WO2014003678A1

WO2014003678A1 - Pharmaceutical compositions comprising ambrisentan and solid dispersion particles containing tadalafil

Info

Publication number: WO2014003678A1
Application number: PCT/SE2013/050808
Authority: WO
Inventors: Gérald JESSON; Mustafa Demirbüker; Magnus Brisander
Original assignee: Xspray Microparticles Ab
Priority date: 2012-06-28
Filing date: 2013-06-27
Publication date: 2014-01-03

Abstract

The present invention relates to pharmaceutical compositions comprising solid dispersion particles containing tadalafil and a dispersing component; and ambrisentan, which composition further optionally comprises at least one pharmaceutically acceptable excipient, such as a solubilizer. Further, the present invention relates to a method of treating disorders in a patient in need thereof, comprising administering a therapeutically effective amount of said composition.

Description

Pharmaceutical compositions comprising ambrisentan and solid dispersion particles containing tadalafil

Field of the invention

The present invention relates to the field of pharmaceutical compositions and formulations comprising a combination of the PDE5 inhibitor tadalafil, 5 and the Type A endothelin receptor-selective antagonist ambrisentan. In particular the present invention relates to a pharmaceutical composition comprising a solid dispersion product of tadalafil and a dispersing component in combination with ambrisentan.

10 Background of the invention

Tadalafil is an established type 5 cGMP-specific phosphodiesterase (PDE5) inhibitor, which is known as being useful in treatment of pulmonary arterial hypertension and sexual dysfunction disorders. For instance, tadalafil may be used to treat erectile dysfunction, where it is believed to

15 increase penile blood flow resulting from the relaxation of penile arteries and the smooth muscle of the corpus cavernosum. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP relaxes smooth muscle and increases blood flow 0 to the corpus cavernosum. The inhibition of PDE5 enhances erectile

function by increasing the amount of cGMP, and tadalafil inhibits PDE5. The recommended tadalafil starting dose for most men is 10 mg, taken as needed before sexual activity (but not more than once daily). The dose may be increased to 20 or 40 mg or decreased to 5 mg, per its efficacy 5 and the man's personal tolerance of the drug. To avoid the inconvenience of a man having to program and plan using tadalafil around the time of his anticipated sexual activity, it may be desireable to provide an alternative formulation or composition, wherein the uptake rate and bioavailability of tadalafil is increased.

0 Ambrisentan, also known as (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3- methoxy- 3,3-diphenylpropanoic acid, is a Type A endothelin receptor- selective antagonist particularly in the treatment of hypertension, pulmonary arterial hypertension.

Major objectives of formulation chemistry are to improve bioavailability, stability and convenience to the patient. Bioavailability means the rate and extent to which an active substance or therapeutic is absorbed from a pharmaceutical form and becomes available at the site of action. The most common and preferred method of delivery due to convenience, ease of ingestion and high patient compliance to treatment is the oral route of drug delivery. A measure of the potential usefulness of an oral dosage form of a pharmaceutical agent, is the bioavailability observed after oral

administration of the drug. However, for certain drugs, drug absorbtion from the small intestine tract is limited by poor aqueous solubility and/or poor membrane permeability of the drug molecules.

Several methods to improve the dissolution characteristics of compounds have been reported, including particle size reduction, formation of solvates, complexes and microspheres. Additionally, attempts have been made to improve bioavailability provided by solid dosage forms by forming solid dispersions of drugs. Solid dispersions create a mixture of a poorly water soluble drug and highly soluble carriers. Solid dispersions may increase bioavailability by decreasing the energy required for solubilizing the drug and increasing the stability of the drug in solution. Traditionally these methods carry inherent limitations concerning physical stabilities of the solid dispersion on storage, problems with grinding or difficulty of removal of the solvent. Furthermore, it is important that the drug released from the solid phase does not precitipitate in the small intestine tract but remains water-soluble in the aqueous fluids of the small intestine tract, since such precipitation results in low bioavailability. EP1200092 discloses tadalafil as a free drug particulate form, as well as compositions comprising tadalafil, wherein the compound is present as solid particles not embedded in a polymeric co-precipitate.

US 5,985,326 discloses solid dispersions of inter alia tadalafil.

WO 2009/152453 discloses methods of treating pulmonary hypertension with a PKG effector agent in combination with e.g. tadalafil and/or ambrisentan.

WO 2008/073928 discloses compositions useful for treatment of pulmonary hypertension conditions under particular dosage regimens. Primarily, the compositions comprise ambrisentan, however combination treatments are also disclosed, wherein a second active ingredient may be a PDE5 inhibitor (such as tadalafil).

WO 2006/026395 discloses methods of treating pulmonary hypertension by combination therapy with a PDE5 inhibitor and an endothelin A receptor (ET_A) antagonist. Tadalafil is mentioned, whereas ambrisentan is not.

US2012/0003325 is provides compositions of a helium-oxygen gas mixture which comprises one or more drugs. These drugs may be selected from (amongst others) ambrisentan and tadalafil.

