EP2672959A1

EP2672959A1 - Granulated composition comprising tadalafil and a disintegrant

Info

Publication number: EP2672959A1
Application number: EP11703449.6A
Authority: EP
Inventors: Marta VIVANCOS MARTINEZ
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2011-02-10
Filing date: 2011-02-10
Publication date: 2013-12-18
Also published as: WO2012107090A1

Abstract

The present invention relates to a co-granulate comprising tadalafil and a superdisintegrant, advantageously croscarmellose sodium, to a process of making the same and to pharmaceutical compositions and dosage forms comprising the same.

Description

GRANULATED COMPOSITION COMPRISING TALADAFIL AND A DIS INTEGRANT

The present invention relates to a co-granulate comprising tadalafil and a

superdisintegrant, advantageously croscarmellose sodium, to a process of making the same and to pharmaceutical compositions and dosage forms comprising the same.

BACKGROUND OF THE INVENTION

Tadalafil of formula (1)

is a known pharmaceutically active compound, which is marketed, e.g., under brand name CIALIS®, for the treatment of erectile dysfunction and pulmonary arterial hypertension. The marketed product is a film-coated tablet for oral administration comprising 2.5, 5, 10 or 20 mg of the active substance. Inactive ingredients in CIALIS® are lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, microcrystalline cellulose, sodium laurylsulfate and magnesium stearate.

Tadalafil and its pharmaceutical compositions have been disclosed, e.g., in WO 95/19978 and WO 00/66099.

From a therapeutic point of view, tadalafil is in a certain aspect a follow-up product to the well known compound sildenafil (Viagra). Its main advantage is longer duration of action and minimized potential for side effects such as vision abnormalities.

Its main disadvantage is its very low aqueous solubility (about 2 μ/ml), which may cause formulation problems in making solid dosage forms and irreproducible clinical response. Various attempts aiming to solve this problem have been published in the prior art.

One possibility of improving the dissolution rate of tadalafil from solid pharmaceutical compositions is to use the active ingredient with low average particle size. For instance, the patent applications WO 01/08688 and WO 01/08686 disclose a population of tadalafil particles characterized by an average particle size (expressed as d(0.9)) less than 40 μηι. Such particulated form of tadalafil may exhibit better dissolution from pharmaceutical

compositions.

The patent application WO 2007/033239 discloses tadalafil particles having an effective average size of less than 2000 nm (= 2 μιη).

The patent applications WO 2006/069419 and WO 2008/000042 disclose a tadalafil nanoparticle composition, wherein the nanoparticles have an average size less than 200 nm, and a process for making such a composition, resp.

Another possibility for improving the dissolution rate of tadalafil from solid dosage forms is to provide an intimate mixture of the compound with a suitable solid carrier. In general, tadalafil is thereby finely dispersed in the carrier, which may result in improved dissolution due to enhanced surface area of the drug substance. Several examples of solid dispersions comprising tadalafil have been disclosed, e.g., in WO 96/38131. Molecular dispersions of tadalafil in a polymeric carrier have been disclosed, e.g., in WO 2009/000493. A pharmaceutical composition comprising a combination of tadalafil and starch has been disclosed in WO 2008/134557. An adsorbate of tadalafil on the surface of silica has been disclosed in EP 2238979.

Yet another possibility of improving the dissolution rate of tadalafil from solid dosage forms is to formulate it into quickly disintegrating sublingual dosage forms. Examples of such compositions have been disclosed, e.g., in WO 00/20033, WO 01/41807, WO 2007/002125 or WO 2008/005039.

While many possibilities of enhancing the dissolution rate of tadalafil from solid oral pharmaceutical compositions have been addressed in the prior art, an improvement in the matter is still desirable. In particular, it is desirable to make a solid dosage form, which is not dependent on micronizing tadalafil into a population of low average particle size.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising a granulated product comprising tadalafil and a superdisintegrant, preferably croscarmellose sodium. In a first aspect, the present invention provides a co-granulate, preferably a free-flowing co-granulate, comprising tadalafil, a superdisintegrant, and, preferably, at least one binder and/or filler. A preferred superdisintegrant is croscarmellose sodium. Preferably, the weight ratio between croscarmellose sodium and tadalafil is equal to or higher than 5 : 1.

