FIELD OF THE INVENTION

Present invention relates to pharmaceutical tablet composition of 30 to 34 mg, 15 to 17 mg, 7.5 to 8.5 mg, 3.75 to 4.25 mg and 1.875 to 2.125 mg of tadalafil which is bioequivalent to 40 mg, 20 mg, 10 mg, 5 mg and 2.5 mg of tadalafil tablets (CIALIS®) respectively under fasted and fed condition. The pharmaceutical tablet composition of present invention also exhibits minimum difference in C _ma x and AUC between fed and fasted condition. Further the present invention also relates to process for preparing the said tablet composition.

BACKGROUND OF THE INVENTION

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) and chemically known as pyrazino[1 ',2': 1 ,6]pyrido[3,4-b]indole-1 ,4-dione, 6-(1 ,3-benzodioxol-5- yl)-2,3,6,7, 12,12ahexahydro-2-methyl-, (6R, 12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. In USA it is approved as CIALIS® for treating erectile dysfunction and ADCIRCA® for the treatment of pulmonary arterial hypertension. CIALIS® is available as almond-shaped tablets for oral administration as 2.5, 5, 10 and 20 mg strengths and contains inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin. US5859006 discloses a class of β-carboline compound including tadalafil and also describes pharmaceutical compositions thereof which are useful in the treatment of conditions which required the inhibition of PDE5.

US5985326 discloses solid dispersion in the form of co-precipitates of poorly water soluble drugs like selective inhibitors of cGMP specific PDE5, process for preparing the same and their use in the pharmaceutical composition.

US6821975 discloses tadalafil in the form of free drug wherein at least 90% of the particles have a particle size of less than about 40 microns and pharmaceutical composition of the same with pharmaceutically acceptable carriers, diluents or excipients.

US7417044 describes particulate tadalafil having particle size distribution such that at least 90% of the particles, by volume, have a particle size of about 200 to about 600 microns.

US20080009502 discloses pharmaceutical composites for making pharmaceutical formulation for oral administration that provides rapid dissolution of the PDE5 inhibitor tadalafil wherein the tadalafil is in the form of solid solution.

US200909821 1 discloses compressed solid dosage form of tadalafil with starch wherein weight ratio of starch to tadalafil is about 4:5:1 or more and tadalafil has a particle size distribution such that d(0.9) is greater than or equal to 40 microns.

US201 1263606 describes buccal and/or sublingual oral film dosage form and process for preparing the same using solubility enhancer for better absorption and improved bioavailability. US20120189694 relates to a co-precipitate comprising a phosphodiesterase-5 inhibitor (PDE-5-inhibitor) and a pharmaceutically compatible copolymer carrier comprising 2 or more different acrylic acid derivatives, a method for production thereof and a medication comprising the co-precipitate.

US20120088774 relates to dosage forms comprising active pharmaceutical ingredients (API) such as tadalafil, simvastatin, fenofibrate and lovastatin that are practically insoluble in water, adsorbed on a carrier. Further it relates to an adsorbate comprising API being practically insoluble in water and to a process for the preparation of said adsorbate with non-polar solvent (s) such as chlorinated hydrocarbon, diisopropylethes and hexane and process for the preparation of the dosage form, as well as to the use of the adsorbate for the preparation of the dosage form.

Many techniques like size reduction of API, modified process for manufacturing pharmaceutical formulation, preparing solid dispersions, addition of solubilising agents have been employed to improve the solubility and thereby dissolution of the active ingredients like tadalafil having poor aqueous solubility to improve solubility and thereby bioavailability but are not up to the mark for bioavailability improvement.

Epidemiological studies suggest that erectile dysfunction is a common disorder in men, affecting up to 52% of men between the age of 40 and 70 years (Feldman et al 1994). Consistent with increasing life expectancies, the prevalence and the severity of erectile dysfunction increases in the elderly because of the aging process and related organic, iatrogenic and social problems (Feldman et al 1994; Parazzini et al 2000; Derby et al 2001 ; Kubin et al 2003). Starting dose of 2.5 mg of tadalafil may sometime not effective to treat the erectile dysfunction while highest dose of 20 mg is efficient to treat the erectile dysfunction of human being but associated with certain adverse effects like back pain, nasal congestion, myalgia, flushing, headache and dyspepsia.