WO 2012/037665 discloses inhalable compositions comprising

compounds. The compositions may further comprise a cyclooxygenase inhibitor and further an endothelin receptor antagonist, such as

ambrisentan and also further a PDE inhibitor, such as tadalafil. The inhalable "cocktail" may comprise even further components. WO 2007/050783 discloses combination therapies with fasudil (a Rho- kinase inhibitor) for treatment of pulmonary arterial hypertension. Fasudil may be combined with ambrisentan and tadalafil. Summary of the invention

The present invention relates to pharmaceutical compositions comprising solid dispersion particles of tadalafil and at least one polymeric dispersing component which particles are formulated in combination with

ambrisentan; which composition optionally further comprises at least one pharmaceutically acceptable excipient, such as a solubilizer. Further, the present invention relates to methods of treating disorders, such as pulmonary arterial hypertension, in a patient in need thereof, comprising administering a therapeutically effective amount of said composition. Brief description of the drawings

Figure 1 provides a graph showing the concentration of tadalafil in compositions of the invention. The details of the compositions are described in Example 1 , in Table 1 . Briefly, experiment 1 represents a composition, comprising raw tadalafil and ambrisentan in crystalline form. Experiment 2 represents a coprecipitated mixture of tadalafil and ambrisentan. Experiment 3 represents solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinylpyrrolidone (PVP).

Experiments 4 and 5 represent solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinyl acetate phthalate (PVAP). The experiments illustrated in the graphs were carried out at pH 6.5, in FaSSIF. Figure 2 provides a graph showing the concentration of ambrisentan in compositions of the invention. The details of the compositions are described in Example 1 , in Table 1 . Briefly, experiment 1 represents a composition, comprising raw tadalafil and ambrisentan in crystalline form. Experiment 2 represents a coprecipitated mixture of tadalafil and ambrisentan. Experiment 3 represents solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinylpyrrolidone (PVP).

Experiments 4 and 5 represent solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinyl acetate phthalate (PVAP). The experiments illustrated in the graphs were carried out at pH 6.5, in FaSSIF.

Figure 3 provides a graph showing the concentration of tadalafil in compositions of the invention. The details of the compositions are described in Example 2, in Table 3. Briefly, experiment 1 1 represents a composition, comprising raw tadalafil and ambrisentan in crystalline form. Experiment 12 represents a coprecipitated mixture of tadalafil and ambrisentan. Experiment 13 represents solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinylpyrrolidone (PVP). Experiments 14 and 15 represent solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinyl acetate phthalate (PVAP). The experiments illustrated in the graphs were carried out at pH 1 .4, in SGF.

Figure 4 provides a graph showing the concentration of ambrisentan in compositions of the invention. The details of the compositions are described in Example 2, in Table 3. Briefly, experiment 1 1 represents a composition, comprising raw tadalafil and ambrisentan in crystalline form. Experiment 12 represents a coprecipitated mixture of tadalafil and ambrisentan. Experiment 13 represents solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinylpyrrolidone (PVP). Experiments 14 and 15 represent solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan, wherein the dispersing component is polyvinyl acetate phthalate (PVAP). The experiments illustrated in the graphs were carried out at pH 1 .4, in SGF. Detailed description of the invention

All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

As used herein, the term "pharmaceutical composition" is intended to encompass compositions containing a) solid dispersion particles comprising tadalafil and at least one dispersing component, preferably a polymeric dispersing component, b) ambrisentan, and c) optionally at least one pharmaceutically acceptable excipient, such as a solubilizer. A used herein, the term "solid dispersion" refers to a system in a solid state, comprising at least two components, wherein one component is dispersed evenly throughout the other component or components. In the context of the present invention, the term solid dispersion is generally, but not limited to, solid dispersion particles comprising a matrix, typically hydrophilic and often soluble in an aqueous medium, and tadalafil dispersed therein. The matrix can be either crystalline, partly crystalline, amorphous or a mixture thereof. Tadalafil is present within the matrix or particles as an essentially amorphous form or essentially crystalline form, or a mixture thereof. Solid dipersions can be classified into different categories, but are not limited to, for example: eutectics, amorphous precipitations in crystalline matrix, solid solutions (such as continuous solid solutions, discontinuous solid solutions, interstitial solid solutions), glass suspensions and glass solutions. The amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X- Ray Powder Diffraction (XRPD) as described elsewhere in the present disclosure.

By the phrase "tadalafil" is meant the compound named (6R-frans)-6-(1 ,3- benzodioxol-5-yl)- 2,3,6,7, 12, 12a-hexahydro-2-methyl-pyrazino [1 ', 2':1 ,6] pyrido[3,4-Jb]indole-1 ,4-dione. An alternative name is (6R, 12aR)- 2,3,6,7, 12, 12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)- pyrazino(2', 1 ':6, 1 )pyrido(3,4-b)indole-1 ,4-dione. The structure of tadalafil can be illustrated as:

By the phrase "ambrisentan" is meant the compound named (2S)-2-[(4,6- dimethylpyrimidin-2-yl)oxy]-3-methoxy- 3,3-diphenylpropanoic acid. The structure of ambrisentan can be illustrated as:

By the phrase "dispersing component" is meant a component present in the solid dispersion together with tadalafil and possibly one or more other drugs. Typically, said dispersing component represents, but is not limited to, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. HPC ef, HPC If and HPC jf), hydroxypropyl methylcellulose (e.g. Methocel E3 and E15 and Pharmacoat 645), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (e.g. HPMCP-HP55), polyvinylpyrrolidone (e.g. PVP 30K and PVP 90K), polyvinyl acetate phthalate (PVAP), copolyvidone (e.g. Kollidon VA 64), crospovidon (e.g. Kollidon CL), methacrylic acid and ethylacrylate copolymer (e.g. Kollicoat ME), methacrylate acid and methyl methacrylate copolymer (e.g. Eudragit L100), polyethylene glycol (e.g. PEG20K), DL lactide/glycolide copolymer (PDLG), poly DL-lactide (PDL), cellulose acetate phthalate (CAP), aminoalkyl methacrylate copolymers (e.g.

