WO2023227185A1

WO2023227185A1 - Improved pharmaceutical composition containing tadalafil and nanomilling process for the preparation thereof

Info

Publication number: WO2023227185A1
Application number: PCT/EP2022/000049
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: 2022-05-27
Filing date: 2022-05-27
Publication date: 2023-11-30
Anticipated expiration: 2024-11-27
Also published as: EP4531815A1

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 the application of nanomilling process to effectively reduce the particle size of Tadalafil.

Description

IMPROVED PHARMACEUTICAL COMPOSITION CONTAINING TADALAFIL AND NANOMILLING 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, having an improved solubility, bioavailability and onset of action. Furthermore, the present invention relates to a nanomilling 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’s chemical name is 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). Tadalafil 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 2.5mg, 5mg, lOmg, 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.

Various methods are already known for the industrial preparation of dosage forms comprising Tadalafil as a pharmaceutically active ingredient, due to its usefill 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.

CONFIRMATION COPY 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 self-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 exhibit a faster therapeutic onset compared to the commercially available product Cialis® (reference product).

According to another embodiment of the present invention, a cost effective and simple process for manufacturing a solid pharmaceutical composition for oral administration is provided containing Tadalafil as an active ingredient, thereby offering a pharmacotechnical linearity and used in the treatment of erectile dysfunction. Said process comprises the use of nanomilling as a dissolution enhancing process which facilitates drug release and increases the bioavailability of the active ingredient.

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 manufacturing 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, is provided, wherein said process comprises nanomilling.

Said process further comprises the following steps:

A. Dispensing of active ingredient suspension phase for nanomilling ingredients: Weight individually the active ingredient (Tadalafil), Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and pass them through the appropriate sieve. B. Preparation of Tadalafil suspension phase for nanomilling: Dilute in water the quantity of Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and add the active ingredient Tadalafil.

C. Nanomilling: Pass the suspension from step B through nanomill.

D. Dispensing of active ingredient micro-suspension phase ingredients: Weight individually the active ingredient (Tadalafil), Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and pass them through the appropriate sieve.

E. Preparation of active ingredient micro-suspension phase: Dilute in water the quantity of Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and add the active ingredient Tadalafil.

F. Nano and micro Suspension mixing: Mix the intermediate nanosuspension obtained from step C and the microsuspension obtained from step E for appropriate time and under appropriate temperature.

G. Preparation of Sucrose solution: Weight Sucrose and dilute it in adequate quantity of water and mix till a clear solution is obtained.

H. Preparation of slurry: Mix the suspension obtained from step F and the sucrose solution obtained from step H for appropriate time and under appropriate temperature.

I. Dispensing and sieving of intra-granular excipients: Weight individually Lactose Monohydrate and Microcrystalline Cellulose and sieve through appropriate sieve.

J. Wet granulation: Add the intra-granular excipients from step I in a high shear mixer granulator and granulate by adding the slurry obtained from step H as granulation liquid, until a homogenized wet mixture is observed.

K. Drying: The granules obtained from step J are dried in fluid bed dryer to appropriate loss on drying (LOD).

L. Sizing: The granules prepared from step K are sized through suitable mesh sieve.

M. Dispensing and sieving of extra-granular excipients: Weigh individually Croscarmellose Sodium, Aspartame and Flavour Peppermint and sieve through appropriate sieve.

N. Mixing: Mix the granules obtained from step L with the extra-granular excipients from step M for appropriate time.

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

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

According to another embodiment of the present invention an immediate release oral solid dosage form, preferably chewable pharmaceutical nanoparticulate composition for oral administration, comprising a therapeutically effective quantity of tadalafil or a pharmaceutically acceptable salt, or derivative thereof, as an active ingredient wherein the particle size of Tadalafil active ingredient is effectively reduced by employing the nanomilling process of the present invention.

Further preferred embodiments of the present invention are defined in dependent claims 2, 3 and 5 to 9.

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 2 of the present invention prepared by nanomilling process and composition 2a prepared without the application of nanomilling process. Fig. 2: Comparative XRD of pure Tadalafil API, placebo of composition 2 and Tadalafil in the composition 2 of the present invention produced by nanomilling process.

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

Fig. 4: Comparative dissolution profiles of composition 2 of the present invention and reference product at 50 rpm and under FED conditions.

