FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION (SECTION 10; RULE 13)
"PHARMACEUTICAL FORMULATION OF TADALAFIL AND PROCESS FOR
THE PREPARATION THEREOF"
V-ENSURE PHARMA TECHNOLOGIES PRIVATE LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT MUMBAI - 4000, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical formulation of Tadalafil i.e., (6R-trans)-
6-(l,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-[l',2':l,6]
pyrido [3,4-b] indole- 1,4-dione" or a pharmaceutically acceptable salt thereof and process
for the preparing thereof.
BACKGROUND OF THE INVENTION
Tadalafil has been used for the treatment of male erectile dysfunction and has the chemical name (6R-trans)-6-(l ,3 -benzodioxol -5-yl)-2,3 ,6,7, 12,12a-hexahydro-2-methyl- pyr-azino[r,2': 1,6]pyrido[3,4-b]indole-l ,4-dione.

Tadalafil is a solid that is understood to be practically insoluble in water and only very slightly soluble in some organic solvents. The extremely limited solubility of Tadalafil poses many major difficulties and challenges when formulating a dosage form that demonstrates acceptable bioavailability.
Daugan U.S. Pat. No. 5,859,006 discloses a class of [3-carbolines, and pharmaceutical compositions thereof, which are useful in the treatment of conditions wherein inhibition of PDE5 is desired.

WO 96/38131 describes a method of production of a solid dispersion, which contains a sparingly soluble active substance. The solubility of the active substance is said to be improved by coprecipitation. Tests on release of the active substance tadalafil have shown, however, that tablets that contain the coprecipitates release the active substance more slowly than tablets containing pure active substance. Moreover, in coprecipitates there are also proportions of tadalafil particles that are not embedded in the solid material, but are free. These free particles dissolve more quickly than the particles embedded in the coprecipitate. This may possibly lead to undesirable, bimodal release of the tadalafil. Furthermore, coprecipitates are not easily reproducible, i.e. large-scale production is complicated.
Another possibility for improving the solubility of sparingly soluble active substances is to increase the surface area of the particles of active substance by grinding or micronizing, as disclosed in WO 01/08688 or WO 01/08686. Oral formulations with rapid release are known from WO01/08688. The desired solubility or release could be achieved by reducing the tadalafil particle size to below 40fim. Grinding or micronizing of active substances can, however, have disadvantages. Micronized particles tend to form agglomerates. This results in particle sizes that are difficult to define, and accordingly solubility that is difficult to define. A possible additional electrostatic charge on the active substance also has an adverse effect on processability. Another possible disadvantage is poor flowability of the ground active substance. Especially if tablets are to be compressed or capsules are to be filled, further processing steps, e.g. granulation, are necessary. Although the particles are small, it is often necessary to add a lot of surfactant to obtain adequate solubility
WO 01/08687 discloses the soft capsules made of gelatin, which are filled with a tadalafil solution. The solvent for tadalafil is a mixture of PEG (polyethylene glycol) 400 NF LA and polypropylene glycol. Alternatively the capsules can be filled with a tadalafil suspension. Soft capsules made of gelatin are also known from WO 00/66099, using exclusively PEG 400 NF as solvent for the active substance. However, soft gelatin capsules have the disadvantage that filling is complicated. For example, special machines and strictly climate-controlled manufacturing rooms are required. In contrast, hard capsules can