Eudragit RL100, RL PO or RS PO), carbomer homopolymer Type A (e.g. Carbopol 971 P), carbomer homopolymer Type B (e.g. Carbopol 974P) , sodium dodecyl sulfate, d-alpha-tocopherol acid polyethylene glycol 1000 succinate (TPGS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and poloxamers (e.g. Pluronics, Lutrol 68, Lutrol F127, Kolliphor). The terms "polymer" or "polymeric" is here used to mean a compound that exhibits a polymeric structure, i.e. several monomers which have the same or similar structure which are covalently connecting to each other to form a larger structure, e.g. a polymeric chain that may be unbranched (straight) or branched. A polymer generally consists of 20 or more monomers connected together, however less that 20 monomers connected together are here also referred to as polymers.

By the phrase "solubilizer" is meant a pharmaceutically acceptable detergent, such as an ionic, anionic, cationic, amphiphilic or non-ionic component. The solubilizer may be a detergent devoid of polymeric structure or a detergent exhibiting a polymeric structure (surface active polymer), which preferably help to further improve the dissolution rate of the active agent. The solubilizer may prevent emulsification of the active ingredient released from the pharmaceutical composition and/or prevent precipitation of the active ingredient(s) in the aqueous fluids of the small intestine tract. A single solubilizer as well as a combination of two or more solubilizers may be used. Solubilizers of the invention include but are not limited to polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus), d-alpha-tocopherol acid polyethylene glycol 1000 succinate (TPGS), Tween 80, PEG20K, sodium dodecyl sulfate, Lutrol 68 and Lutrol F127. Solubilizers above may also function as dispersing components in the invention. The solubilizer may be included in the solid dispersion particles, or may be included outside the particles as such but within the compostion.

By the phrase stabilizing agent is meant a pharmaceutically acceptable recipient that stabilizes the solid dispersion particles containing tadalafil. Stabilizing agents of the invention include, but are not limited to, hypromellose, such as methylcellulose USP, hypromellose 2910, hypromellose 2906 and hypromellose 2208 (also known as Methocel K4M); ethylcellulose, such as ethylcellulose 10cP (also known as Ethocel standard 10 premium), paraffin, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, glyceryl behenate and talc.

Stabilizing agents above may also function as dispersing components in the invention. The Stabilizing agent may be included in the solid dispersion particles, or may be included outside the particles as such but within the compostion.

By the phrase "area under the curve (AUC)" is meant the area under the concentration-time curve, where the x-axis represents time and the y-axis represents concentration of solubilized tadalafil.

By the phrase "% solubilized at XX min" such as "% solubilized at 60 min" is meant the concentration of tadalafil in solubilized form at a certain time, such as 60 minutes.

By the phrase "apparent solubility" is meant the concentration of tadalafil in solution at apparent equilibrium. As used herein, the term "PVAP" refers to polyvinyl acetate phthalate.

As used herein, the term "PVP 30K" refers to polyvinylpyrrolidone K-30.

As used herein, the term "HPMCP-AS" refers to hydroxypropyl

methylcellulose acetate succinate.

As used herein, the term "HPMCP HP55" refers to hydroxypropyl methyl cellulose phthalate. As used herein, the term "PDLG" refers to DL-lactide/glycolide copolymer. As used herein, the term "PDL" refers to poly DL-lactide.

The dissolution mediums used for purposes of this invention, are Fasted State Simulated Intestinal Fluid, referred to as FaSSIF, Fed State

Simulated Intestinal Fluid, referred to as FeSSIF and Simulated Gastric Fluid, referred to as SGF. FaSSIF media is tailored to represent a fasting state and has a pH of about 6.5 as well as specific osmolaric properties. FeSSIF media is tailored to represent a fed state and has a pH of about 5 as well as specific osmolaric properties. SGF is tailored to represent gastric fluid and has a pH of about 1 .4 as well as specific osmolaric properties. FaSSIF, FeSSIF and SGF media are generally used in in vitro models for dissolution of poorly water-soluble drugs. The choice of solution will be dependent on where in the small intestine tract and under what conditions (fasted or fed) the composition is desired to dissolve and be taken up.

By the phrase "amorphous form" is meant non-crystalline solid form. The ease of dissolution may at least in part be attributed to the amount of energy required for dissolution of the components from a crystalline or amorphous solid phase. Amorphous particles require less energy for dissolution as compared to crystalline particles of the same compound. The amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X-Ray Powder Diffraction (XRPD or XRD) as described elsewhere in the present disclosure.

The term tadalafil as used herein is intended to encompass hydrates, solvates (alcoholates), N-oxides, pharmaceutically acceptable acid or base salts of tadalafil. The solid dispersions included in the pharmaceutical compositions of the present invention typically comprises particles ("solid dispersion particles"), which are amorphous, partly amorphous, partly crystalline or crystalline forms. The amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X-Ray Powder Diffraction (XRPD or XRD) as described elsewhere in the present disclosure.

There are a number of different methods for the formation of solid dispersion particles containing drugs, e.g. granulation, melt extrusion, spray drying, precipitation etc. all of which typically encompass starting with formation of a mixture in which tadalafil and the dispersing component are evenly distributed. Potentially most of these processes can be used for manufacturing solid dispersion particles to be used in the present invention, i.e. a particular method can be used as long it enables production of solid dispersion particles to be incorporated into

pharmaceutical composition of the invention in which tadalafil has dissolution characteristics as described for the present invention elsewhere in the present disclosure. Methods forming solid dispersion particles by precipitation are preferred based on results so far obtained.

