WO2015000853A1

WO2015000853A1 - Pharmaceutical composition comprising a solid dispersion of tadalafil

Info

Publication number: WO2015000853A1
Application number: PCT/EP2014/063863
Authority: WO
Inventors: Deepak Murpani; Manuel GAGO GUILLAN; Marta VIVANCOS MARTINEZ
Original assignee: Synthon B.V.
Priority date: 2013-07-05
Filing date: 2014-06-30
Publication date: 2015-01-08

Abstract

The present invention relates to a pharmaceutical composition comprising a solid dispersion of tadalafil in a polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer and a process to prepare said composition in a fluid bed granulator or a high shear granulator.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A SOLID DISPERSION OF TADALAFIL

Tadalafil ((6R-trans)-6-(l,3-benzodioxol-5-yl)- 2,3 ,6,7,12, 12a-hexahydro-2-methyl- pyrazino [Γ, 2':1,6] pyrido[3,4-b]indole-l ,4-dione) of formula (1)

is a pharmaceutically active compound used for the treatment of erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) under the name Cialis® and, under the name Adcirca®, for the treatment of pulmonary arterial hypertension. The compound was discovered by ICOS and disclosed in W09519978. Tadalafil is poorly soluble in water; therefore it needs to be formulated in such a way that the dissolution and bioavailability is improved.

W09638131 discloses solid dispersions in the form of co-precipitates of tadalafil with hydroxypropyl methylcellulose phthalate. However, when measuring the dissolution of formulations prepared with these co-precipitates, we found that these were too low to expect a good bioavailability. Therefore, co-precipitation with hydroxypropyl methylcellulose phthalate is not a suitable method to increase the bioavailability of tadalafil.

WO0108688 discloses that a formulation comprising tadalafil milled to a particle size with d90 less than 10 microns has improved bioavailability. However, milling to such small particle sizes can result in reduced flowability, loss of active substance and can influence chemical and polymorphic stability of the active ingredient. WO2008005039 discloses composites of tadalafil and water soluble polymers, prepared by dissolving tadalafil and a hydrophilic polymer in ethanol and subsequently spray drying the solution to obtain a powder that can be used to prepare a pharmaceutical formulation (no examples given of the pharmaceutical formulation). All examples given use large quantities of ethanol, about 1000 ml per gram tadalafil, which makes the process unsuitable for commercial scale.

WO2011012217 discloses formulations comprising a co-precipitate of tadalafil with an acrylate polymer with cationic character. The co-precipitate is mixed with other excipients and compressed into tablets. The process to prepare the co-precipitate is tedious, the co-precipitate needs to be dried at relatively high temperature (50°C) for a long period of time (20 hours), which may result in degradation of the active ingredient.

WO2012095151 discloses formulations prepared by fluid bed granulation using a solution of tadalafil and spraying it on a water insoluble polymer mixed with a diluent. It is necessary to perform the fluid bed granulation at high temperatures, which might increase levels of impurities. The obtained granulate is mixed with other excipients and compressed into tablets. The examples mention the use of ethyl cellulose as water insoluble polymer, which is often used in extended release formulations and can negatively influence dissolution and hence

bioavailability.

In view of the cited prior art above there is a need of compositions comprising tadalafil and processes to prepare these compositions that do not have the disadvantages mentioned above.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical composition comprising a solid dispersion of tadalafil in a polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, exhibiting a dissolution rate of at least about 85 wt% within 15 min when tested in 1000 ml of aqueous medium containing 0.35 wt% SDS in a USP apparatus II at 50 rpm.

Additionally, the invention provides a process for preparing said pharmaceutical composition comprising the steps of:

a. dissolving tadalafil and a polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer in a suitable solvent or mixture of solvents;

b. granulating a suitable filler using the solution of step a; and

c. drying the granulate.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 Dissolution profile of a pharmaceutical formulation in accordance with the present invention comprising a solid dispersion of amorphous tadalafil compared to the dissolution profile of Cialis ® 20 mg IR tablets in 1000 ml of aqueous 0.35 wt% SDS in a USP apparatus II at 50 rpm.

Fig. 2 XRPD of a granulate obtained by fluid bed granulation of tadalafil: Soluplus (weight ratio 1 :5) indicating tadalafil to be present in an amorphous form in said granulate

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is provided so that the subject invention may be more fully understood by those skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the meaning as commonly understood by one of ordinary skill in the art.

