KR102646431B1 - Solid formulation containing tadalafil with improved productivity and uniformity and preparation method thereof - Google Patents

Abstract

One aspect includes tadalafil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and about 10 to 40% by weight of particles having a particle size of 250 to 450 ㎛, and particles having a particle size of 75 to 150 ㎛. It relates to a solid preparation containing about 18% by weight or less, and provides a solid preparation containing tadalafil or a pharmaceutically acceptable salt thereof with improved productivity and uniformity, and a method for manufacturing the same.

Description

Solid formulation containing tadalafil with improved productivity and uniformity and preparation method thereof}

The present invention relates to a solid formulation containing tadalafil or a pharmaceutically acceptable salt thereof with improved productivity and uniformity, and a method for manufacturing the same.

Phosphodiesterase-5 (PDE-5) inhibitors are selective inhibitors of cyclic guanosine 3', 5'-monophosphate phosphodiesterase type 5 (cGMP PDE-5) and are generally It is used as a treatment for erectile dysfunction, and is currently being developed and sold commercially as a drug. One of these PDE-5 inhibitors is 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) is used for the treatment of erectile dysfunction and benign prostatic hyperplasia, or for the treatment of erectile dysfunction and benign prostatic hyperplasia. It is known that it can be used in the treatment of patients (Patent Document 1).

Tadalafil is commercially available as "Cialis ^TM tablets" for the treatment of erectile dysfunction and "Adcirca ^TM tablets" for the treatment of pulmonary arterial hypertension. Cialis tablets were also approved by the FDA in 2011 for the treatment of benign prostatic hyperplasia. I have received it. In addition, tadalafil has a half-life that is more than 3 times longer than that of sildenafil or vardenafil, which are PDE-5 inhibitors, so its efficacy lasts longer, side effects such as facial flushing are less, and the 5 mg formulation of tadalafil has the advantage of maintaining its efficacy by taking it once daily. there is.

However, tadalafil is a poorly water-soluble substance and is known to dissolve only about 2 μg/mL in water (Patent Document 2). In order for a poorly soluble active substance to exhibit sufficient bioavailability, improvement in solubility is necessary. To this end, efforts have been made to prepare tadalafil as a solid dispersion, rapid-release oral preparation, or micronized preparation. However, in this case, reproducibility is not secured or a special machine is required, making it uneconomical and unsuitable for large-scale production, and the micronized active material tends to form unpredictable aggregates, resulting in poor fluidity and processability.

In addition, due to the drug characteristics of tadalafil, tabletting problems such as capping, laminating, sticking, and picking, or increased mass deviation, decreased content uniformity, and mixing may occur during the large-quantity tabletting or filling process. It has the disadvantage of being prone to filling problems such as heterogeneity, making it difficult to develop various solid formulations.

Accordingly, the present inventors made efforts to develop a solid formulation that can ensure productivity and uniformity, and as a result, completed the present invention by developing a solid formulation that can improve tableting properties and secure content uniformity and appropriate dissolution.

WO2000/066099 WO2001/008687

One aspect is to provide a solid formulation containing tadalafil or a pharmaceutically acceptable salt thereof with improved productivity and uniformity.

Another aspect is to provide a method for manufacturing the solid formulation.

One aspect includes tadalafil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and includes about 10 to 40% by weight of particles with a particle size of 250 to 450 ㎛, and a particle size of 75 to 150 ㎛. A solid formulation containing about 18% by weight or less of particles is provided.

The other aspect of work is

(a) mixing tadalafil or a pharmaceutically acceptable salt thereof, excipients, and disintegrants;

(b) assembling the mixture by adding a binder solution to the mixture of step (a);

(c) sizing the granulated product of step (b) to obtain granules; and

(d) optionally adding an excipient, a disintegrant, and a lubricant to the granule of step (c) to formulate the solid formulation.

According to one aspect, a solid formulation containing tadalafil or a pharmaceutically acceptable salt thereof can secure high productivity by significantly reducing tableting disorders such as capping and sticking phenomenon that occur during the tableting process by improving tableting properties. In addition, it is possible to provide a safe medicine with excellent content uniformity, and a solid preparation showing an appropriate dissolution pattern to demonstrate effective and safe drug effects.