Most of the methods given in the preceding paragraph are known to be performed in a batch mode or in a continuous mode where the latter in most cases are preferred, in particular if solid dispersion particles to be used in the present invention are to be manufactured. Continuous processes in this context means that particle formation is continuously ongoing while at the same time continuously withdrawing/collecting/ retaining solid dispersion particles from the mixture after their formation. In the preferred methods, i.e. precipitation methods, this means that a fluid which is a solution of tadalafil, preferably in the form of a fluid stream, is mixed with an anti-solvent fluid (anti-solvent in relation to tadalafil), preferably in the form of an anti-solvent fluid stream. The dispersing component may be present in either one or both of the two fluids or in a separate third fluid stream depending on its solubility characteristics. The mixing of the two fluids is taking place in a mixing function, e.g. a mixing chamber. In the case the process is continuous, i.e. the two fluids are fluid streams, the mixing function typically is associated with a particle formation and separation function permitting the mixed fluid stream to pass through while retaining the solid dispersion particles. Agents modifying the particle characteristics without being incorporated into the particles may be added to either of the fluids before the mixing step. The fluids typically are conventional liquids or supercritical fluids, where supercritical fluids also includes subcritical fluids (i.e. fluids for which only one of pressure and temperature is above its supercritical value). Typical combinations are a) conventional liquids for both the solution of tadalafil and the antisolvent, b) solution of tadalafil combined with conventional liquid for the anti-solvent, c) conventional liquid for the solution of tadalafil combined with fluid for the anti-solvent, and d) supercitical fluids for both of the two fluids. In certain variants the anti-solvent may be omitted. A fluid stream, containing both tadalafil and the dispersing component is then allowed to expand into the particle formation function. It is preferred that at least one of the fluids is in a subcritical or supercritical state in the precipitation methods described above. These kinds of precipitation methods are thoroughly discussed in WO 2005061090 (Censdelivery AB), WO 2009072950 (XSpray

Microparticles AB), WO 2009072953 (XSpray Microparticles AB), WO 201 1 159218 (XSpray Microparticles AB) and references cited in these publications. The term "anti-solvent" in this disclosure primarily refers to a fluid which is capable of precipitating tadalafil from a solution containing the tadalafil when mixed with the solution. The term anti-solvent also applies to a liquid which is capable of precipitating a dispersing component from a solution containing this component. The term "solution" encompasses that the solute is either a true solute or minutes particles of colloidal dimensions and less than the particles to be produced. A preferred particle formation system is the "Right Size system" developed by XSpray microparticles AB, Sweden. A detailed description of the technology can be found in the WO-publications given in the preceding paragraph. An important characteristic of the system is that the two fluid streams should merge within a nozzle at an angle in the interval 45°-135°, with preference for about 90° and sprayed into a particle

formation/separation function.

In principle the system allows for producing particles of predetermined size and/or morphology. Here the Right Size system and apparatus will be described using the non-limiting example of using tadalafil in the form of a liquid solution and CO2 as a fluid anti-solvent for tadalafil. The dispersing component may then be present in either one or both of the tadalafil solution and the anti-solvent fluid depending on the solubility

characteristics of this component.

This basic system consists of one pumping set-up for the tadalafil dissolved in a liquid solvent and one pumping set-up for an anti-solvent, for example CO2, however other anti-solvents may be used when suitable. Each pumping set-up includes instruments such as a flow meter and a pressure meter that are used to control the process conditions. These two pumping set-ups are fluidically connected at a spray nozzle.

A stream of tadalafil solution is mixed with a stream of CO2 under flow conditions within the spray nozzle. The mixed stream is then sprayed at the outlet of the nozzle into a precipitation vessel under controlled conditions (typically pressure and temperature). CO2 acts as an anti- solvent. Tadalafil precipitates to form an essentially amorphous phase and/or an essentially crystalline phase dispersed within a a carrier matrix, which during the process is formed as fine particles containing the matrix. Particles are retained in the vessel by a filtering set-up. A back pressure regulator is typically used to control the pressure inside the precipitation vessel.

For preparing solid dispersion particles containing tadalafil, it may be advantageous to have an extra pumping set-up for injecting an additional solvent, referred to as a modifier, into the CO2. Here a pumping set-up control is set up for the modifier and the modifier is mixed with the CO2 in a mixer before entering the nozzle.

When using the system, the system operator typically starts with equilibrating the system by pumping CO2, a "tadalafil-like solution" (a solution similar in composition to the tadalafil solution but containing no tadalafil, no dispersing component,and no excipient) and the modifier (if used) through the system until flow rates, pressure and temperature have reached a desired steady state. Critical parameters for setting up the system are tadalafil solution composition, tadalafil solution flow rate, CO2 flow rate, CO2 pressure and temperature, nature and

amount/concentration of the optional modifier and modifier flow rate, if such is used. Next, the "tadalafil-like solution" is exchanged for the tadalafil solution and particles are produced and retained downstream of the mixing, e.g.

downstream of the outlet of the nozzle. Afterwards, the system is typically cleaned by pumping the "tadalafil-like solution" through the system. The particles are dried by flushing CO2 through the retained particles in order to extract any remaining solvent. The precipitation vessel is then

depressurized and the particles can be collected. In one aspect, the invention provides a pharmaceutical composition comprising

a) solid dispersion particles containing tadalafil and at least one

dispersing component;

b) ambrisentan; and optionally

c) at least one pharmaceutically acceptable excipient, such as a

solubilizer.