be filled relatively easily with standard capsule filling machines, equipped with feed systems for semi-solid substances instead of powder feed systems. Apart from gelatin as capsule material, it is also possible to use cellulose-based materials. A pharmaceutically employed oral film is formulated to exhibit instant hydration followed by rapid dissolution disintegration upon administration into the oral cavity. Upon administration and dissolution, the patient will not feel any discomfort during and/or immediately after its dissolution. The disintegration time can be varied through the suitable adjustment of the composition and physical properties of the matrix. Film forming polymers of common pharmaceutical use are water-soluble or water dispersible polymers that conform to the required properties, including, but not limited to, film instant hydration potential, mucoadhesion and solubility overtime. Examples of film forming polymers include cellulose derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, starches, polyacrylates, gums (xanthane gum, arabic gum, guar gum, etc.) and/or mixtures thereof. Film forming polymers may be used in combinations chosen based on the desired characteristics of the delivery form (e.g., rapid disintegration, higher mucoadhesion, longer residence time, etc.).
WO 2005/000296 discloses an orally deliverable pharmaceutical composition comprising a drug with low water solubility and pregelatinized starch having low viscosity and/or exhibiting a multimodal particle size distribution. The formulation disclosed in WO2005/ 000296 is reported to exhibit increased drug dissolution rate consistency.
In US Publication No. 2008/0009502, which is incorporated herein by reference, a solid composite and a method of making thereof is disclosed. The publication discloses solid composite comprising tadalafil and at least one carrier. Preferably, the carrier is a hydrophilic polymer such as povidone, hydroxypropyl methylcellulose, and polyethylene glycol.
US patent 7182958 discloses a pharmaceutical formulation of Tadalafil, wherein Tadalafil is provided as free drug comprising particles and at least 90% of the particles of the Tadalafil has a particle size of less than about 40 microns. However, about 50% to about 85%, by weight, of a water-soluble diluent; a lubricant; a hydrophilic binder selected from

the group consisting of a cellulose derivative, povidone, and a mixture thereof; and a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and a mixture thereof.
The prior art discloses several methods to improve the bioavailability of poorly soluble drugs, for example, modifying the drug itself. The physical properties of an active ingredient can be altered using various techniques to optimize the rate at which the drug is dissolved. The most commonly employed of these techniques and the one most relevant to the present invention is particle size reduction. Particle size reduction has been a non specific formulation approach that can be applied to almost any drug to enhance solubility. The increase in surface area results in a significant increase in surface energy leading to greater solubilization.
There are many challenges associated with the manufacture of oral film dosage forms ranging from brittleness, tackiness, the hygroscopic nature and potential lack of homogeneity within the dosage form. Ideal physical characteristics of the oral film include dosage uniformity throughout the dosage form, adequate flexibility and tensile strength to facilitate processing, handling, and packaging of the film in a consumer-friendly form. Attaining ideal conditions for one characteristic usually comes at the expense of other, often equally important, properties, resulting in a necessary compromise in various properties to achieve a working film dosage form.
The preparation of an oral film dosage form requires that the final blend has a critical lower viscosity limit as this greatly affects the film casting potential. This is due to the fact that the final blend is transferred onto a surface of a suitable carrier material upon which the blend is cast and dried to form a film. Optimal viscosity ranges from 1000 centipoise to 90,000 centipoise. If the viscosity of the blend is too low there is a significant risk of not facilitating the formation of film after coating the blend on the carrier. The mixtures may not be homogeneous, and the drying resistance of a film tends to be low. In order to produce a solid oral film dosage form comprising Tadalafil and demonstrating improved bioavailability of the Tadalafil, a blend must be produced that provides sufficient solubilization of the Tadalafil as to produce a blend containing a film forming polymer

