Tadalafil oral suspension

Abstract

The present invention relates to a tadalafil oral suspension comprising 0.01-5% (w / v), cyclodextrin, co-processed crystalline cellulose and sodium carboxymethylcellulose, xanthan gum and water as a vehicle. The suspension is chemically and physically stable and exhibits a dissolution profile equivalent to that of commercially available tadalafil film-coated tablets. The tadalafil suspension is suitable for the treatment of male erectile dysfunction and prostatic hyperplasia. The present invention also relates to a fixed dose combination dosage form comprising the tadalafil and either tamsulosin, particularly in the form of a modified release tablet, or dutasteride. The combination dosage form is useful for the treatment of lower urinary tract symptoms associated with prostatic hyperplasia. The present invention also relates to a method for the preparation of the tadalafil composition.

Description

[Technical field]

[0001] The present invention relates to a tadalafil pharmaceutical composition in the form of an oral suspension that is stable and provides an equivalent dissolution profile compared to commercially available solid oral tadalafil formulations. [Background technology]

[0002] Tadalafil is a selective inhibitor of phosphodiesterase 5 (PDE5). It is known that the inhibition of PDE5 by tadalafil increases the cyclic guanosine monophosphate (cGMP) level in various tissues, particularly in the corpus cavernosum of the penis under sexual stimulation, as well as in the prostate, bladder and lung tissues, resulting in the relaxation of vascular smooth muscle, increased blood perfusion and / or vasodilation of these tissues. Based on this pharmacological mechanism, tadalafil is used in therapies for the treatment of various pathologies, particularly erectile dysfunction, benign prostatic hyperplasia (BPH) and pulmonary arterial hypertension (PAH).

[0003] For example, the drug Cialis® contains tadalafil as the active ingredient and is available as film-coated tablets in strengths of 2.5, 5, 10 and 20 mg. All of these are indicated for the treatment of erectile dysfunction, and the various doses available are intended to meet the needs of specific patients. Typically, it is recommended to take a specific dose of either 10 mg or 20 mg before the expected sexual activity. However, in some cases, a once-daily regimen of lower doses of 2.5 mg or 5 mg may be advantageous.

[0004] Alternatively, the 5 mg strength tablet is also indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

[0005] Solid pharmaceutical formulations as tablets or capsules are the most common form available for administration of active ingredients.However, in certain circumstances, their use is not entirely satisfactory, for example, because patients find it difficult to swallow.For these patients, it may be useful to have an alternative liquid formulation available.In addition, liquid formulations may offer additional advantages, such as the lack of need to swallow liquid, more convenient administration, and the possibility of better adjusting the required dose of active ingredient, i.e., tadalafil.

[0006] However, the formulation of liquid formulations is generally more complicated than that of standard tablets and capsules, and is particularly challenging for those active ingredients such as tadalafil, which are practically insoluble in water. For these cases, suspension formulations are generally a good choice. However, chemically and physically stable suspension formulations, i.e., suspension formulations in which both chemical degradation and sedimentation problems are minimized, are not common. Furthermore, it is also desirable to develop simple formulations that contain only small amounts of excipients other than water, both for economic reasons and to reduce the risk of possible adverse effects or intolerance problems to excipients.

[0007] Another challenge in developing new tadalafil suspension formulations is that these suspension formulations must provide a pharmacokinetic profile equivalent to that of the commercial solid formulation already available on the market, i.e., Cialis® film-coated tablets. For a low-solubility drug such as tadalafil, dissolution is typically the rate-limiting step of absorption, and therefore in vitro dissolution tests generally show good correlation with in vivo absorption behavior. Therefore, in this regard, a tadalafil suspension formulation that provides an in vitro dissolution profile similar to that of Cialis® film-coated tablets would be a first target.

[0008] On the other hand, the combination of tadalafil with other active ingredients may be advantageous for treating certain conditions. In particular, the combination of tadalafil and tamsulosin, an adrenergic alpha 1 receptor antagonist, has been widely reported in the art for treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), as disclosed, for example, in Sebastianelli et al., J. Clin. Med., 2019, 8, 1126. In addition, the advantages of the combination of tadalafil and dutasteride, a testosterone 5α reductase inhibitor, have also been disclosed in the art, as disclosed, for example, in Ozkidik et al., Turk. J. Urol., 2018, 44, 294.

[0009] Therefore, it would be desirable for the tadalafil suspension formulation to also include certain useful fixed dose combinations with other drugs, particularly tamsulosin or dutasteride. However, these types of combination formulations would be particularly difficult to formulate due to the different physicochemical properties and administration requirements of each of the combined drugs. In particular, the tadalafil-tamsulosin combination is particularly challenging, since it is known that tamsulosin is preferably provided in a delayed release formulation, for example, to provide a more consistent release of tamsulosin (Prabhu et al., Drugs Ther. Perspect., 2019, 35, 181-184).

[0010] Some tadalafil suspensions have been disclosed in the prior art. For example, WO 2020 / 039263 generally relates to oral suspension formulations of insoluble drugs, including, for example, quetiapine, sildenafil, tadalafil, cinacalcet, ticagrelor, mycophenolate esters, aprepitant, zonisamide or primidone. An extensive list of suitable excipients is provided, including suspending agents, binders / fillers and buffers. For drugs with low wettability and logP higher than 2.5, such as tadalafil, the suspension contains 300-400 mg / ml glycerin.

[0011] WO 2018 / 142189 discloses a method for preparing nanoparticles or stable suspensions of tadalafil or sildenafil citrate with improved bioavailability, comprising preparing a solution of the active ingredient in dimethylsulfoxide (DMSO) and adding this solution to an aqueous dispersing agent, preferably lecithin, gelatin, starch or combinations thereof, under continuous homogenization.

[0012] The proposals available in the art so far do not meet all the desired requirements for a tadalafil suspension. Thus, there remains a need to provide a tadalafil suspension that is chemically and physically stable, simple, and provides an in vitro dissolution profile equivalent to that of Cialis® commercially available film-coated tablets. Summary of the Invention

[0013] An object of the present invention is a pharmaceutical composition of tadalafil in the form of an aqueous oral suspension.

[0014] Another embodiment of the present invention is a fixed dose combination dosage form comprising the above tadalafil pharmaceutical composition and tamsulosin.

[0015] Another embodiment of the present invention is a fixed dose combination dosage form comprising the above-mentioned tadalafil pharmaceutical composition and dutasteride.

[0016] Another aspect of the present invention is a process for preparing the above tadalafil pharmaceutical composition.

[0017] Another aspect of the invention is a tadalafil composition for pharmaceutical use and a fixed dose combination dosage form.

[0018] The objectives of the present invention are as follows: a) tadalafil in an amount between 0.01% (weight / volume) and 5% (weight / volume); b) cyclodextrin; and c) coprocessed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC); d) xanthan gum; e) water; A pharmaceutical composition for oral administration in the form of an aqueous suspension comprising:

[0019] The present inventors have developed a liquid pharmaceutical composition in the form of an aqueous suspension comprising tadalafil as an active ingredient, cyclodextrin, co-processed MCC-NaCMC and xanthan gum, which surprisingly not only has optimal physicochemical properties but also provides an in vitro dissolution profile that is very similar to that of the commercially available Cialis® film-coated tablets.

[0020] Generally, throughout this specification, as well as the claims, singular expressions preceded by the articles "a," "an," or "the" are intended to include the plural unless the context clearly indicates otherwise. Furthermore, numerical values ​​preceded by "about" or "approximately" are intended to include the exact stated value and certain variations about such value, i.e., variations in the stated amount or ±5%. Numerical ranges defined by lower and upper limits are intended to include the endpoints stated above.

[0021] Unless otherwise specified, throughout this specification as well as the claims, the disclosed percentages of each component of the composition are weight / volume (% w / v), i.e., grams of each component in 100 ml of composition.

[0022] Excipients used in the preparation of the compositions of the present invention are well known in the art and are widely available, and are described, for example, in the reference PJ Sheskey, WG Cook and CG Cable, Handbook of Pharmaceutical Excipients, Eighth Edition, Pharmaceutical Press, 2017 [ISBN: 978-0-8571-1271-2]. In addition, general excipients and procedures for preparing compositions are described in the reference JP Remington and AR Genaro, Remington, The Science and Practice of Pharmacy, 20 th edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472] or in the literature ME Aulton and KMG Taylor, Aulton's Pharmaceutics, the design and manufacture of medicines, 4th edition, Churchill Livingstone Elsevier, 2013 [ISBN: 978-0-7020-4290-4].

[0023] Tadalafil The pharmaceutical composition of the present invention comprises tadalafil as an active ingredient.

[0024] Tadalafil is the International Nonproprietary Name (INN) of the product (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,12,12a-tetrahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4(6H,7H)-dione (CAS 171596-29-5).

[0025] Tadalafil may be used in the composition, i.e., as a free base or in the form of a pharma- ceutically acceptable salt thereof. In a preferred embodiment, tadalafil is used as a free base.

[0026] Methods for preparing tadalafil are known in the art, for example, as disclosed in Chapter 38 (Drugs for Treatment of Erectile disfunction) of the document R. Vardanyan and V. Hruby, Synthesis of best-seller drugs, Elsevier, 2016. Tadalafil is also commercially available from several suppliers.

[0027] The composition of the present invention comprises tadalafil in the form of an aqueous suspension at a concentration comprised between 0.01% and 5.0%, preferably between 0.02% and 2.0%, more preferably between 0.05% and 1.5%, even more preferably between 0.08% and 1.2%, even more preferably between 0.09% and 1.1%, and even more preferably between 0.1% and 1.0%.

[0028] The authors of the present invention have found that the suspensions of the present invention are chemically and physically stable along the above range of tadalafil concentrations, which allows the formulation of suspensions of various concentrations of the active ingredient according to specific therapeutic needs.

[0029] In one particular embodiment, the concentration of tadalafil is comprised between 0.01% and 0.40%, preferably between 0.02% and 0.30%, more preferably between 0.05% and 0.20%, even more preferably between 0.08% and 0.15%, even more preferably between 0.09% and 0.12%, and even more preferably about 0.1%.