In one embodiment of this aspect, said solid dispersion particles are prepared by a solid dispersion process using CO2 as antisolvent. Such solid dispersion particles may be produced by a process utilizing CO2, for the formation of solid dispersion particles containing tadalafil, typically as described in this disclosure. In another embodiment of this aspect, said dispersing component is a polymeric dispersing component.

In another embodiment of this aspect, said dispersing component in said solid dispersion particles is a pharmaceutically acceptable polymer selected from polymer selected from is a pharmaceutically acceptable polymer selected from methacrylate acid and methyl methacrylate copolymer, d-alpha-tocopherol acid polyethylene glycol 1000 succinate, methyl cellulose, polyethylene glycol, hypromellose acetate succinate, hypromellose, hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate,

polyvinylpyrrolidone, polyvinyl acetate phthalate, polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol copolymer, DL lactide/glycolide copolymer and poly DL-lactide. The weight ratio (w/w) between tadalafil and the dispersing component varies, typically from about 1 : 1000 to about 100: 1 , such as from about 1 : 100 to about 100: 10. Preferably, said weight ratio is from about 1 :20 to about 20: 1 , such as from about 1 :6 to about 6: 1 . More preferably, said weight ratio is from about 1 :5, to about 1 :3.

In another embodiment of this aspect, tadalafil in said solid dispersion particles is present in amorphous form.

In another embodiment of this aspect, there is provided a composition, which produces a solubility increase of tadalafil in a dissolution medium, said increase measured as the area under the curve (AUC) during 60 to 90 minutes, in said dissolution medium and compared with the AUC obtained with tadalafil in crystalline, raw form in said dissolution medium. Preferably, said increase is from to about 2: 1 to about 100: 1 , or more, wherein 1 represents AUC obtained with tadalafil in crystalline, raw form. In another embodiment of this aspect, there is provided a composition, which provides at least 20% solubilized tadalafil after 20 minutes as measured in a dissolution medium.

In another embodiment of this aspect, there is provided a composition, which provides at least 40% solubilized tadalafil after 20 minutes as measured in a dissolution medium.

In another embodiment of this aspect, there is provided a composition, wherein tadalafil, in said particles, is present, at least partly, in crystalline form. Preferably, when tadalafil, in said particles, is present, at least partly, in crystalline form, said dispersing component, in said particles, is selected from polyvinyl acetate phthalate, poly DL-lactide and DL lactide/glycolide copolymer. More preferably, said dispersing component, in said particles, is polyvinyl acetate phthalate. Such compositions may be useful when a controlled release of tadalafil is desireable. Multilayer tablets may be advantagous if it is desired to deliver tadalafil in combination with ambrisentan in one tablet. Multilayer tablets may further be advantagous if it is desired to control the release characteristics of the active agents. For example, an outer layer may compise an initial dose by including the active agent, such as ambrisentan, into one of the outer layer while inner layers comprise an maintainance dose which is release slowly, such as solid disperson particles containing tadalafil and a dispersing component. The dissolution characteristics of the inner and outer layers may be varied as desired by choosing different agents and/or solubilizer within and between the layers.

For understanding how the compostion will dissolve in vivo in the different environments of the stomach, small intestine and colon, it is important to choose an appropriate solution for in vitro dissolution testing. It is critical that the in vitro test conditions mimic the in vivo environment as closely as possible, for example pH and osmolarity. Typically, for small intestine uptake, the pH is between 6 and 7. Therefore, the solution may hold a pH from about pH 6 to about pH 7, such as about pH 6.5.

In another embodiment of this aspect, the solution has a pH from about pH 1 to about pH 8, such as about pH 6.5, such as about pH 5, or such as about pH 1 .4.

In another embodiment of this aspect, there is provided a composition, wherein the dissolution medium represents a Fasted Simulated State Intestinal Fluid (FaSSIF).

Typically, for small intestine uptake during food intake, the pH is between 4.5 and 6. Therefore, the solution may hold a pH from about pH 4.5 to about pH 6, such as about pH 5. In another embodiment of this aspect, there is provided a composition, wherein the dissolution medium represents a Fed Simulated State

Intestinal Fluid (FeSSIF).

Typically, for gastric uptake, the pH is between 1 and 2. Therefore, the solution may hold a pH from about pH 1 to about pH 2, such as about pH 1 .4. In another embodiment of this aspect, there is provided a composition, wherein the dissolution medium represents a Simulated Gastric Fluid (SGF).

The choice of dissolution medium will be dependent on where in the small intestine tract and under what conditions (fasted or fed) the composition is desired to dissolve and be taken up. Recepies and preparation of these solutions may be prepared in accordance with information provided by the manufacturer (e.g. biorelevant.com, United Kingdom). In another embodiment of this aspect, there is provided a composition in which a solubihzer is present in from about 0.5% by weight to about 95 % by weight, relative to the total weight of the solid dispersion product and the solubihzer, such as at least 10% by weight, such as in at least from 25% to 65% by weight, relative to the total weight of the solid dispersion product and the solubihzer. A solubihzer present in the composition may be an integral part of the solid dispersion particles possibly acting as a dispersing component, or be separate from the particles.

In another embodiment of this aspect, there is provided a composition wherein said solubihzer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer and d-alpha-tocopherol acid polyethylene glycol 1000 succinate.

In another embodiment of this aspect, there is provided a composition wherein said solubilizer is polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol copolymer.

