WO2014202797A1

WO2014202797A1 - Pharmaceutical composition comprising a solid dispersion of tadalafil

Info

Publication number: WO2014202797A1
Application number: PCT/EP2014/064359
Authority: WO
Inventors: Deepak Murpani; Lisardo ÁLVAREZ FERNÁNDEZ; Manuel GAGO GUILLAN; Marta VIVANCOS MARTINEZ
Original assignee: Synthon B.V.
Priority date: 2013-07-05
Filing date: 2014-07-04
Publication date: 2014-12-24
Also published as: MX2015016865A; RU2016103637A; RU2673228C2; RU2016103637A3

Abstract

The present invention relates to a pharmaceutical composition comprising a solid dispersion of tadalafil in at least two different types of polymers: a. At least one polymer soluble in aqueous medium up to pH 5.0; b. At least one polymer with pH dependent solubility soluble above pH 5.0; exhibiting a dissolution rate of at least about 85 wt% within 20 min when tested in 1000 ml of phosphate buffer (pH 6.8) + 0.35 wt% SDS in a USP apparatus II (peak vessels) at 50 rpm and a wet granulation process to prepare said composition.

Description

P1644PC01

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- 1,4-dione) of formula (1)

is a pharmaceutically active compound used for the treatment of erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) marketed under the name Cialis® as a 2.5, 5, 10 and 20 mg tablet and, under the name Adcirca® as a 20 mg tablet, for the treatment of pulmonary arterial hypertension. The compound was discovered by ICOS Corporation and first 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 a formulation comprising tadalafil milled to a particle size with d90 less than 10 microns having 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 a relatively high temperature for a long period of time (20 hours), which may result in degradation of the active ingredient.

WO2012095151 discloses formulations prepared by fluid bed hot melt 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 prior art cited above there is a need for compositions comprising tadalafil exhibiting good dissolution and bioavailability and processes to prepare these compositions that do not have the disadvantages mentioned above. BRIEF DESCRIPTION OF THE INVENTION

It has now been found that a solid dispersion of tadalafil stabilizing tadalafil in an amorphous form in at least two different types of polymers: at least one polymer soluble in aqueous medium up to pH 5.0 and at least one polymer with pH dependent solubility soluble above pH 5.0 provide the optimal level of bioavailability of tadalafil such that the

pharmaceutical composition is bioequivalent in fed and fasting state to the currently marketed product Cialis®.

In one embodiment the present invention provides a pharmaceutical composition comprising a solid dispersion of tadalafil in at least two different types of polymers, at least one polymer soluble in aqueous medium up to pH 5.0 and at least one polymer with pH dependent solubility soluble above pH 5.0, exhibiting a dissolution rate of at least about 85 wt within 20 min when tested in 1000 ml of phosphate buffer (pH 6.8) + 0.35 wt% SDS in a USP apparatus II (peak vessels) at 50 rpm.

In a second embodiment the invention provides a process for preparing said

pharmaceutical composition comprising the steps of:

a. Preparing two solutions in a solvent or mixture of solvents of:

i. tadalafil and at least one polymer soluble in aqueous medium up to pH 5.0; ii. tadalafil and at least one polymer with pH dependent solubility soluble above pH 5.0;

b. Spraying sequentially the solutions of step a. over a filler;

c. Granulating the mixture of step b;

d. Drying the granulate. In a third embodiment the pharmaceutical composition is characterized in that the composition is stabilized by a moisture barrier with a WVTR of less than 0.35 g/m /day at 38°C/90 RH. BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 Dissolution profile of the pharmaceutical formulation obtained in example 1 comprising a solid dispersion of amorphous tadalafil compared to the dissolution profile of Cialis® 20 mg IR tablets in 1000 ml of phosphate buffer (pH 6.8) + 0.35 wt% SDS in a USP apparatus II (peak vessels) at 50 rpm.