[0030] In another particular embodiment, the concentration of tadalafil is comprised between 0.1% and 4.0%, preferably between 0.2% and 3.0%, more preferably between 0.5% and 2.0%, even more preferably between 0.8% and 1.5%, even more preferably between 0.9% and 1.2%, and even more preferably about 1.0%.

[0031] The particle size of tadalafil used in the composition of the present invention is not limited, and any particle size can be suitable.The particle size can be expressed as a volume diameter Dv, which represents the diameter of a sphere having the same volume as the particle, as is well known in the art.In detail, for example, the particle size can be expressed as a volume diameter median (Dv90 or Dv0.9), which represents the diameter at which 90% of the product has a smaller particle size.The particle size can be determined as a volume diameter by methods known to those skilled in the art, such as laser diffraction, inter alia, based on the use of a suitable device, such as, for example, Malvern Mastersizer 3000 (Malvern Instruments Ltd., Malvern, Worcestershire, UK).

[0032] Tadalafil particles suitable for use in the present compositions may have a Dv90 value comprised, for example, between 10 and 100 microns. In certain embodiments, the tadalafil particles have a Dv90<50 microns, or a Dv90<40 microns, or a Dv90<20 microns, or a Dv90<15 microns.

[0033] Cyclodextrin As is well known in the art, cyclodextrins are cyclic oligosaccharides derived from starch that contain at least six D-(+)-glucopyranose units linked by (1→4) glycosidic bonds. The most commonly used forms are α-, β-, and γ-cyclodextrins, which have six, seven, and eight glucose units, respectively. Highly branched cyclodextrins (HBCDs), which typically have a large molecular weight of about 462 kDa, are also available and are also included in the cyclodextrin category.

[0034] The term cyclodextrin is intended to include cyclodextrin derivatives, especially methylcyclodextrins, 2-hydroxyethylcyclodextrins or 2-hydroxypropylcyclodextrins. Thus, for example, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin are intended to be included within the β-cyclodextrin group.

[0035] Cyclodextrins are typically produced by the enzymatic degradation of starch using specialized bacteria and are widely available from commercial suppliers.

[0036] In particular, HBCD is produced from waxy maize starch by the cyclization reaction of branching enzymes as disclosed, for example, in Tanaka et al., Carbohydr. Res., 1996, 295, 91-101, or in Takata et al., J. Bacteriol., 1996, 178, 1600-1606, or Takata et al., J. Ferment. Bioeng., 1997, 84, 119-123, or Fuji et al., Biocatal. Biotransformation, 2003, 21, 167-172. HBCD is also commercially available from various suppliers, for example, Glico Nutrition, Inc. under the trade name Cluster Dextrin®.

[0037] The amount of cyclodextrin in the composition is typically comprised between 0.01% and 0.25%, preferably between 0.02% and 0.20%, more preferably between 0.03% and 0.10%. Preferred concentrations of cyclodextrin are, for example, about 0.03%, or about 0.04%, or about 0.05%, or about 0.06%, or about 0.07%, or about 0.08%, or about 0.09%, or about 0.10%.

[0038] Any type of cyclodextrin may be used to prepare the composition of the present invention. In particular, the cyclodextrin may be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, highly branched cyclodextrin (HBCD), and mixtures thereof. In one embodiment, the cyclodextrin is selected from α-cyclodextrin and β-cyclodextrin.

[0039] In one embodiment, the cyclodextrin is a highly branched cyclodextrin (HBCD).

[0040] In one embodiment, the cyclodextrin is a β-cyclodextrin.

[0041] In one embodiment, the cyclodextrin is an α-cyclodextrin.

[0042] In one embodiment, the cyclodextrin is gamma-cyclodextrin.

[0043] Co-processed microcrystalline cellulose and sodium carboxymethylcellulose Another component of the pharmaceutical composition according to the invention is co-processed microcrystalline cellulose (CMC) and sodium carboxymethylcellulose (NaCMC), also known as microcrystalline cellulose and carmellose sodium (European Pharmacopoeia 7.0) or as microcrystalline cellulose and sodium carboxymethylcellulose (United States Pharmacopoeia), which may be abbreviated herein as co-processed MCC-NaCMC.

[0044] MCC-NaCMC, as is well known in the art, is a spray-dried or bulk-dried blend of microcrystalline cellulose and carmellose sodium. It is commercially available, for example, under the trade name Vivapur® MCG, typically in several grades that differ in the ratio of MCC to NaCMC and / or particle size, from JRS Pharma. The amount of NaCMC in the co-processed MCC-NaCMC is typically about 22% by weight or less, typically comprised between about 5% by weight and about 22% by weight. For example, all types and grades of co-processed MCC-NaCMC are suitable for use in the present composition. For example, the following grades may be used: Vivapur® MCG581P, Vivapur® MCG591P, Vivapur® MCG611P or Vivapur® MCG811P.

[0045] The amount of co-processed CMC-NaCMC in the composition is typically comprised between 0.5% and 2.0%, preferably between 0.6% and 1.4%, more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%.

[0046] Xanthan gum As is well known, xanthan gum is a high molecular weight polysaccharide formed by D-glucose, D-mannose and D-glucuronic acid units. Xanthan gum is produced by bacteria of the genus Xanthomonas.

[0047] Xanthan gum can be obtained commercially from a number of companies, for example under the trade names Keltrol® (CP Kelco) or Rhodopol® (Solvay), among others. Xanthan gum is also available in different grades according to different particle sizes, all of which are suitable for the preparation of suspensions according to the invention.

[0048] The amount of xanthan gum in the composition is typically comprised between 0.10% and 1.50%, preferably between 0.20% and 1.00%, more preferably between 0.25% and 0.90%, even more preferably between 0.30% and 0.85%, even more preferably between 0.35% and 0.75%, even more preferably between 0.40% and 0.65%, and even more preferably between 0.45% and 0.60%.

[0049] In one embodiment, the amount of xanthan gum is comprised between 0.10% and 0.75%, preferably between 0.20% and 0.60%, even more preferably between 0.25% and 0.40%, and even more preferably about 0.30%.

[0050] In one embodiment, the amount of xanthan gum is comprised between 0.10% and 0.75%, preferably between 0.25% and 0.65%, even more preferably between 0.36% and 0.54%, even more preferably between 0.40% and 0.50%, and even more preferably about 0.45%.

[0051] In one embodiment, the amount of xanthan gum is comprised between 0.20% and 1.50%, preferably between 0.30% and 0.95%, more preferably between 0.42% and 0.80%, even more preferably between 0.48% and 0.72%, even more preferably between 0.55% and 0.65%, and even more preferably about 0.60%.

[0052] Additional ingredients included as needed Surfactants The compositions of the present invention may optionally contain surfactants. As is well known, surfactants are amphiphilic molecules, i.e. one part of the molecule is hydrophilic and one part is lipophilic, and they may be ionic or non-ionic.

[0053] Preferably, the composition comprises a surfactant.

[0054] In one embodiment, the composition comprises a non-ionic surfactant.The non-ionic surfactant may be selected from, for example, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, polyoxyethylene alkyl ether and polyoxyethylene nonylphenol ether, among others.

[0055] In one embodiment, the composition typically comprises an anionic surfactant selected from sodium lauryl sulfate and docusate sodium.

[0056] When a surfactant is added to a composition according to the invention, the surfactant is typically present in a proportion that may range from about 0.001% to about 2%.

[0057] In one preferred embodiment, the composition comprises sodium lauryl sulfate in an amount preferably comprised between 0.010% and 0.100%, preferably between 0.020% and 0.085%, more preferably between 0.030% and 0.090%.

[0058] Preservatives The composition may further comprise a preservative to ensure its protection against microbial contamination. Suitable preservatives are, inter alia, for example, butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, chloroxylenol, imidurea, cresol, phenol, sorbic acid, potassium sorbate or thimerosal, or mixtures thereof.

[0059] Preferably, the composition comprises a preservative.

[0060] The amount of preservative generally depends on the particular preservative used, as is well known in the art, and may typically range from about 0.001% to about 5%. A person skilled in the art should have no difficulty in selecting the appropriate amount in each case, as disclosed in references in the art.

[0061] In one embodiment, the preservative is selected from parabens, benzoic acid and their sodium or potassium salts and mixtures thereof, typically at a concentration comprised between about 0.01% and about 1.00%, preferably between 0.05% and 0.50%. In one embodiment, the preservative is selected from butylparaben, butylparaben sodium, propylparaben sodium, propylparaben, propylparaben sodium, methylparaben, methylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof. In one embodiment, the preservative is a paraben or a mixture of parabens, for example, selected from methylparaben sodium, propylparaben sodium, and mixtures thereof. In one particular embodiment, the preservative is a mixture of methylparaben sodium and propylparaben sodium. In another embodiment, the preservative is selected from sorbic acid, potassium sorbate, and mixtures thereof. In another embodiment, the preservative is a mixture of benzoic acid and sodium benzoate.

[0062] pH adjuster The composition of the present invention may contain a pH adjuster as necessary to maintain the pH of the suspension in the desired pH range. The pH of the composition is generally comprised between 2.5 and 7, preferably between 4.0 and 6.5, and more preferably between 5.5 and 6.

[0063] The amount and type of pH adjusting agent in the composition will be such as is appropriate to obtain the desired pH, as can be readily determined and adjusted by one of ordinary skill in the art.

[0064] Preferably, the composition comprises a pH adjuster.

[0065] When present, the pH adjuster is typically present in an amount ranging from about 1% to about 4%, preferably from about 1.5% to about 3.5%, and more preferably from about 2% to about 3%.

[0066] The pH adjuster may be an acidifying agent, such as, for example, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, or sulfuric acid, and / or an alkalizing agent, such as, for example, ammonia solution, diethanolamine, monoethanolamine, potassium bicarbonate, sodium bicarbonate, potassium citrate, sodium citrate, sodium bicarbonate, or sodium borate. In general, the above acidifying and alkalizing agents are used in combination as buffers, which in general comprise an acid and its conjugate base, inter alia, for example, citrate buffer, acetate buffer, citrate phosphate buffer, Tris buffer, or phosphate buffer.