Figure 1 shows mesh profiles according to particle size analysis for the granules prepared in Examples 1 to 4. In this specification, #n passing indicates granules that passed when sieved through an n mesh sieve, and #n remaining amount indicates granules remaining on the sieve when sieved through an n mesh sieve. In Figure 1, for example, #200 passage represents the granules that passed when sieved with a 200mesh (75㎛) round body, and #200 remaining represents the granules remaining on the round body when sieved with a 200mesh (75㎛) round body.
Figure 2 shows the mesh profile according to particle size analysis for the granules prepared in Comparative Examples 1 to 3 and Examples 4, 5, and 7.
Figure 3 is a photograph observing whether capping and sticking occurred in tablets prepared in (a) Example 4 and (b) Comparative Example 3, respectively.
Figure 4 shows the dissolution rate (%) according to the dissolution test for the tablets prepared in Examples 4 and 5 and Comparative Examples 1 and 3.
Figure 5 shows the dissolution rate (%) according to the dissolution test for the tablets prepared in Example 6 and Example 8.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art in the field related to the present invention. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods are also included in the scope of the present invention. The contents of all publications incorporated by reference herein are hereby incorporated by reference in their entirety.

In the process of researching the formulation of tadalafil, it was discovered that productivity decreased when the particle size of the granules constituting the tablet or capsule was reduced, and that the dissolution rate decreased when the particle size of the granules was increased. After continued research, the present inventors developed a solid formulation that can improve productivity, uniformity, and dissolution of the solid formulation by controlling the particle size of the solid formulation containing tadalafil or a pharmaceutically acceptable salt thereof.

Accordingly, one aspect of the present invention is

It contains tadalafil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and contains about 10 to 40% by weight of particles with a particle size of 250 to 450 ㎛, and about 75 to 150 ㎛ particles. A solid formulation containing 18% by weight or less is provided. The particle size was measured using a test sieve according to the particle size test method in the General Information of the Korean Pharmacopoeia.

In solid formulations that do not meet the above particle size range, mixing uniformity and dissolution are likely to be reduced. In addition, solid formulations that do not meet the above particle size range are prone to tabletting problems such as capping, laminating, sticking, and picking. When manufacturing a solid formulation, the particle size of the granules can be adjusted to the above particle size range using a sieve or oscillator.

In this specification, the terms capping, laminating, sticking, or picking all refer to tableting failure phenomena caused by various causes such as inappropriate tableting conditions or mixing, excessive mixing of fine powder, excessive or insufficient drying, and attachment of flaws on the punch surface.

The term “capping” refers to the phenomenon in which the top of a tablet peels off into a hat shape. The term “laminating” refers to the phenomenon of tablets peeling off into layers.

The term “sticking” refers to the phenomenon where powder adheres to the surface of the upper or lower punch during tableting, creating grooves on the surface of the tablet. The term “picking” refers to the degree to which uneven spots appear on the surface of the tablet.

The term "particle size" refers to the size of the granule in terms of diameter (unit: ㎛), and refers to the particle size measured from the opening size of the eye that passes through the granules when sieved for sizing, for example, and is the average of the granule. It can be expressed in terms of particle size.

According to one embodiment, in the solid formulation, the particles having a particle size of 250 to 450㎛ are about 10 to 40% by weight, for example, about 20 to 40% by weight, 15 to 38% by weight, 20 to 38% by weight, 25 to 40% by weight. It may comprise 38% by weight, or 20 to 37.5% by weight.

According to one embodiment, in the solid formulation, particles having a particle size of 75 to 150 μm may be included in an amount of about 20% by weight or less, or about 18% by weight or less, for example, 15% by weight or less, or 13% by weight or less.

In another embodiment, the solid formulation may contain about 15 to 38% by weight of particles with a particle size of 250 to 450㎛, and about 15% by weight or less of particles with a particle size of 75 to 150㎛.

