WO2023232215A1

WO2023232215A1 - Improved pharmaceutical composition containing tadalafil and process for the preparation thereof

Info

Publication number: WO2023232215A1
Application number: PCT/EP2022/000051
Authority: WO
Inventors: Agni GRYPIOTI; George Papandreou; Panagiotis TSITSAS
Original assignee: Pharos Ltd; Rontis Hellas SA
Current assignee: Pharos Ltd; Rontis Hellas SA
Priority date: 2022-06-02
Filing date: 2022-06-02
Publication date: 2023-12-07
Anticipated expiration: 2024-12-02

Abstract

The present invention relates to an improved pharmaceutical composition comprising a therapeutically effective quantity of tadalafil or a pharmaceutically acceptable salt or derivative thereof, as an active ingredient and an effective quantity of non-ionic water dispersible surfactant as a solubilizing enhancing agent to effectively increase drug release, aqueous solubility and oral bioavailability.

Description

IMPROVED PHARMACEUTICAL COMPOSITION CONTAINING TADALAFIL AND PROCESS FOR THE PREPARATION THEREOF TECHNICAL FIELD OF THE INVENTION

The present invention relates to an improved pharmaceutical composition for oral administration, and in particular to a chewable pharmaceutical composition comprising a therapeutically effective quantity of tadalafil or a pharmaceutically acceptable salt or derivative thereof, as an active ingredient, and an effective quantity of a non-ionic water dispersible surfactant as solubilizing agent in order to improve the solubility, bioavailability and onset of action of said active ingredient. Furthermore, the present invention relates to a process for the preparation of said pharmaceutical composition.

BACKGROUND OF THE INVENTION

Erectile dysfunction (ED) can have a range of causes, both physical and psychological. Possible physical causes include heart disease, diabetes, high blood pressure (hypertension) and hormonal problems. Possible psychological causes include stress, anxiety, depression, and relationship problems. ED is treatable at any age, and awareness of this fact has been growing. Oral phosphodiesterase-5 inhibitors (PDE-5 inhibitors) have become the preferred first-line treatment for erectile dysfunction worldwide. PDE-5 inhibitors are competitive inhibitors of phosphodiesterase type 5 (PDE-5), an enzyme that breaks down cyclic guanosine monophosphate (cGMP) in various tissues, the second messenger of Nitric Oxide (NO). By inhibiting cGMP breakdown, PDE-5 inhibitors enhance the vasodilatory effect of NO and restore the ability to achieve an erection in patients with erectile dysfunction.

Tadalafil, is a potent and selective PDE-5 inhibitor, a secondary messenger for the smooth muscle relaxing effects of NO, which plays an important role in the vasodilation of erectile tissues.

Tadalafil has the IUPAC name of pyrazino[l',2':l,6]pyrido[3,4-b]indole-l, 4-dione, _6-(l,3- benzodioxol-5-yl)-2,3,6,7,12,12a- hexahydro-2-methyl-, (6R,12aR). It is a crystalline solid, practically insoluble in water and very slightly soluble in ethanol.

Tadalafil is commercially available under the brand name Cialis® (a film-coated, almond-shaped tablet for oral administration). Each tablet contains 2.5, 5, 10, or 20 mg of Tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

Tadalafil is well absorbed after oral administration with a mean maximum observed plasma concentration (Cmax) of 378 ng/mL after oral administration of the 20-mg tablet. Cmax is achieved at a mean time of 2 hours after dosing. Tadalafil mean volume of distribution is approximately 63 L, with a mean half-life of 17.5 hours in healthy subjects.

The aqueous solubility of an active ingredient is one of the most important physicochemical properties as low aqueous solubility and low dissolution rate can reduce the active ingredient absorption in the gastro-intestinal tract. Low active ingredient solubility also directs to decreased bioavailability, increased chance of food effect, more frequent incomplete release from the dosage form and higher interpatient variability.

Poorly water soluble active ingredients, namely compounds having solubility in water below 0.1 mg/ml, consist a large majority of the pharmaceutical active ingredients, thereby limiting their potential uses and increasing the difficulty of formulating bioavailable pharmaceutical products. Poorly soluble active ingredients have stimulated the development of active ingredient delivery technologies to overcome the obstacles to their solubilization through either chemical or mechanical modification of the environment surrounding the active ingredient molecule, or physically altering the macromolecular characteristics of aggregated active ingredient particles. These technologies include both traditional methods of solubility enhancement, such as particle size reduction, addition of surfactants and inclusion in cyclodextrin-active ingredient complexes, and the use of more novel mechanisms such as self-emulsifying systems, micronisation via nanoparticles, pH adjustment and salting-in processes.