[0067] A preferred buffer is a citrate buffer, which may typically be prepared using sodium citrate and citric acid, for example, using sodium citrate and anhydrous citric acid in a weight ratio of 8:1 to 5:1, preferably about 7:1.

[0068] sweetener If necessary, the composition may contain a sweetener to improve the palatability of the suspension, and a strong sweetener may be used. Strong sweeteners generally refer to non-nutritive high-intensity sweeteners, generally about 100 to about 13,000 times sweeter than sucrose.

[0069] Suitable strong sweeteners for use in the present compositions are, for example, aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, or mixtures thereof.Preferably, the sweetener is selected from aspartame, acesulfame potassium, saccharin and sodium saccharin.

[0070] The amount of sweetener can vary widely depending on the sweetness intensity of the sweetener, but generally falls in the range of 0.0001% to 0.5%.

[0071] fragrance The composition may further comprise a flavoring agent to provide the composition with a pleasant aroma and / or smell, if necessary.Suitable flavoring agents include natural and artificial flavoring agents.Natural flavoring agents include natural oils and extracts from plants, leaves, flowers and fruits.Some suitable flavoring agents are, among others, for example, menthol, cinnamon, clove, anise, eucalyptus, peppermint, spearmint, thyme, vanilla, chocolate, fruit flavors such as cherry flavor, grape flavor, orange flavor, banana flavor, strawberry flavor, lemon flavor, apple flavor, peach flavor, raspberry flavor, pineapple flavor and apricot flavor, and combinations thereof.

[0072] The amount of flavoring can be easily adjusted by one skilled in the art depending on the particular flavoring and the desired sensory effect. Typically, the amount of flavoring, if present in the composition, ranges from about 0.001% (w / v) to about 0.1% (w / v).

[0073] composition Water is the main solvent of the formulation. Typically, purified water for pharmaceutical use is used, which is commercially available and can be generally obtained from drinking water by distillation, ion exchange or other suitable methods. When adjusted to a specific final volume, the exact percentage of water is not quantified, but rather obtains the desired concentration of every component.

[0074] Preferably, the solvent of the suspension of the present invention consists of water, ie the composition preferably does not contain any additional organic solvents, in particular does not contain glycerin.

[0075] In an embodiment, the suspension of the present invention is free of ethanol, isopropanol, propan-1-ol, glycerin, propylene glycol, 1,3-propanediol, and combinations thereof; even more preferably, the suspension of the present invention is free of glycerin.

[0076] The composition of the present invention is in the form of a suspension.As is well known in pharmaceutical formulation, a suspension is a two-phase system that consists of a solid that is neither dissolved nor mixed with liquid and dispersed therein.Tadalafil is a poorly soluble drug that exists as a solid dispersed phase in the suspension.

[0077] The viscosity of the suspension of the present invention is generally within the range of 100 to 3000 cPs, preferably within the range of 125 to 2500 cPs, more preferably within the range of 150 to 1500 cPs.

[0078] In one embodiment, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: a) tadalafil in an amount of 0.01% to 5%, preferably 0.02% to 2.0%, more preferably 0.05% to 1.5%, even more preferably 0.08% to 1.2%, even more preferably 0.09% to 1.1%, and even more preferably 0.1% to 1.0%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount of preferably 0.10% to 1.50%, more preferably 0.20% to 1.00%, even more preferably 0.25% to 0.90%, even more preferably 0.30% to 0.85%, even more preferably 0.35% to 0.75%, even more preferably 0.40% to 0.65%, even more preferably 0.45% to 0.60%, and e) water; f) optionally, a surfactant in an amount of preferably 0.001% to about 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) if necessary, a preservative in an amount of preferably 0.001% to 5%, more preferably 0.01% to 1.00%, and even more preferably 0.05% to 0.50%, and preferably butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol a preservative selected from butylparaben, sodium butylparaben, propylparaben, sodium propylparaben, methylparaben, sodium methylparaben, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof, and even more preferably selected from sodium methylparaben and sodium propylparaben; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, said pH adjuster being preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof, more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin; j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e. g of each component per 100 ml of suspension. It relates to a pharmaceutical composition for oral administration in the form of an aqueous suspension.

[0079] In one embodiment, the composition comprises components a) to f), with components g) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant.

[0080] In one embodiment, the composition comprises components a) to g), with components h) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant and a preservative.

[0081] In one embodiment, the composition comprises components a) to h), where components i) to j) are options corresponding to preferred embodiments of the invention in which the composition further comprises a surfactant, a preservative and a pH adjuster.

[0082] In one embodiment, the composition consists of the above components a) to j), either mandatory or optional as defined above, i.e. the composition does not contain any additional excipients or active ingredients.

[0083] In one embodiment, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: a) tadalafil in an amount comprised between 0.01% and 0.40%, preferably between 0.02% and 0.30%, more preferably between 0.05% and 0.20%, even more preferably between 0.08% and 0.15%, even more preferably between 0.09% and 0.12%, and even more preferably about 0.1%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount preferably comprised between 0.10% and 0.75%, more preferably between 0.25% and 0.65%, even more preferably between 0.36% and 0.54%, even more preferably between 0.40% and 0.50%, and even more preferably about 0.45%; e) water; f) optionally, a surfactant in an amount of preferably 0.001% to 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) if necessary, a preservative in an amount of preferably 0.001% to 5%, more preferably 0.01% to 1.00%, and even more preferably 0.05% to 0.50%, and preferably butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol a preservative selected from butylparaben, sodium butylparaben, propylparaben, sodium propylparaben, methylparaben, sodium methylparaben, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof, and even more preferably selected from sodium methylparaben and sodium propylparaben; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, which is preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof; more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin, j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e. grams of each component per 100 ml of suspension. It relates to a pharmaceutical composition for oral administration in the form of an aqueous suspension.

[0084] In one embodiment, the composition comprises components a) to f), with components g) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant.

[0085] In one embodiment, the composition comprises components a) to g), with components h) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant and a preservative.

[0086] In one embodiment, the composition comprises components a) to h), where components i) to j) are options corresponding to preferred embodiments of the invention in which the composition further comprises a surfactant, a preservative and a pH adjuster.

[0087] In one embodiment, the composition consists of the above components a) to j), either mandatory or optional as defined above, i.e. the composition does not contain any additional excipients or active ingredients.

[0088] In one embodiment, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: a) tadalafil in an amount comprised between 0.1% and 4.0%, preferably between 0.2% and 3.0%, more preferably between 0.5% and 2.0%, even more preferably between 0.8% and 1.5%, even more preferably between 0.9% and 1.2%, and even more preferably about 1.0%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount preferably comprised between 0.20% and 1.50%, more preferably between 0.30% and 0.95%, even more preferably between 0.42% and 0.80%, even more preferably between 0.48% and 0.72%, even more preferably between 0.55% and 0.65%, even more preferably about 0.60%; e) water; f) optionally, a surfactant in an amount of preferably 0.001% to 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) optionally, a preservative in an amount preferably between 0.001% and 5%, more preferably between 0.01% and 1.00%, even more preferably between 0.05% and 0.50%, preferably selected from butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, chloroxylenol, imidurea, cresol, phenol, sorbic acid, potassium sorbate, thimerosal and mixtures thereof, more preferably selected from butylparaben, butylparaben sodium, propylparaben, propylparaben sodium, methylparaben, methylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate and mixtures thereof, even more preferably selected from methylparaben sodium and propylparaben sodium; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, which is preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof, more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin; j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e. grams of each component per 100 ml of suspension. It relates to a pharmaceutical composition for oral administration in the form of an aqueous suspension.

[0089] In one embodiment, the composition comprises components a) to f), with components g) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant.

[0090] In one embodiment, the composition comprises components a) to g), with components h) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant and a preservative.

[0091] In one embodiment, the composition comprises components a) to h), where components i) to j) are options corresponding to preferred embodiments of the invention in which the composition further comprises a surfactant, a preservative and a pH adjuster.

[0092] In one embodiment, the composition consists of the above components a) to j), either mandatory or optional as defined above, i.e. the composition does not contain any additional excipients or active ingredients.

[0093] In one embodiment, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: a) tadalafil in an amount comprised between 0.1% and 4.0%, preferably between 0.2% and 3.0%, more preferably between 0.5% and 2.0%, even more preferably between 0.8% and 1.5%, even more preferably between 0.9% and 1.2%, and even more preferably about 1.0%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount preferably comprised between 0.10% and 0.75%, more preferably between 0.20% and 0.60%, even more preferably between 0.25% and 0.40%, and even more preferably about 0.30%; e) water; f) optionally, a surfactant in an amount of preferably 0.001% to 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) optionally, a preservative in an amount preferably between 0.001% and 5%, more preferably between 0.01% and 1.00%, even more preferably between 0.05% and 0.50%, preferably selected from butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, chloroxylenol, imidurea, cresol, phenol, sorbic acid, potassium sorbate, thimerosal and mixtures thereof, more preferably selected from butylparaben, butylparaben sodium, propylparaben, propylparaben sodium, methylparaben, methylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate and mixtures thereof, even more preferably selected from methylparaben sodium and propylparaben sodium; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, which is preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof, more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin; j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e. grams of each component per 100 ml of suspension. It relates to a pharmaceutical composition for oral administration in the form of an aqueous suspension.

[0094] In one embodiment, the composition comprises components a) to f), with components g) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant.

[0095] In one embodiment, the composition comprises components a) to g), with components h) to j) being options corresponding to the preferred embodiment of the invention in which the composition further comprises a surfactant and a preservative.

[0096] In one embodiment, the composition comprises components a) to h), where components i) to j) are options corresponding to preferred embodiments of the invention in which the composition further comprises a surfactant, a preservative and a pH adjuster.