The present invention relates to a pharmaceutical composition comprising a solid dispersion of tadalafil in a polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, exhibiting a dissolution rate of at least about 85 wt% within 15 min when tested in 1000 ml of aqueous medium containing 0.35 wt% SDS in a USP apparatus II at 50 rpm.

In accordance with the present invention with the term "solid dispersion" is meant a solid product consisting of a hydrophobic drug, i.e. tadalafil, and a hydrophilic matrix, i.e. the copolymer, in which the drug tadalafil is molecularly dispersed in said copolymer. In said solid dispersion, tadalafil is present in an amorphous form.

The weight ratio tadalafil: copolymer ranges from 1 :2 to 1 :8, preferably from 1 :3 to 1 :7, more preferably from 1 :4 to 1 :6, most preferred is a ratio of 1 :5.

A suitable polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer is marketed by BASF under the trade name Soluplus®.

Preferably, the composition of the present invention additionally comprises a filler. The filler to be used in accordance with the present invention may be any filler known to a person of ordinary skill in the art. Particularly, the filler to be used in accordance with the present invention is an inorganic filler, polysaccharide, mono-or disaccharide or sugar alcohol. Advantageously, the filler used in accordance with the present invention is selected from the group consisting of microcrystalline cellulose, magnesium aluminometasilicate and starch. Microcrystalline cellulose is a particularly preferred filler.

Preferably, the composition of the present invention additionally comprises a disintegrant. The disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of croscarmellose,

crospovidone and sodium starch glycolate. Croscarmellose is a particularly preferred

disintegrant.

Preferably, the composition of the present invention additionally comprises a lubricant. The lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant.

XRPD analysis experiments of the compositions of the present invention show no crystalline peaks (see e.g. Fig. 2), indicative of the absence of free (crystalline) tadalafil and indicative of an amorphous solid dispersion. The pharmaceutical composition of the present invention displays dissolution behavior typical for immediate release formulations (see e.g. Fig. 1), without the need of using a micronized tadalafil as active pharmaceutical ingredient. In the compositions of the present invention, tadalafil is not present in the composition as particles, but it is molecularly dispersed in a hydrophilic matrix, which is the polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, wherein the interaction with the water soluble polymer contributes to the enhanced dissolution of tadalafil.

The present invention further provides a process for preparing said pharmaceutical composition comprising a solid dispersion of tadalafil in a copolymer described above comprising the steps of:

a. dissolving tadalafil and a polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer in a solvent or mixture of solvents;

b. granulating a suitable filler using the solution of step a; and

c. drying the granulate. The solvent or mixture of solvents to be used in accordance with the present invention may be any solvent or mixture of solvents known to a person of ordinary skill in the art. Importantly, both tadalafil and copolymer are completely dissolved.

Advantageously, the solvent used in accordance with the present invention may be a polar organic solvent while the mixture of solvents may be a mixture of polar organic solvents or a mixture of a polar organic solvent with water. Suitable polar organic solvent to be used in accordance with the present invention include aprotic polar organic solvents selected from the group consisting of ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, and acetone. Particularly preferred aprotic polar organic solvents are tetrahydrofuran and acetone. A particularly preferred mixture of an aprotic polar organic solvent with water is a mixture of acetone and water.

Especially preferred is a mixture of acetone and water in a weight ratio of from about 8:2 to about 9:1 , more preferably a weight ratio of from 8.5:1.5 to 9:1. Typically, lgram of tadalafil and 5 grams of copolymer (Soluplus) are dissolved in about 18 to 20 grams of the

aforementioned solvent mixture.

Step a of the process in accordance with the present invention typically is performed at a temperature of from about 25 °C to about 50°C. In an advantageous variant of the invention process, step a is performed at a temperature of from about 40°C to about 50°C.

Preferably, the process of the present invention is performed in a fluid bed granulator or a high sheer granulator, most preferably in a fluid bed granulator.

Preferably, the process according to the present invention further comprises the steps of mixing the dried and optionally sieved granulate with a disintegrant, a lubricant, and optionally one or more additional pharmaceutically acceptable excipients, and compressing the mix into a tablet, using procedures and equipment well-known to a person skilled in the art.

The process of the present invention is advantageous as it avoids the use of large quantities of solvents and tedious communition procedures. Furthermore, the process of the invention requires short granulation times. For these reasons it is easy to perform the process of the invention on a commercial scale.