capable of producing a solid oral film dosage form, and with sufficient viscosity as to be coated onto a carrier system and successfully form a solid oral film dosage form with acceptable dimensions and drug loading. If the solubility of the Tadalafil is too low the solvent required to dissolve the Tadalafil would make it extremely difficult or impossible to achieve optimal viscosity, acceptable dimensions, and adequate drug loading. Due to the nature of the solid oral film dosage form manufacturing process, the low vapor pressure of preferred Tadalafil liquid solvents, regulatory body (e.g., the United States Food and Drug Administration) imposed residual solvent limits, and the undesirability of heating a system to well above room temperature, preferred systems include solvents with reasonably high residual limits and low boiling points. The prior art discloses many solvent systems for dissolving Tadalafil, but does not fully address the difficulty associated with achieving the desired improved solubility of Tadalafil when preparing a pharmaceutical film capable of achieving improved bioavailability of the Tadalafil upon buccal and/or sublingual oral administration.
Accordingly, there is a continuing need in the art for an improved pharmaceutical
formulation of Tadalafil i.e., (6R-trans)-6-(l,3-benzodioxol-5-yl)~2,3,6,7,12,12a-
hexahydro-2-methylpyrazino-[1,2':l,6] pyrido[3,4-b]indole-l,4-dione" or a
pharmaceutically acceptable salt thereof and process for the preparing thereof.
Surprisingly, it was found that a pharmaceutical formulations made using defined particle size distributions of tadalafil, including its salts, esters, polymorphs, isomers, hydrates, solvates and derivatives, wherein the particle size is in the range of about 45 micron to about 200 micron. Because of its poor solubility and poor bioavailability, there exists a need for developing improved formulations containing tadalafil which are stable and possess desired bioavailability. There is a need for improved pharmaceutical formulations comprising tadalafil or its salts having desirable bioavailability characteristics. It was also found that a pharmaceutical formulation of Tadalafil, wherein more than 85%, by weight, of a water-soluble diluent; a lubricant; a hydrophilic binder selected from the group consisting of a cellulose derivative, povidone, and a mixture thereof; and a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and a mixture thereof can be achieved.

The present invention meets the unfulfilled needs of the pharmaceutical industry by providing an improved pharmaceutical formulation of Tadalafil or a pharmaceutically acceptable salt thereof, that overcomes the problems of the prior art.
The problem to be solved by the present invention was therefore to provide an improved formulation method for the production of a pharmaceutical containing Tadalafil, in which the aforementioned dis-advantages and in particular the difficult solubility of Tadalafil are essentially avoided or overcome.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a pharmaceutical formulation of Tadalafil
i.e., (6R-trans)-6-(l,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-
[l',2':l,6] pyrido[3,4-b]indole-l,4-dione or a pharmaceutically acceptable salt thereof and process for the preparing thereof.
It is also an object of the present invention to provide a pharmaceutical formulation comprising Tadalafil as an active agent including its salts, esters, polymorphs, isomers, hydrates, solvates and derivatives, and wherein at least one surfactant, and at least one diluent, wherein active agent has the 90% of particles size about 45 microns to about 200 microns.
It is another object of the present invention to provide a pharmaceutical formulation of Tadalafil, wherein more than 85%, by weight, of a water-soluble diluent; a lubricant; a hydrophilic binder selected from the group consisting of a cellulose derivative, povidone, and a mixture thereof; and a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and a mixture thereof can be achieved.
Accordingly, it is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical formulation of (6R-trans)-6-(l,3-
benzodioxol-5-yl)-2,3,6,7,12,12a4iexahydro-2-methylpyrazino-[l,,2':l,6] pyrido[3,4-
b]indole-l,4-dione or a pharmaceutically acceptable salt thereof and process for the preparing thereof.
In an one embodiment of the present inventon, pharmaceutical formulation comprising Tadalafil as an active agent including its salts, esters, polymorphs, isomers, hydrates, solvates and derivatives, and wherein at least one surfactant, and at least one diluent, wherein active agent has the 90% of particles size about 45 microns to about 200 microns. In another preferred embodiment, the pharmaceutical formulation of Tadalafil, wherein more than 85%, by weight, of a water-soluble diluent; a lubricant; a hydrophilic binder selected from the group consisting of a cellulose derivative, povidone, and a mixture thereof; and a disintegrant selected from the group consisting of croscarmeliose sodium, crospovidone, and a mixture thereof can be achieved.
In addition to the pharmaceutical formulation, another important physical property is stability. The present invention also provides Pharmaceutical formulations with improved stability over prior pharmaceutical formulations.
The specific dose of Compound I administered according to the present invention is determined by the particular circumstances surrounding the case including, for example, the route of administration, the dosage form, the condition of the patient, and the pathological condition being treated. A typical daily dose contains a dosage level of about 1 to about 20 mg/day of the compound of structural formula (I). Preferred daily doses generally are about 1 to about 10 mg/day, particularly about 5 mg or about 10 mg tablets or capsules, administered once per day. The most preferred dosage form is a tablet. Multiple

