FIELD OF INVENTION

The invention relates to tadalafil compositions comprising tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient, wherein said composition comprises a solid dispersion of crystalline tadalafil. The invention also relates to process of preparing a solid dispersion of crystalline tadalafil and compositions of tadalafil comprising the same.

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 the US under the brand name of Cialis® and Adcirca® by Eli Lilly.

Tadalafil is practically insoluble in water and very slightly soluble in ethanol. Because of its insoluble nature, conventional formulations of tadalafil exhibit very poor dissolution rate and bioavailability. Thus, it is required to increase the dissolution rate and bioavailability of the drug for faster and quicker onset of action. A number of methods have been developed to increase the bioavailability of poorly soluble drugs like tadalafil which includes use of surfactants, particle size reduction, inclusion complexation and different solid dispersion methods.

US5985326 relates to solid dispersions of poorly soluble drugs like tadalafil 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.

US20080009502 and US20100099687 relate to solid composites including tadalafil and at least one carrier, wherein at least about 85 wt % of the tadalafil is in intimate association with the at least one carrier. Preferably, at least 85 wt % of the tadalafil is not in crystalline form.
It is well known in the art that, solid dispersion technique is employed to enhance the solubility and dissolution. This enhanced solubility and dissolution is by virtue of the drug being in the amorphous state in said dispersion which has increased solubility and dissolution as compared to crystalline form due to difference in thermodynamic properties. However, this conversion in phase may affect the stability as well as quality and purity of the product. It is quite difficult to make a solid dispersion wherein, the drug retains its original form during its further processing as well as during the shelf-life of the formulation containing said dispersion.

The present inventors have been successful in preparing a solid dispersion of tadalafil, wherein tadalafil remains crystalline in nature, as well as the composition comprising said dispersions also remains crystalline.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 illustrates an XRPD pattern of crystalline tadalafil active ingredient.

Figure 2 illustrates an overlay of the XRPD pattern of crystalline tadalafil active ingredient, placebo and the solid composite.

Figure 3 illustrates an overlay of the XRPD pattern of crystalline tadalafil active ingredient, placebo and the tablet.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to tadalafil compositions comprising tadalafil or its pharmaceutically acceptable salts thereof and atleast one or more pharmaceutically acceptable excipient, wherein the composition comprises a solid dispersion of crystalline tadalafil. The invention also relates to process of preparing a solid dispersion of crystalline tadalafil and composition of tadalafil comprising solid dispersion.

In one embodiment, the invention provides solid dispersion of crystalline tadalafil or its pharmaceutically acceptable salts thereof and optionally other pharmaceutically acceptable excipients.

In another embodiment, the invention provides compositions comprising solid dispersion of crystalline tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient.

In further embodiment, the invention relates to a process of preparing a solid dispersion of crystalline tadalafil or its pharmaceutically acceptable salts thereof.

In yet another embodiment, the invention relates to a process of preparing compositions of tadalafil comprising solid dispersion of crystalline tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient.

The invention also provides an invitro drug dissolution profile of the composition prepared according to the invention which comparatively matches with the commercially available Cialis®.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to tadalafil compositions comprising tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient, wherein the composition comprises a solid dispersion of crystalline tadalafil.

The invention also relates to a process of preparing a solid dispersion of crystalline tadalafil and composition of tadalafil comprising solid dispersion.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for tadalafil or its pharmaceutically acceptable salts thereof.

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 "dispersion" or "solid dispersion" as used herein is defined as a system in a solid state that comprises at least two components, wherein one component is dispersed substantially evenly throughout the other component or components. It may be used interchangeably and synonymously for "pre-mix" or "admixture" or "composite" or "solid composite" to name a few.

The term "crystalline," as used herein, means having a physical state that is a regular three-dimensional array of atoms, ions, molecules or molecular assemblies.

The term "amorphous," as used herein, means a physical state without having regular arrangement of atoms, ions, molecules or molecular assemblies i.e., an unorganized structure.

Solid dispersion is a well known method for enhancement of solubility and dissolution of poorly soluble drugs. The solid dispersion of the present invention may be prepared by a number of techniques including solvent evaporation, melt adsorption, fusion, spray drying, spray granulation, spray freezing, spray congealing, melt extrusion, and supercritical fluid precipitation etc.

According to an embodiment of the invention, preferred method of preparing the solid dispersion comprising tadalafil and atleast one pharmaceutical excipient is by spray granulation or solvent evaporation technique. The method involves atomization of the feed solution or suspension in the chamber of a fluid bed-type processor or a pan-coater which is charged with inert filler material. During drying the filler becomes agglomerated and/or coated and/or layered by the in-situ formation of the solid dispersion by evaporation or spray-drying of the feed solution or dispersion comprising tadalafil. Either of the bottom spray mode or a top spray mode can be used.

The solid dispersion prepared according to an embodiment of the invention is formulated in to suitable dosage forms by methods known in the art.

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-formers, plasticizers, coloring agents, flavoring agents, sweetening agents, preservatives, antioxidants and the like.