In another embodiment, the solid formulation may contain about 20 to 38% by weight of particles with a particle size of 250 to 450㎛, and about 15% by weight or less of particles with a particle size of 75 to 150㎛.

In another embodiment, the solid formulation is granules, and the particles having a particle size of 250 to 450㎛ are about 10 to 40% by weight, for example, about 20 to 40% by weight, 20 to 38% by weight, and 25 to 38% by weight. , or it may be included in 20 to 37.5% by weight.

In another embodiment, the solid formulation is granules, and the particles having a particle size of 75 to 150㎛ may be included in an amount of about 20% by weight or less, or about 18% by weight or less, for example, 15% by weight or less, or 13% by weight or less. You can.

When the solid formulation according to the present invention has the above particle size range, productivity and fillability are excellent, content uniformity is excellent, and a dissolution rate suitable for medicinal efficacy can be secured.

In one embodiment, when the particle size is smaller than the solid formulation range, productivity is lowered, filling properties are poor, and the occurrence of capping or sticking increases during tableting. In addition, there is a problem that the amount of fine powder generated increases and the dissolution rate increases unpredictably.

In one embodiment, if the particle size is larger than the range of the solid preparation, the possibility of layer separation during mixing increases due to the difference in particle size between the granule part and the post-mixed part, and thus the mixing uniformity is reduced when formulating into tablets, capsules, etc. Reduces dissolution rate.

In one embodiment, examples of pharmaceutically acceptable salts of tadalafil include hydrobromide, phosphate, sulfate, hydrochloride, malate, fumarate, lactate, tartrate, citrate, besylate, camsylate, gluconate, etc. or, for example, tadalafil free type, but is not limited thereto.

Considering the known daily dosage, the tadalafil or a pharmaceutically acceptable salt thereof in free form is about 2 mg to about 20 mg, preferably about 2.5 mg to 10 mg, based on the total weight of the solid preparation. Preferably, it may be contained in an amount of about 5 mg to about 10 mg or about 2.5 mg to about 5 mg.

In one embodiment, the solid preparation may be administered several times a day or once a day, depending on the purpose of treatment, and may be administered daily.

The pharmaceutically acceptable additive included in the solid preparation according to the above aspect may be any one selected from the group consisting of excipients, disintegrants, binders, lubricants, or mixtures thereof.

For example, the excipients (diluents) include microcrystalline cellulose, lactose, lactose monohydrate, ludipress, mannitol, calcium dihydrogen dioxide, starch, low-substituted hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose, and mixtures thereof. may be selected from the group consisting of, but is not limited to; The binder is hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, pregelatinized starch, polyvinylacetic acid, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, synthetic aluminum silicate. , silicate derivatives such as calcium silicate or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, pregelatinized starch, gums such as acacia gum, gelatin, cellulose derivatives such as ethylcellulose, and mixtures thereof. may be selected from the group consisting of, but is not limited to; The disintegrant may be selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid or sodium salt thereof, and mixtures thereof, but is limited thereto. It is not; The lubricant may be selected from the group consisting of stearic acid, stearic acid metal salts (magnesium stearate, etc.), talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oil, wax, glyceryl fatty acid esters, and combinations thereof. , but is not limited to this.

In one embodiment, the excipient is any one selected from the group consisting of lactose monohydrate, mannitol, starch, low-substituted hydroxypropylcellulose, microcrystalline cellulose, and mixtures thereof; The binder is any one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, and mixtures thereof; The disintegrant is any one selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, and mixtures thereof; The lubricant may be any one selected from the group consisting of stearic acid, stearic acid metal salts, talc, colloidal silica, and mixtures thereof.

In one embodiment, based on the total weight of the solid formulation, the excipient may be included in an amount of about 70 to 95% by weight, the binder may be included in an amount of about 0.5 to 2.5% by weight, and the disintegrant may be included in an amount of about 3 to 10% by weight. The lubricant may be included in an amount of about 0.1 to 2% by weight.

According to one embodiment, the productivity, uniformity, and dissolution rate of the active ingredient can be improved by selecting specific additives (see Test Examples 2 to 5).