[0097] In one embodiment, the composition consists of the above components a) to j), either mandatory or optional as defined above, i.e. the composition does not contain any additional excipients or active ingredients.

[0098] In addition, all of the compositions disclosed above may optionally comprise colorants to improve their appearance and make them more sensory appealing.

[0099] As is well known in the art, any coloring agent suitable for use in pharmaceutical preparations may be used, such as those disclosed in the section "Coloring Agents" of the reference "Handbook of Pharmaceutical Ingredients," supra.

[0100] Combination with tamsulosin or dutasteride The compositions of the invention in the form of an oral suspension comprising tadalafil as an active ingredient can optionally further comprise or be combined with one or more suitable additional active ingredients to provide a fixed dose combination dosage form.

[0101] One particularly useful treatment strategy is the combination of tadalafil and tamsulosin for the treatment of patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), as disclosed, for example, in Sebastianelli et al., supra. Another useful combination is tadalafil and dutasteride for the treatment of LUTS associated with BPH.

[0102] Tamsulosin is the International Nonproprietary Name (INN) of the substance (R)-5-(2-((2-(2-ethoxyphenoxy)ethyl)amino)propyl)-2-methoxybenzenesulfonamide. Tamsulosin is an alpha 1 adrenergic receptor antagonist and is also used as monotherapy for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Tamsulosin may be used as the free base or a pharma- ceutically acceptable salt or solvate thereof. Tamsulosin is generally commercially available as the hydrochloride salt.

[0103] Dutasteride is the International Nonproprietary Name (INN) of the substance (1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-[2,5-bis(trifluoromethyl)phenyl]-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide.Dutasteride is a 5α-reductase inhibitor commonly used for treating symptoms of benign prostatic hyperplasia (BPH).Dutasteride may be used as its pharmaceutically acceptable salt or solvate.Preferably, the free base is used.

[0104] Methods for preparing tamsulosin and dutasteride are well known in the art, for example as disclosed in chapters 12 (Adrenoblockers) and 27 (Steroid Hormones), respectively, of the document R. Vardanyan and V. Hruby, Synthesis of best-seller drugs, Elsevier, 2016. Tamsulosin and its pharma- ceutically acceptable salts, particularly tamsulosin hydrochloride, as well as dutasteride, can also be commercially obtained from several suppliers.

[0105] Fixed dose dosage formulations comprising tadalafil and tamsulosin or comprising tadalafil and dutasteride are therapeutically advantageous, particularly due to improved drug compliance.Furthermore, it is particularly useful to include the advantages of the tadalafil suspension disclosed herein in a combination oral dosage form.

[0106] Therefore, another aspect of the present invention is a fixed dose combination dosage form comprising a tadalafil aqueous suspension according to the present invention and tamsulosin, or a pharma- ceutically acceptable salt thereof.

[0107] Tamsulosin is commonly used in therapy in the form of modified release oral dosage forms, since delayed or extended release has proven to be therapeutically advantageous for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

[0108] Thus, the fixed dose combination dosage form preferably comprises tamsulosin in the form of a modified release tablet.

[0109] Advantageously, for this aspect of the invention, the tadalafil suspension and tamsulosin tablet are provided in the combination dosage form together, but physically separate, for mixing immediately prior to administration.

[0110] Surprisingly, the authors of the present invention have found that the tadalafil suspension according to the present invention has optimal properties, in particular optimal viscosity and rheological properties, which allow it to be easily mixed, if necessary, with other solid ingredients in granular form, in particular with tamsulosin tablets, and a homogeneous mixture can be easily obtained by simply shaking, and therefore it is easy to swallow and also has good palatability.

[0111] Advantageously, the fixed dose combination dosage form is adapted to deliver the following doses of both components: a dose of tadalafil comprised between 1 mg and 10 mg, preferably between 2 mg and 8 mg, more preferably between 3 mg and 7 mg, even more preferably between 4 mg and 6 mg, and even more preferably about 5 mg; and A dose of tamsulosin comprised between 0.05 mg and 1 mg, preferably between 0.08 mg and 0.8 mg, more preferably between 0.15 mg and 0.65 mg, even more preferably between 0.30 mg and 0.50 mg, and even more preferably about 0.4 mg

[0112] A preferred fixed dose combination dosage form comprises about 5 mg of tadalafil and about 0.4 mg of tamsulosin.

[0113] Advantageously, for example, the combination may be provided in a single dose vial, with an appropriate dose of tadalafil in the tadalafil suspension of the present invention in the vial, and preferably an appropriate dose of tamsulosin in the tamsulosin tablet, enclosed in a cap that includes a means for piercing to release the tablet into the tadalafil suspension prior to administration. Both components can then be easily mixed by gentle shaking to obtain a homogenous mixture of both ingredients.

[0114] Any concentration of tadalafil suspension may be used for its combined use with tamsulosin. Accordingly, the appropriate volume of suspension is calculated to provide the appropriate dose to mix with tamsulosin.

[0115] Any type of modified release tamsulosin tablet can be used and mixed with the tadalafil suspension.

[0116] As is well known in the art, pharmaceutical tablets are multiparticulate drug delivery systems in which the total dose is divided into multiple subunits having a spherical shape and a narrow particle size distribution within the range of about 0.1 mm to about 1.5 mm.

[0117] Typically, the tablet comprises a core comprising the active ingredient, i.e., tamsulosin, and one or more coating layers comprising one or more release modifying polymers. The release modifying film coatings may be further classified as either delayed release (e.g., gastroresistant) or sustained release coatings.

[0118] As is well known in the art, film coating method comprises applying coating liquid to the core containing active ingredient.Film coating formulations typically comprise polymer, plasticizer, and solvent / vehicle.Some common release-modifying coating polymers are, among others, some cellulose derivatives such as ethyl cellulose and cellulose acetate; methyl methacrylate copolymers; methacrylic acid copolymers; and phthalates such as hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and polyvinyl acetate phthalate.

[0119] For example, the cores may be prepared using inert spheres, typically sugar spheres, onto which a suitable tadalafil solution or suspension, e.g., an aqueous solution or suspension containing tadalafil together with a binder and optionally other excipients, is coated. Alternatively, the tablet cores may be prepared by extrusion / spheronization methods, as is well known in the art.

[0120] In addition, uncoated modified release tablets may be used which may be prepared by embedding tamsulosin in a modified release matrix composition and manufacturing the tablets by extrusion / spheronization methods.

[0121] Some examples of tamsulosin delayed release tablets that can be used in the present invention are, for example, those disclosed in the following patent documents: EP 3473245, WO 2004 / 043449, WO 2005 / 060939, WO 2005 / 004851, WO 2007 / 021101, WO 2007 / 117110, WO 2014 / 203137, WO 2016 / 155682 and WO 2018 / 030862.

[0122] In one embodiment, one aspect of the invention is: A) a) tadalafil in an amount of 0.01% (weight / volume) to 5%, preferably 0.02% to 2.0%, more preferably 0.05% to 1.5%, even more preferably 0.08% to 1.2%, even more preferably 0.09% to 1.1%, and even more preferably 0.1% to 1.0%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount of preferably 0.10% to 1.50%, more preferably 0.20% to 1.00%, even more preferably 0.25% to 0.90%, even more preferably 0.30% to 0.85%, even more preferably 0.35% to 0.75%, even more preferably 0.40% to 0.65%, even more preferably 0.45% to 0.60%, and e) water; f) optionally, a surfactant in an amount of preferably 0.001% to 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) if necessary, a preservative in an amount of preferably 0.001% to 5%, more preferably 0.01% to 1.00%, and even more preferably 0.05% to 0.50%, and preferably butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol a preservative selected from butylparaben, sodium butylparaben, propylparaben, sodium propylparaben, methylparaben, sodium methylparaben, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof, and even more preferably selected from sodium methylparaben and sodium propylparaben; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, which is preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof, more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin; j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e., g of each component per 100 ml of suspension; Preferably, the composition comprises components a) to f) and optionally comprises components g) to j), more preferably the composition comprises components a) to g) and optionally comprises components h) to j), even more preferably the composition comprises components a) to h) and optionally comprises components i) to j); Preferably, the composition consists of the above components a) to j) as defined above either obligatorily or optionally, i.e. the composition does not contain any additional excipients or active ingredients. a pharmaceutical composition for oral administration in the form of an aqueous suspension; B) tamsulosin, preferably in the form of a modified release tablet, or a pharma- ceutical acceptable salt thereof; The present invention relates to a fixed dose combination dosage form comprising:

[0123] In another embodiment, one aspect of the invention is: A) a) tadalafil in an amount comprised between 0.01% and 0.40%, preferably between 0.02% and 0.30%, more preferably between 0.05% and 0.20%, even more preferably between 0.08% and 0.15%, even more preferably between 0.09% and 0.12%, and even more preferably about 0.1%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount preferably comprised between 0.10% and 0.75%, more preferably between 0.25% and 0.65%, even more preferably between 0.36% and 0.54%, even more preferably between 0.40% and 0.50%, and even more preferably about 0.45%; e) water; f) optionally, a surfactant in an amount of preferably 0.001% to 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) if necessary, a preservative in an amount of preferably 0.001% to 5%, more preferably 0.01% to 1.00%, and even more preferably 0.05% to 0.50%, and preferably butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol a preservative selected from butylparaben, sodium butylparaben, propylparaben, sodium propylparaben, methylparaben, sodium methylparaben, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof, and even more preferably selected from sodium methylparaben and sodium propylparaben; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, which is preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof, more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin; j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e., g of each component per 100 ml of suspension; Preferably, the composition comprises components a) to f) and optionally comprises components g) to j), more preferably the composition comprises components a) to g) and optionally comprises components h) to j), even more preferably the composition comprises components a) to h) and optionally comprises components i) to j); Preferably, the composition consists of the above components a) to j) as defined above either obligatorily or optionally, i.e. the composition does not contain any additional excipients or active ingredients. a pharmaceutical composition for oral administration in the form of an aqueous suspension; B) tamsulosin, preferably in the form of a modified release tablet, or a pharma- ceutical acceptable salt thereof; The present invention relates to a combination oral dosage form comprising:

[0124] Another aspect of the present invention is a fixed dose combination dosage form comprising the tadalafil aqueous suspension according to the present invention and dutasteride, or a pharma- ceutically acceptable salt thereof.

