TECHNICAL FIELD

A method of manufacturing a suspension of nanoparticles of tadalafil or sildenafil citrate.

BACKGROUND ART

Sildenafil is a Phosphodiesterase 5 Inhibitor. Sildenafil functions as a selective and competitive inhibitor of type 5 phosphodiesterases (PDE5). PDE5 is a cyclic guanosine-3 '^'-monophosphate (cGMP)-specific phosphodiesterase belonging to a class of phosphodiesterases which regulate various cell functions by catalyzing the hydrolysis of the second messenger molecules (cGMP) and cyclic adenosine-3',5'-monophosphate (cAMP). Sildenafil is used extensively for erectile dysfunction and less commonly for pulmonary hypertension. Sildenafil citrate has subsequently been commercially developed by Pfizer, Inc. and is available under the trademark VIAGRA. Tadalafil is a carboline-based compound with vasodilatory activity. Tadalafil selectively inhibits the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase- (PDE-5)-mediated degradation of cGMP, which is found in the smooth muscle of the corpus cavernosa and corpus spongiosum of the penis. Inhibition of cGMP degradation by tadalafil results in prolonged muscle relaxation, vasodilation, and blood engorgement of the corpus cavernosa, and, so, prolonged penile erection. Tadalafil is used primarily to treat erectile dysfunction; benign prostatic hyperplasia and primary pulmonary hypertension. In USA tadalafil is approved as CIALIS for treating erectile dysfunction and ADCIRCA for the treatment of pulmonary arterial hypertension.

Patent application US2005042177A1 discloses nanoparticulate compositions comprising sildenafil free base. The sildenafil free base particles of the composition have an effective average particle size of less than about 2000 nm. The method of making this composition consists in dissolving the sildenafil free base particles in a solvent; adding the resulting sildenafil free base solution to a solution comprising at least one surface stabilizer; and precipitating the solubilized sildenafil free base having at least one surface stabilizer associated with the surface thereof by the addition thereto of a non- solvent. Stabilizers may be selected from a group consisting of inter alia gelatine, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, and stearic acid.

Patent application US2012128740 discloses sildenafil base or citric salts nanostructures having an average particle size of less than 500 nm, and a method of its manufacturing consisting of dissolving sildenafil base or its pharmaceutically acceptable salt or co-crystal and optionally one or more stabilizer or polyelectrolytes or a mixture thereof in a suitable solvent; adding the obtained formulation to a solution comprising one or more polyelectrolytes or stabilizers or a mixture thereof, if desired in the presence of a pharmaceutically acceptable acid or base; and precipitating the whole formulation.

Patent application HU 1000214 discloses a method of manufacturing a sildenafil citrate nanoparticles composition in a microfluidic device. The method consists in dissolving sildenafil citrate in water, and adding Carbopol 980 dissolved in distilled water, where both solution are fed to the first microfluidic reactor unit. The resulting colloidal solution is fed to the second reactor unit where nanoparticles of sildenafil citrate are obtained. The nanoparticles size ranges from 70 nm to 500 nm.

Patent application WO2007033239A2 discloses compositions comprising nanoparticulate tadalafil, or a salt or derivative thereof. The nanoparticulate tadalafil particles of the composition have an effective average particle size of less than about 2000 nm and may be useful in the treatment of sexual dysfunction and vascular-, pulmonary- and cardiac- related diseases and conditions.

Patent application WO2007033239A1 discloses a method comprising dispersing particles of tadalafil, or a salt or derivative thereof, in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of a tadalafil to the desired effective average particle size. The tadalafil particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the tadalafil particles can be contacted with one or more surface stabilizers either before or after attrition. Other compounds, such as a diluent, can be added to the tadalafil/surface stabilizer composition either before, during, or after the size reduction process. Dispersions can be manufactured continuously or in a batch mode.

DISCLOSURE OF THE INVENTION

The method in accordance with the present invention solves the problem of preparation of a stable suspension a suspension of nanoparticles of tadalafil or sildenafil citrate, and thus improving their bioavailability and efficacy.

A method of manufacturing a suspension of nanoparticles of tadalafil or sildenafil citrate of the present invention consists in that, a solution of tadalafil or sildenafil citrate in dimethyl sulfoxide (DMSO) is prepared, and an aqueous solution of a least one dispersing agent is prepared, then under continuous homogenization a solution of tadalafil or sildenafil citrate is added portion-wise to the aqueous solution of at least one dispersing agent, afterwards homogenization is continued until a suspension of tadalafil or sildenafil citrate nanoparticles is obtained.

Preferably the dispersing agent is dissolved in water in temperature not higher than 90°C. Preferably the concentration of sildenafil citrate in DMSO is from 200 to 400 g/dm ³ or the concentration of tadalafil in DMSO is from 20 to 650 g/dm ³ .

Preferably the dispersing agent is chosen from a group consisting of lecithin, gelatin and starch.

Preferably the aqueous solution of dispersing agents contains lecithin in concentration from 25.0 to 66.67 g/dm ³ and gelatin in concentration from 3.33 to 20 g/dm ³ .

Preferably aqueous solution of dispersing agents contains lecithin in concentration from 25.0 to 66.67 g/dm ³ and starch in concentration from 3.33 to 20 g/dm ³ .

Preferably the aqueous solution of dispersing agents contains lecithin in concentration from 25.0 to 66.67 g/dm ³ and starch in concentration from 3.33 to 6.67 g/dm ³ , and gelatine in concentration from 3.33 to 6.67 g/dm ³ .