Incase of tadalafil, most of the side effects reported in the clinical trials are dose-dependent and consistent with the vasodilatatory effect of PDE-5 inhibition. When tadalafil was administered on an on-demand basis headache and dyspepsia were the most frequent symptoms, followed by back pain, nasal congestion, myalgia, and flushing. (Giovanni et al, Clin Interv Aging. 2006 December; 1 (4): 439-449. Published online 2006 December)

Generally the erectile dysfunction patient population ranges in between 40 year to 70 years who are already suffering one or more diseases. In such case side effects of tadalafil may get exaggerated and may lead to fatal result. To avoid such a situation there exist a need to develop pharmaceutical formulation with lower dose strength of tadalafil which exhibits similar efficacy to treat erectile dysfunction while reducing the severity or the proportion of side effects.

Thus still there is need for the improved pharmaceutical formulation of tadalafil which provides desired effective treatment of erectile dysfunction with lower side effects.

The inventors of the present invention have surprisingly found that the tablet composition of tadalafil can be prepared using lower dose strength which exhibits bioequivalence with tadalafil tablets (CIALIS®) composition with reduced side effects and minimum difference of C _ma x and AUC between fasted and fed condition.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a pharmaceutical tablet composition comprising 30 to 34 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 40 mg (2 tablets of 20 mg) tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C _ma x and AUCo-t and AUCo-inf of fasted and fed condition is less than 7%.

One aspect of the present invention is to provide a pharmaceutical tablet composition comprising 15 to 17 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 20 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C _max and AUC ₀ -t and AUC ₀ -inf of fasted and fed condition is less than 7%.

One more aspect of the present invention is to provide a pharmaceutical tablet composition comprising 7.5 to 8.5 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 10 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C _ma x and AUCo-t and AUCo- inf of fasted and fed condition is less than 7%. Yet another aspect of the present invention is to provide a pharmaceutical tablet composition comprising 3.75 to 4.25 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 5 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C _ma x and AUCo-t and AUCo- inf of fasted and fed condition is less than 7%.

Yet another aspect of the present invention is to provide a pharmaceutical tablet composition comprising 1.875 to 2.125 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 2.5 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C _ma x and AUCo-t and AUCo-inf of fasted and fed condition is less than 7%.

Yet another aspect of the present invention is to provide process for preparing tadalafil tablet composition comprising the steps of:

a) granulating at least one pharmaceutically acceptable carrier with solution comprising tadalafil and at least one pharmaceutically acceptable carrier in solvent,

b) granulating step a) with binder solution,

c) drying the granules of step b),

d) mixing the dried granules with at least one pharmaceutically acceptable carrier and

e) compressing the resulting blend of step d) into tablets and

f) optionally coating the tablets of step e). DETAILED DESCRIPTION OF THE INVENTION

Almost all the pharmaceutical dosage forms are having certain side effects or adverse effects along with beneficial therapeutic effect. These side effects are generally goes on increasing with the increase of dose strength. Therefore it is very critical to select or optimize a dose strength which exhibit balance between therapeutic benefit and adverse effects. Pharmaceutical development poses very difficulty in screening such a dose strength which exhibits reduced side effects with maintaining required therapeutic efficacy. This reveals the optimized steady state concentration which provides desirable therapeutic efficacy and reduced side effects.

In one embodiment, the present invention provides a pharmaceutical tablet composition comprising 30 to 34 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 40 mg (2 tablets of 20 mg) tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003, under fasted and fed condition.

In one embodiment, the present invention provides a a pharmaceutical tablet composition comprising 15 to 17 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 20 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003, under fasted and fed condition. In another embodiment, the present invention provides a a pharmaceutical tablet composition comprising 7.5 to 8.5 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 10 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 under fasted and fed condition.

In one more embodiment, the present invention provides a pharmaceutical tablet composition comprising 3.75 to 4.25 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 5 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 under fasted and fed condition.

In one more embodiment, the present invention provides a pharmaceutical tablet composition comprising 1 .875 to 2.125 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 2.5 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 under fasted and fed condition. As used herein, "tadalafil" means the free base tadalafil and pharmaceutically acceptable salts, solvates and polymorphs thereof. In a preferred embodiment, tadalafil is in the form of free base.

