersion according to the present invention together with additional pharmaceutically acceptable adjuvants.

In another embodiment, the present invention provides a solid dispersion according to the present invention for use as a medicament for the treatment of cancer, in particular AML or prostate cancer.

In another embodiment, the present invention provides the use of a solid dispersion according to the present invention for the manufacture of a medicament for the treatment of cancer, in particular AML or prostate cancer.

Extremely low solubility/bioavailability pose challenges to attaining desirable exposure and safety margins for Compound A. Since the low bioavailability of hydrophobic drugs with extremely low water solubility can be a serious problem, different approaches have been explored to achieve the desirable high levels of drug solubility and dissolution rate. These approaches will now be further illustrated by the following examples.

Below are the details (example <NUM>) of various different formulation approaches with crystalline form or salt form of the compound. Table <NUM> illustrates the relative bio-availability obtained with those formulation approaches.

The crystalline formulations were produced as follows:.

Crystalline suspension was prepared by dispersing the crystalline Compound A in aqueous based vehicle consisting <NUM>% hydroxypropylcellullose, <NUM>% polysorbate <NUM>, <NUM>% methylparaben and <NUM>% of propylparaben. The suspension was milled to achieve the median particle size of <<NUM> (d<NUM>).

Salt screening had identified several potential salts of Compound A (see Table <NUM> below). Among them, Meglumine was a promising salt with the most improved aqueous solubility and was therefore tested in an animal pharmacokinetics study in solid dosage form in capsule containing Compound A meglumine salt as granules with poloxamer <NUM>, crospovidone, colloidal silica and magnesium stearate. The bioavailability (exposure) was not improved (<FIG>).

It was found that amorphous solid dispersion of Compound A exhibited significantly higher bioavailability than crystalline or salt form of the compound.

Various available technologies were evaluated to generate the suitable amorphous formulation i.e. spray drying, hot melt extrusion, and microprecipetated bulk powder technology, as shown in examples <NUM>-<NUM>.

The various carriers which were explored include, hypromellose, hypromellose acetate succinate, Kollidon PVP, Kollidon PVP VA64, Soluplus, copolymers of acrylic and methacrylic acid, such as Eudragit L100-<NUM>, Eudragit L100, Eudragit EPO. The experiments were done at various drug loadings ranging from <NUM>%-<NUM>%.

Compound A, copovidone (or SoluPlus®, HPMCAS), with or without docusate sodium were melted using a hot melt extruder at <NUM> to <NUM> at drug loading of <NUM>% to <NUM>%. The milled extrudates with copovidone was tested in animal with the following composition: <NUM>% Compound A, <NUM>% of Copovidone, <NUM>% Docusate sodium, and <NUM>% colloidal silicon dioxide. The final constituted dosing suspension concentration was <NUM>/ mL of Compound A.

The drug and polymer (HPMCAS or Eugragit L100) were dissolved in the dimethyl-acetamide (DMA) by stirring at room temperature. The solution with or without filtration was then added to the cold, temperature-controlled anti-solvent aqueous media (dilute HCl, around pH <NUM>, temperature of <NUM> to <NUM>) that allows rapid co-precipitation of the drug and the polymer. The residual DMA was extracted with frequent washing with cold acidic water and cold water, followed by separation of the wash and the wet precipitate and drying of the precipitate. The dried powder is the so-called MBP subjected to further processing to dosing suspension or tablets. All of the formulations below showed amorphous XRD pattern.

Compound A as amorphous solid dispersion (MBP), powder for constitution containing <NUM>% Compound A and <NUM>% Eudragit L <NUM> polymer. The final dosing concentration was equivalent to <NUM>/mL of Compound A in aqueous vehicle containing <NUM>% w/w hydroxypropylcellulose, <NUM>% polysorbate <NUM> and <NUM>% methylparaben and <NUM>% propylparaben.

Example <NUM> (reference): Amorphous solid dispersion of Compound A with HPMCAS at <NUM>% drug load: Compound A as amorphous solid dispersion by coprecipitation (MBP) at <NUM>% drug load with <NUM>% HPMC-AS polymer. The final constituted dosing suspension concentration was <NUM>/ mL of Compound A in aqueous vehicle containing <NUM>% w/w hydroxypropylcellulose, <NUM>% polysorbate <NUM> and <NUM>% methylparaben and <NUM>% propylparaben.

Example <NUM> (reference): Amorphous solid dispersion of Compound A with HPMCAS at <NUM>% drug load: Compound A as amorphous solid dispersion (MBP) containing <NUM>% Compound A and <NUM>% HPMC-AS polymer. The MBP was then constituted to a dosing suspension at concentration of <NUM>/ mL of Compound A in aqueous vehicle containing <NUM>% w/w hydroxypropylcellulose, <NUM>% polysorbate <NUM> and <NUM>% methylparaben and <NUM>% propylparaben.

Example <NUM> (reference): Amorphous solid dispersion of Compound A with HPMCAS at <NUM>% drug load: Compound A as amorphous solid dispersion (MBP), powder for constitution containing <NUM>% Compound A and <NUM>% HPMC-AS polymer. Suspension concentration upon constitution was <NUM>/ mL.