In one embodiment, the binder may be hydroxypropyl cellulose, and more specifically, it may be hydroxypropyl cellulose-E extra fine (HPC-EXF) grade. there is. The HPC-EXF refers to hydroxypropyl cellulose exhibiting the characteristics of molecular weight: about 80,000 Da and viscosity: 300 to 600 mPas in about 25°C/10% aqueous solution.

In one embodiment, the binder may be a hydroxypropylcellulose solution having a viscosity of about 300 to 600 mPas at 25°C when it is a 10% aqueous solution.

In one embodiment, the binder solution is sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid ester, and these. It may further include any one surfactant selected from the group consisting of mixtures. In one embodiment, the solution may include sodium lauryl sulfate (SLS) along with hydroxypropylcellulose (HPC-EXF).

The binder solution may be a hydroxypropyl cellulose solution with a viscosity of about 30 to 50 mPas at 25°C when made as a 4.5% aqueous solution further containing sodium lauryl sulfate (SLS). For example, the binder solution may be hydroxypropyl cellulose. It may contain propylcellulose (HPC-EXF).

The binder may be included in an amount of 0.5 to 4% by weight, more preferably 0.5 to 2.5% by weight, based on the total weight of the composition. When the binder is included within the above range, it can improve the productivity, uniformity, and dissolution rate of the active material.

The solid dosage form may further contain any additives known in the pharmaceutical field that are useful for improving the processability, fluidity, stability, or moldability of the unit dosage form. For example, the solid preparation may further include other excipients selected from the group consisting of colorants, flavoring agents, sweeteners, stabilizers, surfactants, antioxidants, or combinations thereof.

In one embodiment, the solid preparation may be for oral administration or parenteral administration. In one embodiment, the solid preparation is any one solid preparation for oral administration selected from fine granules, granules, tablets, capsules, pills, pellets, mini-tablets, and dry syrups, or patches, cataplasma preparations, injections, ointments, It may be any one solid preparation for parenteral administration selected from and suppositories. The solid preparation may be a mixture of the above preparations, for example, it may be provided as a pellet or mini tablet contained in a capsule, for example, it may be in the form of a multi-unit spheroidal tablet (MUST). You can.

In one embodiment, the solid formulation may be in the form of granules manufactured through wet processing. Granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient can be manufactured according to a conventional granulation process. The granulation process refers to a process in which tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient is made into a moisture-absorbed state to have adhesiveness, and the active ingredient having adhesiveness is agglomerated to produce large powder particles, that is, granules. .

The granulation process may preferably be a conventional wet granulation process using a binder. The binder solution can be prepared using the binder mentioned above. The binding solution is prepared by adding additives commonly used in the pharmaceutical field, such as binders, surfactants, buffers, or combinations thereof, to pharmaceutically usable solvents such as purified water, ethanol, isopropanol, and mixtures thereof. can be manufactured.

When preparing the binding solution, a solubilizing agent may be additionally added to reduce the interfacial tension between the particles of the active ingredient and the dissolving medium to aid dissolution or absorption of the active ingredient. The solubilizer may include, for example, a surfactant such as sodium lauryl sulfate (SLS) or polyoxyethylene sorbitan fatty acid ester.

According to one embodiment, the binding solution can be prepared by dissolving sodium lauryl sulfate together with hydroxypropyl cellulose (HPC-EXF) in purified water.

Another aspect of the present invention is

(a) mixing tadalafil or a pharmaceutically acceptable salt thereof, an excipient, and a disintegrant;

(b) assembling the mixture of step (a) by adding a binder;

(c) sieving (sieving) the granulated product of step (b) to obtain granules; and

(d) Optionally adding an excipient and a disintegrant to the granule of step (c) to formulate a solid formulation.

One specific example of the present invention is

(a) mixing tadalafil or a pharmaceutically acceptable salt thereof, excipients, and disintegrants;

(b) assembling the mixture by adding a binder solution to the mixture of step (a);

(c) sizing the granulated product of step (b) to obtain granules; and

(d) Optionally, it may be a method of producing a solid formulation, including the step of formulating by adding an excipient, a disintegrant, and a lubricant to the granule of step (c).