Fig. 2 XRPD of the granulate of the solid dispersion of tadalafil obtained in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a solid dispersion of tadalafil in at least two different types of polymers: at least one polymer soluble in aqueous medium up to pH 5.0 and at least one polymer with pH dependent solubility soluble above pH 5.0 exhibiting a dissolution rate of at least about 85 wt within 20 min when tested in 1000 ml of phosphate buffer (pH 6.8) + 0.35 wt% SDS in a USP apparatus II (peak vessels) at 50 rpm.

Suitable polymers soluble in aqueous medium up to pH 5.0 are for example: cationic methacrylate copolymers, povidone, hypromellose, poloxamer, polyethylene glycol, polyvinyl caprolactam, polyvinyl acetate , polyethylene glycol graft copolymer. The polymer soluble in aqueous medium up to pH 5.0 preferably is a cationic methacrylate copolymer. Most preferably it is a copolymer based on dimethylaminoethyl methacrylate - butyl methacrylate - methyl methacrylate with a ratio of 2: 1 : 1

Suitable copolymers based on dimethylaminoethyl methacrylate - butyl methacrylate - methyl methacrylate with a ratio of 2: 1 : 1 are marketed by Evonik under the trade names

Eudragit® E 100, E PO and E 12,5.

Suitable polymers with pH dependent solubility soluble above pH 5.0 are for example: anionic methacrylic acid copolymers, hypromellose acetate succinate and hypromellose phtalate.

The polymer with pH dependent solubility soluble above pH 5.0 preferably is an anionic methacrylic acid copolymer. Most preferably it is a copolymer based on methacrylic acid - ethyl acrylate copolymer (1: 1).

Suitable copolymers based on methacrylic acid - ethyl acrylate copolymer (1: 1) are marketed by Evonik under the trade names Eudragit® L 100-55 and L30 D-55.

The term "ratio of 2: 1: 1" as used throughout the present specification refers to the (molar) ratio of dimethylaminoethyl methacrylate groups to butyl methacrylate groups to methyl methacrylate groups present in the copolymer.

The term "ratio of 1: 1" as used throughout the present specification refers to the (molar) ratio of methacrylic acid to ethyl acrylate groups present in the copolymer.

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 matrix, i.e. the methacrylate and methacrylic acid copolymers, in which the drug tadalafil is molecularly dispersed in said copolymers. In said solid dispersion, tadalafil is present in an amorphous form. The weight ratio of tadalafil : total amount of polymers in the composition ranges from 1: 1 to 1:8, preferably 1:3.

The weight ratio of polymer(s) soluble in aqueous medium up to pH 5.0 and polymer(s) with pH dependent solubility soluble above pH 5.0 ranges from 1: 1 to 1:4.

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 comprises additionally other excipients.

More 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. Preferably the dose of tadalafil in the pharmaceutical composition of the present invention is 2.5, 5, 10, 20 or 40 mg.

XRPD analysis experiments of the compositions of the present invention show no crystalline material peaks indicative of the absence of free (crystalline) tadalafil and indicative of an amorphous solid dispersion (see e.g. Fig. 2).

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 is molecularly dispersed in a matrix, which is formed by the polymer(s) soluble in aqueous medium up to pH 5.0 and by the polymer(s) with pH dependent solubility soluble above pH 5.0, wherein the interaction with the polymers contributes to the enhanced dissolution of tadalafil improving the bioavailability of tadalafil such that the pharmaceutical composition is bioequivalent to the currently marketed product Cialis® in fed and fasting state.

During stability testing of pharmaceutical compositions with diverse solid dispersions of tadalafil, a small but significant decrease in the dissolution rate was observed. It has now been found that the source of this problem lies in the constant penetration of a sufficient amount of water vapor through the pores of the packaging material. Water vapor transmission rate