Various methods are already known for the industrial preparation of dosage forms comprising Tadalafil as a pharmaceutically active ingredient, due to its useful therapeutic properties. However, the prior art has encountered substantial difficulties in the production of oral solid formulations of a desirable bioavailability because of the very poor solubility of said active ingredient.

EP-B-0828479 relates to a solid dispersion comprising Tadalafil and a carrier or excipient thereof and a manufacturing process comprising the co-precipitating of the poorly water soluble drug and the carrier or excipient.

EP-A- 1200090 refers to a pharmaceutical formulation comprising Tadalafil in “free drug” (not intimately embedded in a polymeric co-precipitate) form in a mixture with a diluent, lubricant, a hydrophilic binder, and a disintegrant.

EP-B- 1200092 claims a pharmaceutical composition comprising a free drug form of Tadalafil, salts and solvates thereof and at least one carrier, diluent or excipient, in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate and wherein at least 90 % of the particles have a particle size of <40 microns

Although each of the patents above represents an attempt to provide an improved solid dosage form of Tadalafil,. there still exists the need for a pharmaceutical composition which overcomes the related problems of low aqueous solubility and bioavailability of said active ingredient,

SUMMARY OF THE INVENTION

It is therefore, an object of the present invention to provide an improved solid pharmaceutical composition for oral administration comprising Tadalafil as an active ingredient, which is bioavailable, with sufficient shelf-life and good pharmacotechnical properties.

Another aspect of the present invention is to achieve a solid immediate release formulation for oral administration comprising Tadalafil as an active ingredient, with improved solubility and bioavailability characteristics which further may exhibits a faster therapeutic onset compared to the commercially available product Cialis® (reference product). Moreover, it is another object of the present invention to provide a suitable process for the preparation of an immediate release pharmaceutical composition for oral administration comprising a therapeutically effective quantity of Tadalafil or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, which is cost effective and reproducible.

A further aspect of the present invention is to afford a method for the preparation of a solid pharmaceutical composition for oral administration which overcomes the difficulties encountered in pharmaceutical production because of the low solubility of Tadalafil.

In accordance with the above objects of the present invention, a pharmaceutical composition for oral administration, preferable chewable pharmaceutical composition is provided comprising a therapeutically effective quantity of Tadalafil or a pharmaceutically acceptable salt or derivative thereof, as an active ingredient and an effective quantity of a non-ionic water dispersible surfactant as a solubilizing agent in order to improve the solubility, bioavailability and onset of action of the active ingredient in the finished dosage form. According to another embodiment of the present invention, a process for the preparation of a pharmaceutical dosage form for oral administration comprising a therapeutically effective quantity of Tadalafil or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and an effective quantity of a non-ionic water dispersible surfactant as a solubilizing agent in order to improve the solubility, bioavailability and onset of action of the active ingredient in the finished dosage form, is provided, wherein said process comprises the following steps:

1. Dispensing of active ingredient: Weight individually the active ingredient (Tadalafil) and sieve through appropriate sieve.

2. Melting: Weight individually a solubilizing agent such as Lauroyl macrogol-32 glycerides mixture and melt it at temperature 75°C.

3. Melt mixing: Add sieved active ingredient from step 1 to the molten liquid obtained from step 2, and mix for appropriate time.

4. Dispensing and sieving of intra-granular excipients: Weight and mix diluents Lactose Monohydrate and Microcrystalline Cellulose and sieve through appropriate sieve. 5. Loading: Add the intra-granular excipients in a high shear mixer granulator and load the active ingredient dispersion in molten liquid mixture of Lauroyl macrogol-32 glycerides from step 3 on the intra-granular excipients, and mix until a homogenized waxy mixture is obtained and allow granules to cool down.

6. Sizing: Pass the granules obtained from step 5 to an appropriate sieve. 7. Dispensing and sieving of extra-granular excipients: Weigh Hydroxypropyl Cellulose-SL,

Croscarmellose Sodium, colloidal silicon dioxide, Aspartame, Sodium Lauryl Sulfate and Flavour Peppermint and sieve through appropriate sieve.