The % of tadalafil in tablet composition of present invention is 0.2 to 10% w/w. Preferably the % of tadalafil present in the tablet composition is 0.2 to 5% w/w.

In one embodiment, a method of treating a patient in need of treatment erectile dysfunction comprises administering to the patient a tadalafil tablet composition of present invention.

In one embodiment, the tablet composition comprising 15 to 17 mg of tadalafil is bioequivalent to the reference drug CIALIS® 20 mg. "Reference drug" means a tadalafil product as described in U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 as provided in the U.S. Federal Food and Drug Administration's Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations. CIALIS® is a tadalafil tablet product at a strength of 2.5 to 20 mg. CIALIS® 20 mg strength is the "reference listed drug" under 21 CFR 314.94(a)(3)), i.e., the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its AN DA.

As per USFDA guideline titled "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations" Bioequivalence is defined as: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. " In one embodiment, bioequivalence is any definition thereof as promulgated by the U.S. Food and Drug Administration or any successor agency thereof. In a specific embodiment, bioequivalence is determined according to the Federal Drug Administration's (FDA) guidelines and criteria, including "GUIDANCE FOR INDUSTRY BIOAVAILABILITY AND BIOEQUVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS-GENERAL CONSIDERATIONS" available from the U.S. Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) March 2003 Revision 1 ; and "GUIDANCE FOR INDUSTRY STATISTICAL APPROACHES TO ESTABLISHI NG BIOEQUIVALENCE" DHHS, FDA, CDER, January 2001 , both of which are incorporated herein in their entirety.

The pharmaceutical table composition of present invention used lower dosage of tadalafil and exhibits bioequivalent to higher dosage strength of CIALIS® which means the tablet composition of present invention that is 30 to 34 mg, 15 to 17 mg, 7.5 to 8.5 mg, 3.75 to 4.25 mg and 1.875 to 2.125 mg is bioequivalent to 40 mg, 20 mg, 10 mg, 5 mg and 2.5 mg tadalafil tablet (CIALIS®) respectively under fasted and fed condition. Further as the amount of tadalafil is reduced without affecting the efficacy, may lead to reduction in the side effects or adverse effects associated with the higher amount of tadalafil.

In one more embodiment, the present invention provides a process for preparing tadalafil tablet composition comprising the steps of:

a) granulating at least one pharmaceutically acceptable carrier with solution comprising tadalafil and at least one pharmaceutically acceptable carrier in solvent,

b) granulating step a) with binder solution, c) drying the granules of step b),

d) mixing the dried granules with at least one pharmaceutically acceptable carrier and

e) compressing the resulting blend of step d) into tablets and

f) optionally coating the tablets of step e).

In another embodiment, a tadalafil tablet composition of present invention comprises tadalafil, wherein the tablet composition is bioequivalent to a tadalafil tablet (CIALIS®) according to NDA 021368, wherein the tablet composition contains less amount of tadalafil than the tadalafil tablets according to NDA 021368.

Further the difference between C _ma x and AUCo-t and AUCo-inf values of fasted and fed condition bio study of the tablets of present inventions is insignificant or less than 10%.

Cmax is a term refers to the maximum (or peak) concentration that a drug achieves in tested area after the drug has been administrated and prior to the administration of a second dose.

AUC (Area under the curve) means the overall amount of drug in the bloodstream after a dose.

AUCo-t means area under the plasma concentration-time curve from time zero to the last measurable concentration.

AUCo-inf means area under the plasma concentration-time curve from time zero to infinity.

Fed condition as described herein for the bioequivalence study means human volunteers were given meal prior to administration of tablet composition of test and reference. The meal provided was high fat high calorie meal.

When the C _ma x, AUCo-t and AUCo-inf are measured for the tablet composition of present invention under fasted and fed condition, the difference is less than 10% or is insignificant. Hence the tablet composition of present invention can be taken with or without food and food does not affect the pharmacokinetic parameter of the tadalafil from the tablet composition of present invention.

The tablet composition of present invention can be prepared by any known techniques like direct compression, wet granulation, dry granulation, spray drying and solid dispersion. Preferably the preparation of solid dispersion of drug and at least a carrier is preferred which is further mixed with one or more pharmaceutically acceptable carrier and compressed in to tablets.

