FIELD OF INVENTION

The invention relates to compositions comprising tadalafil or its pharmaceutically acceptable salts thereof together with one or more pharmaceutically acceptable excipients, wherein said composition is prepared by using a solution/ dispersion of tadalafil in a suitable solvent, wherein said solution/ dispersion of tadalafil is free of any other pharmaceutically acceptable excipient and further incorporating said solution/ dispersion of tadalafil for granulation.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Tadalafil is a cyclic guanosine monophosphate ("cGMP") specific phosphodiesterase type 5 ("PDE5") inhibitors. It is indicated for the treatment of erectile dysfunction in men and pulmonary hypertension. Tadalafil has a much longer duration of action because of its longer half-life (17.5 hr) than other PDE5 inhibitors like either sildenafil or vardenafil (4-5 hr). It is marketed in US under the brand name of Cialis® and Adcirca® by Eli Lilly.

Tadalafil is practically insoluble in water and very slightly soluble in ethanol. Conventional formulations of tadalafil exhibit very poor dissolution rate and bioavailability due to its insoluble property. So, it is required to increase the dissolution rate and bioavailability of the drug for faster and quicker onset of action. A number of processes for preparing compositions of tadalafil have been found out which results in products with increased bioavailability.

US5985326 relates to solid dispersions of poorly soluble drugs like tadalafil, its method of preparation and its use in pharmaceutical compositions.

US7182958 relates to composition comprising tadalafil wherein the bioavailability is enhanced by milling the active ingredient so that D90 of the active ingredient is less than 40 microns.

US20070104792 relates to compositions comprising nanoparticulate tadalafil, or a salt or derivative thereof, having improved bioavailability, faster rates of absorption and a faster onset of therapeutic effect.

US20100099687 and US20080009502 relates to a solid composite comprising tadalafil and at least one carrier and is prepared by combining tadalafil with at least one carrier, and at least one solvent to form a solution; and finally by removing the solvent from the combination to obtain the solid composite.

US20090098211 relates to a solid pharmaceutical dosage form comprising tadalafil and starch, wherein tadalafil has a particle size distribution such that d (0.9) is greater than or equal to 40 urn, and wherein the weight ratio of starch to tadalafil is about 4.5:1 or more.

Though several processes for preparing compositions comprising tadalafil with enhanced dissolution and bioavailability are known in the prior art, still there is a need to develop a process which is simple, cost effective and less time consuming.

The present inventors have successfully developed a process of preparation of tadalafil compositions which is simple, cost effective and results in product having similar dissolution profile matching with that of Cialis®/ Adcirca.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to compositions comprising tadalafil or its pharmaceutically acceptable salts thereof together with one or more pharmaceutically acceptable excipients, wherein said composition is prepared by using a solution/ dispersion of tadalafil in a suitable solvent wherein said solution/ dispersion is free of any other pharmaceutically acceptable excipients and further incorporating said solution/ dispersion of tadalafil for granulation.

One aspect of the invention relates to a process of preparing tadalafil solution/ dispersion in a suitable solvent wherein said solution/ dispersion is free of any other pharmaceutically acceptable excipient.

Another aspect of the invention relates to a process of preparation of compositions comprising tadalafil or its pharmaceutically acceptable salts thereof together with one or more pharmaceutically acceptable excipients, wherein said composition is prepared by using a solution/ dispersion of tadalafil in a suitable solvent wherein said solution/ dispersion is free of any other pharmaceutically acceptable excipient and further incorporating said solution/ dispersion of tadalafil for granulation.

Yet, another aspect of the invention relates to a process of preparing compositions comprising tadalafil or its pharmaceutically acceptable salts thereof together with one or more pharmaceutically acceptable excipients, wherein said process comprises the steps of: dissolving/ dispersing tadalafil in a suitable solvent to form a solution/ dispersion, granulating the premixed pharmaceutically acceptable excipients with the prepared solution/ dispersion, and finally lubricating the prepared granules followed by compression to obtain tablets.

One more aspect of the invention relates to pharmaceutical compositions comprising tadalafil prepared according to the invention, wherein the invitro drug release profile matches with that of the commercially available Cialis®/ Adcirca .

