FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES. 2003
Complete Specification
[See Sections 10 and rule 13]
Title: "Stable Pharmaceutical Compositions of Tadalafil" Applicant: (a) Astron Research Limited
(b) Nationality: Indian
(c) 10Ih Floor. Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
Gujarat, India.
The following specification particularly describes the invention and the manner in which is to be performed.

FIELD OF INVENTION
The present invention relates to stable pharmaceutical compositions of Tadalafil for oral administration. Further, the present invention also discloses the process for the preparation of the said stable pharmaceutical composition.
BACKGROUND OF THE INVENTION
Tadalafil. the active ingredient in CIALIS® has been used for the treatment of male erectile dysfunction. Tadalafil has chemical name (6R-trans)-6-(1.3-benzodioxol-5-yi)-2,3.6.7.12.]2a-hexahydro-2-methyl-pyr-azino[1'.2':l.6] -pyrido[3.4-b] -indole-1.4 dione. The chemical formula of Tadalafil is C22H19N3O4 representing a molecular weight of 389.41. Tadalafil chemical structure is:

Further, Tadalafil is practically insoluble in water and is very slightly soluble in some organic solvents. US Patent No. 6.841.167 reports that tadalafil has a water solubility of about 2 μmg per mL of water at 25°C. The extremely limited solubility of Tadalafil poses many major difficulties and challenges when formulating a dosage form that demonstrates acceptable bioavailability.
Pharmacologically. Tadalafil is a potent and selective inhibitor of the cyclic guanosine monophosphate (cGMP)--specific phosphodiesterase enzyme PDB5. The inhibition of

PDE5 increases the amount of cGMP. resulting in smooth muscle relaxation and increased blood flow. Tadalafil is therefore currently used in the treatment of male erectile dysfunction.
The prescribing information for CIAL1S' describes this product as film-coated, almond-shaped tablets for oral administration, containing 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.
Different techniques have been applied in an attempt to overcome the apparent poor water solubility of tadalafil. US Patent No. 5.985,326 involves preparing formulations using "co-precipitates" of tadalafil. wherein an "intimate mixture" of tadalafil and a carrier in a non-aqueous water miscible solvent, and. optionally, water are co-precipitated from the "intimate mixture" using an aqueous "co-precipitation medium" in which the carrier is substantially insoluble. However, this method requires the use of significant amounts of organic solvent, which is environmentally undesirable.
US Patent No. 6.821.975 describes synthesis of tadalafil wherein 90% of the particles have a particle size of less than about 40 microns and a pharmaceutical composition containing this particle size. However, this method requires micronization. which can be time-consuming and also raise safety issues due to tine powder produced thereof.
US Patent No. 6,841,167 disclose a soft capsules comprising tadalafil in "free drug" form in admixture with a diluent, lubricant, a hydrophilic binder, and a disintegrant. Soft capsules containing a solution or suspension of tadalafil have been developed in an attempt to prepare formulations of tadalafil with improved bioavailability.

From the above background art, it is evident that particle size of ladalafil and extent of solubilization of tadalafil eventually affects the dissolution and bioavailability of the drug. Different techniques known in the art to improve solubility and dissolution rate for Tadalafil like solid dispersions, co-precipitation, milling, hot melt extrusion and other related approaches. However such techniques are of less importance in formulating a bioequivalent product to CIALIS '
Considering the formulation aspect, it would be highly desirable to produce a stable-pharmaceutical composition for oral administration having high dissolution rate of a poorly soluble drug like tadalafil without any need to reduce particle size of the drug (for example, by micronization).
Surprisingly, it has been found out by the inventors of the present invention that the use of coarser particle size above 40 microns with additional excipients like polymer, surfactant and/or solubilizer in the tadalafil composition resulted into higher dissolution rate and achieve bioequivalence with respect to the reference product CIALIS' available in the market.
OBJECT OF THE INVENTION
The object of the present invention is to provide a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 urn and one or more pharmaceutically acceptable excipients.
Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μm. polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients.

Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 urn. polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients, wherein the polymer is hydrophilic binder.
Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 urn. polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients, wherein the surfactant is non-ionic surfactant.
Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 urn. polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients, wherein the solubilizer is lipid in nature.
Another object of the present invention provides a stable pharmaceutical composition for oral administration comprising tadalafil particles having D90 particle size greater than about 40 urn, polymer, surfactant and/or solubilizer and one or more pharmaceutical^ acceptable excipients, wherein the polymer is hydrophilic binder, surfactant is non-ionic surfactant and solubilizer is lipid in nature.
Another object of the present invention is to provide a process for the preparation of a stable pharmaceutical composition of tadalafil comprising tadalafil particles having D90 particle size greater than about 40 urn. polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide a process for the preparation of granulation blend comprising tadalafil particles having D90 particle size greater than