[0125] Preferably, dutasteride is used as the free base.

[0126] Dutasteride is easily decomposed when in contact with tadalafil.Therefore, advantageously, tadalafil and dutasteride are provided together in a combined dosage form, but are physically separated to avoid the decomposition of dutasteride.For example, both active ingredients may be placed in separate compartments in the same package and mixed shortly before ingestion.Alternatively, dutasteride may be included in tadalafil suspension, but with some kind of protective barrier to avoid interaction, for example, with coated dutasteride particles, or with dutasteride in oil globules, for example, as a microemulsion formulation.

[0127] As mentioned above, the tadalafil suspension according to the present invention has optimal properties, in particular optimal viscosity and rheological properties, which allow it to be easily mixed with other solid ingredients in particulate form, for example with dutasteride particles provided as powder or granules.In this way, a homogeneous mixture comprising tadalafil and dutasteride can be easily obtained by simply shaking lightly, and therefore is easy to swallow and has good palatability.

[0128] Advantageously, this fixed dose combination dosage form comprises the following doses of both components: a dose of tadalafil comprised between 1 mg and 10 mg, preferably between 2 mg and 8 mg, more preferably between 3 mg and 7 mg, even more preferably between 4 mg and 6 mg, and even more preferably about 5 mg; and A dose of dutasteride comprised between 0.05 mg and 1.5 mg, preferably between 0.1 mg and 1.0 mg, more preferably between 0.2 mg and 0.8 mg, even more preferably between 0.4 mg and 0.6 mg, and even more preferably about 0.5 mg The system is designed to deliver the following:

[0129] A preferred fixed dose combination dosage form comprises about 5 mg of tadalafil and about 0.5 mg of dutasteride.

[0130] Advantageously, for example, the combination may be provided in a single dose vial, with an appropriate dose of tadalafil, as the tadalafil suspension of the present invention, placed in the vial, and an appropriate dose of dutasteride, for example, as a powder or granules, enclosed in a cap that includes a means for piercing to release the dutasteride powder or granules into the tadalafil suspension prior to administration. Both components can then be easily mixed by gentle shaking to obtain a homogenous mixture of both ingredients.

[0131] Any concentration of tadalafil suspension may be used for its combined use with dutasteride. Accordingly, the appropriate volume of suspension is calculated to provide the appropriate dose to mix with dutasteride.

[0132] Preferably, dutasteride is in the form of a powder or granules for mixing with the tadalafil suspension.Any specific formulation of the powder or granules may be used.Typically, the powder or granules provide an immediate release of dutasteride.

[0133] Since the amount of dutasteride administered in each combined dose is low, typically in the range of about 0.05 to about 1.5 mg, the formulation of dutasteride powder or granules preferably contains at least one diluent that serves as a bulking agent in order to have an optimal amount of powder or granules that is homogeneously mixed with the tadalafil suspension, the amount being typically comprised between 50 mg and 1000 mg. Suitable diluents are, for example, dextrose, lactose, sucrose, maltose, mannitol, maltitol, sorbitol, xylitol, calcium phosphate, calcium carbonate, sodium carbonate, calcium sulfate, crystalline cellulose, powdered cellulose, starch or pregelatinized starch, or mixtures thereof, among others.

[0134] Typically, to prepare dutasteride powder formulation, powdered dutasteride is mixed with excipient, typically diluent.If necessary, as known in the art, can add additional excipient, such as glidant or coloring agent.Suitable glidant includes colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium stearate and talc, among others.

[0135] When dutasteride is in the form of granules, preferably the formulation also comprises a binder selected from, inter alia, e.g., gelatin, povidone, hypromellose, hydroxypropyl cellulose, polyethylene glycol, sucrose, starch and pregelatinized starch, and mixtures thereof.

[0136] Granules can be prepared according to standard methods, either by dry granulation or by wet granulation. Suitable methods for the preparation of powder and granular formulations are disclosed, for example, in Chapter 28 of ME Aulton and KMG Taylor, supra.

[0137] In one embodiment, this aspect of the invention comprises: A) a) tadalafil in an amount of 0.01% (weight / volume) to 5%, preferably 0.02% to 2.0%, more preferably 0.05% to 1.5%, even more preferably 0.08% to 1.2%, even more preferably 0.09% to 1.1%, and even more preferably 0.1% to 1.0%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount of preferably 0.10% to 1.50%, more preferably 0.20% to 1.00%, even more preferably 0.25% to 0.90%, even more preferably 0.30% to 0.85%, even more preferably 0.35% to 0.75%, even more preferably 0.40% to 0.65%, even more preferably 0.45% to 0.60%, and e) water; f) optionally, a surfactant in an amount of preferably 0.001% to 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) if necessary, a preservative in an amount of preferably 0.001% to 5%, more preferably 0.01% to 1.00%, and even more preferably 0.05% to 0.50%, and preferably butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol a preservative selected from butylparaben, sodium butylparaben, propylparaben, sodium propylparaben, methylparaben, sodium methylparaben, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof, and even more preferably selected from sodium methylparaben and sodium propylparaben; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, which is preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof, more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin; j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e., g of each component per 100 ml of suspension; Preferably, the composition comprises components a) to f) and optionally comprises components g) to j), more preferably the composition comprises components a) to g) and optionally comprises components h) to j), even more preferably the composition comprises components a) to h) and optionally comprises components i) to j), Preferably, the composition consists of the above components a) to j) as defined above either obligatorily or optionally, i.e. the composition does not contain any additional excipients or active ingredients. a pharmaceutical composition for oral administration in the form of an aqueous suspension; B) dutasteride, preferably in powder or granule form, or a pharma- ceutically acceptable salt thereof; The present invention relates to a fixed dose combination dosage form comprising:

[0138] In another embodiment, one aspect of the invention is: A) a) tadalafil in an amount comprised between 0.01% and 0.40%, preferably between 0.02% and 0.30%, more preferably between 0.05% and 0.20%, even more preferably between 0.08% and 0.15%, even more preferably between 0.09% and 0.12%, and even more preferably about 0.1%; b) a cyclodextrin in an amount of preferably 0.01% to 0.25%, more preferably 0.02% to 0.20%, even more preferably 0.03% to 0.10%, preferably selected from α-cyclodextrin and β-cyclodextrin; c) co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC) in an amount preferably comprised between 0.5% and 2.0%, more preferably between 0.6% and 1.4%, even more preferably between 0.7% and 1.3%, even more preferably between 0.8% and 1.2%, even more preferably between 0.9% and 1.1%, and even more preferably about 1.0%; d) xanthan gum in an amount preferably comprised between 0.10% and 0.75%, more preferably between 0.25% and 0.65%, even more preferably between 0.36% and 0.54%, even more preferably between 0.40% and 0.50%, and even more preferably about 0.45%; e) water; f) optionally, a surfactant in an amount of preferably 0.001% to 2%, more preferably 0.010% to 0.100%, even more preferably 0.020% to 0.085%, even more preferably 0.030% to 0.090%, preferably selected from sodium lauryl sulfate and docusate sodium, more preferably sodium lauryl sulfate; g) if necessary, a preservative in an amount of preferably 0.001% to 5%, more preferably 0.01% to 1.00%, and even more preferably 0.05% to 0.50%, and preferably butylparaben, butylparaben sodium, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol a preservative selected from butylparaben, sodium butylparaben, propylparaben, sodium propylparaben, methylparaben, sodium methylparaben, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof, and even more preferably selected from sodium methylparaben and sodium propylparaben; h) if necessary, a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6, which is preferably a citrate buffer; i) optionally, a sweetener, preferably in an amount between 0.0001% and 0.5%, preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof; more preferably selected from aspartame, acesulfame potassium, saccharin, and sodium saccharin, j) optionally, a fragrance, preferably in an amount of 0.001% to 0.1%; comprising The above percentages are expressed as weight / volume (w / v), i.e., g of each component per 100 ml of suspension; Preferably, the composition comprises components a) to f) and optionally comprises components g) to j), more preferably the composition comprises components a) to g) and optionally comprises components h) to j), even more preferably the composition comprises components a) to h) and optionally comprises components i) to j), Preferably, the composition consists of the above components a) to j) as defined above either obligatorily or optionally, i.e. the composition does not contain any additional excipients or active ingredients. a pharmaceutical composition for oral administration in the form of an aqueous suspension; B) dutasteride, preferably in powder or granule form, or a pharma- ceutically acceptable salt thereof; The present invention relates to a combination oral dosage form comprising:

[0139] Preparation method Another aspect of the present invention is a process for preparing the above composition.

[0140] A suitable method for preparing the composition of the present invention comprises the steps of: (i) mixing the cyclodextrin, the co-processed MCC-NaCMC, and the xanthan gum with a portion of the total water to obtain a homogenous mixture; (ii) separately mixing tadalafil with another portion of the total water to obtain a homogenous mixture; (iii) adding the mixture of step (ii) above to the mixture of step (i) above; (iv) adding the remainder of the water; and The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0141] All components are added under continuous stirring. For example, steps (i) and (ii) may be carried out in a stainless steel reactor equipped with a stirring system.

[0142] In step (i), the exact percentage of water used to prepare the first mixture is not critical and can be, for example, from about 30% to about 75% of the total water.

[0143] If the composition comprises a pH adjuster, a preservative and / or a sweetener, these are also preferably added in step (i).

[0144] Typically, after addition of the co-processed MCC-NaCMC, it is activated, typically by several stirring steps according to the manufacturer's instructions, for example by subjecting the mixture to two successive stirring steps, first at a moderate stirring speed of, for example, up to 800 rpm for about 10-60 minutes, and then to a more vigorous second stirring step, for example, at about 1000-1500 rpm for about 2-15 minutes. Typically, between and after both stirring steps, the mixture is left unstirred for about 5-60 minutes.