8. Mixing: Mix the granules obtained from step 6 with the extra-granular excipients from step 7 for appropriate time. 9. Lubrication: Weight individually Magnesium Stearate, sieve it through appropriate sieve and mix with the blend obtained from step 8 for appropriate time.

10. Compression: Compress the homogeneous powder obtained from step 9 in tablets in a rotary tabletting machine using appropriate punches.

Further preferred embodiments of the present invention are defined in dependent claims 2 to 6. Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 : Comparative dissolution profiles of composition 3 of the present invention comprising a solubilizing agent and composition 3a that does not comprise any solubilizing agent.

Fig. 2: Comparative dissolution profiles of the pharmaceutical composition 3 of the present invention and reference product at 50 rpm in water containing a surfactant to provide sink condition.

Fig. 3: Comparative dissolution profiles of the pharmaceutical composition 3 of the present invention and reference product at 50 rpm and under FED conditions.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient (Tadalafil) is considered to be improved if said composition achieves increased solubility, bioavailability and earlier therapeutically effective drug concentration than the known pharmaceutical formulations of Tadalafil.

A major object of the present invention is to provide a solid immediate release formulation of Tadalafil which is simple to manufacture, cost effective, posses good pharmacotechnical properties and linearity.

Another aspect of the present invention is to provide an immediate release formulation of Tadalafil in the form of a chewable tablet, which reaches the minimum effective drug concentration in plasma in a shorter period than the commercially available product Cialis® (hereafter referred to as reference product).

It has been surprisingly found that the object of the present invention is achieved by employing a novel technological platform such as melt granulation process combined with a non-ionic water dispersible surfactant, as a solubilizing agent, such as Lauroyl macrogol-32 glycerides mixture.

The use of said melt granulation process in combination with Lauroyl macrogol-32 glycerides mixture as solubilizing agent has been found to increase the aqueous solubility and oral bioavailability of poorly water soluble drug Tadalafil. Water-miscible surfactant molecules contain both a hydrophobic and hydrophilic portion and can solubilize many poorly water- soluble drugs. Surfactants can also self-assemble to form micelles once the surfactant monomer concentration reaches the critical micelle concentration. Thus, surfactants can solubilize drug molecules by either a direct cosolvent effect or by uptake into micelles.

In the present invention, the active ingredient is suspended in a molten liquid solution comprised of Lauroyl macrogol-32 glycerides mixture and subsequently loaded on intra-granular excipients. The granules pass through appropriate sieve, mixed with extra granular excipients and lubricant. The mixture is compressed into tablets. The water-miscible surfactant molecules containing both a hydrophobic and hydrophilic portion can solubilize many poorly water-soluble drugs which directly correlates to an increase in dissolution rate and bioavailability which is the greatest contribution to the object of the present invention.

Furthermore, in the present invention the melt granulation process combined with Lauroyl macrogol-32 glycerides mixture as a solubilizing enhancing agent has been applied for enhancing solubility, dissolution rates and bioavailability of Tadalafil active pharmaceutical ingredient in solid dosage forms. Melt granulation is a process by which pharmaceutical powders are efficiently agglomerated by the use of a binder which can be a molten liquid, a solid or a solid that melts during the process. For accomplishing this process, apparatus of choice are the high shear mixers, where the product temperature is raised above the melting point of the binder, by a heating jacket or, when the impeller speed is high enough, by the heat of friction generated by the impeller blades or even by melting the binder externally and preparing a suitable dispersion solution with the aim to be added in the high shear mixer.

Lauroyl macrogol-32 glycerides mixture is a well-characterized, safe excipient which conforms to the USP-NF and EP pharmacopoeias and is a waxy solid with low melting point and a suitable candidate for the process of melt granulation. Lauroyl macrogol-32 glycerides is also a solubilizing agent, non-ionic water dispersible surfactant recommended for use in lipid-based formulations to increase the aqueous solubility and oral bioavailability of poorly water soluble drugs. Water-miscible surfactant molecules contain both a hydrophobic and hydrophilic portion and can solubilize many poorly water-soluble drugs. Surfactants can also self-assemble to form micelles once the surfactant monomer concentration reaches the critical micelle concentration. Thus, surfactants can solubilize drug molecules by either a direct cosolvent effect or by uptake into micelles.

The pharmaceutical compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions (tablet/capsule compositions).

Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, glidants, lubricants, flavors, water scavengers, colorants, sweetener, coating agents and preservatives.