In some embodiements, it may be advantagous that the amount of tadalafil in the solid dispersion particles is from 5% by weight to about 50% by weight, from 10% by weight to about 40% by weight, from about 10% by weight to about 30% by weight, such as about 25%.

In another embodiment of this aspect, there is provided a composition, wherein the solid dispersion particles has an average particle size of less than about 5000 nm.

In another embodiment of this aspect, there is provided a composition, wherein the solid dispersion particles has an average particle size of less than about 1000 nm, preferably less than 500 nm. Other particle sizes may be of convenient for specific applications.

The solid dispersion particles may be present as agglomorates, i.e. to larger particles each of which comprises several primary particles.

In another embodiment of this aspect, there is provided a composition, at least one stabilizing agent is added. Typically, said at least one stabilizing agent is present outside the solid dispersion particles but within the composition. Preferably, two stabilizing agents are added, said agents being hypromellose and ethylcellulose. When such stabilizing agents are added to the composition, both tadalafil and said dispersing component is present in amorphous form after one month of storage, such as after one month of storage in 30°C and 60% relative humidity.

In another aspect of the invention, there is provided a composition of the invention for use in therapy.

In another aspect of the invention, there is provided a composition of the invention for use in the treatment of a disease selected from hypertension, pulmonary hypertension, pulmonary arterial hypertension, renal failure, acute renal failure, cerebral vasospasms, myocardial infarct, angina pectoris and restenosis after angioplasty.

In another aspect of the invention, there is provided a composition of the invention for use in the treatment of sexual dysfunction, such as male erectile dysfunction or female sexual arousal disorder.

In another embodiment of this aspect, there is provided a composition of the invention, for use, wherein said composition is provided during food intake. Typically, the compositions of the invention are formulated for oral administration, such as wherein said composition is administered with amounts of up to a maximum of 40 mg tadalafil per day and 40 mg ambrisentan per day. For certain indications, such as sexual dysfunction disorders, said composition may be administered with amounts of up to a maximum of 20 mg tadalafil per day and 40 mg ambrisentan per day.

In another embodiment of this aspect, there is provided a composition of the invention, for use, wherein said solid dispersion particles containing tadalafil and at least one dispersing component; and ambrisentan are co- formulated. In another aspect of the invention there is provided a method of treating a patient suffering from hypertension, pulmonary hypertension, pulmonary arterial hypertension, renal failure, acute renal failure, cerebral

vasospasms, myocardial infarct, angina pectoris or restenosis after angioplasty, comprising administering to a patient in need thereof, a therapeutically effective amount of a composition of the invention. The solid dispersion particles containing tadalafil and at least one dispersing component; and ambrisentan, may be formulated in a single tablet. In another aspect of the invention there is provided a method of treating a patient suffering from sexual dysfunction, comprising administering to a patient in need thereof, a therapeutically effective amount of a composition of the invention. Typically, said sexual dysfunction is selected from male erectile dysfunction or female sexual arousal disorder. The solid dispersion particles containing tadalafil and at least one dispersing component; and ambrisentan, may be co-formulated in a single tablet.

The amount of tadalafil and ambisentan in the compositions of the present invention required for use in treatment will vary with the route of administration, the nature of the condition for which treatment is required and the age, weight and condition of the patient and will be ultimately at the discretion of the attendant physician. The desired dose is conveniently presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.

Dependent on the need of the treatment and/or prevention, the desired dose may also be, for example, once every two days, once every three days, or even once a week.

The composition is conveniently administered in unit dosage form; for example containing 0.5 to 500 mg, conveniently 1 to 100 mg, most conveniently 5 to 75 mg of both tadalafil and ambrisentan per unit dosage form. The compositions of the invention will normally be administrated orally, or by parenteral, intravenous, intramuscular, subcutaneous or other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in a pharmaceutically acceptable dosage form.

Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.

According to one embodiment of the present invention, pharmaceutical compositions include but are not limited to those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compositions may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Pharmaceutical compositions suitable for oral administration are conveniently presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of tadalafil and ambrisentan.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art.

The compositions of the invention may be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents. The above described compositions may be adapted to give sustained release of tadalafil and ambrisentan.

The following examples are provided to illustrate various embodiments of the present disclosure and shall not be considered as limiting in scope.

Examples

Below follows a number of non-limiting examples of compositions of the invention. In the tables, the following abbreviations to "compositions" apply "T" represents tadalafil;

"A" represents ambrisentan;

"P" represents the polymeric dispersing component;

"T+A" represents a physical mix of raw, crystalline tadalafil and raw, crystalline ambrisentan;

"T/A" represents a coprecipitated mixture of tadalafil and ambrisentan. "T/P+A" represents solid dispersion particles containing tadalafil and the dispersing component in mixture with ambrisentan;

"Exp" represents the experiment number. General description of dissolution measurement assay

The method consists of adding the wished amount of powder into a glass vial and then pouring in it the appropriate medium (typically FaSSIF or SGF). The medium was prepared in accordance with the manufacturer's instructions (biorelevant.com, United Kingdom). The amount of powder added depends on the wished "total tadalafil or ambrisntan concentration". For some experiments where powders with high drug loads were tested and compared, the real amount of tadalafil in the solid dispersion was not taken in account. For other experiments, the drug load was first estimated by HPLC and the amount of powder to obtain the drug concentration was calculated. Typically, the powder was added in a 8 ml_ glass bottle and 7 ml_ of solution was added (typically FaSSIF or SGF) and were put on a shaker (approximately 1 rotation per minute) for dissolution. Samples of 500 μΙ where taken after different times, and subsequently centrifuged at approximately 15000 g for 3 minutes. The resulting supernatant was then analyzed by HPLC (Ci8 column Eclipse, 4.6 mm x 15 cm, 1 ml_/min, detection at 270 nM). Generally samples were taken after 5, 30 and 90 min and eventually 150 min.