about 40 μm, polymer, surfactant and/or soluhilizcr and one or more pharmaceutical!}' acceptable excipients.
Another object of the present invention is to provide a stable pharmaceutical composition of tadalafil for oral administration comprising ladalafil for treatment of sexual dysfunction, e.g., male erectile dysfunction and female sexual arousal disorder.
SUMMARY OF THE INVENTION
The present invention relates to a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 urn, polymer, surfactant and/or soluhilizcr and one or more pharmaceutically acceptable excipients. The said composition provides suitable solubility and dissolution of Tadalafil and achieves bioequivalence with respect to the reference product ClALIS® Furthermore, the present invention provides a suitable method for preparation of the said stable pharmaceutical composition of Tadalafil.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.
The present invention refers to a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μm and one or more pharmaceutically acceptable excipients. in order to provide suitable solubility and dissolution of Tadalafil and achieve bioequivalence with respect to the reference product CIALIS®.

The term "stable composition" refers to assay value of tadalafil in tadalafil pharmaceutical composition within the limits of 95% to !05% after stability study according to lCH guidelines which is comparable when compared with reference product CiALIS®.
The compositions known in the prior art utilized micronized form of Tadalafil (i.e. particle size below 40 μm) to achieve desired dissolution and bioavailability. However the present invention avoids the time-consuming step of particle size reduction and is successful in achieving improved dissolution with larger particle size of Tadalafil by incorporation of unconventional excipients in the Tadalafil composition. The said composition may contain Tadalafil either in amorphous or crystalline form or their combination, and provides an immediate release of Tadalafil.
In preferred embodiments, the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 urn. more preferably between 45 urn and 80 urn.
Preferably, the amount of tadalafil in the present invention is between about 0.2% and about 20%, between about 2% and about 18%), between about 2.5% and about 10%. or more preferably between about 3% and about 8% by weight of total composition.
Preferably, tadalafil is in crystalline form. However, amorphous and partially amorphous forms of tadalafil also are contemplated, and are included within the present invention.
Another preferred aspect of the present invention to provide a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μm. polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients.

Further, the inventors of the present invention tried to design composition for oral administration with an aim to provide suitable solubility and bioavailability of Tadalafil, and achieve bioequivalence with respect to the reference product C1ALIS by incorporation of surfactant and/or solubilizer in the composition comprising tadalafil particles having D90 particle size greater than about 40 urn. However, such compositions have significant limitations in terms of manufacturing due to the poor compressibility and waxy nature of lipid materials and surfactants. The present invention overcomes manufacturing limitations of said composition by incorporation of polymer which helps in achieving free flowing powder material with improved compressibility suitable for compression into tablet dosage form.
The term "polymer' as used herein refers to a pharmaceuticaily acceptable binder suitable for use in the present invention that includes for example, but is not limited thereto: low-viscosity hydroxypropylmelhylcellulose (HPMC). hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) or methylcellulose (MC). or povidone or starch or gelatin. Preferably, the polymer is a hydrophilic binder such as HPMC.
The term "surfactant" as used herein refers to a pharmaceuticaily acceptable non-ionic surfactant. Surfactants suitable for use in the present invention include for example, but are not limited thereto: polyoxyethylene alkyl ethers, polyoxyethylene alkyfaryl ethers, polyethylene glycol fatty acid esters (e.g, PBG-200 monolaurate, PEG-200 dilaurate.. PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate), alkylene glycol fatty acid mono esters (e.g. propylene glycol monolaurate). sucrose fatty acid esters (e.g. sucrose monostearate. sucrose distearate. sucrose monolaurate. sucrose dilaurate) or sorbitan fatty acid mono esters such as sorbitan mono laurate (Span ), sorbitan monooleate. sorbitan monopalmitate, or sorbitan slearate, or mixtures of one or more thereof. Preferably, the surfactant of the present invention is sorbitan stearate.

The term "solubilizer" as used herein refers to pharmaceutical!)-' acceptable solubilizer which are lipid in nature and suitable for use in the present invention thai includes for example, but are not limited thereto: phospholipid, glyceryl acetate, a fatty acid ester of an acetylated glyceride, lower alcohol fatty acid ester, propylene glycol ester or a combination thereof. Preferably, the solubilizer of the present invention is Capmul MCM (Glycerol Monocaprylocaprate).
In a preferred object, the present invention provides a process for the preparation of granulation blend comprising tadalafil particles having D90 particle size greater than about 40 urn, polymer, surfactant and/or solubilizer and one or more pharmaceutical!}' acceptable excipients.
"Granulated blend form" according to the present invention is defined as blend comprising tadalafil particles having D90 particle size greater than about 40 pm, polymer, surfactant and/or solubilizer and one or more pharmaceutical!)' acceptable excipients manufactured/prepared with organic solvent in a conventional granulator and shall be conveniently converted to capsules or tablets dosage forms.
Granulated blend form according to the present invention is a blend comprising tadalafil particles having D90 particle size greater than about 40 um is uniformly covered/embedded involving manufacturing process such as high shear granulator or fluidized bed processor with solubilizer and/or surfactant together dissolved in mixture of organic solvents. Additionally the said blend contains other pharmaceutical excipients known in the art suitably for preparation of tablets or capsule dosage form.
The pharmaceutical composition of the present invention is prepared by standard pharmaceutical manufacturing techniques known in prior art like wet granulation, dry granulation and direct compression, more preferably wet granulation method.

Solvents used in wet granulation method are selected from group of isopropyl alcohol, dichloromethane, acetone, ethanol, purified water and mixture thereof, more preferably isopropyl alcohol and dichloromethane are used in this invention.
Further, the composition according to present invention optionally comprises one or more oral, non-toxic, pharmaceutically acceptable excipient such as lactose, gelatin, starch, microcrystalline cellulose, talc, colloidal silicon dioxide, starch, magnesium stearate, stearic acid, and croscarmellose sodium.
According to the present invention, solubilizer and/or surfactant may be included additionally along with lubricants and glidants to the obtained granules post drying stage during granulation.
Another object of the present invention is to provide a process for the preparation of tadalafil comprising tadalafil. polymer, surfactant and one or more pharmaceutically acceptable excipients, wherein atleast 90% of particles of tadalafil having particle size greater than about 40 urn.
More preferably the stable pharmaceutical composition of the present invention provides
a process for the preparation of tadalafil having particle size greater than about 40 μm
comprising the following steps:
(a) sifting of tadalafil. diluents and disintegrant through mesh and transfer to the
granulator;
(b) dissolving binder into an organic solvent:
(c) granulating the ingredients of step (a) using the solution of step (b):
(d) dissolving surfactant and/or solubilizer into organic solvent and granulating with
components of step (c);
(e) drying the wet granules to get LOD less than 2%:
(0 sifting and lubricating the dried granules to get homogenous blend;

(g) compressing the lubricated blend into tablets and/or filled in capsule.
Yet another aspect of the present invention is to provide a method of treating sexual dysfunction in patients in need thereof comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising tadalafil particles having D90 particle size greater than about 40 urn and one or more pharmaceutically acceptable excipients.
Examples
The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.
Example 1:

Ingredients Function % w/w
Intra Granular
Tadalafil Active ingredient 4.17
Microcrvstalline Cellulose Diluent 4,33
Lactose Monohydrate Diluent 63.83
Croscarmellose Sodium Disintcgrant 5.00
Hydroxypropyl methyl cellulose Binder 1.00
Sorbitan stearate Surfactant/solubilizer 0.52
Capmul MCM (Glycerol Monocaprylocaprate) Solubilizer 0.52
Isopropyl alcohol Solvent q.s.
Dichloromethane Solvent q.s.
Extra Granular
Microcrystalline Cellulose Diluent 4.17
Lactose Monohydrate Diluent 10.42
Croscarmellose Sodium Disinteerant 5.00
Magnesium Stearate Lubricant 1.04
Total 100.0

Brief Manufacturing Process:
1. Sift tadalafil. MCC. iactose monohydrate and croscarmellose sodium through 40 mesh and transfer to RMG.
2. Dissolve. HPMC into DCM/1PA solvent mixture (60:40 ratio).
3. Granulate Step I using Step 2 solution using a laboratory scale rapid mixer granulator.
4. Dissolve sorbitan stearate and glycerol monocaprylocaprate into DCM/IPA solvent mixture and granulate step 3.
5. Dry the mass to get LOD less than 2%,
6. Sift the dried granules through 30 meshes for further improvement of homogenous API distribution.
7. Sift MCC. lactose monohydrate and croscarmellose sodium through 40 mesh and blend with step 6.
8. Sift magnesium stearate through 40 meshes and lubricate step 7.
9. Compressed the lubricated blend into tablets using a rotary tableiing machine to obtain immediate release tablets.
Example 2:

Ingredients Function % w/w
Intra Granular
Tadalafi! Active 4.17
Microcrystalline Cellulose Diluent 4.33
Lactose Monohydraie Diluent 63.04
Croscarmellose Sodium Disinteerant 5.00
Hydroxypropyl methyl cellulose Binder 2.31
Sorbitan stearate Surfaclant/solubilizcr 0.52
Isopropyl alcohol Solvent q.s.
Dichloromethane Solvent q.s.
Extra Granular
Microcrystalline Cellulose Diluent 4.17
Lactose Monohydraie Diluent 10.42
Magnesium Stearate Lubricant 1.04
Total 100.0