The optional excipients must be compatible with Tadalafil or salt, metabolite or derivative thereof so that it does not interfere with it in the composition.

Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the shelf-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability and palatability.

The composition of the present invention may include further additives (alone or in a combination) such as absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, ciystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH control agents, plasticizers, retarding agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers etc.

Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 10-90 weight % of the total weight of the composition.

Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, , sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1-4’0 weight % of the total weight of the composition.

Disintegrants may be selected from alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate (SLS), sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 0.1 - 25 weight % of the total weight of the composition.

Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.

Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.01-2 weight % of the total weight of the composition.

Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame and the like.

Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavor, peppermint flavor and the like.

Solubilizers may be selected from sodium lauryl sulphate or complex forming agents such as cyclodextrins, ion exchange resins, crown ethers and mixture of Polyoxylglyceride and the like.

All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated.

According to the present invention the manufacturing process used for the preparation of a pharmaceutical dosage form for oral administration comprising a therapeutically effective quantity of Tadalafil or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and an effective quantity of a non-ionic water dispersible surfactant as a solubilizing agent in order to enhance the solubility, bioavailability and onset of action of the active ingredient in the finished dosage form, comprises the following steps:

2. Melting: Weight individually the solubilizing agent, such as Lauroyl macrogol-32 glycerides mixture and melt it at temperature 75°C.

4. Dispensing and sieving of intra-granular excipients: Weight and mix Lactose Monohydrate and Microcrystalline Cellulose and sieve through appropriate sieve. 5. Loading: Add the intra-granular excipients in a high shear mixer granulator and load the active ingredient dispersion in molten liquid mixture of Lauroyl macrogol-32 glycerides from step 3 on the intra-granular excipients, and mix until a homogenized waxy mixture is obtained and allow granules to cool down.

6. Sizing: Pass the granules obtained from step 5 to an appropriate sieve.

7. Dispensing and sieving of extra-granular excipients: Weigh Hydroxypropyl Cellulose-SL, Croscarmellose Sodium, colloidal silicon dioxide, Sodium Lauiyl Sulfate, Aspartame and Flavour Peppermint and sieve through appropriate sieve.

8. Mixing: Mix the granules obtained from step 6 with the extra-granular excipients from step 7 for appropriate time.

9. Lubrication: Weight individually Magnesium Stearate, sieve it through appropriate sieve and mix with the blend obtained from step 8 for appropriate time.

The pharmaceutical compositions of the present invention may optionally be prepared by fluid bed granulation process.

The immediate release pharmaceutical composition of the present invention comprising Tadalafil as an active ingredient has been compared to reference product Cialis® consisting of Tadalafil with the following excipients croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

The pharmaceutical compositions according to the present invention are characterized by excellent pharmacotechnical properties, such as homogeneity, flowability and compressibility. Thanks to these properties, the solid dosage forms prepared by the process according to the present invention exhibit excellent technical characteristics including dissolution rate, hardness, stability, taste and bioavailability.

One of the most critical pharmacotechnical tests is the Dissolution test as it is strongly correlated with the bioavailability of.the product. For the dissolution method a Paddle Apparatus was used at rotation speed 50rpm, in aqueous dissolution medium with 0.4%SLS.

The following table 1 below illustrates the results of the solubility studies of composition 3 of the present invention and the reference product dissolved in aqueous medium with 0.4% SLS.

As it is shown in Tablet 1, composition 3 according to the present invention has enhanced dissolution rate in comparison to reference product, thereby providing an in vitro release of Tadalafil as depicted in Fig. 2. Table 1: Comparative dissolution results of Composition 3 and reference product

One of the main objects of the present invention was to prepare a product with acceptable stability. For this reason, composition 3 was exposed to normal and accelerated stability studies according to the current ICH guidelines.

The results showed that the stability of the present invention was good (e.g. total impurities were not increased throughout normal and accelerated conditions).

The selection of appropriate materials (excipients, reagents etc.) should be done carefully in order to avoid any incompatibility problems or non-compliance with EMA and FDA guidelines for inactive ingredients.

The tablets may be chewable, film coated with functional or non-functional coating.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:

EXAMPLES

Example 1: Tadalafil composition 1 according to the present invention.

Composition 1 of the present invention is illustrated in TABLE 2 below.