[0145] In step (ii), the amount of water used to prepare the second mixture is also not critical and may be, for example, from about 5% to about 25% of the total water.

[0146] The mixture obtained in step (ii) is a suspension.

[0147] If the composition comprises a surfactant, it is typically added together with the tadalafil in step (ii).

[0148] If present, fragrance is preferably added after mixing of mixtures (i) and (ii).

[0149] The resulting final suspension is then dispensed into appropriate containers.

[0150] For example, the suspension can be packaged in a high density polyethylene bottle equipped with an appropriate dosing system, such as a dosing pump that dispenses a fixed volume of the suspension each time it is pressed, or other suitable metering device, e.g., a measuring cup, oral syringe, or dropper.

[0151] In one embodiment, the dispensing device is a dispensing pump adapted to dispense a fixed volume of suspension with each depression.

[0152] In another embodiment, the dispensing device is a graduated syringe.

[0153] Preferably, the dosing device in combination with an appropriate concentration of tadalafil in the suspension is adapted to deliver a dose of tadalafil contained in between 1 mg and 50 mg of tadalafil, preferably between 2.5 and 20 mg of tadalafil, e.g., a dose of about 2.5 mg, 5 mg, 10 mg or 20 mg.

[0154] Use of the composition The tadalafil compositions according to the present invention can be suitably used for any one of the known therapeutic indications for tadalafil.

[0155] Surprisingly, as shown in Example 5, the suspension according to the present invention, characterized by a specific combination of suspending agents, can provide a dissolution profile similar to that of the commercially available Cialis®, despite being prepared in a different form, i.e., as a film-coated tablet. Thus, the present invention can provide the same therapeutic effect as Cialis®, but in a more convenient and advantageous dosage form.

[0156] Its presentation in the form of an aqueous suspension facilitates oral administration, but also allows the dosage to be adjusted to each therapeutic indication and / or to the specific requirements of each particular patient.

[0157] Thus, another aspect of the present invention is a pharmaceutical composition of the present invention for use in therapy.

[0158] In one particular embodiment, the pharmaceutical composition according to the invention is indicated for the treatment of male erectile dysfunction.

[0159] Erectile dysfunction, also known as male sexual dysfunction, is understood to mean the persistent inability of a man to achieve or maintain a penile erection sufficient for having satisfactory sexual intercourse.

[0160] Thus, a particular embodiment of the present invention is a pharmaceutical composition of the present invention for use in the treatment of male erectile dysfunction or a method of treating male erectile dysfunction comprising administering a pharmaceutical composition of the present invention to a patient in need of said treatment.

[0161] Typically, a dose of about 10 mg or about 20 mg of tadalafil is used, taken before anticipated sexual activity. Alternatively, a once-daily regimen of about 2.5 mg or about 5 mg may be used. Those skilled in the art will have no difficulty in selecting the appropriate therapeutically effective dose and / or dosing regimen for this therapeutic indication.

[0162] In another embodiment, the pharmaceutical composition according to the invention is indicated for the treatment of benign prostatic hyperplasia (BPH).

[0163] As is well known, benign prostatic hyperplasia (BPH) is an age-related phenomenon associated with prostate enlargement and bladder outlet obstruction. Treatment of BPH typically involves treating the signs and symptoms of BPH to improve symptoms and reduce the risk of acute urinary retention and the risk of BPH-related surgery.

[0164] Therefore, another aspect of the present invention is a pharmaceutical composition of the present invention for use in the treatment of benign prostatic hyperplasia, or a method of treating benign prostatic hyperplasia comprising administering a pharmaceutical composition of the present invention to a patient in need of said treatment.

[0165] Doses of about 5 mg of tadalafil are used in the treatment of BPH. A person skilled in the art would have no difficulty in selecting an appropriate therapeutically effective dose and / or dosing regimen for this therapeutic indication.

[0166] Another aspect of the invention is an oral dosage form comprising tadalafil and tamsulosin for use in therapy.

[0167] A more particular embodiment is an oral dosage form comprising tadalafil and tamsulosin for use in the treatment of benign prostatic hyperplasia, or a method of treating benign prostatic hyperplasia comprising administering to a patient in need of said treatment an oral dosage form comprising tadalafil and tamsulosin.

[0168] Another aspect of the invention is an oral dosage form comprising tadalafil and dutasteride for use in therapy.

[0169] A more particular embodiment is a method of treating benign prostatic hyperplasia comprising administering to a patient in need of said treatment an oral dosage form comprising tadalafil and dutasteride for use in the treatment of benign prostatic hyperplasia, or an oral dosage form comprising tadalafil and dutasteride.

[0170] The present invention relates to the following embodiments: 1.a) tadalafil in an amount between 0.01% (weight / volume) and 5% (weight / volume); b) cyclodextrin; and c) Co-processed microcrystalline cellulose and sodium carboxymethylcellulose (MCC-NaCMC); d) xanthan gum; e) water; 1. A pharmaceutical composition for oral administration in the form of an aqueous suspension comprising:

[0171] 2. The composition according to embodiment 1, wherein the amount of tadalafil is contained in an amount of 0.02% (weight / volume) to 2.0% (weight / volume), preferably 0.05% (weight / volume) to 1.5% (weight / volume), more preferably 0.08% (weight / volume) to 1.2% (weight / volume), even more preferably 0.09% (weight / volume) to 1.1% (weight / volume), and even more preferably 0.1% (weight / volume) to 1.0% (weight / volume).

[0172] 3. The composition according to embodiment 1, wherein the amount of tadalafil is comprised between 0.01% (wt / vol) and 0.40% (wt / vol), preferably between 0.02% (wt / vol) and 0.30% (wt / vol), more preferably between 0.05% (wt / vol) and 0.20% (wt / vol), even more preferably between 0.08% (wt / vol) and 0.15% (wt / vol), even more preferably between 0.09% (wt / vol) and 0.12% (wt / vol), and even more preferably about 0.1% (wt / vol).

[0173] 4. The composition according to embodiment 1, wherein the amount of tadalafil is comprised between 0.1% (wt / volume) and 4.0% (wt / volume), preferably between 0.2% (wt / volume) and 3.0% (wt / volume), more preferably between 0.5% (wt / volume) and 2.0% (wt / volume), even more preferably between 0.8% (wt / volume) and 1.5% (wt / volume), even more preferably between 0.9% (wt / volume) and 1.2% (wt / volume), and even more preferably about 1.0% (wt / volume).

[0174] 5. The composition according to any one of embodiments 1 to 4, characterized in that the amount of the cyclodextrin is 0.01% (weight / volume) to 0.25% (weight / volume), preferably 0.02% (weight / volume) to 0.20% (weight / volume), and more preferably 0.03% (weight / volume) to 0.10% (weight / volume).

[0175] 6. The composition according to any one of the preceding embodiments, characterized in that the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and highly branched cyclodextrins (HBCD).

[0176] 7. The composition according to embodiment 6, characterized in that the cyclodextrin is chosen from α-cyclodextrin and β-cyclodextrin, preferably α-cyclodextrin.

[0177] 8. The composition according to any one of the preceding embodiments, characterized in that the amount of said co-processed CMC-NaCMC is comprised between 0.5% (wt / vol) and 2.0% (wt / vol), preferably between 0.6% (wt / vol) and 1.4% (wt / vol), more preferably between 0.7% (wt / vol) and 1.3% (wt / vol), even more preferably between 0.8% (wt / vol) and 1.2% (wt / vol), even more preferably between 0.9% (wt / vol) and 1.1% (wt / vol), and even more preferably about 1.0% (wt / vol).

[0178] 9. The composition according to any one of embodiments 1 to 8, wherein the amount of the xanthan gum is 0.10% (wt / volume) to 1.50% (wt / volume), preferably 0.20% (wt / volume) to 1.00% (wt / volume), more preferably 0.25% (wt / volume) to 0.90% (wt / volume), even more preferably 0.30% (wt / volume) to 0.85% (wt / volume), even more preferably 0.35% (wt / volume) to 0.75% (wt / volume), even more preferably 0.40% (wt / volume) to 0.65% (wt / volume), and even more preferably 0.45% (wt / volume) to 0.60% (wt / volume).

[0179] 10. The composition according to embodiment 9, characterized in that the amount of xanthan gum is comprised between 0.10% (wt / vol) and 0.75% (wt / vol), preferably between 0.20% (wt / vol) and 0.60% (wt / vol), more preferably between 0.25% (wt / vol) and 0.40% (wt / vol), and even more preferably 0.30% (wt / vol).

[0180] 11. The composition according to embodiment 9, characterized in that the amount of xanthan gum is comprised between 0.10% (wt / vol) and 0.75% (wt / vol), preferably between 0.25% (wt / vol) and 0.65% (wt / vol), more preferably between 0.36% (wt / vol) and 0.54% (wt / vol), even more preferably between 0.40% (wt / vol) and 0.50% (wt / vol), and even more preferably 0.45% (wt / vol).

[0181] 12. The composition according to embodiment 9, characterized in that the amount of xanthan gum is comprised between 0.20% (wt / vol) and 1.50% (wt / vol), preferably between 0.30% (wt / vol) and 0.95% (wt / vol), more preferably between 0.42% (wt / vol) and 0.80% (wt / vol), even more preferably between 0.48% (wt / vol) and 0.72% (wt / vol), even more preferably between 0.55% (wt / vol) and 0.65% (wt / vol), and even more preferably about 0.60% (wt / vol).

[0182] 13. The composition according to any one of the preceding embodiments, characterized in that the composition comprises a surfactant, preferably in an amount comprised between 0.001% and 2%.

[0183] 14. The composition according to embodiment 13, wherein the surfactant is an anionic surfactant, preferably selected from sodium lauryl sulfate and docusate sodium.