Solid dispersions of the present invention can be prepared by any of the below mentioned techniques;

Melting method:

In the melting method, physical mixture of a drug and a water-soluble carrier are prepared and heated directly until it gets melted. The melted mixture is then solidified rapidly in cool condition under vigorous stirring. The final solid mass is crushed, pulverized and sieved.

Solvent method:

In solvent method, drug and carrier is dissolved in a common solvent, which is then evaporated by any known means to get solvent free film or powder. The drug-carrier solution can also be spray dried alone or over any suitable pharmaceutically acceptable carrier. The main advantage of the solvent method is thermal decomposition of drugs or carriers can be prevented because of the relatively low temperatures required for the evaporation of organic solvents.

Melting solvent method (melt evaporation):

This method involves preparation of solid dispersions by dissolving the drug in a suitable liquid solvent and then incorporating the solution directly into the melt of any suitable polymer like polyethylene glycol, which is then evaporated until a clear, solvent free powder or film is obtained. The 5 -10% (w/w) of liquid compounds can be incorporated into polyethylene glycol 6000 without significant loss of its solid property. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. Also the liquid solvent used may affect the polymorphic form of the drug, which precipitates as the solid dispersion.

Melt extrusion method:

In this method, the drug-carrier mixture is processed with a twin-screw extruder. The drug-carrier mixture is simultaneously melted, homogenized and then extruded and shaped as tablets, granules, pellets, sheets, sticks or powder. The intermediates can then be further processed into conventional tablets. An important advantage of the hot melt extrusion method is that the drug-carrier mixture is only subjected to an elevated temperature for about 1 min, which enables drugs that are somewhat thermo labile to be processed.

Lyophilisation Technique

Lyophilisation or freeze-drying method involves transfer of heat and mass to and from the product under preparation. This technique was proposed as an alternative technique to solvent evaporation. Lyophilisation has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion.

Melt Agglomeration Process

This technique has been used to prepare solid dispersion wherein the binder acts as a carrier. In addition, solid dispersion(s) are prepared either by heating binder, drug and carrier to a temperature above the melting point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the heated carrier (spray-on procedure) by using a high shear mixer. A rotary processor has been shown to be alternative equipment for melt agglomeration. The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates. The effect of binder type, method of manufacturing and particle size are critical parameters in preparation of solid dispersion(s) by melt agglomeration.

The use of surfactant

The use of the surfactants in solubilization of poorly soluble drugs is well known. Adsorption of surfactant on solid surface can modify their hydrophobisity, surface charge, and other key properties that govern interfacial processes such as flocculation/dispersion, floatation, wetting and solubilization. Surfactants have also been reported to cause solvation/plasticization, manifesting in reduction of melting the active pharmaceutical ingredients, glass transition temperature and the combined glass transition temperature of solid dispersions. Because of these unique properties, surfactants have attracted the attention of investigators for preparation of solid dispersions.

Electrospinning Electrospinning is a method in which solid fibers are produced from a polymeric fluid stream solution or melt delivered through a millimeter- scale nozzle. This process involves the application of a strong electrostatic field over a conductive capillary attaching to a reservoir containing a polymer solution or melt and a conductive collection screen. Upon increasing the electrostatic field strength up to but not exceeding a critical value, charge species accumulated on the surface of a pendant drop destabilize the hemispherical shape into a conical shape. Beyond the critical value, a charged polymer jet is ejected from the apex of the cone (as a way of relieving the charge built-up on the surface of the pendant drop). The ejected charged jet is then carried to the collection screen via the electrostatic force. The coulombic repulsion force is responsible for the thinning of the charged jet during its trajectory to the collection screen. The thinning down of the charged jet is limited by the viscosity increase, as the charged jet is dried. This technique has tremendous potential for the preparation of nanofibres and controlling the release of biomedicine, as it is simplest, the cheapest this technique can be utilized for the preparation of solid dispersions in future.