doses can be taken to achieve a total dose of up to 20 mg/day of the compound of structural formula (I).
The present invention further relates to the use of such formulations for treatment of sexual dysfunction, e.g., male erectile dysfunction and female arousal disorder. The formulations can be administered orally as a compressed tablet or as dry, free-flowing particles encapsulated in a hard shell, for example, a gelatin shell.
The invention may be summarized as given below:
A. A pharmaceutical formulation comprising Tadalafil as an active agent, at least one
surfactant, and at least one diluent, wherein active agent has the 90% of particles size about
45 microns to about 200 microns.
B. An improved pharmaceutical formulation comprising tadalafil as an active agent,
wherein, more than 85%, by weight, of a water-soluble diluent; a lubricant; a hydrophilic
binder selected from the group consisting of a cellulose derivative, povidone, and a mixture
thereof; and a disintegrant selected from the group consisting of croscarmellose sodium,
crospovidone, and a mixture thereof
C. The pharmaceutical formulation as in step A above, wherein the wetting agent or
surfactant selected from the group consisting of sodium lauryl sulfate, docusate sodium,
ethoxylated castor oil, a polyglycolyzed glyceride, an acetylated monoglyceride, a sorbitan
fatty acid ester, a poloxamer, a polyoxyethylene sorbitan fatty acid ester, a
polyoxyethylene, a monoglyceride and ethoxylated derivatives thereof, a diglyceride and
ethoxylated derivatives thereof, and mixtures thereof.
D. The pharmaceutical formulation as in step A above, wherein the water-soluble diluent is
selected from the group consisting of lactose, sucrose, dextrose, a dextrate, a maltodextrin,
mannitol, xylitol, sorbitol, a cyclodextrin, and mixtures thereof.
E. The pharmaceutical formulation as in step B above, wherein the water-soluble diluent is
selected from the group consisting of lactose, sucrose, dextrose, a dextrate, a maltodextrin,
mannitol, xylitol, sorbitol, a cyclodextrin, and mixtures thereof.

F. The pharmaceutical formulation as in step B above, wherein the lubricant is selected
from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid,
colloidal silicon dioxide, calcium silicate, a starch, mineral oil, a wax, glyceryl behenate, a
polyethylene glycol, sodium benzoate, sodium acetate, sodium stearyl fumarate,
hydrogenated vegetable oils, and mixtures thereof.
G. The pharmaceutical formulation as in step B above, wherein the microcrystalline
cellulose selected from the group consisting of hydroxypropylcellulose, hydroxypropyl
methylcellulose, and mixtures thereof.
H. The pharmaceutical formulation as in step B above, wherein the wetting agent or surfactant selected from the group consisting of sodium lauryl sulfate, docusate sodium, ethoxylated castor oil, a polyglycolyzed glyceride, an acetylated monoglyceride, a sorbitan fatty acid ester, a poloxamer, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene, a monoglyceride and ethoxylated derivatives thereof, a diglyceride and ethoxylated derivatives thereof, and mixtures thereof.
I. A tablet comprising the formulation as in step A and B above, wherein the Tadalafil as an active agent is present in an amount of about 1 to about 20 mg per tablet.
J. A tablet comprising the formulation as in step A and B above, wherein the Tadalafil as an active agent is present in an amount of about 5 mg per tablet.
K. A tablet comprising the formulation as in step A and B above, wherein the Tadalafil as an active agent is present in an amount of about 2.5 mg per tablet.
L.A method of treating sexual dysfunction in a patient in need thereof comprising administering to the patient an effective amount of a formulation or a tablet according to of any one of the preceding steps.
DETAILED DESCRIPTION OF THE INVENTION

Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the

present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
For purposes of the invention disclosed and claimed herein, the following terms and abbreviations have the following meanings.
The term "treatment" is defined to include preventing, lowering, stopping, or reversing the progression or severity of a condition or symptom being treated. As such, the present invention includes both medical therapeutic and/or prophylactic administration, as appropriate.
The term "lubricant" refers to pharmaceutically acceptable agents that are commonly used in the art as lubricants or glidants in the preparation of solid pharmaceutical formulations. Representative lubricants include, but are not limited to, agents such as talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, calcium silicate, a starch, mineral oil, a wax, glyceryl behenate, a polyethylene glycol, sodium benzoate, sodium acetate, sodium stearyl fumarate, and hydrogenated vegetable oils. Preferably, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, and stearic acid. Most preferably, the lubricant is magnesium stearate.*
The term "solvate" refers one or more molecules of a solute associated with a molecule of a compound, such as the compound of structural formula (I) associated with a molecule of water or acetic acid.
The term "solid oral dosage form" is used in a general sense to refer to solid pharmaceutical products administered orally. Solid oral dosage forms are recognized by those skilled in the art to include such forms as tablets and capsules, for example.
The term "water-soluble diluent" refers to compounds typically used in the formulation of pharmaceuticals to impart bulk for the manufacture of a tablet of practical size. Water-soluble diluents include, but are not limited to, sugars (including lactose, sucrose, and

dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), and cyclodextrins.
The term "wetting agent" or "surfactant" refers to anionic, cationic, and nonionic surfactants. Nonlimiting, representative wetting agents include sodium lauryl sulfate, docusate sodium (i.e., bis(2-ethyl-hexyl)sodium sulfosuccinate), ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides and ethoxylated derivatives thereof, and diglycerides and ethoxylated derivatives thereof. Preferably the surfactant is sodium lauryl sulfate or a polyoxyethylene sorbitan fatty acid ester, particularly polysorbate 80.
We have found that dosage uniformity, stability, and bioavailability are enhanced by
formulating (6R-trans)-6-(l,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-
methylpyrazino-[l',2':l,6] pyrido[3,4-b]indole- 1,4-dione (i.e., the compound of structural formula (I), as the active compound with a particular combination of pharmaceutical excipients. The formulations of present invention comprise mixtures of the active compound with a water-soluble diluent, a lubricant, a hydrophilic binder, croscarmellose sodium or crospovidone as a disintegrant, and, optionally, microcrystalline cellulose and/or a wetting agent.
A water-soluble diluent is present in the formulation in an amount sufficient to provide adequate bulk to the formulation, and to effect tablet manufacture. A preferred water-soluble diluent is lactose, present in an amount not less than 50 % and preferably about 50% to about 95%, by weight.
A hydrophilic binder is provided in an amount sufficient to act as an adhesive to hold Compound I and excipients together in a tablet. A hydrophilic binder also is present in a powder formulation introduced into a hard gelatin shell. In dry powder formulations, the hydrophilic binder facilitates powder manufacture and handling, and enhances stability of the active compound.