Fig. 5: Comparative mean plasma concentrations of composition 2 (Test product) of the present invention and reference product under FAST conditions for the whole sampling period.

Fig. 6: Comparative mean plasma concentrations of composition 2 (Test product) of the present invention and reference product for the first 4 hrs sampling points.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising 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 dosage form 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 nanomilling, microdispersion and subsequently common wet granulation process. The use of a novel technological platform such as nanomilling, which employs common excipients and practices, combines mechanical energy to physically break down large coarse particles of Tadalafil. The use of nanomilling process has major impact on the present composition as by increasing the surface area of the active ingredient, enhances the solubility and subsequently its bioavailability.

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. Tadalafil belongs to this category of active ingredients. 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.

In the present invention Nanomilling has been applied as a process by which the particle size of Tadalafil is reduced in a liquid vehicle (typically aqueous) via grinding using polymeric or ceramic milling media. Decreasing the particle size has a tremendous increase in surface area which directly correlates to an increase in dissolution rate.

Nanomilling is a “top-down” approach to turning large, coarse particles into smaller, finer particles. It entails the application of mechanical energy to physically break down Tadalafil particles. The main technique used for milling Tadalafil is high energy media milling. This technique relies on milling media beads of 0.2-1 pm diameter size, beads that are made from ceramics or highly crosslinked polystyrene. The beads shear and collide with the active ingredient particles during the milling process, reducing their particle size. During nanomilling, Tadalafil is suspended in a solution containing water and at least one stabilizer to prevent reaggregation of particles over time. The Tadalafil suspension is then pumped from a holding tank through the milling chamber, where the agitator rapidly rotates and creates turbulence in the media. As the suspension enters the milling chamber the shear forces and impaction with milling media break down large coarse particles into smaller particles. The Tadalafil suspension exits the milling chamber through a screen that keeps the suspension separate from the milling media. A coolant is pumped around the milling chamber to maintain a desired temperature. This is important for active ingredients that are thermally sensitive, as the milling process generates a significant amount of heat. The nanomilling process generates an intermediate consisting of nanoparticles suspended in an aqueous vehicle. This is often referred to as a nanoparticulate suspension (or nanosuspension).

The obtained Tadalafil nanosuspension is subsequently used as a granulation liquid in wet granulation step. Decreasing the particle size has a tremendous increase in surface area which directly correlates to an increase in dissolution rate and bioavailability which is the greatest contribution to the object of the present invention.

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, 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 solubility of the drug and the self-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, 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 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 1-40 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, 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 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, comprises the following steps:

A. Dispensing of active ingredient suspension phase for nanomilling ingredients: Weight individually the active ingredient (Tadalafil), Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and pass them through the appropriate sieve

B. Preparation of Tadalafil suspension phase for nanomilling: Dilute in water the quantity of Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and add the active ingredient Tadalafil.

C. Nanomilling: Pass the suspension from step B through nanomill.

O. Lubrication: Weight individually Magnesium Stearate, sieve it through appropriate sieve and mix it with the blend obtained from step N for appropriate time. P. Compression: Compress the homogeneous powder obtained from step O in tablets in a rotary tabletting machine using appropriate punches.

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

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 illustrates the results of the solubility studies of composition 2 and the reference product dissolved in aqueous medium with 0.4 SLS.

Table 1: Comparative dissolution results of Composition 2 and reference product

As it is shown in Tablet 1, composition 2 according to the present invention has dissolution rate similar to reference product, thereby providing an in vitro release of Tadalafil as depicted in Fig. 3.

One of the main objects of the present invention was to prepare a product with acceptable stability. For this reason composition 2 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

TABLE 2 Tadalafil composition 1

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

Tadalafil as active ingredient was weighted individually and passed through appropriate sieve. Hydroxypropyl Cellulose-SL as binder/ Stabilizing agent and Sodium Lauryl Sulfate as surfactant were weighted and passed through the appropriate sieve. Hydroxypropyl Cellulose-SL and SLS were diluted in appropriate quantity of water. The sieved Tadalafil was added in the above solution and mixed for appropriate time. The suspension was passed through nanomill (nanosuspension).