Preferably the aqueous solution of dispersing agents contains potassium sorbate. The potassium sorbate acts as a preservative. Preferably the concentration of potassium sorbate is from 1,33 to 33,33 g/dm ³ .

Preferably the volume ratio of sildenafil citrate or tadalafil solution in DMSO to aqueous solution is from 0.1 to 0.4.

Preferably the suspension of sildenafil citrate or tadalafil nanoparticles is homogenised through the use of ultrasonic frequencies.

Preferably the strength of ultrasound is from 500 to 600 W.

Preferably the homogenization process is carried out from 1 to 90 minutes.

Preferably the ultrasonication is carried out in flow system or in batch system.

The present invention refers also to a suspension of nanoparticles of tadalafil or sildenafil citrate nanoparticles obtained by method according to the invention.

A method of manufacturing a suspension of nanoparticles of tadalafil or sildenafil citrate of the present invention enables obtaining of dispersed nanoparticles of sildenafil citrate or tadalafil having average size from 50 to 700 nm. Obtained suspension is a final product, that may be administered to patients as a medicinal product, or may be used as a starting material for manufacture of medicinal products. The method is technologically very simple, safe and may be easily implemented on large scale production.

While the solution of tadalafil or sildenafil citrate is introduced into aqueous solution of other ingredients, the particles of tadalafil or sildenafil citrate are precipitated. Sonication process enables obtaining of particles having nanometric size. This size is preserved as a result of stabilisation activity of lecithin, gelatine and/or starch. Sonication may be carried out in a batch reactor or in a flow system, each time supplied with a sonication kit having appropriate power - preferably from 500 to 600 W.

BEST MODE OF CARRYING OUT THE INVENTION

The following examples illustrate the invention without setting or delineating its limits.

Example 1

A solution of sildenafil citrate was prepared by dissolving 20 g of sildenafil citrate in 50 cm ³ of DMSO. A solution of dispersing agents was prepared by dissolving 10 g of lecithin and 2 g of gelatine in 150 cm ³ of water in temperature 80°C. Under continuous homogenization conditions a solution of sildenafil citrate was added portion-wise to the dispersing agents solution. Afterwards homogenization was continued for 10 minutes. A homogeneous water suspension of sildenafil citrate was obtained comprising sildenafil citrate nanoparticles, having average size of 217 nm, and concentration of 100 mg/cm ³ .

After 48 hours the average size of nanoparticles was 162 nm. It confirms high stability of sildenafil citrate nanoparticles in the suspension.

Example 2

A solution of sildenafil citrate was prepared by dissolving 40 g of sildenafil citrate in 100 cm ³ of DMSO. A solution of dispersing agents and a preservative was prepared by dissolving 20 g of lecithin, 4 g of gelatine, and 1.6 g of potassium sorbate in 300 cm ³ of water in temperature 80°C. Under continuous homogenization conditions a solution of sildenafil citrate was added portion-wise to the dispersing agents and preservative solution. Afterwards homogenization was continued for 15 minutes. A homogeneous suspension of sildenafil citrate was obtained comprising sildenafil citrate nanoparticles, having average size of 122 nm, and concentration of 100 mg/cm ³ .

Potential zeta was equal to -29 mV. The absolute value of the electrokinetic (zeta) potential confirms high stability of the nanoparticles suspension.

Example 3

A solution of sildenafil citrate was prepared by dissolving 40 g of sildenafil citrate in 100 cm ³ of DMSO. A solution of dispersing agents was prepared by dissolving 20 g of lecithin, 2 g of gelatine, and 2 g of starch in 300 cm ³ of water in temperature 80°C. Under continuous homogenization conditions a solution of sildenafil citrate was added portion-wise to the dispersing agents solution. Afterwards homogenization was continued for 10 minutes. A homogeneous suspension of sildenafil citrate was obtained comprising 89% sildenafil citrate nanoparticles having average size of 390 nm, and 11% sildenafil citrate nanoparticles having average size of 110 nm. The concentration of sildenafil was 100 mg/cm ³ . Example 4

A solution of tadalafil was prepared by dissolving 40 g of tadalafil in 290 cm ³ of DMSO. A solution of dispersing agents and a preservative was prepared by dissolving 100 g of lecithin, 20 g of gelatine, and 8 g of potassium sorbate in 1710 cm ³ of water in temperature 80°C. Under continuous homogenization conditions a solution of tadalafil was added portion-wise to the dispersing agents and preservative solution. Afterwards homogenization was continued for 10 minutes. A homogeneous suspension of tadalafil was obtained comprising 64% tadalafil nanoparticles having average size of 326 nm, and 36% tadalafil nanoparticles having average size of 79 nm. The concentration of tadalafil was 20 mg/cm ³ .

Example 5

A solution of tadalafil was prepared by dissolving 20 g of tadalafil in 50 cm ³ of DMSO. A solution of dispersing agents and a preservative was prepared by dissolving 10 g of lecithin, 2 g of gelatine, and 0.8 g of potassium sorbate in 150 cm ³ of water in temperature 80°C. Under continuous homogenization conditions a solution of tadalafil was added portion-wise to the dispersing agents and preservative solution. Afterwards homogenization was continued for 90 minutes. A homogeneous suspension of tadalafil was obtained comprising tadalafil nanoparticles having average size of 459 nm. The concentration of tadalafil was 100 mg/cm ³ .