Super Critical Fluid (Scf) Technology

This technology has been introduced in the late 1980s and early 1990s, and experimental proofs of concept are abundant in the scientific literature for a plethora of model compounds from very different areas such as drugs and pharmaceutical compounds, polymers and biopolymers, explosives and energy materials, superconductors and catalyst precursors dyes and biomolecules such as proteins and peptides. From the very beginning of supercritical fluid particle generation research, the formation of biocompatible polymer and drug-loaded biopolymer micro- particles for pharmaceutical applications has been studied intensively by a number of researcher groups CFs either as solvent: rapid expansion from supercritical solution (RESS) or antisolvent: gas antisolvent (GAS), supercritical antisolvent (SAS), solution enhanced dispersion by supercritical fluids (SEDS) and/or dispersing fluid: GAS, SEDS, particles from gas-saturated solution (PGSS). The supercritical anti-solvent (SAS) process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing concurrently use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer; it poses no danger to the patient. In addition the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature. Moreover, supercritical fluids are used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component).

Preferably the solvent method is used for the preparation of solid dispersion of present invention wherein the tadalafil and a carrier is dissolved in a solvent system followed by spray drying the solution over the pharmaceutically acceptable carrier followed by drying which is further mixed with one or more pharmaceutically acceptable carrier and compressed to a tablet using suitable punch tooling.

The pharmaceutically acceptable carrier as used herein can be selected from the group consisting of diluent, binder, disintegrant, lubricant, anti- adherent and/or wetting agent.

Suitable diluents in a tablet composition of the present invention may be one or more compounds which are capable of providing bulk to obtain a desired tablet mass. The suitable diluents may be water soluble or water insoluble or mixture thereof. Suitable diluents include inorganic phosphates such as dibasic calcium phosphate; sugars such as lactose monohydrate, lactose anhydrous, mannitol, sorbitol, sucrose, dextrose; and cellulose or cellulose derivatives such as microcrystalline cellulose and the like. The diluent can be added intragranularly and optionally extragranularly. Preferably, a water soluble diluent is to be used. Most preferably the lactose monohydrate having surface area in the range of 0.4648 m ² /g to 0.8632 m ² /g is to be used. The diluent can be present in a suitable amount from about 20-90 % w/w, preferably 40-80 % w/w of the total composition.

Suitable solvents used for dissolving tadalafil can be selected from acetone, isopropanol, methanol, ethanol, ethyl acetate and dichloromethane and the like or mixtures thereof.

Suitable binder in a tablet composition of the present invention may be one or more compounds which are capable of facilitating granulation of tadalafil into aggregates and/or more free-flowing particles and include cellulose, carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyl propyl methylcellulose, methylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch, alginic acid, sodium alginate, gelatin and the like. The binder can be present in a suitable amount from 0.5-10 % w/w of the total composition. Binder may be present either in the dry form or in the solution in appropriate solvent.

Suitable disintegrant in a tablet composition of the present invention may be one or more compounds which are capable of facilitating the break up of a tablet prepared from the composition when placed in contact with an aqueous medium and include cellulose, carboxymethylcellulose sodium, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, pregelatinized starch, low substituted hydroxypropylcellulose, sodium starch glycolate, starch and the like. The disintegrant can be present in a suitable amount from 1 -20 % w/w, preferably 5-18 % w/w of the total composition.

Suitable antiadherent in a tablet composition of the present invention may be one or more compounds capable of prevent sticking to punch faces such as colloidal silicon dioxide, magnesium trisilicate, talc and the like. The antiadherent can be present in a suitable amount from 0.02-7 % w/w, preferably 0.05-5 % w/w, more preferably 0.1-2 % w/w of the total composition.

Suitable lubricant in a tablet composition of the present invention may be one or more compounds capable to decrease friction at the interface between the tablet surface and the die wall during ejection and include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, talc and the like. The lubricant can be present in a suitable amount from 0.02-7 % w/w, preferably 0.05-5 % w/w, more preferably 0.1-2 % w/w of the total composition.

Suitable wetting agent in a composition of the present invention can be selected from the group consisting of anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride and benzethonium chloride. The wetting agent can be present in a suitable amount from 0.01-2 % w/w or 0.05-1 % w/w of the total composition.

Suitable coloring agent in a suitable amount in a composition of the present invention may be one or more compounds which impart a desired color to a tablet prepared from the composition and include FDA approved colors for oral use such as ferric oxides.

A coating can be applied using the materials and methods known to a person skilled in the art. Examples of film coating material includes Opadry® which is Colorcon's customized, one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate. The film coating can be applied in an amount up to about 5% w/w of the formulation.