A preferred hydrophilic binder is a cellulose derivatives, including, for example, hydroxypropylcellulose and hydroxypropyl methylcellulose. Another nonlimiting hydrophilic binder is povidone. Preferably, the amount of hydrophilic binder present in the formulation is more than 1% to about 5%, by weight of the formulation.
While binders such as povidone provide suitable adhesive characteristics, it has been found that the binder is important with respect to the stability of the P-carboline compound. Hydroxypropylcellulose and hydroxypropyl methylcellulose offer acceptable adhesion, while avoiding the oxidative instability attributed to povidone, and thus are preferred binders.
The croscarmellose sodium and crospovidone promote disintegration of the formulation, and especially a tablet dosage form, after administration and upon contact with water. Croscarmellose sodium and crospovidone are particularly advantageous when used in an amount of more than 3% to about 15%, and especially more than 3% to 10%, by weight of the formulation. Croscarmellose sodium, also known as carboxymethylcellulose sodium crosslinked, is the preferred disintegrant. Crospovidone is crosslinked povidone.
A lubricant is provided in an amount sufficient to reduce die wall friction during compression of the formulation into tablets. Preferably, the lubricant is magnesium stearate, present in an amount of more than 0.25% to 2.0%, by weight of the formulation. A lubricant also facilitates handling of the dry powder form of the formulation.
Microcrystalline cellulose is present at 0 to more than 40% by weight in the present compositions. Microcrystalline cellulose can serve multiple functions in the formulation, e.g., a disintegrant and/or a second diluent in addition to the water-soluble diluent.Additional optional ingredients, such as coloring or flavoring agents, can be incorporated into the formulation in an amount sufficient to perform their intended function without adversely affecting either the powder formulation or tablets manufactured using the formulation.
The formulations of the present invention can be prepared by a variety of techniques recognized in the art. Such techniques include, for example, wet granulation followed by

drying, milling and compression into tablets with or without film coating, dry granulation followed by milling, compression into tablets with or without film coating, dry blending followed by compression into tablets, with or with film coating, molded tablets, wet granulation, dried and filled into gelatin capsules, dry blend filled into gelatin capsules, or suspension or solution filled into gelatin capsules. Generally, the compositions have identifying marks which are debossed or imprinted on the surface.
The term 'stable' as used herein refers to chemical stability of (6R-trans)-6-(l,3-
benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-[r,2':l,6] pyrido[3,4-
b]indole-l,4-dione or a pharmaceutically acceptable salt thereof, in solid dosage forms wherein there is no change in impurities percentages and dissolution profile when kept at 40°C / 75% RH for 3 months.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto. Example 1:
The following formula is used to prepare the finished dosage form of a tablet providing 20 mg of Tadalafil.
Table I:

Ingredient Quantity (nig)
Granulation
Tadalafil (d 90 of 50ri to 200 a) 20.00
Lactose Anhydrous 311.50
Croscarmellose Sodium 12.00
Sodium Lauryl Sulfate 1.00
Hydroxy Propyl Cellulose 2.00
Hydroxy Propyl Cellulose (EF) 1.00
Polysorbate 2.00
Acetone qs
Outside Powders
Croscarmellose Sodium 9.00
Magnesium Stearate 1.50
Total 360.00
Uncoated tablet weight 10.00

Acetone USP grade was used in the manufacturing of the tablets for all strength i.e. 1 to 20mg. The acetone was removed during processing and not remained in the finished tablets.
Tablets were manufactured using granulation process. A step by step description of the process follows; Tadalafil and excipients to be granulated are security sieved. Tadalafil was dry blended with lactose monohydrate, Croscarmellose Sodium, Sodium Lauryl Sulfate and Hydroxy Propyl Cellulose. The resulting powder blend is granulated with solution of Polysorbate Hydroxy propyl cellulose and Acetone using a high shear granulator. The granulated mass was dried using either a fluid bed drier or a dried oven. After drying the material can be sized to eliminate any large agglomerates. Croscarmellose sodium and magnesium stearate were security sieved and added to the dry sized granules and lubricated.
Following a procedure similar to that described in Example -1, tablets of the following composition are prepared.
Example: 2 Table 2:

Ingredient Quantity (mg)
Granulation
Tadalafil (d 90 of 50µ to 75 n) 20.00
Lactose Anhydrous 239.07
Croscarmellose Sodium 12.60
Sodium Lauryl Sulfate 0.98
Hydroxy Propyl Cellulose 5.60
Hydroxy Propyl Cellulose(EF) 2.45
Polysorbate 2.00
Outside Powders
Croscarmellose Sodium 9.80
Microcrystalline Cellulose 52.50
Magnesium Stearate 5.00
Total 350.00
Film Coat (approximately) 10.00

Example 3:
The samples are conducted for dissolution as per dissolution methods published by USFDA database last updated on 01/26/2006 i. Media: 0.5% Sodium Lauryl Sulfate ii. USP Apparatus: Type II iii. RPM: 50 iv. Volume: lOOOmL v. Recommended Sampling Times (minutes): 10, 20, 30, 45
Dissolution results of Cialis 20 mg, Example 1 and Example 2 are as mentioned in the Table 3:

Time Points Cialis 20 mg Example -1 Example -2
10 86.3 87.0 85.2
20 97.4 96.7 95.3
30 99.1 99.3 98.8
45 99.7 100.0 99.1
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Claims:
1. A pharmaceutical formulation comprising Tadalafil as an active agent, at least one surfactant, and at least one diluent, wherein active agent has the 90% of particles size about 45 microns to about 200 microns.
2. An improved pharmaceutical formulation comprising tadalafil as an active agent, wherein, more than 85%, by weight, of a water-soluble diluent; a lubricant; a hydrophilic binder selected from the group consisting of a cellulose derivative, povidone, and a mixture thereof; and a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and a mixture thereof
3. The pharmaceutical formulation according to claim 1, wherein the wetting agent or surfactant selected from the group consisting of sodium lauryl sulfate, docusate sodium, ethoxylated castor oil, a polyglycolyzed glyceride, an acetylated monoglyceride, a sorbitan fatty acid ester, a poloxamer, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene, a monoglyceride and ethoxylated derivatives thereof, a diglyceride and ethoxylated derivatives thereof, and mixtures thereof.
4. The pharmaceutical formulation according to claim 1, wherein the water-soluble diluent is selected from the group consisting of lactose, sucrose, dextrose, a dextrate, a maltodextrin, mannitol, xylitol, sorbitol, a cyclodextrin, and mixtures thereof.
5. The pharmaceutical formulation according to claim 2, wherein the water-soluble diluent is selected from the group consisting of lactose, sucrose, dextrose, a dextrate, a maltodextrin, mannitol, xylitol, sorbitol, a cyclodextrin, and mixtures thereof.
6. The pharmaceutical formulation according to claim 2, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, calcium silicate, a starch, mineral oil, a wax, glyceryl behenate, a polyethylene glycol, sodium benzoate, sodium acetate, sodium stearyl fumarate, hydrogenated vegetable oils, and mixtures thereof.

7. The pharmaceutical formulation according to claim 2, wherein the microcrystalline cellulose selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, and mixtures thereof.
8. The pharmaceutical formulation according to claim 2, wherein the wetting agent or surfactant selected from the group consisting of sodium lauryl sulfate, docusate sodium, ethoxylated castor oil, a polyglycolyzed glyceride, an acetylated monoglyceride, a sorbitan fatty acid ester, a poloxamer, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene, a monoglyceride and ethoxylated derivatives thereof, a diglyceride and ethoxylated derivatives thereof, and mixtures thereof.
9. A tablet comprising the formulation of claim land 2, wherein the Tadalafil as an active agent is present in an amount of about 1 to about 20 mg per tablet.

10. A tablet comprising the formulation of claim land 2, wherein the Tadalafil as an active agent is present in an amount of about 5 mg per tablet.
11. A tablet comprising the formulation of claim land 2, wherein the Tadalafil as an active agent is present in an amount of about 2.5 mg per tablet.
12.A method of treating sexual dysfunction in a patient in need thereof comprising administering to the patient an effective amount of a formulation or a tablet according to of any one of the preceding claim.