(WVTR), also moisture vapor transmission rate (MVTR), is a measure of the passage of water vapor through a substance. Various techniques are available to measure WVTR, ranging from gravimetric techniques that measure the gain or loss of moisture by mass, to highly sophisticated instrumental techniques that in some designs can measure extremely low transmission rates. Commercial instruments are available to determine WVTRs using either a pressure-modulated infrared detector or a mechanically modulated infrared detector. Numerous standard methods are described in e.g. ISO, ASTM, BS and DIN, like ASTM F1249 and DIN53122. The conditions under which the measurement is made has a considerable influence on the result. Both the temperature and the humidity gradient across the sample need to be measured, controlled and recorded with the result. We have discovered that the dissolution rate of the pharmaceutical compositions of the invention can be maintained by a moisture barrier with a WVTR of less than 0.35 g/m2/day at 38°C/90 RH. Preferably, the WVTR of the moisture barrier is kept below 0.2 g/m2/day at 38°C/90 RH. More preferably, the WVTR is kept below 0.1 g/m2/day at

38°C/90 RH and most preferably, the WVTR is kept below 0.01 g/m2/day at 38°C/90 RH.

Blisters belong to the group of primary packaging material in pharmaceutical industry.

They are useful for protecting the pharmaceutical composition against external factors such as humidity and contamination for extended periods of time. The type of blister pack material used and its film thickness, determines the WVTR value. Typical WVTR values of a 250 μιη PVC blister film and of a duplex 250 μιη PVC/90 g/m2 PVDC blister film are >3.0 g/m2/day and 0.35 g/m2/day at 38°C/90 RH respectively. Cold Form Foil, also known as Alu-Alu foil, has a WVTR value of 0.005 g/m2/day at 38°C/90 RH.

In another embodiment of the invention, the pharmaceutical composition as described above is stabilized by a moisture barrier with a WVTR of less than 0.35 g/m2/day at 38°C/90 RH. Preferably, created by means of packaging the pharmaceutical composition in blister pack material with a WVTR of less than 0.35 g/m2/day at 38°C/90 RH. Most preferably by packaging the pharmaceutical composition in Cold Form Foil. The present invention further provides a process for preparing said pharmaceutical composition comprising a solid dispersion of tadalafil in at least two different types of polymers as described above comprising the steps of:

a. Preparing two solutions in a solvent or mixture of solvents of:

b. Spraying sequentially the solutions of step a. over a filler;

c. Granulating the mixture of step b;

d. 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 polymer(s) 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 solvents 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 from about 8:2 to about 9: 1, more preferably a weight ratio from 8.5: 1.5 to 9: 1. 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 from about 40°C to about 50°C.

During step b. both solutions are sprayed sequentially over a filler. Preferably the order of the sequence of step b. is as follows:

1. Spraying the solution of tadalafil and at least one polymer soluble in aqueous

medium up to pH 5.0 over a filler;

2. Spraying the solution of tadalafil and at least one polymer with pH dependent

solubility soluble above pH 5.0 over a filler.

Preferably, the process of the present invention is performed in a fluid bed granulator or a high shear 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 comminution 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 commercial scale.

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

Example 1

Manufacturing process 135 g of acetone and 15 g of water was mixed and heated at 45-50°C. 12.5 g of Eudragit

L100-55 was added and completely dissolved in solvent. 4.17 g of Tadalafil was then added and dissolved. The intragranular fraction of Microcrystalline Cellulose (MCC) was weighed (127.7 g) and added into the Fluid Bed. The solution was sprayed over the MCC and granulated in the Fluid Bed with around 6-7 g/min of spray rate. Once the first spraying is finished, 135 g of acetone and 15 g of water was mixed in other recipient and heated at 45-50°C. 12.5 g of Eudragit E100 was added and completely dissolved in solvent. 4.17 g of Tadalafil was then added and dissolved. The second solution was sprayed over the powder obtained from previous spraying and granulated in the Fluid Bed at the same flow rate. After addition of the solution, drying continued until a LOD < 3% and sieved through a 0.8 mm mesh sieve (XRPD granules in fig 2. show amorphous tadalafil with no crystalline peaks). The remaining portion of the MCC (31.93 g) and Sodium Croscarmellose (6 g) was weighed, sieved and mixed with the sieved granules for 15 min. 1 g of Magnesium Stearate was sieved through a 0.500 mm mesh sieve and mixed with the previous blend for 5 min. The resulting homogeneous powder mix was compressed under monitored humidity conditions on a rotary tabletting machine to get tablets of 480 mg and hardness of 150N. The tablets were coated with an Opadry II suspension. Tablet weigh increase was 4%. The tablets were packed in Alu/Alu blisters. The dissolution of the tablets (see Fig.l) was measured in 1000 ml of phosphate buffer containing 0.35wt SDS in a USP apparatus II (peak vessels) at 50rpm, the tablets showed a dissolution of 96 wt within 15 min.