Composition 1 comprises Tadalafil and Lauroyl macrogol-32 glycerides mixture as solubilizing agent, wherein the weight ratio of Tadalafil to Lauroyl macrogol-32 glycerides mixture is 1 : 1. TABLE 2: Tadalafil composition 1

Chewable tablets of composition 1 of Example 1 were prepared according to the following manufacturing process:

At a first stage, Tadalafil as active pharmaceutical ingredient was weighted individually and passed through appropriate sieve. Solubilizing agent Lauroyl macrogol-32 glycerides mixture was weighted individually and then, melted at temperature of about 75°C. The sieved Tadalafil, was added in the molten liquid of the solubilizing agent and mixed for appropriate time until fully dispersed.

At a second stage, the intra-granular excipients Lactose Monohydrate and Microcrystalline Cellulose as diluents were weighted, sieved, and transferred in a high shear mixer granulator. Subsequently, the Tadalafil dispersion is loaded onto the intra-granular excipients and the obtained granules were left to cool down and then passed through an appropriate sieve. The extra-granular excipients Hydroxypropyl Cellulose-SL as binder , Croscarmellose Sodium as disintegrant, colloidal silicon dioxide (Aerosil™ 200) as glidant, Sodium Lauryl Sulfate as solubiliser, Aspartame as sweetener and Flavor Peppermint as flavor were weighted, sieved and mixed together with the granules obtained from the second stage for appropriate time until complete homogeneity. Magnesium stearate as lubricant was weighted sieved and mixed with the mixture obtained from previous stage. The resulting powder was compressed in tablets in a rotary tabletting machine using appropriate punches. The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications

Example 2: Tadalafil composition 2 according to the present invention is illustrated in TABLE 3 below Composition 2 comprises Tadalafil and Lauroyl macrogol-32 glycerides mixture as solubilizing agent, wherein the weight ratio of Tadalafil to Lauroyl macrogol-32 glycerides mixture is 1:2.

TABLE 3: Tadalafil composition 2

Chewable tablets of composition 2 of Example 2 according to the present invention were prepared according to the same manufacturing process as described in composition 1 of Example 1.

The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications. Example 3: Tadalafil composition 3 according to the present invention is illustrated in TABLE 4 below.

Composition 3 comprises Tadalafil and Lauroyl macrogol-32 glycerides mixture as solubilizing agent, wherein the weight ratio of Tadalafil to Lauroyl macrogol-32 glycerides mixture is 1 :3.

TABLE 4: Tadalafil composition 3

Chewable tablets of composition 3 of Example 3 according to the present invention were prepared according to the same manufacturing process as described in composition 1 of Example 1.

The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications. For comparative purposes, composition 3a comprising Tadalafil and the same excipients as composition 3 of the present invention, however without non-ionic water dispersible surfactant, Lauroyl macrogol-32 glycerides mixture as solubilizing agent is prepared by using dry blending process instead of the application of solubilising agent on the active pharmaceutical ingredient and using melt granulation process. The manufacturing process of composition 3a comprises the following steps: Weight individually the active ingredient (Tadalafil) and Microcrystalline Cellulose and pass them through the appropriate sieve. Mix Tadalafil and Microcrystalline Cellulose for appropriate time. The obtained mixture is mixed with the following pre-lubrication blend excipients: Lactose Monohydrate, Hydroxypropyl Cellulose-SL, Sodium Lauryl Sulfate (SLS), Croscarmellose Sodium, Aspartame and Flavour Peppermint for appropriate time. Subsequently, the obtained blend is mixed with Magnesium Stearate for appropriate time and the final obtained homogeneous powder is compressed in tablets.

The comparative solubility studies of composition 3 of the present invention comprising a nonionic water dispersible surfactant as a solubilizing agent and composition 3 a comprising no solubilizing agent and prepared by dry blending process are shown in Fig. 1. The results indicate that composition 3 of the present invention has a significantly higher drug release rate when compared with composition 3a when tested with the same dissolution method, which is also the Quality Control dissolution method, a method adequate to distinguish the good from bad composition. More than 90% of the drug of composition 3, is released within lOmin using a nonionic water dispersible surfactant as solubilizing agent while about 70% is released within 10 min of composition 3 a without any solubilizing agent and when a conventional process such as dry blending process is used.

Furthermore, the dissolution profile of composition 3 of the present invention was tested at several aqueous buffers and compared with the reference product. As it is shown in Fig. 2, composition 3 of the present invention has enhanced dissolution profile compared to the reference product when tested with the same dissolution method.