[0184] 15. The composition according to embodiment 14, characterized in that the surfactant is sodium lauryl sulfate in an amount of preferably 0.010% (wt / volume) to 0.100% (wt / volume), preferably 0.020% (wt / volume) to 0.085% (wt / volume), more preferably 0.030% (wt / volume) to 0.090% (wt / volume).

[0185] 16. The composition according to any one of embodiments 1 to 15, characterized in that the composition contains a preservative at a concentration preferably between 0.001% (weight / volume) and 5% (weight / volume), more preferably between 0.01% (weight / volume) and 1.00% (weight / volume), and even more preferably between 0.05% (weight / volume) and 0.50% (weight / volume).

[0186] 17. The composition according to embodiment 16, wherein the preservative is selected from butylparaben, butylparaben sodium, propylparaben sodium, propylparaben, propylparaben sodium, methylparaben, methylparaben sodium, benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, potassium sorbate, and mixtures thereof, preferably methylparaben sodium, propylparaben sodium, and mixtures thereof, more preferably a mixture of methylparaben sodium and propylparaben sodium.

[0187] 18. The composition according to any one of the preceding embodiments, characterized in that the composition comprises a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7, preferably between 4.0 and 6.5, more preferably between 5.5 and 6.

[0188] 19. The composition according to embodiment 18, wherein the pH adjuster is a buffer selected from the group consisting of citrate buffer, acetate buffer, citrate phosphate buffer, Tris buffer, and phosphate buffer.

[0189] 20. The composition according to embodiment 19, wherein the pH adjuster is a citrate buffer.

[0190] 21. The composition according to any one of the preceding embodiments, characterized in that it comprises a sweetener preferably selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin, and mixtures thereof, more preferably selected from aspartame, acesulfame potassium, saccharin and sodium saccharin.

[0191] 22. The composition according to embodiment 21, characterized in that the amount of the sweetener is comprised between 0.0001% (weight / volume) and 0.5% (weight / volume).

[0192] 23. The composition according to any one of the preceding embodiments, characterized in that the composition comprises a fragrance.

[0193] 24. The composition according to embodiment 23, characterized in that the amount of the fragrance is comprised between 0.001% (weight / volume) and 0.1% (weight / volume).

[0194] 25. The composition according to any one of the preceding embodiments, characterized in that the composition consists of: a) tadalafil; b) cyclodextrin; c) co-processed MCC-NaCMC; d) xanthan gum; e) water; f) optionally a surfactant; g) optionally a preservative; h) optionally a pH adjuster; i) optionally a sweetener; and j) optionally a flavoring.

[0195] 26. The composition of embodiment 25, wherein the composition consists essentially of: a) tadalafil; b) cyclodextrin; c) co-processed MCC-NaCMC; d) xanthan gum; e) water; f) surfactant; g) optionally a preservative; h) optionally a pH adjuster; i) optionally a sweetener; and j) optionally a flavoring.

[0196] 27. The composition of embodiment 26, wherein the composition consists essentially of: a) tadalafil; b) cyclodextrin; c) co-processed MCC-NaCMC; d) xanthan gum; e) water; f) surfactant; g) preservative; h) optionally a pH adjuster; i) optionally a sweetener; and j) optionally a flavoring.

[0197] 28. The composition of embodiment 27, wherein the composition consists of: a) tadalafil; b) cyclodextrin; c) MCC-NaCMC; d) xanthan gum; e) water; f) surfactant; g) preservative; h) pH adjuster; i) optionally a sweetener; and j) optionally a flavoring.

[0198] 29. The composition according to any one of the preceding embodiments, further comprising k) a colorant, if desired.

[0199] 30. The composition according to any one of the preceding embodiments, characterized in that the composition does not contain ethanol, isopropanol, propan-1-ol, glycerin, propylene glycol, 1,3-propanediol, and combinations thereof; more preferably, the composition does not contain glycerin.

[0200] 31. A fixed dose combination dosage form comprising the tadalafil aqueous suspension of any one of embodiments 1-30 and a second drug selected from tamsulosin, or a pharma- ceutically acceptable salt thereof, and dutasteride, or a pharma- ceutically acceptable salt thereof.

[0201] 32. The fixed dose combination dosage form according to embodiment 31, characterized in that said fixed dose combination dosage form comprises tamsulosin, or a pharma- ceutically acceptable salt thereof, preferably in the form of tamsulosin hydrochloride.

[0202] 33. The fixed dose combination dosage form according to embodiment 32, wherein said tamsulosin is in the form of a modified release tablet.

[0203] 34. The fixed dose combination dosage form comprises the following doses of both components: a dose of tadalafil comprised between 1 mg and 10 mg, preferably between 2 mg and 8 mg, more preferably between 3 mg and 7 mg, even more preferably between 4 mg and 6 mg, and even more preferably about 5 mg; and a dose of tamsulosin comprised between 0.05 mg and 1 mg, preferably between 0.08 mg and 0.8 mg, more preferably between 0.15 mg and 0.65 mg, even more preferably between 0.30 mg and 0.50 mg, even more preferably about 0.4 mg; 34. The fixed dose combination dosage form according to embodiment 32 or 33, characterized in that it is adapted to deliver

[0204] 35. The fixed dose combination dosage form according to any one of embodiments 32-34, wherein the fixed dose combination dosage form is provided in a single dose vial, the tadalafil suspension is contained in the vial, and the tamsulosin is enclosed in the cap.

[0205] 36. The fixed dose combination dosage form according to embodiment 31, wherein said fixed dose combination dosage form comprises dutasteride, or a pharma- ceutically acceptable salt thereof, preferably dutasteride free base.

[0206] 37. The fixed dose combination dosage form according to embodiment 36, wherein the dutasteride is in the form of a powder or granules.

[0207] 38. The fixed dose combination dosage form comprises the following doses of both components: a dose of tadalafil comprised between 1 mg and 10 mg, preferably between 2 mg and 8 mg, more preferably between 3 mg and 7 mg, even more preferably between 4 mg and 6 mg, and even more preferably about 5 mg; and A dose of dutasteride comprised between 0.05 mg and 1.5 mg, preferably between 0.1 mg and 1.0 mg, more preferably between 0.2 mg and 0.8 mg, even more preferably between 0.4 mg and 0.6 mg, and even more preferably about 0.5 mg; 38. The fixed dose combination dosage form according to embodiment 36 or 37, characterized in that it is adapted to deliver

[0208] 39. The fixed dose combination dosage form according to any one of embodiments 36-38, wherein the fixed dose combination dosage form is provided in a single dose vial, the tadalafil suspension is contained in the vial, and dutasteride is enclosed in the cap.

[0209] 40. Next steps: (i) mixing the cyclodextrin, the co-processed MCC-NaCMC, and the xanthan gum with a portion of the total water to obtain a homogenous mixture; (ii) separately mixing tadalafil with another portion of the total water to obtain a homogenous mixture; (iii) adding the mixture of step (ii) above to the mixture of step (i) above; (iv) adding the remainder of the water; and 31. A method for preparing a composition according to any one of embodiments 1 to 30, comprising:

[0210] 41. A composition according to any one of embodiments 1 to 30 or a fixed dose combination dosage form according to embodiments 31 to 39, for use in therapy.

[0211] 42. A composition according to any one of embodiments 1 to 30 for use in the treatment of erectile dysfunction or benign prostatic hyperplasia in men.

[0212] 43. A fixed dose combination dosage form according to any one of embodiments 31-39, for use in the treatment of benign prostatic hyperplasia. EXAMPLES

[0213] Example 1: Suspension composition comprising 1% tadalafil Examples 1A-1D, having a strength of 1% tadalafil, were prepared using the ingredients listed in the table below:

[0214] [Table 1]

[0215] The MCC-NaCMC used was VivaPur MCG811P (JRS Pharma). The tadalafil had a particle size of Dv90 11.2 microns (Compositions 1A-1D) or 10.5 microns (Composition 1E). The cyclodextrin used for Compositions 1A, 1B, 1C and 1D was HBCD (Cluster Dextrin, Glico Nutrition), and for Composition 1E the cyclodextrin was α-cyclodextrin (Cavamax® W6 Pharma, Wacker Chemie AG).

[0216] A similar method was used for the preparation of compositions 1A, 1B, 1C, 1D and 1E, as disclosed below.

[0217] A stainless steel reactor equipped with stirring system was filled with purified water equivalent to about 50% of the final batch, then anhydrous citric acid, sodium citrate, sodium methylparaben, sodium propylparaben, aspartame and cyclodextrin were added stepwise to the reactor with continuous stirring until all were dissolved. After that, MCC-NaCMC and xanthan gum were added slowly and the mixture was properly stirred to activate MCC-NaCMC.

[0218] A second stainless steel reactor equipped with stirring was filled with about 15% of the total water, then SLS and tadalafil were added stepwise under stirring, and the mixture was homogenized under stirring for about 10 minutes. This mixture was mixed with the contents of the first reactor, the reactor was carefully rinsed with water to collect any material attached to the walls, and the remaining water was added to the final volume, maintaining continuous stirring until a uniform suspension was obtained.

[0219] In all four cases, the final product was a white or almost white viscous suspension (230-2550 cPs) with a pH value of approximately 5.7.

[0220] The suspension was filled into 30 ml PET amber bottles fitted with either a pump suitable for dispensing 0.5 ml of suspension per pump stroke or a plug closed with a child resistant cap fitted with a suitable syringe to measure the required volume.

[0221] Example 2: Suspension composition comprising 0.1% tadalafil Examples 2A, 2B and 2C with a strength of 0.1% tadalafil were prepared using the ingredients listed in the table below:

[0222] [Table 2]

[0223] The MCC-NaCMC used in all compositions was VivaPur MCG811P (JRS Pharma). The tadalafil had a particle size of Dv90 11.2 microns.

[0224] The cyclodextrin used for compositions 2A, 2B and 2C was HBCD (Cluster Dextrin, Glico Nutrition), and the cyclodextrin used for composition 2D was α-cyclodextrin (Cavamax® W6 Pharma, Wacker Chemie AG).

[0225] For the preparation of compositions 2A, 2B, 2C, and 2D, the procedure was similar to that described in Example 1.