Sucrose as re-suspending Agent was weighted and diluted to appropriate quantity of water and then the solution was added in the nanosuspension and mixed for adequate time and appropriate temperature. The resulting slurry was used as a granulation liquid. Lactose Monohydrate and Microcrystalline Cellulose as diluents were weighted, sieved, and transferred in a high shear mixer granulator and granulated by adding slurry. The obtained granules were dried in fluid bed dryer to appropriate loss on drying (LOD) and subsequently passed through an appropriate sieve. Croscarmellose Sodium as disintegrant, Aspartame as sweetener and Flavor Peppermint as flavor were weighted sieved and mixed with dried granules for appropriate time until complete homogeneity.

Magnesium stearate as lubricant was weighted sieved and mixed the obtained mixture from previous steps. The resulting powder was compressed in tablets in a rotary tabletting machine using appropriate punches.

Example 2: A preferred composition 2 according to the present invention is illustrated in Table 3 below.

Composition 2 comprises nanosuspension Tadalafil and microsuspension Tadalafil. The mixture as intermediate step and with the addition of sucrose solution will be the granulation liquid wherein the weight ratio of nanosuspension Tadalafil to microsuspension Tadalafil is 60:40.

Tablets of composition 2 according to the present invention were prepared according to the following manufacturing process:

Tadalafil active ingredient was weighted individually and passed through appropriate sieve. Hydroxypropyl Cellulose-SL as binder/ Stabilizing agent and Sodium Lauryl Sulfate as surfactant were weighted and passed through the appropriate sieve. Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate (SLS) were diluted in appropriate quantity of water. The sieved Tadalafil was added in the above solution and mixed for appropriate time. The suspension was passed through nanomill (nanosuspension).

Tadalafil suspension without passing through nanomill was prepare. Tadalafil active ingredient was weighted individually and passed through appropriate sieve. Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate were weighted and passed through the appropriate sieve. Hydroxypropyl Cellulose-SL and SLS were diluted in appropriate quantity of water. The sieved Tadalafil was added in the above solution and mixed for appropriate time (microsuspension). Nanosuspension and microsuspension in a weight ratio 60:40 were mixed for adequate time and under appropriate temperature.

Sucrose as re-suspending Agent was weighted and diluted to appropriate quantity of water and then the solution was added in the nano/micro suspension and mixed for adequate time and appropriate temperature. The resulting slurry was used as a granulation liquid. Lactose Monohydrate and Microcrystalline Cellulose as diluents were weighted, sieved, and transferred in a high shear mixer granulator and granulated by adding slurry. The obtained granules were dried in fluid bed dryer to appropriate loss on drying (LOD) and subsequently passed through an appropriate sieve. Croscarmellose Sodium as disintegrant, Aspartame as sweetener and Flavor Peppermint as flavor were weighted sieved and mixed with dried granules for appropriate time until complete homogeneity.

TABLE 3: Tadalafil composition 2 according to the present invention

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.

Furthermore, the results of the XRD studies of composition 2 of the present invention indicates that the active ingredient Tadalafil remains stable and there is no conversion into amorphous state or another crystalline form (Fig. 2).

For comparative purposes, composition 2a comprising Tadalafil and the same excipients as composition 2 of the present invention is prepared by using dry blending process instead of nanomilling process on the active pharmaceutical ingredient. The manufacturing process of composition 2a comprises the following steps: Mix Tadalafil and Microcrystalline Cellulose for appropriate time. The obtained mixture is mixed with the following excipients: Lactose Monohydrate, Hydroxypropyl Cellulose-SL, Sodium Lauryl Sulfate, 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 2 of the present invention prepared by nanomilling process and composition 2a prepared by dry blending process are shown in Fig. 1. The results indicate that the dissolution rate of Tadalafil is increased by using the nanomilling process. More than 90% is released within 10 min using nanomilling process while about 70% is released when a conventional process such as dry blending process is used.

Furthermore, the dissolution profile of composition 2 of the present invention was tested at several aqueous buffers and compared with the reference product. As it is shown in Fig. 3, composition 2 of the present invention and the reference product havesimilar dissolution profiles when tested with the same dissolution method which is also the Quality Control dissolution method, a methos adequate to distinguish the good from bad composition.