In addition, composition 3 of the present invention and the reference product were tested at several dissolution conditions simulated those that could exist at the gastrointestinal tract. According to the dissolution results as shown in Fig. 3, the enhanced release profile of composition 3 compared to the reference product is also confirmed at FED conditions. Bioequivalence at FED conditions between composition 3 and reference product has also been proved and dissolution profiles at pH=4.5 provides data to support that.

Example 4: Tadalafil composition 4 according to the present invention is illustrated in TABLE 5 below.

Composition 4 comprises Tadalafil and Lauroyl macrogol-32 glycerides mixture as solubilizing agent, wherein the weight ratio of Tadalafil to Lauroyl macrogol-32 glycerides mixture is 1 :5.

Chewable tablets of composition 4 of Example 4 according to the present invention were prepared according to the same manufacturing process described in composition 1 of Example 1.

The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications. TABLE 5: Tadalafil composition 4

The dissolution test of compositions 1, 2, 3 and 4 of the present invention have been performed under the same conditions as in table 1. TABLE 5: Comparative dissolution results of Compositions 1, 2, 3 and 4 of the present invention and reference product

The dissolution profiles of the compositions 3 and 4 of the present invention in table 5 indicate that Tadalafil solid dosage formulation prepared with solubilizing excipient Lauroyl macrogol- 32 glycerides mixture and melt granulation process are enhanced than the dissolution profile of reference product.

According to the present invention the use of Lauroyl macrogol-32 glycerides mixture as a dissolution enhancing agent in combination with the melt granulation process, facilitates the drug release and increases the bioavailability of the active ingredient.

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

1. An immediate release oral solid dosage form, preferably chewable pharmaceutical composition for oral administration comprising a therapeutically effective quantity of tadalafil or a pharmaceutically acceptable salt, or derivative thereof, as an active ingredient and an effective quantity of a non-ionic water dispersible surfactant as a solubilizing agent in order to increase the drug release, aqueous solubility and oral bioavailability of the active ingredient in the dosage form.

2. The pharmaceutical composition according to claim 1, wherein said solubilizing agent is Lauroyl macrogol-32 glycerides mixture.

3. The pharmaceutical composition according to claim 1, wherein the weight ratio of Tadalafil to Lauroyl macrogol-32 glycerides mixture as solubilizing agent is from 1 :3 to 1 :5.

4. The pharmaceutical composition according to claim 1, wherein it further comprises at least one pharmaceutically acceptable excipient as diluent, selected from Lactose Monohydrate and Microcrystalline cellulose in an amount of 50% -60%.

5. The pharmaceutical composition according to claim 1, wherein it further comprises at least one pharmaceutically acceptable excipient as disintegrant, such as Croscarmellose Sodium in an amount of 5%- 10%.

6. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition further comprises pharmaceutically acceptable additives selected from a group comprising of absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH control agents, plasticizers, retarding agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers and their combinations thereof.

7. A process for the preparation of a pharmaceutical dosage form for oral administration comprising a therapeutically effective quantity of Tadalafil or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and an effective quantity of a non-ionic water dispersible surfactant as a solubilizing agent in order to improve the solubility, bioavailability and onset of action of the active ingredient in the finished dosage form, wherein said process comprises the following steps:

2. Melting: Weight individually the solubilizing agent, such as Lauroyl macrogol-32 glycerides . mixture and melt it at temperature 75°C.

3. Melt mixing: Add sieved active ingredient from step 1 to the molten liquid obtained from step

2, and mix for appropriate time.

4. Dispensing and sieving of intra-granular excipients: Weight and mix Lactose Monohydrate and Microcrystalline Cellulose and sieve through appropriate sieve. - 5. Loading: Add the intra-granular excipients in a high shear mixer granulator and load the active ingredient dispersion in molten liquid mixture of Lauroyl macrogol-32 glycerides from step 3 on the intra-granular excipients, and mix until a homogenized waxy mixture is obtained and allow granules to cool down.

6. Sizing: Pass the granules obtained from step 5 to an appropriate sieve.

7. Dispensing and sieving of extra-granular excipients: Weigh Hydroxypropyl Cellulose-SL, Croscarmellose Sodium, colloidal silicon dioxide, Sodium Lauryl Sulfate, Aspartame and Flavour Peppermint and sieve through appropriate sieve.