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

Suitable solvents that may be used for preparing the 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; 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 tablets 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 invention also relates to process for preparing tadalafil compositions comprising solid dispersion of tadalafil or its pharmaceutically acceptable salts thereof, wherein, said process comprises the steps of:

i) Adding drug , surfactants and binder in the solvent under stirring,

ii) Granulating lactose with the dispersion of step (i).

iii) Adding diluent and disintegrant to the granules of step (ii) followed by lubrication;

iv) Compressing the lubricated blend of step (iii) in to tablets.

v) Optionally coating the tablets with a film former.

Determination of phase conversion of tadalafil either in pure form or in the pharmaceutical compositions comprising the dispersions of said drug can be determined by using analytical techniques like X-ray diffraction analysis, differential scanning calorimetry, optical microscopy etc. The invention uses X-ray diffraction analysis to determine the physical form of the drug in pure form as well as in the composition.

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.

Exam pie-1

Composition for Tadalafil Solid Composite:

Table

Brief Manufacturing Process:

1. Add Tadalafil, Sodium lauryl sulfate and Povidone in Dimethyl sulfoxide and Acetone solvent mixture under stirring to form solution.

2. Disperse poloxamer 188 to step-1 under stirring.

3. Remove the solvent to get solid composite.

Example-2

Unit Composition:

Table

Brief manufacturing Process:

1. Add tadalafil, sodium lauryl sulfate and povidone in a mixture of acetone and dimethyl sulfoxide solvent under stirring.

2. Add poloxamer to step-1 under stirring.

3. Granulate lactose using step-2 dispersion.

4. Add microcrystalline cellulose, croscarmellose sodium & colloidal silicon dioxide to step-3 granulates and blends.

5. Lubricate the step-4 materials using Magnesium stearate.

6. Compress the step-5 blend to tablet.

Example-3

Unit Composition:

Table

Brief Manufacturing Process:

1. Add Tadalafil, Sodium lauryl sulfate and Povidone in Dimethyl sulfoxide and Acetone solvent mixture under stirring to form solution.

2. Disperse poloxamer 188 to step-1 under stirring.

3. Granulate lactose using step-2 dispersion in Fluid bed processor.

4. Add microcrystalline cellulose, croscarmellose sodium & Colloidal silicon dioxide to step-3 granules and blend.

5. Lubricate the step-4 materials using Magnesium stearate.

6. Compress the step-5 blend to tablet.

7. Disperse Opadry or Instacoat in water and film coat the step-6 core tablets.

Dissolution Study:

The composition as disclosed in Example 2 & 3 comprising the dispersion of crystalline tadalafil were studied for drug release in 1000 ml of aqueous media, containing 0.25 wt% sodium lauryl at 37°C, USP apparatus II (paddle) rotating at a speed of 25 rpm; and the results are tabulated in Table 1 given below:

Table 1

WE CLAIM:

1. A solid dispersion comprising tadalafil or its pharmaceutically acceptable salts thereof and optionally other pharmaceutically acceptable excipients, wherein said tadalafil is substantially in crystalline state.

2. A pharmaceutical composition comprising solid dispersion of tadalafil or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient, wherein said solid dispersion comprises tadalafil in substantially crystalline state.

3. A process for preparing solid dispersion comprising tadalafil or its pharmaceutically acceptable salts thereof in substantially crystalline state and optionally other pharmaceutically acceptable excipients, wherein said process comprises the steps of:

i. Dissolving / Dispersing tadalafil, and one or more pharmaceutically acceptable excipients in a solvent to get a solution/ dispersion; and

ii. Drying said solution/ dispersion of step (i) to get the solid dispersion of tadalafil.

4. A process for preparing a pharmaceutical composition comprising crystalline tadalafil solid dispersion and at least one pharmaceutically acceptable excipient, wherein said process involves the following steps:

i. Preparing granulate comprising tadalafil dispersion along with at least one filler and optionally other excipients, by wet granulation;

ii. Drying said granulate;

iii. Blending said granulate of step (ii) with extra-granular excipient;

iv. Compressing said blended granulate of step (iii) to get the tablet; and

v. Optionally coating said tablet with a film coating material.

5. The solid dispersion according to claim 1, wherein said excipient is selected from a group consisting of binders, surfactants, and hydrophilic polymers or combinations thereof.

6. The process according to claim 3, wherein said solvent is selected from a group consisting of acetone, dimethylsulfoxide, isopropyl alcohol, dimethylformamide, dichloromethane, ethanol, methanol, methyl ethyl ketone, ethyl acetate, acetonitrile, and combinations thereof.

7. The process according to claim 3, wherein said drying is carried out by evaporation or spray drying or spray granulation of the solution or dispersion comprising tadalafil.

8. The excipient according to claim 2 or 4, is selected from a group consisting of fillers, diluents, binders, disintegrants, lubricants, glidants or their combinations thereof.

9. A solid dispersion of tadalafil having the following ingredients:

Table

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

Table