[0226] In all three cases, the final products were white or almost white viscous suspensions (270-420 cPs).The pH values ​​were around 5.7 for all products (2A, 2B, 2C and 2D).

[0227] Example 3: Fixed-dose combination comprising a 0.1% suspension of tadalafil and a delayed-release tamsulosin tablet A fixed dose combination of tadalafil and tamsulosin was prepared in a single dose vial using the suspension composition of Example 2 and modified release tamsulosin tablets.

[0228] Tamsulosin modified release tablets were prepared similarly as disclosed in WO 2018 / 030862.

[0229] The content of tamsulosin in the final delayed release tablet was 0.125% by weight.

[0230] A temporary single dose vial was filled with 5 ml of the suspension of Example 2A, equivalent to 5 mg of tadalafil. The cap was filled with 320 mg of tamsulosin tablets, equivalent to 0.4 mg of tamsulosin.

[0231] The caps of these temporary single-dose vials were to be pierced immediately prior to administration to allow the tablet to be released into the vial, and the mixture was then gently swirled to homogenize and prepare for easy administration.

[0232] Example 4: Fixed-dose combination comprising a 0.1% suspension of tadalafil and dutasteride A fixed dose combination of tadalafil and dutasteride was prepared in a single dose vial using the suspension composition of Example 2 and a dutasteride powder formulation.

[0233] Dutasteride powder formulations were prepared by vigorously mixing dutasteride (0.125 wt%), anhydrous lactose (about 59-75 wt%), microcrystalline cellulose (about 24-40 wt%) and colloidal silicon dioxide (about 0.5-1.0 wt%).

[0234] A temporary single dose vial was filled with 5 ml of the suspension of Example 2A, equivalent to 5 mg of tadalafil. The cap was filled with 400 mg of the dutasteride powder formulation, equivalent to 0.5 mg of dutasteride.

[0235] The caps of these temporary single dose vials were to be pierced immediately prior to administration to allow the dutasteride powder to be released into the vial, and the mixture was then gently swirled to homogenize and prepare for easy administration.

[0236] Example 5: Dissolution assay of suspensions of the present invention compared to Cialis® film-coated tablets Comparative dissolution assays were performed to evaluate the dissolution behavior of tadalafil in the prepared suspensions compared to Cialis® commercial film-coated tablets.

[0237] For Examples 1A, 1B, 1C and 1D, comparative dissolution assays were performed by placing into a vessel 2 ml of each suspension or, for comparison, one 20 mg Cialis® film-coated tablet.

[0238] For Example 1E, a comparative dissolution assay was performed by placing into a vessel 0.5 ml of the suspension or, for comparison, one 5 mg Cialis® film-coated tablet.

[0239] For Examples 2A, 2B, 2C, and 2D, comparative dissolution assays were performed by placing 5 ml of each suspension or, for comparison, one 5 mg Cialis® film-coated tablet in a container. The comparative assay for Example 2D was performed independently of Examples 2A, 2B, and 2C, and therefore an independent dissolution assay of the reference compound Cialis® was performed for this comparative study.

[0240] For each assay, 900 ml of dissolution medium was used.

[0241] Dissolution media were prepared in each case with purified water and pH adjusted to the following values ​​1.2, 4.5 and 6.8 with HCl (pH 1.2) or acetate buffer (pH 4.5) or phosphate buffer (pH 6.8) + 0.5% SLS, e.g. as disclosed in the European Pharmacopoeia 6.0 (Eur. Phar. 6.0), Chapter 2.9.3: Dissolution Test for Solid Dosage Forms.

[0242] The dissolution assay was performed with stirring at 50 rpm. Samples were taken at the following time points: 0, 5, 10, 15, 20, 30 and 45 minutes and the amount of tadalafil dissolved in the samples was analyzed using HPLC with the equipment and conditions disclosed below:

[0243] [Table 3]

[0244] For each sample, the assay was repeated 6 times and the average value was calculated. For Cialis® film-coated tablets, the dissolution assay was repeated 12 times and the average value was also calculated. The percentage of tadalafil dissolved at each time point under the three pH conditions is summarized in the table below:

[0245] [Table 4]

[0246]

Table 5

[0247]

Table 6

[0248]

Table 7

[0249]

Table 8

[0250]

Table 9

[0251] To quantitatively compare the dissolution similarity between the reference compounds (Cialis® 20 mg film-coated tablets or Cialis® 5 mg film-coated tablets) and the suspension according to the invention, the similarity factor f2 was used, as disclosed in Moore et al., Mathematical comparison of curves with an emphasis on in vitro dissolution profiles, Pharm. Tech., 1996, 20(6), 64-74 or Helmy et al., In vitro dissolution similarity as a surrogate for in vivo bioavailability and therapeutic equivalence, Dissolution Technologies, August 2016, 32-39, and the Guideline on the investigation of bioequivalence CMPM / EWP / QWP / 1401 / 98 Rev. 1.

[0252] As is well known in the art, factor f2 is a measure of the similarity between the dissolution curves obtained from the test and reference products. This factor is calculated from the average of the dissolution profiles at each sampling time point using the following formula:

[0253]

number

[0254] In the above formula: n = number of sampling timings Rt = average percentage of reference drug dissolved at time t Pt = average percentage of test drug dissolved at time t

[0255] Points where the percentage of drug dissolved is greater than 85% are not considered in the f2 calculation.

[0256] Comparisons were made for each sample versus the corresponding reference compound (either Cialis® 5 mg or 20 mg) and each pH value (1.2, 4.5 and 6.8).

[0257] The value of f2 varies from 0 to 100. If the value is 50 or greater, the product is considered to satisfy the similarity factor to the reference product.

[0258] Furthermore, if in the dissolution assay more than 85% of the substance is already dissolved at 15 min in both formulations, there is no need to calculate an exact value for f2 and the similarity factor is also deemed to be satisfied.

[0259] The following table summarizes the values ​​of the similarity factor f2 for the assayed compositions. The value "nc" means that the similarity factor f2 was not calculated since more than 85% dissolution was already achieved at 15 min.

[0260] [Table 10]

[0261] It can be observed that for all suspensions assayed, the similarity factor is satisfied for at least two of the three pH conditions assayed, as the value of f2 is greater than 50 or greater than 85% dissolution is achieved at 15 minutes.

[0262] Example 6: Stability Assay The compositions of Example 1 (1A, 1B, 1C, 1D, and 1E) and Example 2 (2A, 2B, 2C, and 2D) were tested for stability and to this end were stored at 25° C.±2° C. and 60%±5% relative humidity (RH) for up to 9 months in some cases, and at 40° C.±2° C. and 75%±5% RH for up to 6 months in all of them. Samples of each composition were analyzed for tadalafil, tadalafil-related substances, and other impurities by HPLC with UV detection after 1, 3, 6, and 9 months. Other stability parameters were also assessed in the assays as appearance, viscosity, pH, microbiology, preservative content, and tadalafil dissolution.

[0263] All test samples were found to meet the required stability criteria.

Claims

1. a) tadalafil in an amount between 0.01% (w / v) and 5% (w / v); b) a cyclodextrin; and c) co-processed microcrystalline cellulose and sodium carboxymethyl cellulose (MCC-NaCMC); d) xanthan gum; e) water; and 1. A pharmaceutical composition for oral administration in the form of an aqueous suspension comprising:

2. 2. The composition of claim 1, wherein the amount of tadalafil is comprised between 0.02% (weight / volume) and 2.0% (weight / volume).

3. The composition of claim 1, wherein the amount of said cyclodextrin is comprised between 0.01% (wt / vol) and 0.25% (wt / vol).

4. 4. The composition of claim 3, wherein the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, highly branched cyclodextrin (HBCD), and mixtures thereof.

5. The composition of claim 4, wherein the cyclodextrin is selected from α-cyclodextrin and β-cyclodextrin.

6. 2. The composition of claim 1, wherein the amount of the co-processed CMC-NaCMC is 0.5% (wt / vol) to 2.0% (wt / vol).

7. The composition of claim 1, wherein the amount of xanthan gum is comprised between 0.10% (w / v) and 1.50% (w / v).

8. The composition of claim 1, wherein the composition comprises a surfactant in an amount comprised between 0.010% (wt / vol) and 0.100% (wt / vol).

9. The composition of claim 8, wherein the surfactant is sodium lauryl sulfate.

10. The composition of claim 1 , wherein the composition comprises a preservative.

11. 2. The composition of claim 1, wherein the composition comprises a pH adjuster for adjusting the pH of the composition to a value comprised between 2.5 and 7.

12. 12. The composition of claim 11, wherein the pH adjuster is a buffer that is a citrate buffer, an acetate buffer, a citrate phosphate buffer, a Tris buffer, or a phosphate buffer.

13. 13. A fixed-dose combination dosage form comprising the tadalafil aqueous suspension of any one of claims 1 to 12 and a second drug selected from tamsulosin or a pharmaceutically acceptable salt thereof and dutasteride or a pharmaceutically acceptable salt thereof.

14. 14. The fixed dose combination dosage form of claim 13 comprising tamsulosin.

15. The fixed-dose combination dosage form of claim 14, comprising tamsulosin hydrochloride in the form of a modified-release tablet.

16. Next steps: (v) mixing the cyclodextrin, co-processed MCC-NaCMC, and xanthan gum with a portion of the total water to obtain a homogeneous mixture; (vi) separately mixing tadalafil with another portion of the total water to obtain a homogeneous mixture; (vii) adding the mixture of step (ii) to the mixture of step (i); (viii) adding the remainder of the water; A method for preparing a composition according to any one of claims 1 to 12, comprising:

17. A composition according to any one of claims 1 to 12 for use in therapy.

18. A fixed-dose combination dosage form according to claim 13 for use in therapy.

19. A composition according to any one of claims 1 to 12 for the treatment of male erectile dysfunction or benign prostatic hyperplasia.

20. A fixed-dose combination dosage form as described in claim 13 for the treatment of benign prostatic hyperplasia.