Amorphous MBP solid dispersion of Compound A containing <NUM>% Compound A and <NUM>% HPMC-AS was further processed to tablets. The composition was <NUM>% of Compound A as amorphous solid dispersion (MBP), with <NUM>% croscarmellose sodium, <NUM>% colloidal silicon dioxide, and <NUM>% of magnesium stearate.

Amorphous solid dispersion of Compound A containing <NUM>% Compound A and <NUM>% HPMC-AS was further processed to tablets. The tablets consisted of <NUM>% of Compound A (<NUM>% Compound A and <NUM>% HPMC-AS) as amorphous solid dispersion (MBP), with <NUM>% croscarmellose sodium, <NUM>% colloidal silicon dioxide, <NUM>% hydroxypropyl cellulose, and <NUM>% of magnesium stearate.

Amorphous solid dispersion MBP of Compound A containing <NUM>% Compound A and <NUM>% HPMC-AS was further processed to tablets. The tablets consisted of <NUM>% of MBP (<NUM>% Compound A and <NUM>% HPMC-AS) as amorphous solid dispersion, with <NUM>% croscarmellose sodium, <NUM>% mannitol, <NUM>% crospovidone, <NUM>% colloidal silicon dioxide, and <NUM>% of magnesium stearate. The tablet kernels can then be coated with a conventional aqueous film coating mixture.

Approximately <NUM> of Compound A as MBP was placed in <NUM> of <NUM> bio-relevant fluids (Fasted State Simulated Intestinal Fluid and Fed State Simulated Intestinal Fluid) and was filtered through a <NUM> filter over time. The filtrate was then analyzed by HPLC.

As showing in the X-ray powder diffraction (XRPD) that the MBP remained as amorphous after <NUM>-month storage at <NUM>/<NUM>%RH and <NUM>-month at <NUM>/<NUM>%RH.

Comparing the amorphous MBP solid dispersion to the physical mixture of the same components using differential scanning calorimetry (DSC) heating cycling method showed that the physical mixture crystalized while MBP remained amorphous.

FTIR (Fourier Transform Infrared) Spectroscopy illustrated (<FIG>) that in MBP the drug and polymer are molecularly dispersed providing greater stability and not prone to crystallization. On the other hand Amorphous API in physical mixture is not molecularly dispersed and therefore prone to crystallization. Therefore homogeneous molecular dispersion is the primary factor for excellent stability even at high drug loading.

The tablet contains <NUM> of the spray dried powder (SDP) of compound A and Copovidone (PVP VA <NUM>), equivalent to <NUM> of compound A (free base).

X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu K alpha radiation, primary monochromator, silicon strip detector, angular range <NUM>° to <NUM>° 2Theta, approximately <NUM> minutes total measurement time). The samples were prepared and analyzed without further processing (e.g. grinding or sieving) of the substance (Fig's 8a, b).

The XRPD pattern of the solid dispersion according to Example <NUM>, i.e. spray dried solid dispersion comprising <NUM>% of Compound A and Copovidone (PVP VA <NUM>), corresponds to the pattern of the placebo, demonstrating that initially no crystalline API (Compound A) is detectable (<FIG>).

The XRPD patterns of said solid dispersion after <NUM> months of storage in duplex blisters and HDPE bottles (storage conditions: <NUM> and <NUM>% relative humidity (RH)) correspond to the pattern of the initially measured solid dispersion, demonstrating that no crystalline API (Compound A) is detectable (<FIG>).

In vitro dissolution tests were conducted with two formulations of Compound A as Film-Coated Tablets comprising solid dispersion obtained by <NUM>) microprecipitation (MBP with <NUM>% Compound A and HPMCAS); and <NUM>) spray drying (<NUM>% Compound A and PVP VA <NUM>, Example <NUM>). The media used were <NUM> molar (<NUM>. 01N) hydrochloride acid (HCl), simulating the fasted stomach as well as Fasted State Simulated Intestinal Fluid (FaSSIF), simulating the fasted small intestine. The exact setup is summarized in the following Table <NUM>.

Weigh (<NUM>) HCL37% fuming in a <NUM> volumetric flask prefilled with <NUM> of dest. water and fill up to <NUM>. Mix well, allow to cooling to room temperature before use.

To prepare buffer, dissolve <NUM> of NaOH (pellets), <NUM> of NaH<NUM>PO<NUM> Dihydrate and <NUM> of NaCl, in about <NUM> of purified water. Adjust the pH to <NUM> with either <NUM> N NaOH or <NUM> N HCl. Make up to volume (<NUM>) with purified water at room temperature.

Add <NUM> of SIF Powder Original to about <NUM> of buffer. Stir until powder is completely dissolved. Make up to volume (<NUM>) with buffer at room temperature.

Claim 1:
A physically stable solid dispersion comprising the compound <NUM>-{[(2R, <NUM>, 4R, <NUM>)-<NUM>-(<NUM>-Chloro-<NUM>-Fluoro-Phenyl)-<NUM>-(<NUM>-Chloro-<NUM>-Fluoro-Phenyl)-<NUM>-Cyano-<NUM>-(<NUM>,<NUM>-Dimethyl-Propyl)-Pyrrolidine-<NUM>-Carbonyl]-Amino}-<NUM>- Methoxy -Benzoic Acid, of the formula (A)
<CHM>
together with a stabilizing polymer, wherein the stabilizing polymer is EUDRAGITR L-<NUM>, Eudragit L100-<NUM> or Copovidone (PVP VA <NUM>).