In addition, composition 2 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. 4, the enhanced release profile of composition 2 compared to that of reference product is also confirmed at FED conditions.

Moreover, the results as depicted in Figs. 5 and 6, indicate that composition 2 (in the figures referred as test product) of the present invention achieves an enhanced therapeutic onset and drug plasma concentration at earlier time after administration than the reference product.

Example 3: Composition 3 according to the present invention is illustrated in Table 4 below.

Composition 3 comprises nanosuspension Tadalafil and microsuspension Tadalafil. The mixture as intermediate step and with the addition of sucrose solution will be the granulation liquid wherein the weight ratio of nanosuspension Tadalafil to microsuspension Tadalafil is 50:50.

Tablets of the above composition 3 according to the present invention were prepared according to the same manufacturing process as in Example 2 of the present invention. However, the nanosuspension and microsuspension were mixed in a weight ratio of 50:50 for adequate time and under appropriate temperature. TABLE 4: Tadalafil composition 3

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

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

The dissolution profiles of the compositions according to the present invention in table 5 indicate that Tadalafil solid dosage formulations prepared with nanomilling process is rapidly dissolved and are similar with the dissolution profile of the reference product.

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. 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, wherein said process comprises nanomilling.

2. The process according to claim 1, wherein said process comprises the following steps:

A. Dispensing of active ingredient suspension phase for nanomilling ingredients: Weight individually the active ingredient Tadalafil, Hydroxypropyl Cellulose-SL as binder/stabilizing agent and Sodium Lauryl Sulfate as surfactant and pass them through the appropriate sieve

C. Nanomilling:_Pass the suspension from step B through nanomill.

D. Dispensing of active ingredient micro-suspension phase ingredients: Weight individually the active ingredient Tadalafil, Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and pass them through the appropriate sieve.

F. Nano and micro Suspension mixing: Mix the intermediate Tadalafil nanosuspension obtained from step C and the Tadalafil microsuspension obtained from step E for appropriate time and under appropriate temperature.

G. Preparation of Sucrose solution: Weight Sucrose as re-suspending agent and dilute it in adequate quantity of water and mix till a clear solution is obtained.

I. Dispensing and sieving of intra-granular excipients: Weight individually Lactose Monohydrate and Microcrystalline Cellulose as diluents and sieve through appropriate sieve.

M. Dispensing and sieving of extra-granular excipients: Weigh individually Croscarmellose Sodium as disintegrant, Aspartame as sweetener and Flavour Peppermint and sieve through appropriate sieve.

O. Lubrication: Weight individually Magnesium Stearate as lubricant, sieve it through appropriate sieve and mix it with the blend obtained from step N for appropriate time.

3. The process according to claim 2, wherein the weight ratio of Tadalafil nanosuspension to Tadalafil microsuspension is from 50:50 to 100:0.

4. An immediate release oral solid dosage form, preferably chewable pharmaceutical nanoparticulate composition for oral administration, comprising a therapeutically effective quantity of tadalafil or a pharmaceutically acceptable salt, or derivative thereof, as an active ingredient wherein the particle size of Tadalafil active ingredient is effectively reduced by employing the nanomilling process according to claim 1.

5. The pharmaceutical composition according to claim 4, wherein said composition is a chewable tablet.

6. The pharmaceutical composition according to claim 4, wherein said composition further comprises at least one pharmaceutically acceptable excipient as stabilizing agent, such as Hydroxypropyl Cellulose-SL to inhibit the over-growth of nanoparticles and prevent their aggregation/coagulation

7. The pharmaceutical composition according to claim 4, wherein it further comprises at least one pharmaceutically acceptable excipient as re-suspending agent, such as Sucrose to inhibit the overgrowth of nanoparticles and prevent their aggregation/coagulation

8. The pharmaceutical composition according to claim 4, 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.

9. The pharmaceutical composition according to claim 4, wherein it comprises a) Hydroxypropyl Cellulose-SL as binder/ Stabilizing agent b) Sodium Lauryl Sulfate as surfactant c) Sucrose as re-suspending agent d) Lactose Monohydrate as diluent e) Microcrystalline Cellulose as diluent f) Croscarmellose Sodium as disintegrant g) Aspartame as sweetener h) Flavor Peppermint as flavor, and i) Magnesium stearate as lubricant