The present invention relates to pharmaceutical formulations comprising tadalafil that shall be used in the treatment of erectile dysfunction.

The present invention further relates to effervescent form of tadalafil.

Tadalafil was first disclosed in the application numbered W09519978. In said document, it was disclosed that use of tadalafil is effective in the treatment of erectile dysfunction.

Tadalafil is available in 5 mg, 10 mg and 20 mg tablet forms on the market.

However, these dosage forms existing in the prior art are disadvantageous for pediatric and geriatric patients and for those who have swallowing difficulties. Furthermore, they are not preferred by most of the patients. An alternative for removing this problem is to formulate the pharmaceutical composition in effervescent form.

The most frequently encountered problem when preparing tadalafil in effervescent form is that tadalafil is a molecule which is insoluble in water and slightly soluble in alcohol. It has been seen that effervescent formulations comprising the active agent tadalafil having low solubility dissolve slowly when they are put in water during use and some part of the formulation remains without dissolving and therefore a homogeneous solution cannot be obtained. This reduces absorption and bioavailability of tadalafil and therefore the patient cannot take sufficient active agent required for an efficient treatment.

It is apparent that since effervescent formulations are used as dissolved preferably in a glass of water or in another liquid, water solubility of the formulations is a significantly important parameter in order to provide an effective treatment and therefore bioavailability. Various methods were tried in order to increase water solubility of the active agent in the prior art. For instance, substances such as hyper-branched polymers and ethyl cellulose were used. Some problems like low bioavailability of tadalafil due to its low solubility in water were emphasized in the patent application numbered WO2010099323 and crystalline molecular complexes comprising tadalafil were used in order to solve said problems. In said document, pharmaceutical formulations comprising crystalline molecular complexes of tadalafil and formulated in different dosage forms (for instance, effervescent formulations) to be delivered to human body via different routes were disclosed. However, it has been observed that when these effervescent formulations comprising said crystalline molecular complexes of tadalafil are put into water, they do not dissolve entirely and therefore bioavailability is low.

According to this, there is still need for new approaches and solutions in order to develop effervescent formulations comprising tadalafil which can dissolve in water quickly when put into water during use and which enable to obtain a homogeneous solution wherein the active agent tadalafil has a high absorption and bioavailability.

The inventors have surprisingly seen that in the case that the average particle size (d ₅₀ value) of the active agent tadalafil in the effervescent formulations comprising tadalafil obtained is in the range of 5- 50 μηι, said formulations disperse quickly and easily when they are put into water, and they have a high active agent absorption and bioavailability and therefore an effective treatment is provided.

The subject of the present invention is that the average particle size (d ₅₀ value) of tadalafil used as the active agent in the effervescent formulation comprising tadalafil is in the range of 5- 50 μιη.

Another characteristic feature of the formulations according to the present invention is that the average particle size of the active agent tadalafil is preferably in the range of 10- 40 μιη, more preferably in the range of 12- 30 μιη.

Tadalafil comprised in the formulations of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in amorphous or crystalline form or a combination thereof in terms of polymorphic structure. The characteristic feature of the effervescent formulations of the present invention is that said formulations are in effervescent powder, effervescent tablet and effervescent granule form. The formulations are preferably in effervescent tablet form.

The characteristic feature of the effervescent formulations of the present invention is that said formulations comprise tadalafil in the range of 0.01-10%, preferably in the range of 0.05-5%, more preferably in the range of 0.1- 3%.

During preparation of the effervescent formulations comprising tadalafil, particle size of the active agent tadalafil is one of the major factors leading to failure in providing tablet weight and content uniformity in the case that said formulations do not have proper flow characteristics and thus they are compressed in tablet form. The inventors have found that the fact that d ₁₀ :d ₅₀ ratio and d ₅₀ :d9 ₀ ratio are in optimum ranges is an important parameter to obtain good flow characteristics and to provide weight and content uniformity of the tablets obtained during compressing the effervescent formulations comprising the active agent tadalafil in tablet form.