In a second aspect, the present invention provides a process comprising a step of aqueous granulation of tadalafil with a superdisintegrant, e.g. croscarmellose sodium, preferably in the presence of a binder, followed by drying the resulting granulate.

In a particular aspect, the tadalafil starting material for making the co-granulate comprises a population of tadalafil particles characterized by a particle size d(0.9) > 40 μιη.

In a third aspect, the present invention provides a pharmaceutical composition comprising the co-granulate as defined above and at least one pharmaceutically acceptable excipient.

In a fourth aspect, the present invention provides a process for making a tadalafil- comprising pharmaceutical composition, comprising a step of providing a co-granulate comprising tadalafil and a superdisintegrant, preferably croscarmellose sodium, followed by a step of dry mixing the above co-granulate with at least one pharmaceutically acceptable excipient.

In a fifth aspect, the present invention provides a pharmaceutical oral dosage form comprising tadalafil, preferably a compressed dosage form, comprising a dose of the pharmaceutical composition as defined above. In a preferred aspect, the dosage form exhibits a dissolution rate of at least about 70 wt% within about 15 min when tested by the Ph. Eur. paddle method in 1000 ml of an aqueous medium containing 0.35% of SLS with the paddle rotating at a speed of 50 rpm.

In a sixth aspect, the present invention provides a process for making a pharmaceutical oral dosage form comprising tadalafil, comprising the steps of:

- wet granulating tadalafil with a superdisintegrant, preferably croscarmellose sodium, preferably in the presence of a binder, followed by drying the resulted co-granulate,

- dry mixing the above co-granulate with at least one pharmaceutically acceptable excipient, and

- formulating the dry mixture into an oral dosage form, preferably by compression. The composition and/or dosage form preferably comprises from 2 to 10% of tadalafil (w/w). The dosage form preferably comprises from 1 to 50 mg of tadalafil.

In another aspect, the invention relates to the use of the co-granulate of tadalafil with croscarmellose sodium, preferably in free-flowing particulate form, in medicine, in particular in the treatment of erectile dysfunction and pulmonary arterial hypertension.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the enhancement of the inherently poor dissolution of tadalafil from solid pharmaceutical compositions by formulating tadalafil into a co-granulate with a superdisintegrant, preferably with croscarmellose sodium, and, optionally, a binder.

The "superdisintegrant" in our application is a conventionally used term in the pharmaceutical industry and refers to a compound, which exhibits a rapid and a high degree of swelling when in contact with saliva or intestinal fluid. Typical examples, which are also subject of our invention, are modified celluloses, e.g. croscarmellose sodium or low substituted hydroxypropyl cellulose, cross-linked polymers, e.g. crospovidone, or modified starches, e.g. sodium starch glycolate.

While the present invention will be further explained with respect to croscarmellose sodium, it should be understood that it is not limited thereto.

Croscarmellose sodium is the sodium salt of a cross-linked, partly O- (carboxymethylated) cellulose. It is a well known and well defined excipient in the pharmaceutical industry, typically useful as a disintegrant. It is commercially available under various brand names. For more details about this excipient, see ,e.g., Arthur H. Kibbe (Ed.), Handbook of Pharmaceutical Excipients, Third Edition 2000, p. 160-162).

The present invention typically provides a co-granulate of tadalafil with croscarmellose sodium. Preferably, the weight ratio between croscarmellose sodium and tadalafil in the co- granulate is equal to or higher than 5 : 1. This co-granulate, preferably in amounts, which assure the final concentration of tadalafil therein of between 2 to 10% (w/w), may be formulated in solid pharmaceutical compositions, e.g. by a dry mixing with extragranular excipients.