Claims

A pharmaceutical composition comprising a solid dispersion of tadalafil in at least two different types of polymers:

a. At least one polymer soluble in aqueous medium up to pH 5.0;

b. At least one polymer with pH dependent solubility soluble above pH 5.0;

exhibiting a dissolution rate of at least about 85 wt within 20 min when tested in 1000 ml phosphate buffer (pH 6.8) + 0.35 wt SDS in a USP apparatus II (peak vessels) at 50 rpm. A composition of claim 1 wherein the at least one polymer soluble in aqueous medium up to pH 5.0 is a cationic methacrylate copolymer and the at least one polymer with pH dependent solubility soluble above pH 5.0 is an anionic methacrylic acid copolymer.

A composition of claim 2 wherein the cationic methacrylate copolymer is based on dimethylaminoethyl methacrylate - butyl methacrylate - methyl methacrylate with a ratio of 2: 1: 1 and the anionic methacrylic acid copolymer is based on methacrylic acid - ethyl acrylate copolymer (1: 1).

A composition according to any one of claims 1 to 3 wherein the weight ratio of tadalafil: total amount of polymers in the composition ranges of from 1: 1 to 1:8.

A composition according to any one of claims 1 to 4 wherein the weight ratio of tadalafil: total amount of polymers is 1:3.

A composition according to any one of claims 1 to 5 wherein the weight ratio of polymer(s) soluble in aqueous medium up to pH 5.0 and polymer(s) with pH dependent solubility soluble above pH 5.0 ranges from 1: 1 to 1:4.

A composition according to any one of claims 1 to 6 further comprising a filler.

A composition according to claim 7 wherein the filler is Microcrystalline cellulose.

9. A composition according to any one of claims 1 to 8 further comprising other pharmaceutical excipients.

10. A composition according to any one of claims 1 to 9 further compressed into a tablet.

11. A composition according to any one of the claims 1 to 10 wherein the dose of tadalafil in the composition is selected from the group of 2.5, 5, 10, 20 or 40 mg.

12. A process for preparing the composition according to any one of claims 1 to 11,

comprising the steps of:

a. Preparing two solutions in a solvent or mixture of solvents of:

b. Spraying sequentially the solutions of step a. over a filler;

c. Granulating the mixture of step b;

d. Drying the granulate.

13. The process according to claim 12 wherein the solvent is selected from the group

consisting of ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone and a mixture of acetone with water.

14. The process according to claim 13 wherein the solvent is a mixture of acetone with water.

15. The process according to claim 14 wherein the mixture of acetone and water has a weight ratio from about 8:2 to about 9:1.

16. The process according to any one of claims 12 to 15 wherein step a. is performed at a temperature of from about 25°C to about 50°C. The process according to any one of claims 12 to 16 wherein step a. is performed at temperature of from about 45°C to about 50°C.

18. The process according to any one of claim 12 to 17 wherein the sequence of step b. is:

1 Spraying the solution of tadalafil and at least one polymer soluble in aqueous

medium up to pH 5.0 over a filler;

solubility soluble above pH 5.0 over a filler.

The process according to any one of claims 12 to 18 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.

20. A composition according to any one of claims 1 to 11 characterized in that the composition is stabilized by a moisture barrier with a WVTR of less than 0.35 g/m2/day at 38°C/90 RH.

21. A composition according to claim 20 wherein the moisture barrier is created by means of packaging the tablet in blister pack material.

22. A composition according to claim 21 wherein the blister pack material is Cold Form Foil.