RU2673228C2 - Pharmaceutical composition comprising a solid dispersion of tadalafil - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: present invention relates to a pharmaceutical composition comprising a tadalafil solid dispersion and at least two different types of polymers: at least one cationic methacrylate copolymer and at least one anionic copolymer of methacrylic acid. Cationic methacrylate copolymer is obtained based on dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate in a ratio of 2:1:1. Anionic copolymer of methacrylic acid is obtained based on a methacrylic acid-ethyl acrylate copolymer in a ratio of 1:1. Also described is a method for preparing a composition by wet granulation. Composition according to the invention exhibits a tadalafil dissolution rate of at least 85 wt% for 20 minutes when tested in 1,000 ml of phosphate buffer (pH 6.8) + 0.35 wt% sodium dodecyl sulphate (SDS) in a USP apparatus II (peak vessels) at 50 rpm.EFFECT: disclosed is a pharmaceutical composition comprising a solid dispersion of tadalafil.20 cl, 2 dwg, 1 tbl, 1 ex

Description

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

is a pharmaceutically active compound used to treat erectile dysfunction (ED) and benign prostatic hyperplasia (BHP), which is marketed under the name Cialis® in the form of tablets of 2.5, 5, 10 and 20 mg and under the name Adcirca® in the form of tablets 20 mg for the treatment of pulmonary arterial hypertension. This compound was discovered by ICOS and was first described in WO 9519978. Tadalafil is poorly soluble in water; therefore, it is necessary to include this compound in such dosage formulations that provide improved solubility and bioavailability.

WO 9638131 discloses solid dispersions in the form of co-precipitation products (co-precipitates) of tadalafil and hydroxypropyl methylcellulose phthalate. However, when measuring the solubility of the formulations obtained using these coprecipitate, the authors found that this solubility is too low to expect good bioavailability. Thus, co-precipitation with hydroxypropyl methylcellulose phthalate is not a suitable way to increase the bioavailability of tadalafil.

WO 0108688 discloses a composition comprising tadalafil, milled to particles with a d90 size of less than 10 microns and having improved bioavailability. However, grinding to particles of such a small size can lead to a decrease in flowability, loss of the active substance and can affect the chemical and polymorphic stability of the active ingredient.

WO 2008005039 discloses compositions of tadalafil and water-soluble polymers obtained by dissolving tadalafil and a hydrophilic polymer in ethanol and then spray drying the solution to obtain a powder that can be used to obtain a pharmaceutical composition (examples of pharmaceutical formulations are not shown). In all examples available in the application, significant amounts of ethanol are used, amounting to about 1000 ml per gram of tadalafil, which makes the method not applicable on an industrial scale.

WO 2011012217 discloses compositions comprising a co-precipitate of tadalafil and a cationic acrylate polymer. This coprecipitate is mixed with other excipients and compressed into tablets. A method of obtaining said coprecipitate is laborious; drying of the coprecipitate at a relatively high temperature for a long time (20 hours) is required, which can lead to the destruction of the active ingredient.

WO 2012095151 discloses compositions that are prepared by granulating a hot fluid in a fluidized bed using a tadalafil solution and spraying the resulting product onto a water-insoluble polymer mixed with a diluent. Fluidized bed granulation must be carried out at high temperatures, which can increase the content of impurities. The granulate obtained is mixed with other excipients and compressed into tablets. The examples mention the use of ethyl cellulose as a water-insoluble polymer, which is often used in sustained release formulations and can adversely affect dissolution and therefore bioavailability.

In light of the prior art described above, there is a need for compositions comprising tadalafil exhibiting good solubility and bioavailability, as well as a process for preparing these compositions that does not have the disadvantages mentioned above.

SUMMARY OF THE INVENTION

In the present invention, it was found that a solid dispersion of tadalafil stabilizing tadalafil in amorphous form in at least two different types of polymers: at least one polymer soluble in an aqueous medium at pH not higher than 5.0 and at least one polymer with a pH dependent solubility, soluble at pH above 5.0, provides the optimal level of bioavailability of tadalafil, so that the pharmaceutical composition is the biological equivalent, both after eating and on an empty stomach, available on the market Cialis® product.

In one embodiment, the present invention relates to a pharmaceutical composition comprising a solid dispersion of tadalafil in at least two different types of polymers, where at least one of these polymers is soluble in an aqueous medium at pH not higher than 5.0 and at least one polymer possesses pH-dependent solubility and soluble at pH above 5.0, showing a dissolution rate of at least about 85 wt.% for 20 min when tested in 1000 ml of phosphate buffer (pH 6.8) +0.35 wt.% SDS in apparatus II USP (containers with peak n and bottom) at 50 rpm.

In a second embodiment, the present invention relates to a method for producing said pharmaceutical composition, comprising the steps of:

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

i. tadalafil and at least one polymer soluble in an aqueous medium at a pH of not higher than 5.0;

ii. tadalafil and at least one polymer with a pH-dependent solubility, soluble at pH above 5.0;

b. Sequential spraying of the solutions obtained in stage a above the filler;

c. Granulating the mixture obtained in step b;

d. Drying the resulting granulate.

In a third embodiment, the pharmaceutical composition of the present invention is characterized in that the composition is stabilized by a moisture barrier with a WVTR (water vapor permeation rate) of less than 0.35 g / m ² / day at 38 ° C / 90% rel. ow (relative humidity).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a dissolution profile of the pharmaceutical composition obtained in example 1, including a solid dispersion of amorphous tadalafil, compared with the dissolution profile of Cialis® 20 mg IR tablets in 1000 ml of phosphate buffer (pH 6.8) +0.35 mass. % SDS in apparatus II USP (containers with a peak at the bottom) at 50 rpm

Figure 2 is a picture of powder x-ray diffraction (XRPD) of the granulate solid dispersion of tadalafil obtained in example 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising a solid dispersion of tadalafil in at least two different types of polymers, where at least one of these polymers is soluble in an aqueous medium at pH not higher than 5.0 and at least one polymer has a pH-dependent solubility and soluble at pH above 5.0, showing a dissolution rate of at least about 85 mass. % for 20 min when tested in 1000 ml of phosphate buffer (pH 6.8) +0.35 mass. % SDS in apparatus II USP (containers with a peak at the bottom) at 50 rpm

Suitable polymers which are soluble in an aqueous medium at pH not higher than 5.0 are, for example, cationic methacrylate copolymers, povidone, hypromellose, poloxamer, polyethylene glycol, polyvinylcaprolactam, polyvinyl acetate, grafted polyethylene glycol copolymers.

Preferably, the polymer soluble in an aqueous medium at pH not higher than 5.0 is a cationic methacrylate copolymer. More preferably, it is a copolymer based on dimethylaminoethyl methacrylate - butyl methacrylate - methyl methacrylate in a ratio of 2: 1: 1.

Suitable copolymers based on dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate in a 2: 1: 1 ratio are marketed by Evonik under the trade names Eudragit® E100, E PO and E 12.5.

Suitable polymers with pH-dependent solubility soluble above pH 5.0 are anionic methacrylic acid copolymers, hypromellose acetate succinate and hypromellose phthalate.

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

Suitable copolymers based on a 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 “2: 1: 1 ratio” as used herein refers to the (molar) ratio of dimethylaminoethyl methacrylate groups present in the copolymer to butyl methacrylate groups and methyl methacrylate groups.

The term “1: 1 ratio” as used herein refers to the (molar) ratio of methacrylic acid residues to ethyl acrylate groups present in the copolymer.

In accordance with the present invention, the term “solid dispersion” means a solid product consisting of a hydrophobic drug, i.e. tadalafil, and matrices, i.e. copolymers of methacrylates or methacrylic acid, in which tadalafil is molecularly dispersed in these copolymers. In these solid dispersions, tadalafil is in amorphous form.

The mass ratio of tadalafil: the total amount of polymers in the composition of the present invention is in the range from 1: 1 to 1: 8, preferably 1: 3.

The mass ratio of polymer (s) soluble in an aqueous medium at pH not higher than 5.0 and polymer (s) with pH-dependent solubility, soluble at pH above 5.0, is in the range from 1: 1 to 1: 4.

Preferably, the composition of the present invention further comprises a filler. The filler to be used according to the present invention may be any filler known to those of ordinary skill in the art. Specifically, the excipient to be used according to the present invention is an inorganic excipient, polysaccharide, mono- or disaccharide or sugar alcohol. Advantageously, the filler used according to the present invention is selected from the group consisting of microcrystalline cellulose, magnesium aluminum metasilicate and starch. Microcrystalline cellulose is a particularly preferred filler.

Preferably, the composition of the present invention further includes other excipients.

More preferably, the composition of the present invention further includes a disintegrant. The disintegrant to be used according to the present invention may be any disintegrant known to one of ordinary skill in the art. Suitable disintegrants for use in the present invention are selected from the group consisting of croscarmellose, crospovidone and sodium starch glycolate. A particularly preferred disintegrant is croscarmellose.

Preferably, the composition of the present invention further includes a lubricant. The lubricant to be used according to the present invention may be any lubricant known to one of ordinary skill in the art. A particularly preferred lubricant is magnesium stearate.

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

The XRPD analysis experiments of the composition of the present invention do not show peaks of crystalline material, which indicates the absence of free (crystalline) tadalafil and indicates the presence of an amorphous solid dispersion (see, for example, FIG. 2).

The pharmaceutical composition of the present invention exhibits a solubility pattern typical of immediate release formulations (see, for example, FIG. 1) without the need for finely divided tadalafil as an active pharmaceutical ingredient. In the compositions of the present invention, tadalafil is not present in particulate form, but it is molecularly dispersed in a matrix that is formed by polymer (s) soluble in an aqueous medium at pH not higher than 5.0 and polymer (s) with pH-dependent solubility, soluble at pH above 5.0, where the interaction with the polymers increases the solubility of tadalafil, improving its bioavailability, as a result of which the pharmaceutical composition of the present invention is biologically equivalent to the marketed Cialis® product after meals and on an empty stomach.

When studying the stability of pharmaceutical compositions with various solid dispersions of tadalafil, there was a small, but statistically significant decrease in dissolution rate. In the present invention, it was 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. The rate of penetration of water vapor (WVTR), also referred to as the rate of penetration of moisture vapor (MVTR), is an indicator of the passage of water vapor through a substance. Various methods are available for measuring WVTR, ranging from gravimetric methods that measure moisture gain or loss from mass changes to complex instrumental methods that in some cases are capable of measuring extremely low moisture transfer rates. Commercial instruments are available for determining WVTR using either a pressure modulated infrared detector or a mechanically modulated infrared detector. Numerous standard procedures are described in sources such as ISO, ASTM, BS and DIN, for example ASTM F1249 and DIN53122. The conditions under which measurements are made have a significant impact on the result. Together with the result, it is necessary to measure, control and record both temperature and humidity gradient in the sample volume. The authors found that the dissolution rate of the pharmaceutical compositions of the present invention can be maintained using a moisture barrier with a WVTR of less than 0.35 g / m ² / day at 38 ° C / 90% rel. ow (relative humidity). Preferably, the WVTR of the moisture barrier is maintained at a level of less than 0.2 g / m ² / day at 38 ° C / 90% rel. ow More preferably, the WVTR of the moisture barrier is maintained at a level of less than 0.1 g / m ² / day at 38 ° C / 90% rel. moisture and, most preferably, the WVTR of the moisture barrier is maintained at a level of less than 0.01 g / m ² / day at 38 ° C / 90% rel. ow

Blister packs belong to the group of main packaging materials in the pharmaceutical industry. They are used to protect pharmaceutical compositions from external factors such as humidity and contamination for extended periods of time. The type of blister packaging material used and its film thickness determine the WVTR value. Typical WVTR values of a 250 μm PVC blister film and a 250 μm double layer blister film of PVC / 90 g / m ² PVDC are> 3 g / m ² / day and 0.35 g / m ² / day at 38 ° C / 90% rel. ow., respectively. The cold-formed film, also known as alpha, has a WVTR value of 0.005 g / m ² / day at 38 ° C / 90% rel. ow

In another embodiment of the present invention, the pharmaceutical composition described above is stabilized using a moisture barrier with a WVTR of less than 0.35 g / m ² / day at 38 ° C / 90% rel. ow Preferably, this layer is created by packaging the pharmaceutical composition in a blister packaging material with a WVTR of less than 0.35 g / m ² / day at 38 ° C / 90% rel. ow Most preferably, by packaging the pharmaceutical composition in a cold formed film.

Further, the present invention relates to a method for producing 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. Obtaining two solutions in a solvent or mixture of solvents:

i. tadalafil and at least one polymer soluble in an aqueous medium at a pH of not more than 5.0;

ii. tadalafil and at least one polymer with a pH-dependent solubility, soluble at pH above 5.0;

b. Sequential spraying of the solutions obtained in stage a above the filler;

c. Granulating the mixture obtained in step b;

d. Drying the resulting 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 those of ordinary skill in the art. It is important that tadalafil and the polymer (s) are completely dissolved.

Advantageously, the solvent used according to the present invention may be a polar organic solvent, while the solvent mixture may be a mixture of polar organic solvents or a mixture of a polar organic solvent with water. Suitable polar organic solvents for use in 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 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 mass ratio of from about 8: 2 to about 9: 1, more preferably in a mass ratio of from 8.5: 1.5 to 9: 1.

The steps of the method of the present invention are typically carried out at a temperature of from about 25 ° C to about 50 ° C. In a preferred embodiment of the method of the present invention, the steps are carried out at a temperature of from about 40 ° C to about 50 ° C. During step b, both solutions are sequentially sprayed over the excipient. Preferably, the spraying order in step b is as follows:

1. Spraying over the filler a solution of tadalafil and at least one polymer soluble in an aqueous medium at a pH of not higher than 5.0;

2. Spraying over the filler a solution of tadalafil and at least one polymer with a pH-dependent solubility, soluble at pH above 5.0.

Preferably, the method of the present invention is implemented in a fluidized bed granulator or in a high shear granulator, more preferably in a fluidized bed granulator.

Preferably, the method of the present invention further includes the steps of mixing the dried and optionally sieved granulate with a disintegrant, a lubricating component, and optionally one or more additional pharmaceutically acceptable excipients, and compressing the mixture into tablets using techniques and equipment well known to those skilled in the art areas of technology.

The method of the present invention is preferred because it avoids the use of large quantities of solvents and laborious grinding procedures. In addition, a short granulation time is required in the method of the present invention. For these reasons, the method of the present invention is easily implemented on an industrial scale.

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

EXAMPLES

Example 1

Ingredients mg per tablet % Tadalafil * 20.00 4.17 Eudragit E100 * 30.00 6.25 Eudragit E100-55 * 30.00 6.25 Microcrystalline cellulose* 306.56 63.87 Eudragit E100 * 30.00 6.25 Eudragit L100-55 * 30.00 6.25 Microcrystalline cellulose* 306.56 63.87 Microcrystalline cellulose 76.64 15.97 Crosscarmellose sodium 14.40 3.00 Magnesium stearate 2.40 0.50 Acetone: Water 9: 1 ** 720 - Total 480 one hundred Opadry II four% * The ingredients that make up the granules (intragranular)
** It is evaporated at the granulation stage

Production method

135 g of acetone and 15 g of water were mixed and heated to 45-50 ° C. 12.5 g of Eudragit L100-55 was added and completely dissolved in the solvent. Then 4.17 g of tadalafil was added and dissolved. An intragranular portion of microcrystalline cellulose (MCC) (127.7 g) was weighed and added to the fluidized bed. The solution was sprayed over MCC and granulated in a fluidized bed at a spray rate of about 6-7 g / min. After the first spraying, 135 g of acetone and 15 g of water were mixed in another container and heated to 45-50 ° C. 12.5 g of Eudragit E100 was added and completely dissolved in the solvent. Then 4.17 g of tadalafil was added and dissolved. The second solution was sprayed over the powder obtained from the previous spraying and granulated in a fluidized bed at the same flow rate. After the addition of the second solution, drying was continued to LOD <3% and sieved through a 0.8 mm sieve (XRPD granules in Fig. 2 show the presence of amorphous tadalafil without peaks corresponding to the crystal structure). The remaining part of MCC (31.93 g) and croscarmellose sodium (6 g) were weighed, sieved and mixed with sieved granules for 15 minutes. 1 g of magnesium stearate was sieved through a 0.500 mm sieve and mixed with the previously obtained mixture for 5 minutes. The obtained homogeneous powder mixture was pressed under conditions of controlled humidity on a rotary tabletting machine to obtain 480 mg tablets with a hardness of 150N.

Claims (34)

1. A pharmaceutical composition comprising a solid dispersion of tadalafil and at least two different types of polymers: a. At least one cationic methacrylate copolymer; b. At least one anionic methacrylic acid copolymer; where the cationic methacrylate copolymer is obtained on the basis of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate in a ratio of 2: 1: 1, and the anionic methacrylic acid copolymer is obtained on the basis of a methacrylic acid-ethyl acrylate copolymer in a ratio of 1: 1, showing a dissolution rate of at least 85 mass. % for 20 min when tested in 1000 ml of phosphate buffer (pH 6.8) +0.35 mass. % sodium dodecyl sulfate (SDS) in apparatus II USP (containers with a peak at the bottom) at 50 rpm 2. The composition according to claim 1, where the mass ratio of tadalafil: the total amount of polymers in the composition is in the range from 1: 1 to 1: 8. 3. The composition according to claim 1, where the mass ratio of tadalafil: the total amount of polymers in the composition is 1: 3. 4. The composition according to claim 2, where the mass ratio of cationic methacrylate copolymer (s) and anionic copolymer (s) of methacrylic acid is in the range from 1: 1 to 1: 4. 5. The composition according to claim 4, further comprising a filler. 6. The composition according to claim 5, where the filler is microcrystalline cellulose. 7. The composition according to claim 5, further comprising other pharmaceutical excipients. 8. The composition according to claim 7, further extruded into tablets. 9. The composition according to claim 7, where the dose of tadalafil in the composition is selected from the group comprising 2.5, 5, 10, 20 or 40 mg. 10. The composition according to any one of claims 1 to 9, characterized in that this composition is stabilized by a moisture barrier with a water vapor penetration rate (WVTR) of less than 0.35 g / m ² / day at 38 ° C / 90% rel. ow 11. The composition of claim 10, where the moisture barrier is created by packing the tablets in blister packaging material. 12. The composition of claim 10, where the blister packaging material is a blister pack of cold forming. 13. A method of obtaining a composition according to any one of claims 1 to 9, comprising the steps of: a. Obtaining two solutions in a solvent or mixture of solvents: i. tadalafil and at least one cationic methacrylate copolymer; ii. tadalafil and at least one anionic methacrylic acid copolymer; b. Sequential spraying of the solutions obtained in stage a above the filler; c. Granulating the mixture obtained in step b; d. Drying the resulting granulate. 14. The method according to item 13, where 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. 15. The method according to 14, where the solvent is a mixture of acetone with water. 16. The method according to clause 15, where the mass ratio of acetone and water in the mixture is from 8: 2 to 9: 1. 17. The method according to item 13, where stage a is carried out at a temperature of from 25 ° C to 50 ° C. 18. The method according to item 13, where stage a is carried out at a temperature of from 45 ° C to 50 ° C. 19. The method according to item 13, where the sequence of stage b is as follows: 1. spraying over the filler a solution of tadalafil and at least one cationic methacrylate copolymer; 2. spraying over the filler a solution of tadalafil and at least one anionic methacrylic acid copolymer. 20. The method according to item 13, further comprising the steps of: a. mixing dried and optionally sieved granulate with a disintegrant, a lubricating component, and optionally one or more additional pharmaceutically acceptable excipients; and b. compressing the resulting mixture into tablets.

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