The compositions were prepared as follows:

Predetermined amounts of tadalafil (T) and polymeric dispersing component (P) were diluted in TFE or a DMSO/TFE mixture. The resulting tadalafil solution was subsequently precipitated by using CO2 as antisolvent as described above. Tadalafil solution and CO2 were pumped respectivelty at 1 ml/min and 100 g/min through a lab size XSpray's RigthSize noozle. The temperature and pressure of the process are given in the tables below. The powder produced was collected and its drug load was determined by HPLC analysis.

The amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X-Ray Powder Diffraction (XRPD). X-Ray Powder Diffraction (XRPD) experiments were run on an X^'Pert Pro multipurpose diffractometer with radius 240.0 mm (PANanalytical,

Netherlands) set in Bragg-Brentano geometry. The diffractometer was equipped with an X'Celerator real time multi strip detector with an active length of 2.122° 2 theta. A representative sample was placed on a zero background quarts single crystal specimen support (Siltronix, France) and the sample was spinned with a rotation at time of 2.0 seconds during the measurement. Experiments were run using Cu KQ radiation (45kV and 40mA) at ambient temperature and humidity. Scans were run in continues scan mode in the range 4.5-40° 2 theta with a step size of 0.0167° 2 theta and a counting time of 299.720 seconds. The incident beam path contained a soller slit with 0.02 rad opening, a fixed mask with a width of 10 mm and automatic anti-scatter and divergence slits with irradiated length of 10.0 mm. The diffracted beam path contained an automatic anti-scatter slit with an observed length of 10.0 mm, a soller slit with 0.02 rad opening and a 0.020 mm thick Nickel filter.

Data collections were done with the application software X^'Pert Data Collector version 2.2h and instrument control software version 2. OA, and pattern analysis was done X^'Pert HighScore Plus version 2.2c. All software comes from PANanalytical, Netherlands.

Example 1. Compositions with tadalafil solid dispersion particles and ambrisentan - solubility at pH 6.5.

A number of experiments were carried out with compositions comprising tadalafil solid dispersion particles and ambrisentan at pH 6.5. The experiments were carried out by measuring concentration of solubilized tadalafil (mg/L) and ambrisentan (mg/L) after 3, 20, 45 and 90 minutes dissolution in a solution at about pH 6.5, namely FaSSIF (Fasted State Simulated Intestinal Fluid). Samples of the solution were taken at various time intervals and the amounts of tadalafil and ambrisentan were measured by the dissolution measurement assays described above.

Representative results in FaSSIF dissolution medium are provided below in Table 1 and 2, where Table 1 provides data of concentration of tadalafil and ambrisentan, respectively (mg/L) after 3, 20, 45 and 90 minutes dissolution, whereas Table 2 provides data of the Area Under the Curve (AUC - mg/min/L) during 90 minutes dissolution and the AUC increase of compositions and percentage solubilized tadalafil and ambrisentan, respectively after 90 minutes dissolution compared to tadalafil and ambrisentan in raw form added to the dissolution medium (experiments 1 - 5).

Table 1 . Concentration of tadalafil and ambrisentan after 3, 20, 45 and 90 minutes dissolution in FaSSIF dissolution medium (pH 6.5).

Table 1.

Table 2. Percentage solubilized tadalafil and ambrisentan after 90 minutes dissolution, the Area Under the Curve (AUC - mg/min/L) during 90 minutes dissolution and the AUC increase of compositions, compared to tadalafil and ambrisentan in raw form added to the FaSSIF dissolution medium (pH 6.5). Table 2.

Example 2. Compositions with tadalafil solid dispersion particles and ambrisentan - solubility at pH 1.4.

A number of experiments were carried out with tadalafil solid dispersion particles and ambrisentan at pH 1 .4. The experiments were carried out by measuring concentration of solubilized tadalafil and ambrisentan (mg/L) after 7, 20, 40 and 60 minutes dissolution in a dissolution medium at about pH 1 .4, namely SGF (Simulated Gastric Fluid). Samples of the dissolution medium were taken at various time intervals and the amount of tadalafil and ambrisentan was measured by the dissolution measurement assays described above. Representative results in SGF dissolution medium are provided below in Table 3 and 4, where Table 3 provides data of concentration of tadalafil and ambrisentan (mg/L) after 7, 20, 40 and 60 minutes dissolution, whereas Table 4 provides data of the Area Under the Curve (AUC - mg/min/L) during 60 minutes dissolution, percentage solubilized tadalafil and ambnsentan after 60 minutes dissolution and the AUC increase of compositions, compared to tadalafil and ambrisentan in raw form added to the dissolution medium (experiments 1 1 -15). Table 3. Concentration of tadalafil and ambrisentan after 7, 20, 40 and 60 minutes dissolution in SGF dissolution medium (pH 1 .4).

Table 3.

Table 4. Percentage solubilized tadalafil and ambrisentan after 60 minutes dissolution, the Area Under the Curve (AUC - mg/min/L) during 60 minutes dissolution and the AUC increase of compositions, compared to tadalafil and ambrisentan in raw form added to the SGF dissolution medium (pH 1 .4). Table 4.