This inventive solution is based on the finding that dissolution of the inherently poorly soluble tadalafil may be sufficiently increased by this co-granulation, when comparing it with a composition, wherein croscarmellose sodium has been formulated into a tadalafil- comprising solid pharmaceutical composition in conventional concentrations (0.5-5%) and without pre-granulation with tadalafil. Furthermore, it was found that it is not necessary to provide a population of tadalafil particles of an average particles size (when expressed by the d(0.9) value) of less than 40 μιη. While the dissolution rate can be, in general, enhanced by increasing the surface area of the drug by micronization, the micronized particles have a tendency to agglomerate and this effect can result in a decreased effective surface for dissolution. Without wishing to be bound by any theory, the inventor speculates that the granulation causes deposition of the drug upon the surface of the hydrophilic and strongly swelling superdisintegrant. Once digested, the superdisintegrant discomposes the medicament delivering a fine suspension of drug particles, which prevents agglomeration and improves the dissolution.

As a result, it is possible and in certain aspects advantageous, to use batches of tadalafil substance having an average particle size d(0.9) higher than 40 μιη, e.g. tadalafil directly produced by a chemical synthesis. For clarity, the "d(0.9)value" in association with a number means that the size of 90% of the particles of the population are less than or equal to the size expressed by that number when measured by a light scattering method.

Apart from tadalafil and croscarmellose sodium, the co-granulate of the invention may also comprise at least one binder, for instance microcrystalline cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone, sodium alginate etc. The binder may improve physical properties of the co-granulate, particularly it may assure that the co-granulate is obtained as a free-flowing particulate material with good handling properties. Furthermore, the co-granulate may optionally comprise one or more inert fillers/diluents, e.g., lactose, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, lactitol, maltitol, maltodextrins, maltose, calcium phosphates, xylitol, which assure a proper final concentration of tadalafil in the final composition.

Typically, the co-granulate of the invention does not comprise starch.

The use of a surfactant, which might also contribute to an improvement in the dissolution rate, is in general not necessary, but it is not excluded.

The co-granulate of the present invention is advantageously prepared by a wet granulation process. Quite surprisingly, water may be advantageously used as the granulation liquid in the process of the invention despite the prejudice that superdisintegrants are sensitive to water. However, in the amounts that are used in the granulation process of the invention (typically 10 to 50 weight % in respect to the solid material), water does not substantially affect the disintegration ability, rather it aids in assuring a uniform content of tadalafil within the granulate. Furthermore, the use of water is advantageous over similar processes of the prior art, which use organic solvents, e.g. ethanol, as granulation liquids (e.g.

WO 2008/134557) because of safety issues.

A useful process of making the co-granulate comprises the following steps:

1] Mixing, under stirring, tadalafil with croscarmellose sodium and other excipients in a high shear mixer.

2] Granulating the mixture by adding water, which optionally also comprises binder dissolved or dispersed therein, under stirring, preferably at ambient temperature.

3] Drying the resulting mixture, typically to a moisture content of less than 2%.

The mixing and granulating is typically performed with the same equipment, at a speed of about 100 to 200 rpm. Croscarmellose sodium and tadalafil are preferably mixed in the weight ratio equal to or higher than 5 : 1. The relative weight amount of the binder is typically between 1/5 to 1/10 of the weight of tadalafil. The relative weight amount of water is typically 10 to 50 weight % in respect to the solid material. Advantageously, the drying step is performed in fluid bed equipment, at a temperature of about 40°C to about 60°C, typically at about 50°C.

4] Optionally, the dry co-granulate may be milled and/or sieved on a suitable

equipment.

By the above process, a homogeneous, free-flowing particulate product is obtained.