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to compositions comprising tadalafil or its pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients, wherein said composition is prepared by using a solution/ dispersion of tadalafil in a suitable solvent, wherein said solution/ dispersion is free of any other pharmaceutically acceptable excipient and further incorporating said solution/ dispersion of tadalafil for granulation.

The invention also relates to a process of preparation of compositions comprising tadalafil or its pharmaceutically acceptable salts thereof together with one or more pharmaceutically acceptable excipients, wherein said composition is prepared by using a solution/ dispersion of tadalafil in a suitable solvent wherein said solution/ dispersion is free of any other pharmaceutically acceptable excipient and further incorporating said solution/ dispersion of tadalafil for granulation.

Yet in other aspects, the invention relates to a process of preparing tadalafil solution/ dispersion in a suitable solvent wherein said solution/ dispersion is free of any other pharmaceutical acceptable excipient.

The term "compositions" as used herein refers to dosage form for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets.

The term "pharmaceutically acceptable excipient" as used herein refers to any ingredient that may be added to the formulation besides the active ingredient.

The term "incorporating" as used herein refers to adding said solution/ dispersion of drug in to other excipients and granulating them together.

The term "solution" as used herein refers to a system where the drug is homogeneously dissolved in a suitable solvent, which solution is free of any other pharmaceutically acceptable excipient.

The term "dispersion" as used herein refers to a system where the drug particles are dispersed in a suitable solvent, which dispersion is free of any other pharmaceutically acceptable excipient.

Different methods used for enhancing solubility and bioavailability of poorly soluble drugs like, the use of surfactant, size reduction, complexation and solid dispersions etc. are complicated, time consuming and also involve use of advanced equipments. In comparison to other processes using organic solvents, like co-precipitation, the process disclosed in the invention requires lesser amount of solvent, thereby making it environment friendly and commercially viable. In solid dispersion techniques there is always a chance of phase conversion which may affect the stability and purity of the dosage form. The current invention discloses tadalafil compositions which are prepared by a process which neither consumes much time like size reduction nor shows the problems associated with solid dispersion but results in an enhanced bioavailable product.

The composition according to an embodiment of the invention in addition to the active ingredient may comprise one or more pharmaceutically acceptable excipients which include, but are not limited to diluents, lubricants, binders, surfactants, film-former, plasticizers, coloring agent, flavoring agents, sweetening agents, preservatives, antioxidants and the like or combinations thereof.

Diluents used include, but are not limited to microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.

Binders used include, but are not limited to acacia, alginic acid, carbomer copolymer, carbomer interpolymer, copovidone, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose and the like.

Surfactants used as solubilizer include, but not limited to (a) nonionic surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines (b) anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, negatively charged phospholipids and negatively charged glyceryl esters (c) cationic surfactants such as quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitosans and lauryldimethylbenzylammonium chloride.

Lubricants used include, but are not limited to colloidal silicon dioxide, talc, stearic acid and its salts.

Suitable solvents that may be used for preparing the solution/ dispersion include organic, aqueous, or a mixture thereof. Organic solvents may be aliphatic alcohols such as methanol, ethanol, n-propanol, and isopropanol; aliphatic ketones such as acetone and methyl ethyl ketone; aliphatic carboxylic esters such as ethyl acetate; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile; chlorinated hydrocarbons such as dichloromethane; aliphatic sulfoxides such as dimethyl sulfoxide (DMSO); and the like, as well as mixtures comprising at least one of the foregoing organic solvents. Aqueous solvents include solvent comprising water and/ or a water-miscible organic solvent such as a lower alcohol, acetonitrile, tetrahydrofuran, dimethylacetamide, dimethyl formamide, and the like. Combination of various solvents can also be used.

The compositions comprising tadalafil or its pharmaceutically acceptable salts thereof, disclosed according to an embodiment of the invention, are prepared by a process comprising the following steps:

(i) Dissolving/ dispersing tadalafil in a suitable solvent, to form a solution/ dispersion;

(ii) Granulating the pharmaceutically acceptable excipients with the prepared solution/ dispersion of step (i) to get granules;

(iii) Lubricating said granules of step (ii) to get lubricated granules;

(iv) Compressing said lubricated granules into tablets.