According to this, a preferred embodiment of the present invention is that d ₁₀ :d ₅₀ ratio of the active agent tadalafil is in the range of 2:1 to 1:15, preferably in the range of 1 :1 to 1:10 and dio:d ₅ o ratio of the active agent tadalafil is in the range of 5:1 to 1 :5, preferably in the range of 2:1 to 1:4.

The term "d ₅₀ " used herein signifies that half of the said substance by volume has a particle size below the value stated with d ₅₀ and the other half of the substance by volume has a particle size over the value stated with d _50.

The term d ₁₀ used herein signifies that 10% of the said substance by volume has a particle size below the value stated with d ₁₀ and the rest of the substance has a particle size over the value stated with d ₁₀ .

The term d ₉₀ used herein signifies that 90% of the said substance by volume has a particle size below the value stated with d ₉₀ and the rest of the substance has a particle size over the value stated with d ₉₀ . d ₅₀ , d ₁₀ , d ₉₀ values can be measured by one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.). Another characteristic feature of the effervescent formulations of the present invention is that said formulations comprise at least one pharmaceutically acceptable excipient along with tadalafil.

The pharmaceutically acceptable excipients that can be used in the effervescent formulations of the present invention can be selected from a group comprising effervescent acid, effervescent base, binder, filling agent, sweetener, flavouring agent, coloring agent and anti- foaming agent.

The effervescent formulations comprising tadalafil according to the present invention, characterized in that the filling agent to be used is in the range of 1 -20%, preferably in the range of 2-18%, more preferably in the range of 5-15% in proportion to total formulation.

The filling agent that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from a group comprising D-mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate, anhydrous, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and combinations thereof. Preferably maltodextrin is used as the filling agent in the formulations.

The effervescent acid that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid and tartaric acid or a combination thereof.

The effervescent base that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from a group comprising sodium bicarbonate, sodium citrate dihydrate, sodium hydroxide or combinations thereof.

The binder that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, sorbitol, methylcellulose, povidone.

The sweetener that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from a group comprising acesulfame potassium, aspartame, fructose, maltitol, xylitol, saccharin, sodium cyclamate, sucralose, sucrose. The flavouring agent that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from menthol, methane, anethole, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, lemon, orange, strawberry, blackberry or combinations thereof

The colouring agent that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from titanium dioxide, chlorophyll, yellow iron oxide, other synthetic iron oxides, beta-carotene or combinations thereof.

The anti-foaming agent that can be used in the effervescent formulations of the present invention and comprising tadalafil can be selected from polydimethylsiloxane, simethicone, other silicones, stearates, alcohols, glycols or combinations thereof.

The effervescent formulations of the present invention comprising tadalafil, characterized in that the amount of the active agent is in the range of 0.01-10%, effervescent acid in the range of 1-80%, effervescent base in the range of 1-70%, binder in the range of 1-30%, sweetener in the range of 1-30%, flavouring agent in the range of 0.1-10%, colouring agent in the range of 0.01-10%, anti-foaming agent in the range of 0.001-2% in proportion to total formulation.

The method for preparation of the effervescent formulations of the present invention and comprising tadalafil can be composed of the following steps:

I. The effervescent acid, the effervescent base, the binder, the sweetener and the filling agent are mixed and granulated with the granulation solution comprising tadalafil. The granulation solution used herein can comprise a solvent in addition to tadalafil.

II. The granules obtained in the I ^st step are dried and sieved.

III. The flavouring agent, the colouring agent and the anti foaming agent are added into the granules obtained in the II ^nd step and final mixture is obtained.

IV. The final mixture obtained is compressed in tablet form or filled into the sachets.

The pharmaceutical formulation according to the present invention can be used in prevention and treatment of erectile dysfunction. EXAMPLES

Example 1: Formulation and process for preparation of tadalafil effervescent tablet

a) The effervescent acid, the effervescent base, the binder, the sweetener and maltodextrin are mixed and granulated with the granulation solution comprising tadalafil. b) The granules obtained in the II ^nd step are dried and sieved. c) The flavouring agent, the colouring agent and the anti-foaming agent are added into the granules in the II ^nd step and the final mixture is obtained. d) The final mixture obtained is compressed in tablet form or filled into sachets.