Brief Manufacturing Process:
1. Sift tadaiafil. MCC, lactose monohydrate and croscarmellosc through 40 mesh and transfer to RMG.
2. Dissolve HMPC into DCM/IPA solvent mixture (60:40 ratio).
3. Granulate Step 1 using Step 2 solution using a laboratory scale rapid mixer granulator.
4. Dissolve sorbitan stearatc into DCM/IPA solvent mixture and granulate step 3.
5. Dry the mass to get LOD less than 2%.
6. Sift the dried granules through 30 meshes for further improvement of homogenous API distribution.
7. Sift MCC and lactose monohydrate through 40 meshes and blend with step 6.
8. Sift magnesium slearate through 40 meshes and lubricate step 7.
9. Compressed the lubricated blend into tablets using a rotary tableting machine to
obtain immediate release tablets.
Dissolution study
Dissolution study of reference product and composition of example i & 2 of the invention were carried with USP dissolution apparatus II at 50 rpm using 1000ml of different medium & given in below tables.
Table 1: Comparable study of dissolution profile in 0.1N HCI with 0.5% SLS, Paddle, 50 rpm, 1000 ml

Time (Min) % Drug Release
CIA LIS* Example 1 D90=>40μm Example 2 D90= >40 μm
10 72 75 70
15 81 8! 83
20 86 85 87
30 90 89 90
45 92 90 91
60 93 90 92

Table 2: Comparable study of dissolution profile in Purified water with 0.5% SLS, Paddle, 50 rpm, 1000 ml (OGD)

Time (Min) % Drug Release

CIALIS® Example 3 D90=>40μm Example 2 D90=>40μm
10 83 91 80
15 90 94 89
20 93 96 92
30 94 96 93
45 95 97 93
60 97 97 94
As per the present invention, the pharmaceutical composition of ladalafil having particle size greater than 40 μm exhibits similar dissolution profile of tadalafil when compared with reference product ClALIS® shown in above table I and 2..
In view of the above, it is anticipated that the pharmaceutical composition of tadalafil as per the present invention is also bioequivalenl with the reference product CIALIS®.
Stability Study
Tablet of the above example 1 and 2 were packed and subjected to stability testing at long term (25cC/60% RH) and accelerated (40°C/ 75% RH) for 6 month in a thermostat chamber. HPLC method is used to determine the stability study and found to be stable by showing the assay of tadalafil in the range of 99%.
The invention that is intended to be protected herein, however, is not construed to be limited to the particular forms disclosed because they are to be regarded as illustrative rather than restrictive.

We claim:
1. A stable pharmaceutical composition of tadalafil comprising tadalafil and one or more pharmaceutically acceptable excipients. wherein atleast 90% of particles of tadalafil having particle size greater than about 40 urn.
2. A stable pharmaceutical composition of tadalafil comprising tadalafil. polymer, surfactant and one or more pharmaceuticallly acceptable excipients, wherein atleast 90% of particles of tadalafil having panicle size greater than about 40 μm.
3. The stable pharmaceutical composition according to claim 2. wherein the surfactant is nonionic surfactant.
4. The stable pharmaceutical composition according to claim 3, wherein the non ionic surfactant can be selected from polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid mono esters or mixtures thereof.
5. The stable pharmaceutical composition according to claim 2. wherein the polymer is hydrophilic binder.
6. The stable pharmaceutical composition according to claim 5. wherein the hydrophilic binder can be selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose. methyl cellulose or mixture thereof.
7. The stable pharmaceutical composition according to anyone of claim 1 to 6, further comprising a solubilizer.
8. The stable pharmaceutical composition according to claim 7, wherein the solubilizer is lipid in nature.
9. The stable pharmaceutical composition according to anyone of claim 1 to 8, wherein the excipients are selected from lactose, gelatin, microcrystalhne cellulose, talc, colloidal silicon dioxide, starch, magnesium stearate, stearic acid, and croscarmellose sodium and mixtures thereof.

10. A process for the preparation of stable pharmaceutical composition of tadalafil comprising tadalafil and one or more pharmaceutically acceptable excipients. wherein atleast 90% of particles of tadalafil having particle size greater than about 40 μm comprising following steps:
(a) sifting of tadalafil and one or more pharmaceutically acceptable excipients through mesh and transfer to the granulator;
(b) dissolving binder into an organic solvent;
(c) granulating the ingredients of step (a) using the solution of step (b);
(d) dissolving surfactant and/or solubilizer into organic solvent and granulating with components of step (c);
(e) drying the wet granules;
(f) sifting and lubricating the dried granules to get homogenous blend;
(g) compressing the lubricated blend into tablets and/or filled in capsule.