Polymeric

Drug Process % AUC/

disp. AUC

Exp Comp. API (T & A) load CondSolubilized 60 min

Component increase (%) itions (60 min) Mg/min/L

(P)

Tadalafil 2 mg

T66.6 T1.5 T126 -

11 T+A Ambrisentan - - A 33.3 A 0.8 A 29

1 mg

Tadalafil 2.8

DMSO

mg T85 T2.2 T297 T2.4

12 T/A - Water

Ambrisentan A 15 A 42.0 A 609 A 21

25"C

0.5 mg

Tadalafil 50

DMSO/TFE

mg T22 PVP 30K T43.9 T3667 T29.1

13 T/P+A 25"C 110

Ambrisentan A 11 150 mg A 0.1 A 17 A 0.6

Bar

25 mg

Tadalafil 50

DMSO/TFE

mg T22 PVAP T1.8 T150 T1.2

14 T/P+A 25"C 110

Ambrisentan A 11 150 mg A 0.8 A 31 A 1.1

Bar

25 mg

Tadalafil 50

TFE

mg T22 PVAP T3.1 T356 T2.8

15 T/P+A 15"C 110

Ambrisentan A 11 150 mg A 0.6 A 28

Bar A 1.0 25 mg

Claims

A pharmaceutical composition comprising

a) solid dispersion particles containing tadalafil and at least one dispersing component;

b) ambrisentan; and optionally

c) at least one pharmaceutically acceptable excipient, such as a solubilizer.

The composition according to claim 1 , wherein said dispersing component is a polymeric dispersing component.

The composition according to claim 1 or 2, wherein said dispersing component in said solid dispersion particles is a pharmaceutically acceptable polymer selected from is a pharmaceutically acceptable polymer selected from methacrylate acid and methyl methacrylate copolymer, d-alpha-tocopherol acid polyethylene glycol 1000 succinate, methyl cellulose, polyethylene glycol, hypromellose acetate succinate, hypromellose, hydroxyethyl cellulose, hydroxy propyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, polyvinyl acetate phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, DL lactide/glycolide copolymer and poly DL-lactide.

The composition according to claim 1 or 2, wherein the weight ratio (w/w) between tadalafil and said polymeric dispersing component, in said particles, is from about 1 :6 to about 6: 1 . 5. The composition according to any one of claims 1 to 4, wherein tadalafil, in said particles, is present in amorphous form. The composition according to any one of claims 1 to 5, which produces a solubility increase of tadalafil in a dissolution medium, said increase measured as the area under the curve (AUC) during 60 to 90 minutes, in said dissolution medium and compared with the AUC obtained with tadalafil in crystalline, raw form in said dissolution medium.

The composition according to claim 6, wherein said increase is from to about 2: 1 to about 100: 1 , or more, wherein 1 represents AUC obtained with tadalafil in crystalline, raw form.

The composition according to any one of claims 1 to 7, which provides at least 20% solubilized tadalafil after 20 minutes as measured in a dissolution medium.

The composition according to claim 8, which provides at least 40% solubilized tadalafil after 20 minutes as measured in a dissolution medium. 10. The composition according to any one of claims 1 to 3, wherein

tadalafil, in said particles, is present, at least partly, in crystalline form.

1 1 . The composition according to claim 10, wherein said polymeric

dispersing component, in said particles, is selected from polyvinyl acetate phthalate, poly DL-lactide and DL lactide/glycolide

copolymer.

12. The composition according to claim 1 1 , wherein said dispersing

component, in said particles, represents polyvinyl acetate phthalate.

13. The composition according to any one of claims 1 to 3 and 10 to 12, which produces a controlled release of tadalafil and ambrisentan.

14. The composition according to any one of claims 6 to 13, wherein said dissolution medium has a pH from about pH 1 to about pH 8. 15. The composition of claim 14, wherein said dissolution medium has a pH at about pH 6.5.

16. The composition of claim 15, wherein said dissolution medium

represents a Fasted Simulated State Intestinal Fluid (FaSSIF).

17. The composition of claim 14, wherein said dissolution medium has a pH at about pH 1 .4.

18. The composition of claim 17, wherein said dissolution medium

represents a Simulated Gastric Fluid (SGF).

19. The composition according to any one of claims 1 to 18, wherein a solubilizer is present in from about 0.5% by weight to about 95 % by weight, relative to the total weight of the solid dispersion particles and the solubilizer.

20. The composition according to claim 19, wherein said solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer and d-alpha-tocopherol acid polyethylene glycol 1000 succinate.

21 . A composition according to any one of claims 1 to 20, for use in

therapy. 22. A composition according to any one of claims 1 to 20, for use in the treatment of a disease selected from hypertension, pulmonary hypertension, pulmonary arterial hypertension, renal failure, acute renal failure, cerebral vasospasms, myocardial infarct, angina pectoris and restenosis after angioplasty.

23. The composition for use, according to claim 22, wherein said composition is formulated for oral administration.

24. The composition for use, according to claim 22 or 23, wherein said solid dispersion particles containing tadalafil and at least one dispersing component; and ambrisentan are co-formulated in a single tablet.

25. A method of treating a patient suffering from hypertension, pulmonary hypertension, pulmonary arterial hypertension, renal failure, acute renal failure, cerebral vasospasms, myocardial infarct, angina pectoris or restenosis after angioplasty, comprising administering to a patient in need thereof, a therapeutically effective amount of a composition to any one of claims 1 to 20.

26. The method according to claim 25, wherein said composition is

formulated for oral administration.

27. The method according to claim 25 or 26, wherein said solid

dispersion particles containing tadalafil and at least one dispersing component; and ambrisentan are co-formulated in a single tablet.