The co-granulate of the present invention and/or the co-granulate made by the above process may be formulated into solid pharmaceutical compositions, preferably into tablet compositions, by combining it with at least one extragranular pharmaceutically acceptable excipient. A typical process of such formulation comprises a step of providing the above co- granulate followed by a step of dry mixing it with at least one pharmaceutically acceptable excipient. As rapid dissolution of tadalafil from the composition is therapeutically

advantageous, the composition typically does not comprise any excipient serving as a release- controlling agent. The excipients typically comprise:

a] at least one water soluble or water insoluble filler/binder. The examples are, without any limitation, lactose, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, dextrates, dextrins, dextrose, fructose, lactitol, maltitol, maltodextrins, maltose, calcium phosphates, xylitol, starch, modified starch, polyvinylpyrrolidone, copovidone, sodium alginate, etc.

b] an extragranular disintegrant. The examples are, without any limitation, starches, cross-linked celluloses, or cross-linked polymers such as starch, modified starch,

croscarmellose sodium, crospovidone, sodium starch glycolate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, guar gum, magnesium aluminium silicate, methylcellulose, polacrilin potassium, sodium alginate, etc.

c] at least one lubricant. The examples are, without any limitation, talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, palmitic acid, carnauba wax, mineral oil, sodium stearyl fumarate, polyethylene glycol, etc.

The relative amount of tadalafil in the solid pharmaceutical composition is typically from about 2 to about 10 weight %. Accordingly, the relative amount of croscarmellose sodium in the composition is typically from about 10 to 50%, based on the total weight of the composition.

In pharmaceutical use, the composition of the present invention is advantageously formulated into a dosage form; such dosage form comprises a desired dose of the

composition. In an advantageous mode, the dosage form is a compressed dosage form, which is typically a tablet. Preferably, the compressed dosage form is formulated by a process of direct compression. This process comprises adjusting the composition to portions - dose units - comprising a therapeutic amount of the active substance and compressing the doses of the composition to tablets on a suitable tablet press. With respect to hardness, the tablets should have a suitable hardness in order to obtain tablets with a friability below 0.5% preferably below 0.1%. The typical hardness of the tablets is 75N.

The dosage form typically comprises from 1 to 50 mg of tadalafil, preferably 2.5, 5, 10 or 20 mg of tadalafil.

The compressed dosage form preferably exhibits a dissolution rate which is characterized by a dissolution of more than 70 wt% of tadalafil in 15 min when a sample of the composition is tested by a Ph. Eur. paddle method in 1000 ml of an aqueous medium containing 0.35% of sodium laurylsulfate with the paddle rotating at a speed of 50 rpm.

The tablets may be optionally further coated by a film-coat. The coating serves generally for cosmetic purposes. The coating material typically has no influence on the release rate, except of an inherent short initial delay in dissolution due to the time necessary to dissolve the coat.

The coating may be selected from amongst one or more of those suitable coating materials known in the art. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension. Coating is done using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.

Thus, in summary, the co-granulate of tadalafil with a superdisintegrant, which advantageously is croscarmellose sodium, typically in a weight ratio of croscarmellose sodium and tadalafil equal to or higher than 5 : 1, as well as pharmaceutical compositions and dosage forms comprising it are useful in medicine, specifically for the treatment of diseases and conditions known to be treated with tadalafil. Typically these conditions include erectile dysfunction and pulmonary arterial hypertension, but are not limited thereto. Accordingly, the present invention provides a method of treatment, particularly that of erectile dysfunction or pulmonary arterial hypertension, comprising orally administering to a patient in need thereof a solid pharmaceutical composition comprising a therapeutical amount of tadalafil within a co-granulate with a superdisintegrant, advantageously croscarmellose sodium, typically in a weight ratio of croscarmellose sodium and tadalafil equal to or higher than 5 : 1.

The invention is further illustrated by the following examples but they should not be construed as limiting the scope of this invention in any way.