More particularly, the compositions according to an embodiment of the invention are prepared by a process comprising the steps of:

(i) dissolving 1 part of tadalafil in 2 parts of dimethyl sulfoxide or ethanol under stirring at room temperature;

(ii) granulating the premixed pharmaceutically acceptable excipients with the prepared solution/ dispersion of step (i);

(iii) lubricating the prepared granules of step (ii) and

(iv) compressing said lubricated granules of step (iii) in to tablets.

The granulation according to the invention involves wet kneading, high shear granulation, fluid bed granulation, rotor processing or spray granulation or any other suitable wet granulation process.

The tablets prepared according to the invention may be optionally coated with a film-former that comprises polymers such as cellulose derivatives or other commercially available coating compositions such as Instacoat , Opadry etc.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example-1

Unit Composition:


Brief manufacturing Process:

1. Dissolve/ disperse tadalafil in water.

2. Granulate mixture of sodium lauryl sulfate, poloxamer, lactose and crsocarmellose sodium using step - 1 drug solution.

3. Blend MCC, croscarmellose sodium and colloidal silicon dioxide along with granules of step-2.

4. Lubricate the step-3 materials using magnesium stearate.

5. Compress the step-4 blend to tablets.

Example-2

Unit Composition:

The composition given in Example 2 was prepared according to the procedure given for Example 1.

Example-3

Unit Composition:

Brief manufacturing Process:

1. Dissolve/disperse tadalafil in DMSO.

2. Granulate mixture of sodium lauryl sulfate, poloxamer, lactose and crsocarmellose sodium using step - 1 drug solution.

3. Blend MCC, extragranular crsocarmellose sodium and colloidal silicon dioxide along with granules of step-2.

4. Lubricate the step-3 materials using magnesium stearate.

5. Compress the step-4 blend to tablets and

6. Optionally coated the tablets of step 5 with Opadry™ solution.

Dissolution Study:

The tablets as disclosed in Example 1 and 2 were studied for drug release in 1000 ml of aqueous media containing 0.14 wt% sodium lauryl sulfate at 37°C, using USP dissolution apparatus II (paddle) with the paddle speed set at 50 rpm; and the corresponding results are tabulated in Table 1 below:

Table 1

Further, the tablet as disclosed in Example 3 was subjected to accelerated conditions [40°C/75% RH] for 8 weeks and parameters such as assay, drug dissolution and related substances were analyzed. Samples were analyzed by HPLC method and the results are summarized in Table 2.

Table-2

WE CLAIM:

1. A solution consisting of tadalafil, dissolved in a suitable solvent, wherein said solution is free of any other pharmaceutically acceptable excipient, used for preparing a composition comprising tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

2. A dispersion consisting of tadalafil, dispersed in a suitable solvent, wherein said dispersion is free of any other pharmaceutically acceptable excipient, used for preparing a composition comprising tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

3. A composition comprising tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein said composition is prepared using a solution/ dispersion of tadalafil in a suitable solvent, wherein said solution/ dispersion is free of any other pharmaceutically acceptable excipient.

4. A process for preparing a tablet comprising tadalafil or its pharmaceutically acceptable salts thereof, and atleast one pharmaceutically acceptable excipient, wherein said process comprises the steps of:

(i) Dissolving/ dispersing tadalafil in a suitable solvent, to form a solution/ dispersion;

(ii) Granulating the pharmaceutically acceptable excipients with the prepared solution/ dispersion of step (i) to get granules;

(iii) Lubricating said granules of step (ii) to get lubricated granules;

(iv) Compressing said lubricated granules into tablets.

5. The solvent according to any of the preceding claims is an organic solvent or an aqueous solvent or their combinations thereof.

6. The organic solvent according to claim 5, is selected from a group comprising of methanol, ethanol, n-propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, toluene, xylene, hexane, acetonitrile, dichloromethane, dimethyl sulfoxide or their combinations thereof.

7. The aqueous solvent according to claim 5, is either water or water-miscible lower alcohols or their combination thereof.

8. The pharmaceutically acceptable excipient according to any of the claims 1-4, is selected from a group comprising diluents, binders, surfactants, preservatives, antioxidants, glidants, lubricants, film-former, plasticizers, coloring agent, flavoring agents, sweetening agent, or their combination thereof.

9. A tablet composition of tadalafil having the following ingredients per
unit:

10. A tablet composition of tadalafil having the following ingredients per unit: