EA028561B1 - Solid dosage forms of tadalafil - Google Patents

Abstract

The invention relates to medicine, particularly to a preparation in the form of a solid dosage form having improved solubility, comprising a PDE-5 tadalafil selective inhibitor. The invention also discloses a process for preparation of new pharmaceutical compositions of tadalafil and formulation thereof.

Description

The present invention relates to solid dosage forms of a selective ΡΌΕ-5 inhibitor, such as tablets, and to methods for their manufacture. In particular, the invention relates to pharmaceutical compositions containing an active pharmaceutically active substance with low solubility in water, such as tadalafil.

State of the art

The preferred method of administration of the compounds of this invention, namely the selective ΡΌΕ-5 inhibitor tadalafil, is oral administration, due to their biological activity due to the manifested selective inhibition of ΡΌΕ-5, the level of COMP is increased, which, in turn, promotes relaxation of the tissue of the cavernous body and determine the effectiveness of the use of compounds of this class in the treatment and prevention of erectile dysfunction. Oral administration is the most convenient and preferred because it avoids the disadvantages associated with other types of administration with known methods of treatment and prevention of erectile dysfunction.

Currently, drugs are widely used that provide oral administration of an ΡΌΕ-5 inhibitor such as sildenafil in tablet form, manufactured, in particular, under the trademark Viagra®. Despite the significant commercial success of sildenafil, significant side effects have been identified, such as flushing of the face, visual impairment, which lead to restrictions on the use of this drug in patients, especially with hypertension or the use of organic nitrate preparations (OOCHST C1 A1., THc No.ν Εη ^ ίαηά 1oigia1 οί Meyushu, ν.338, No. 20, 1998, OKL δΙΕΌΕΝΑΕΊΕ ΙΝ ΤΗΕ ΤΚΕΑΤΜΕΝΤ ОР ΕΚΕί'ΊΊΕΕ ΌΥδΡυΝΟΤΙΟΝ).

An alternative inhibitor of ΡΌΕ-5, largely devoid of these drawbacks, is tadalafil. A method for treating sexual dysfunction and pharmaceutical compositions containing from 1 to 20 mg of tadalafil, as described in Eurasian Patent No. 5416, have significantly less side effects. A significant drawback of tadalafil, as one of the most promising ΡΌΕ-5 inhibitor, when creating solid dosage forms for oral administration was its low solubility and the associated bioavailability problems.

When solid dosage forms are administered orally, in many cases the drug must be dissolved in aqueous gastrointestinal juices, for example in the patient’s stomach, before the drug can exhibit a therapeutic effect. A common problem for compressed oral dosage forms, such as tablets, is that the dissolution rate of certain drugs from the dosage form limits their bioavailability. This problem is especially common for drugs that are small organic molecules with low solubility in aqueous liquids.

There are several ways to solve the problem of increasing solubility for poorly soluble drugs. For example, you can modify the medicine itself. The physical form of the drug can be modified through various techniques to optimize the dissolution rate of the drug. Of these techniques, the most suitable for the present invention is to increase the surface area of a solid, which is directly proportional to the increase in the rate of dissolution of the solid. Since the rate of dissolution of solids, as a rule, depends on the surface area exposed to the solvent medium; and therefore, the surface area of a certain mass of substance, as a rule, is inversely proportional to the particle size of the substance, and a decrease in the particle size of the powder, as a particulate or granular solid, generally increases its dissolution rate by increasing the surface area exposed to the solvent medium.

However, reducing particle size (by increasing) is not always effective for increasing the dissolution rate of a drug in a compressed solid dosage form. During the process of manufacturing a dosage form from ground particles, many hydrophobic drugs have a pronounced tendency to agglomerate the ground particles into larger particles, which leads to a general decrease in the effective surface area and poor solubility and bioavailability. κν. 201N her. 656,657, Α.Κ. Oeiiago G., IrrtotsOC HUppap & ΑίΙΕίηδ, Ρ1ιί1; · ^ 1ρ1ιί; · ι 2000), incorporated by reference in this application, contains a more detailed discussion of the concept of effective surface area and the effect of particle size on dissolution. A medicine that was first pulverized (for example, ground) to small particles, sometimes when applied in solid form, exhibits the worst dissolution characteristics of larger particles due to agglomeration or a similar effect.

In the prior art, various techniques have been undertaken in an attempt to overcome the observed poor solubility of tadalafil in water. For example, US Pat. No. 6,821,975 relates to a milled form of a free tadalafil drug containing particles of a compound in which at least 90% of the particles are less than about 40 microns in size. Preferably, at least 90% of the particles are less than 10 microns in size.

- 1 028561

The above methods of increasing the bioavailability of tadalafil suffer from disadvantages in economic terms and in terms of safety. For example, carrying out fine grinding, as described in US patent No. 6821975, can be time-consuming, and there may also be problems associated with safety, due to the obtained fine powder from it. US patent No. 5985326 proposes the use of significant amounts of organic solvent, which is undesirable for the environment. Thus, a method that uses large particles of a drug (with a b (0.9) of 40 μm or more) while maintaining the desired bioavailability will improve the economy and safety of the production process of tadalafil tablets.

Levy et al. (Beuu e! A1.) Reported the effect of starch on the dissolution rate of salicylic acid from tablets obtained by double pressing (Beuu S. e! A1., I. Ryag. 5eg 1963, 52, 1047). It was reported that an increase in starch content from 5 to 20% increased the rate of dissolution of salicylic acid three times. This observation was attributed to the faster disintegration of the tablets at a higher starch content. In 1966, Finholt et al. (ΡίπΗοΙί е! А1.) It was observed that finely divided starch particles added to phenobarbital tablets increased the dissolution rate of phenobarbital from tablets. Coming to a different conclusion than that proposed by Levy et al. (Beuu e! A1.), Finholt et al. (ΡίπΗοΐ! Е! А1.) Suggested that starch acted as a coating for phenobarbital crystals and imparted to it a hydrophilic property that improved contact between the phenobarbital particles and the aqueous dissolution medium (ΡίπΗο1! R. Mebb Wogz Ragsch. 566 En. 1966, 28 , 238).

Starch is a common component of tablets, where it is used for a number of reasons. It is usually used, for example, as a diluent, a binder, a disintegrant and a glidant. Diluents increase the volume of the solid pharmaceutical composition and can make the pharmaceutical dosage form containing this composition more convenient to handle for the patient and caregiver.

Moreover, in some cases, the use of starch and its derivatives in solid dosage forms is extremely undesirable, for example, in patients with diabetes, and also due to the need to minimize the size of the dosage form.

In this regard, the basis of the creation of the present invention is the creation of starch-free pharmaceutical compositions of solid dosage forms of tadalafil for oral administration while maintaining characteristics such as high bioavailability, activity and dissolution rate. The intended product may also have an alternative route of administration, such as parenteral administration, for example, sublingual or buccal, used in patients with swallowing reflex disorder.

In the development and manufacture of formulations of drugs that are poorly soluble in water when a high bioavailability of the drug is required, a combination of small particles of the drug (such as micronized particles of the drug) and a suitable manufacturing method (for example, one of the methods described above) are usually used. However, the micronization method may be associated with high time and processing costs, and may also present a safety problem, since the micronization process may result in a finely divided drug powder.

Accordingly, any new composition and / or manufacturing method providing the necessary dissolution and bioavailability levels using relatively large drug particles can provide safer and more economical methods for manufacturing solid dosage forms.

Tadalafil, the active ingredient in Cialis®, is used to treat erectile dysfunction in men. Directions for use triacetin (see. !! p5: //rtSh1u.sosh/i5/s1aN5-rrtrbG).

Tadalafil has the chemical name (6K, 12aK) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4methylenedioxyphenyl) pyrazino (1 ', 2': 1,6) pyrido (3 4-b) indole-1,4-dione. The structure of tadalafil (CA5№171596-29-5) is shown below

Tadalafil is a solid and, in its usual form, practically insoluble in water, and only very slightly soluble in some organic solvents such as methanol, ethanol and acetone. In US patent No. 6841167 it is reported that tadalafil has a solubility in water of about 2 μg per

- 2 028561 ml of water at 25 ° C.

Various techniques have been used to overcome the apparent poor solubility of tadalafil in water. GO 6841167 refers to a pharmaceutical composition containing tadalafil in the form of a free drug in a mixture with a diluent, lubricant, a hydrophilic binding agent and a disintegrant. Soft capsules containing tadalafil suspended in a pharmaceutically acceptable solvent are specially formulated to provide tadalafil formulations with probably improved bioavailability.

Another technique used to improve solubility is described in US Pat. No. 5,985,326, and involves preparing formulations using tadalafil co-precipitation, where a thoroughly mixed mixture of tadalafil and a carrier in a non-aqueous water-miscible solvent and, if necessary, water are precipitated together from a thoroughly mixed mixture using an aqueous medium for co-precipitation, in which the carrier is substantially insoluble.

Eurasian Patent No. 4302 is specifically directed to the particulate form of a free tadalafil drug containing particles of a compound where at least 90% of the particles have a size less than about 40 microns. Preferably, at least 90% of the particles have a size of less than 10 microns.

The above methods for increasing the bioavailability of tadalafil have economic and safety related disadvantages. Thus, the invention according to the Eurasian patent EA4302 requires micronization, which can take a lot of time, and can also aggravate the safety problems associated with the obtained fine powder. GO 5985326 requires the use of significant amounts of organic solvent, which is undesirable for the environment. Accordingly, the method in which large particles of the drug are used (with 6 (0.9) 40 μm or more) while maintaining the necessary bioavailability will increase the economy and safety of the manufacturing process of tadalafil tablets.

Russian Patent No. 2456989 targets a pharmaceutical composition of tadalafil having a particle size distribution such that 6 (0.9) is 40 μm or more and starch.

There remains a need to provide improved pharmaceutical dosage forms of tadalafil with a consistently high dissolution rate, providing good bioavailability and not aimed at reducing the particle size of the drug (for example, by micronization), which eliminates the above disadvantages (agglomeration) and ensures the stability of the form properties when used as well as during storage. This problem is solved, and the technical result is achieved due to the proposed invention.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides a solid pharmaceutical dosage form comprising:

a) from 3 to 5% tadalafil;

b) from 71 to 72% lactose monohydrate;

c) from 0.5 to 0.7% sodium lauryl sulfate; b) from 10 to 11% povidone;

e) from 10 to 11% crospovidone;

ί) from 0.7 to 0.9% sodium stearyl fumarate;

d) from 2.8 to 3.2% of Orabgu II 85P32782 yellow;

where the tadalafil particles used in the preparation of the indicated dosage form have such a particle size distribution that b (0.9) is greater than 40 μm.

In another embodiment, a dissolution profile of a pharmaceutical dosage form of the present invention is provided.

In another embodiment, the present invention provides C _max and A & C values for a pharmaceutical composition.

In another embodiment, the present invention provides a method for preparing said pharmaceutical composition.

Brief Description of the Drawing

The drawing is a graph showing a comparison of the dissolution rate of tadalafil versus time for:

A) a composition containing tadalafil, where the particles of tadalafil used in the preparation of said composition have a particle size distribution such that b (0.9) is greater than 40 μm;

B) Cialis®, 20 mg.

DETAILED DESCRIPTION OF THE INVENTION

As used in this application, the term b (0.9) means the 90th percentile of the particle size distribution. The value of b (0.9) is such a distribution value with which 90% of the particles (by total volume) have a size of this value or less when the particle size distribution is measured by a conventional method, such as laser diffraction. Devices for measuring the distribution of particle size can be obtained from various sources, such as from Layout 1p51gitei 18 Yb. (United Kingdom).

As used herein, the term PVP or povidone means polyvinylpyrrol-3,028,561 dong.

As used herein, the term Oraigu II 85P32782 yellow means a film coating containing partially hydrolyzed polyvinyl alcohol, macrogol, titanium dioxide, talc and yellow iron oxide (supplied by Co1geo®).

As used in this application, unless otherwise indicated, all percentages are weight percent based on the total weight of the solid dosage form.

As used in this application, the product designated as Cialis® was used as series No. A800709.

As used in this application, the dissolution rate was determined by the percentage of tadalafil dissolved in a liquid medium. The analysis conditions were as follows: a sample containing 20 mg of tadalafil was tested in 1000 ml of an aqueous medium containing 0.5% sodium lauryl sulfate in water using a block of 6 vessels for apparatus II (with a paddle mixer) at a speed of 50 rpm.

As used in this application, a similar dissolution rate according to Cialis® means the ratio of the dissolution rate at the same time under the same analysis conditions between the dosage form and Cialis® in the same dosage from 80 to 125%.

As used in this application, bioequivalence or bioequivalent means that the product meets or will meet the bioequivalence requirements of the Food and Drug Administration (ΡΌΑ). In accordance with the U.S. Code of Federal Regulations, Section 21, v. 5, § 320.1, Bioequivalence means that there is no significant difference in the speed and extent to which the active ingredient or active component in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action of the drug when used in one and the same molar dose under similar conditions in a properly performed study. For example, one criterion that ΡΌΑ relies on is defined in statistical procedures ΡΌΑ to determine bioequivalence using a cross-sectional study with two treatment regimens (1992), incorporated herein by reference. Cialis® bioequivalence means a 90% confidence interval for the C _max and / or AIS _max ratios from 80 to 125%.

As used herein, for tadalafil, the term C _max means the maximum plasma concentration of tadalafil after taking a dose of tadalafil; the term T _max refers to the time after administration when C _{max is} achieved; the term AIS _0-1 means the area under the plasma concentration curve of tadalafil over time after administration. The curve usually ends when the concentration falls below the detection limit. The term AIS _0-1 means AIS during I after administration. AIS _0-M means the total area under the curve and is a measure of the total exposure of tadalafil to the patient. When a study is conducted on a plurality of individuals, C _max means geometric mean of C _max of multiple individuals, and AIS means geometric mean of AIS of many individuals in the study.

In one embodiment, a solid pharmaceutical dosage form is provided, comprising:

1ι) from 3 to 5% of tadalafil;

ί) from 71 to 72% of lactose monohydrate;

p from 0.5 to 0.7% sodium lauryl sulfate;

k) 10 to 11% povidone;

l) 10 to 11% crospovidone;

t) from 0.7 to 0.9% sodium stearyl fumarate; o) from 2.8 to 3.2% of Oraigu II 85P32782 yellow;

where the particles of tadalafil used in the preparation of the indicated dosage form have such a particle size distribution that d (0.9) is greater than 40 μm.

Preferably, the pharmaceutical dosage form of the invention includes:

a) 4% tadalafil;

b) from 71 to 72% lactose monohydrate;

c) 0.6% sodium lauryl sulfate; g) from 10 to 11% povidone;

e) from 10 to 11% crospovidone;

I) 0.8% sodium stearyl fumarate;

d) from 2.8% to 3.2% of Oraigu II 85P32782 yellow;

where the particles of tadalafil used in the preparation of the indicated dosage form have such a particle size distribution that d (0.9) is greater than 40 μm.

In a preferred embodiment, the pharmaceutical dosage form of the invention has a dissolution rate of more than 90% tadalafil in 30 minutes when a sample containing 20 mg is tested in 1000 ml of an aqueous medium containing 0.5% sodium lauryl sulfate in water using a block of 6 vessels for apparatus II (with a paddle mixer) at a speed of 50 rpm

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In one embodiment, the pharmaceutical solid dosage form of the present invention provides a geometric mean C _max of 289 to 291 ng / ml when the dose is 20 mg of tadalafil. One skilled in the art will appreciate that the C _max values vary depending on the dose used.

In a preferred embodiment, the minimum C _max value is from 216 to 217 ng / ml. In another preferred embodiment, the maximum C _max value is from 394 to 395 ng / ml. Both values are obtained when the dose is 20 mg of tadalafil.

In one embodiment, the pharmaceutical solid dosage form of the invention provides a geometric mean LIS of 7236 to 7276 ng / ml when the dose is 20 mg of tadalafil. One skilled in the art will recognize that LIS values vary depending on the dose used.

In a preferred embodiment, the minimum LIS is between 2831 and 2832 ng / ml. In another preferred embodiment, the maximum LIS value is from 13897 to 13898 ng / ml. Both values were obtained for a dose of 20 mg of tadalafil.

One embodiment of the invention provides a method for preparing the above solid pharmaceutical dosage form containing tadalafil.

A preferred method includes the following steps.

At the first stage, tadalafil, having a particle size distribution such that 6 (0.9) is more than 40 μm, is granulated in a high shear mixer with lactose and sodium lauryl sulfate in the presence of PVP in ethanol. Preferably, the lactose is spray dried lactose.

In a second step, the wet granulate is milled and then dried. Preferably, the grinding is carried out using a rotary grinder, and the drying is carried out in a fluidized bed dryer.

Then the dry granulate is ground and mixed with extra-granular excipients: crospovidone and sodium stearyl fumarate.

Finally, proportional tablets of 480, 240, 120, and 60 mg (20, 10, 5, and 2.5 mg of tadalafil, respectively) are pressed, then coated with an Orabgu II 85T32782 yellow coating. Preferably, the tablets are compressed by a rotary tabletting machine.

In one embodiment, the invention provides a solid pharmaceutical dosage form of the invention for use in medicine.

In one embodiment, the invention provides the use of the solid pharmaceutical dosage form of the invention in the manufacture of a medicament for the treatment of erectile dysfunction in men.

The following examples of formulations are illustrative only and are not intended to limit the scope of the invention in any way.

Examples

Example 1 (a-6).

An exemplary composition was prepared from the ingredients listed in table. 1-4 using the steps described below.

1. Tadalafil (RRF: 690> 52 μm) was granulated in a high shear mixer with spray dried lactose and sodium lauryl sulfate in the presence of 50 wt.% PVP K-12 in ethanol.

2. The wet granulate was milled using a rotary grinder and then dried in a fluidized bed dryer.

3. Dry granulate was milled using a rotary grinder, and mixed with extra-granular excipients: crospovidone and sodium stearyl fumarate.

4. Proportional tablets of 480, 240, 120, and 60 mg (20, 10, 5, and 2.5 mg of tadalafil, respectively) were pressed with a rotary tabletting machine, then coated with an Orabgu II 85T32782 yellow coating (3% by weight of the tablet).

a) 20 mg of tadalafil

Table 1

Ingredients Weight (mg / tablet) Content, mass% R cancellation Lactose Monohydrate (spray dried) 353 71.3 Tadalafil twenty 4 Sodium Lauryl Sulfate 3 0.6 Povidone K-12 fifty 10.1 Ethanol (96%) * Crospovidone (Ro1ur1azyope XB-10) fifty 10.1 Sodium stearyl fumarate (Rgiu) 4 0.8 Shell Purified water * Horace1gu II 85P32782 yellow fifteen 3.0 Total tablet weight 495 one hundred

- 5,028,561

B) 10 mg of tadalafil

table 2

Ingredients Weight (mg / tablet) Content, mass% R cancellation Lactose Monohydrate (spray dried) 176.5 71.5 Tadalafil 10 4 Sodium Lauryl Sulfate 1,5 0.6 Povidone K-12 25 10.1 Ethanol (96%) * Crospovidone (Ro1ur1az4ope XB-10) 25 10.1 Sodium Stearyl Fumarate (Ρηιν) 2 0.8 Shell Purified water * Horaceu II 85P32782 yellow 7 2,8 Total tablet weight 247 one hundred

c) 5 mg of tadalafil

Table 3

Ingredients Weight (mg / tablet) Content, mass% R cancellation Lactose Monohydrate (spray dried) 88.25 71.2 Tadalafil 5 4 Sodium Lauryl Sulfate 0.75 0.6 Povidone K-12 12.5 10.1 Ethanol (96%) * Crospovidone (Ro1ur1az4ope XB-10) 12.5 10.1 Sodium Stearyl Fumarate (Ρηιν) Shell one 0.8 Purified water * Orabgu II 85P32782 yellow 4 3.2 Total tablet weight 124 one hundred

b) 2.5 mg of tadalafil

Table 4

Ingredients Weight (mg / tablet) Content, mass% R cancellation Lactose Monohydrate (spray dried) 44,125 71.2 Tadalafil 2,5 4 Sodium Lauryl Sulfate 0.375 0.6 Povidone K-12 6.25 10.1 Ethanol (96%) * Crospovidone (Ro1ur1az4ope XB-10) 6.25 10.1 Sodium Stearyl Fumarate (Ρηιν) 0.5 0.8 Shell Purified water * Orabgu II 85P32782 yellow 2 3.2 Total tablet weight 62 one hundred

Dissolution analysis results.

Table 5

The dissolution profile of the composition of example 1A and the control product (% dissolution). Control product Cialis®, coated tablets 20 mg, supplied in Spain and the Teua series used in bioavailability analysis

Tab.> Dissolved substance in% of the specified amount Tadalafil, tablet 20 mg, series K-48300 ori 0.5% NLS in water SialnsSCH), tablet 20 mg, A800709 series at 0.5% NLS in water 10 fifteen thirty 45 60 10 fifteen thirty 45 60 one 57 77 92 ί 96 97 44 ' 66 88 94 98 2 62 80 93 96 97 82 97 101 102 102 3 bb 83 93 96 97 97 98 99 one hundred one hundred 4 61 79 93 96 97 84 94 one hundred 101 101 5 46 65 93 96 97 61 79 94 nine? 99 b 55 76 94 96 97 39 59 89 97 99 57 79 92 94 96 45 66 73 95 97 § 47 71 91 94 95 80 94 96 97 96 nine 61 82 93 95 96 59 82 98 one hundred 101 10 72 85 93 95 96 87 97 99 98 98 eleven 46 66 92 95 96 61 86 97 97 98 eleven 65 85 95 97 98 95 one hundred one hundred one hundred one hundred Average 58 77 93 96 97 & 85 95 98 99 DIS (%) 146 8.8 1,1 1.1 0.9 29.1 16.9 8.6 23 1,6

Example 2. Pharmacokinetic study.

An open, single-dose, randomized, two-period, two-sequence, crossover, comparative bioavailability study was performed in 20 individuals (of which 3 were excluded). The study was designed to compare the relative bioavailability of the composition with tadalafil (Example 1a). The control product was Cialis®, 20 mg. The pharmacokinetic parameters of tadalafil in an empty stomach are listed in table. 6.

Table 6

The results of a pharmacokinetic study of exemplary formulations and control product

Example 1a (ng / ml) Cialis®, series No. A800709 (ng / ml) Geometric Average Stach 290.25 318.44 Stach minimum 216.09 257.50 Stach maximum 394.86 592.42 Geometric mean AiSg 7275.30 8077.63 AiSg minimum 2831.32 3367.36 AiS ₁ maximum 13897.89 14809.34

All A&S values were taken at 1 = 72 hours.

All values of C _max and AiC are presented as the geometric mean of many individuals.

Also, within the framework of the present invention, the properties of the proposed solid pharmaceutical forms were studied during storage for various periods of time on various models (6, 9, 12.18 months - modeling). Tests showed the stability of the composition of the drugs throughout the experiment simulating storage, which proved the solution to the stability problem.

Although some preferred embodiments of the invention are described in the present application, it will be appreciated by those skilled in the art to which the embodiments and modifications of the described embodiments can be made without restricting the nature and scope of the invention. Accordingly, it is understood that the invention is limited only to the extent established by the claims and applicable law.

Claims (11)

CLAIM 1. A solid pharmaceutical dosage form containing: a) from 3 to 5% tadalafil; b) from 71 to 72% lactose monohydrate; c) from 0.5 to 0.7% sodium lauryl sulfate; ά) 10 to 11% povidone; e) from 10 to 11% crospovidone; 1) from 0.7 to 0.9% sodium stearyl fumarate; d) from 2.8 to 3.2% of Oraigu II 85E32782 yellow; where the particles of tadalafil used in the preparation of the indicated dosage form have such a particle size distribution that d (0.9) is greater than 40 μm. 2. The solid pharmaceutical dosage form according to claim 1, containing: a) 4% tadalafil; b) from 71 to 72% lactose monohydrate; c) 0.6% sodium lauryl sulfate; g) from 10 to 11% povidone; e) from 10 to 11% crospovidone; 1) 0.8% sodium stearyl fumarate; d) from 2.8% to 3.2% of Oraigu II 85E32782 yellow; where the particles of tadalafil used in the preparation of the indicated dosage form have such a particle size distribution that d (0.9) is greater than 40 μm. 3. The dosage form according to any one of the preceding paragraphs, where the pharmaceutical dosage form exhibits a dissolution rate of more than 90% tadalafil in 30 minutes, when a sample containing 20 mg of tadalafil is tested in 1000 ml of an aqueous medium containing 0.5% sodium lauryl sulfate in water, using a block of 6 vessels for apparatus II (with a paddle mixer) at a speed of 50 rpm 4. The dosage form according to claim 1, where the geometric mean value C _max is from 289 to 291 ng / ml, when the dose is 20 mg of tadalafil. 5. The dosage form according to claim 1, where the minimum value of C _max is from 216 to 217 ng / ml, when the dose is 20 mg of tadalafil. 6. The dosage form according to claim 1, where the maximum C _max value is from 394 to 395 ng / ml when the dose is 20 mg of tadalafil. 7. The dosage form according to claim 1, where the geometric mean value of the LES is from 7236 to 7276 ng / ml, when the dose is 20 mg of tadalafil. 8. The dosage form according to claim 1, where the minimum value of LES is from 2831 to 2832 ng / ml, when the dose is 20 mg of tadalafil. 9. The dosage form according to claim 1, where the maximum value of AIS ₁ is from 13897 to 13898 ng / ml, when the dose is 20 mg of tadalafil. - 7,028,561 10. The method of preparing the dosage form according to claim 1, comprising the following steps: a) granulating tadalafil having a particle size distribution such that 6 (90) is greater than 40 μm in a high shear mixer with lactose and sodium lauryl sulfate in the presence of KP-12 PVP and ethanol; b) grinding wet granulate; c) drying the mixture; 6) grinding the mixture; e) mixing with crospovidone and sodium stearyl fumarate; ί) compressing the mixture into tablets; d) applying a shell from Orabgu II 85P32782 yellow. 11. The use of the dosage form according to paragraphs. 1-9 in the preparation of a medicament for the treatment of erectile dysfunction in men.