Suitable solvents for coating can be selected from solvents such as water, isopropanol, ethanol, dichloromethane and the like.

The coating solutions may be applied using techniques, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating as known to person skilled in the art.

For the comparison purpose for in-vitro dissolution study as well as for bio study as a reference the immediate release tablets of tadalafil 20 mg marketed by Eli Lilly & company under the brand name Cialis® were used.

The bio study reveals that the pharmaceutical tablet of present invention is bioequivalent to Cilias® (tadalafil) tablets which means that the tablet of present invention is effective to treat the erectile dysfunction and further as the % of tadalafil is reduced in the tablet, it will lead to reduction in the side effects of tadalafil comparatively.

EXAMPLES

The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way Example 1

Procedure

1. Lactose monohydrate (Granulac 200) and Low-substituted hydroxypropylcellulose (LH-31 ) were sifted through 30# sieve.

2. Hydroxypropyl cellulose followed by tadalafil was dissolved in mixture of Dichloro methane and methanol.

3. Povidone K-25 was dissolved in Isopropyl Alcohol to get clear solution followed by dispersing sodium lauryl sulphate.

4. Material of step 1 ) was granulated with solution of step 2) by top spray process.

5. Material of step 4) was further granulated with solution of step 3).

6. Granules of step 5) were dried and sifted through 30# sieve. 7. Low-substituted hydroxypropylcellulose (LH-31 ), croscarmellose sodium and colloidal silicone dioxide were sifted through 40 # and mixed with dried granules of step 6).

8. Magnesium stearate was sifted through 40# and blend of step 7) was lubricated with sifted magnesium stearate.

9. Lubricated blend of step 8) was compressed to tablets using appropriate punch tooling.

10. Compressed tablets of step 9) were coated using the Opadry Yellow 03F520005 dispersion prepared in purified water.

Example 2

Procedure: As per example 1 Example 3

Procedure: As per example 1

Example 4

Example 5

Purified Water q.s. —

Coated tablet weight 460.00 100.00

Procedure: As per example 1

Example 6

Procedure: As per example 1 Example 7

Bio equivalence study

Method: The in-vivo studies were conducted in 13 healthy human male volunteers to asses the bioequivalence of the tablet composition of present invention (Example 1 ) against CIALIS® (tadalafil) 20 mg tablets as per below mentioned conditions;

Fasted study

An open label, balanced, randomized, two-treatment, two-sequence, two- period, single dose, crossover oral comparative bioavailability study in healthy, adult, human male subjects under fasting conditions.

Fed study

An open label, balanced, randomized, two-treatment, two-sequence, two- period, single dose, crossover oral comparative bioavailability study in healthy, adult, human male subjects under fed conditions.

Bio study results

CLAIMS

1. A pharmaceutical tablet composition comprising 30 to 34 mg, 15 to 17 mg, 7.5 to 8.5 mg, 3.75 to 4.25 mg and 1.875 to 2.125 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 40 mg, 20 mg, 10 mg, 5 mg and 2.5 mg tadalafil tablet (CIALIS ^® ) respectively under fasted and fed condition and wherein the difference between C _ma x, AUCo-t and AUCo-inf of tablet composition under fasted and fed condition is less than 7%.

2. The pharmaceutical tablet composition according to claim 1 , wherein pharmaceutical acceptable carrier is selected from group consisting of diluent, binder, disintegrant, lubricant, anti adherent and wetting agent.

3. The pharmaceutically acceptable carrier according to claim 2, where in the wetting agent is selected from the group consisting of anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride and benzethonium chloride.

4. A process for preparing tadalafil tablet composition according to claim 1 , comprises the steps of:

a) granulating at least one pharmaceutically acceptable carrier with solution comprising tadalafil and at least one pharmaceutically acceptable carrier in solvent,

b) granulating step a) with binder solution,

c) drying the granules of step b),

d) mixing the dried granules with at least one pharmaceutically acceptable carrier and e) compressing the resulting blend of step d) into tablets and

f) optionally coating the tablets of step e).

5. The pharmaceutical tablet composition according to claim 1 , wherein the tablet composition is useful for the treatment of erectile dysfunction.

6. A method of treating a patient in need of treatment erectile dysfunction comprises administering to the patient a tadalafil tablet composition of claim 1.