The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

EXAMPLES

Example 1

High shear granulation

Soluplus and tadalafil are mixed and dissolved in acetone, or a mixture of acetone:water 9:1 and optionally heated to 50°C. Microcrystalline cellulose is added to a high shear granulator equipped with double jacket heating and heated to 50-60°C. The tadalafil / Soluplus solution is sprayed onto the microcrystalline cellulose for 1 minute in intervals of 2 minutes during granulation until the total amount of solution is added. Granulation is continued until a loss of drying of < 3%. XRPD is measured of the obtained granules and no peaks indicative of crystalline tadalafil are observed. The obtained granules are sieved through a 0.710 mm mesh sieve. Disintegrant (croscarmellose) is mixed with the sieved granules for 15 min and finally, lubricant (magnesium stearate) is sieved through a 0.500 mm mesh sieve and mixed with the previous blend for 5 min. The lubricated blend is compressed in an eccentric machine to get tablets of 480 mg and hardness of 60N. The dissolution of the tablets is measured in 1000 ml of aqueous medium containing 0.35 wt% SDS in a USP apparatus II at 50 rpm, the tablets showed a dissolution rate of at least about 85 wt% within 15 min.

Example 2

Fluid bed process

Soluplus and tadalafil were mixed and dissolved in an appropriate solvent (acetone, or a mixture of acetone:water, optionally heated to 50°C). Microcrystalline cellulose was added to the fluid bed granulator. The tadalafil/Soluplus solution was sprayed onto microcrystalline cellulose at 10-15 rpm. The process was performed with an inlet air temperature of 60°C. After addition of the solution, granulation was continued until a loss of drying of < 3%. XRPD (see Fig. 2) was measured of the obtained granules and no peaks indicative of crystalline tadalafil were observed. The obtained granules were sieved through a 0.710 mm mesh sieve. Disintegrant (croscarmellose) was mixed with the sieved granules for 15 min and finally, lubricant

(magnesium stearate) was sieved through a 0.500 mm mesh sieve and mixed with the previous blend for 5 min. The lubricated blend was compressed in an eccentric machine to get tablets of 480 mg and hardness of 60N. The dissolution of the tablets (see Fig. 1) was measured in 1000 ml of aqueous medium containing 0.35 wt% SDS in a USP apparatus II at 50 rpm, the tablets showed a dissolution rate of 98 wt% within 15 min.

Claims

1. A pharmaceutical composition comprising a solid dispersion of tadalafil in a polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, exhibiting a dissolution rate of at least about 85 wt% within 15 min when tested in 1000 ml of aqueous medium containing 0.35 wt% SDS in a USP apparatus II at 50 rpm.

2. The composition according to claim 1 , wherein the weight ratio of tadalafil: copolymer ranges of from 1 :2 to 1 :8.

3. The composition according to claim 1 or 2, wherein the weight ratio of tadalafil:

copolymer ranges of from 1 :3 to 1 :7, preferably of from 1 :4 to 1 : 6.

4. The composition according to any one of claims 1 to 3, wherein the weight ratio tadalafil: copolymer is 1 :5.

5. The composition according to any one of claims 1 to 4, further comprising a filler.

6. The composition according to any one of claims 1 to 5, further comprising a disintegrant.

7. The composition according to any one of claims 1 to 6, further comprising a lubricant.

8. A process for preparing the composition according to any one of claims 1 to 7, comprising the steps of

b. granulating a filler using the solution of step a; and

c. drying the granulate.

9. The process according to claim 8, wherein the weight ratio of tadalafil: copolymer ranges of from 1 :2 to 1 :8.

10. The process according to claim 8 or 9, wherein the solvent is selected from the group consisting of ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, and acetone.

11. The process according to any one of claims 8 to 10, wherein the solvent is acetone.

12. The process according to claim 8 or 9, wherein the mixture of solvents is a mixture of acetone and water in a weight ratio of from about 8:2 to about 9:1, preferably of from 8.5:1.5 to 9:1.

13. The process according to any one of claims 8 to 12, wherein the granulation is carried out in a fluid bed granulator or a high sheer granulator.

14. The process according to any one of claims 8 to 12, wherein step a is performed at a temperature of from about 25 °C to about 50°C.

15. The process according to any one of claims 8 to 14, further comprising the steps of

a. mixing the dried and optionally sieved granulate with a disintegrant, a lubricant and optionally one or more additional pharmaceutically acceptable excipients, and b. compressing the mix into a tablet.