EXAMPLES

Example 1 - Pharmaceutical tablet comprising tadalafil and croscarmellose sodium granulate

Formulation:

Intragranular excipients:

Process:

A] Co-granulate of tadalafil with croscarmellose of a weight ratio 1 : 5

A pre-mixture of drug substance, croscarmellose sodium, lactose,

hydroxypropylcellulose and aerosil was made in a high shear mixer for 5 min. After that, a 20% of water w/w of powder was poured onto the powder and mixed at 150 rpm to obtain a granulate. The granulate was dried in a fluid bed equipment until a loss on drying below 2% was obtained. B] Mixing

The resulting granulate was sieved manually through a 1 mm sieve and mixed with microcrystalline cellulose and crospovidone for 15 min. Finally, Mg stearate was added to the blend and mixed for 5 min.

C] Compression

The lubricated blend was compressed in an excentric press machine at a compression force of approx. 13 kN. The resulting tablets showed a hardness of 74 N, a disintegration time < 2 min and a friability of 0.2%.

The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

1. A co-granulate comprising tadalafil and a superdisintegrant selected from a group

comprising: a modified cellulose; a cross-linked polymer; and/or a modified starch.

2. The co-granulate according to claim 1, wherein the superdisintegrant is croscarmellose sodium, preferably in an weight ratio equal to or higher than 5 : 1 with respect to tadalafil.

3. The co-granulate according to claims 1-2, which also comprises at least one binder and/or filler.

4. The co-granulate according to claims 1-3 in a free-flowing particulate form.

5. The co-granulate according to claims 1-4, wherein the tadalafil starting material for making the co-granulate comprises a population of tadalafil particles characterized by a particle size d(0.9) > 40 μιη.

6. A process for making a co-granulate comprising tadalafil and a superdisintegrant, comprising a step of aqueous granulation of tadalafil with a superdisintegrant, preferably with croscarmellose sodium, even more preferably in the presence of a binder, followed by drying the resulting granulate.

7. The process according to claim 6, wherein 10 to 50 weight % of water is used in the aqueous granulation step.

8. A pharmaceutical composition comprising the co-granulate according to claims 1-5 or made by the process according to claim 6-7 and at least one pharmaceutically acceptable excipient.

9. The composition according to claim 8 comprising from 2 to 10% of tadalafil (w/w) and/or 10 to 50% of croscarmellose sodium (w/w).

10. A process for making the composition according to claim 8-9 comprising a step of providing a co-granulate comprising tadalafil and a superdisintegrant, preferably croscarmellose sodium, followed by a step of dry mixing the above co-granulate with at least one pharmaceutically acceptable excipient.

1 1. A pharmaceutical oral dosage form comprising tadalafil, preferably a compressed dosage form, comprising a dose of the pharmaceutical composition according to claim 8-9 and/or made by the process according to claim 10.

12. The pharmaceutical oral dosage form according to claim 11 comprising from 2 to 10% of tadalafil (w/w) and/or from 1 to 50 mg of tadalafil.

13. The dosage form according to claim 11-12, wherein the dosage form exhibits a

dissolution rate of at least about 70 wt% within about 15 min when tested by the Ph. Eur. paddle method in 1000 ml of an aqueous medium containing 0.35% of sodium lauryl sulfate with the paddle rotating at a speed of 50 rpm.

14. A process for making a pharmaceutical oral dosage form comprising tadalafil,

comprising the steps of:

- wet granulating tadalafil with a superdisintegrant, preferably croscarmellose sodium, preferably in the presence of a binder, followed by drying the resulting co-granulate;

- dry mixing the above co-granulate with at least one pharmaceutically acceptable excipient; and

- formulating the dry mixture into an oral dosage form, preferably by compression.

15. A co-granulate of tadalafil with a superdisintegrant, preferably croscarmellose sodium, according to claims 1-5, a composition according to claims 8-9 and/or a dosage form according to claims 11-13 for use in medicine, in particular in the treatment of erectile dysfunction and pulmonary arterial hypertension.