In one embodiment, the sizing step (c) may use 30 to 40 mesh.

In one embodiment, the formulation step (d) may be a tableting step.

In one embodiment, the particle size of the granules may be 10 to 40% by weight of particles of 250 to 450㎛, and 18% by weight or less of particles of 75 to 150㎛.

The mixing step (a) can be performed using a mixer commonly used in the pharmaceutical field, for example, a tumble bin, V mixer, or other suitable mixer.

The assembly step (b) can be performed using an assembly machine commonly used in the pharmaceutical field, for example, a high-speed shear assembly machine.

The (c) sieving step (sizing step) can be performed using a circular sieve of 30 to 40 mesh, and the size of the sieve can be varied depending on the particle size of the desired granule.

The (d) formulation step may be performed according to a method commonly used in the pharmaceutical field, for example, in the form of pellets, capsules, or tablets. According to one embodiment, the formulation step is a tableting step. For tableting, a composite preparation can be manufactured by compressing the tadalafil granules using a commonly used tablet press, for example, a rotary tablet press.

The granules, pellets, capsules, and tablets may be manufactured according to any method for producing granules, pellets, capsules, and tablets known in the art. In one embodiment, the pellets, capsules, and tablets may include granules.

In one embodiment, the pellets can be manufactured by compressing and spherifying the granules. In one embodiment, the capsule may be any soft or hard capsule commonly used in the art. For example, a hard capsule containing hypromellose, flurane, gelatin, polyvinyl alcohol, or any combination thereof may be used as the capsule base. The size of the hard capsule is possible without limitation as long as it is a typical capsule size used in the manufacture of pharmaceuticals.

In one embodiment, the tablet may be a compressed granule tablet prepared by manufacturing dry granules or wet granules according to any method and then compressing the granules into tablets.

In one embodiment, the solid preparation may be administered by administration methods including orally, sublingually, subcutaneously, and by injection, and is preferably administered orally.

The method for producing the solid formulation may further include the step of film coating the granules, pellets, capsules, or tablets. The step of forming a film coating layer on the surface of the tadalafil granules, pellets, capsules, or tablets can be performed according to a conventional film coating layer forming method. For example, a coating solution can be prepared by combining all film coating additives including a film coating base, and then the surface of the tableted composite tablet can be coated with the coating solution. The solvent for preparing the coating solution may vary depending on the type and concentration of the coating base, and for example, distilled water, ethanol, etc. may be used. For example, the film coating layer can be formed by placing tablets in a pan coater and spraying a coating solution.

[Example]

Hereinafter, the present invention will be explained in more detail by the following examples. However, the following examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.

Examples 1 to 7: Preparation of tablets from tadalafil granules

Tadalafil granules were prepared using the ingredients and contents shown in Table 1 below, and the tadalafil tablets according to Examples 1 to 7 were manufactured by compressing them into tablets.

[Table 1]

Tadalafil, lactose monohydrate, hydroxypropyl cellulose (HPC-EXF), and croscarmellose sodium were mixed using the ingredients and contents disclosed in Table 1 above. Additionally, a binding solution was prepared by dissolving hydroxypropyl cellulose (HPC-EXF) and sodium lauryl sulfate (SLS) in purified water. Afterwards, granules were manufactured using a high-speed shear granulator. These granules are sieved and sized into 40 mesh or 30 mesh circular bodies, and then finally mixed with a post-mixing section containing microcrystalline cellulose, spray-dried (SD) lactose monohydrate, and croscarmellose sodium. It was tabletted.

Examples 1 and 2 are samples manufactured in a laboratory at a 1,000T and 5,000T scale, respectively, Example 3 is a sample manufactured in a laboratory at a 30,000T scale considering actual production, and Examples 4 and 5 are This sample was manufactured on a scale of 100,000 T using field production machines in consideration of actual production.

In Example 6, after manufacturing tablets from tadalafil granules, they were additionally coated with 5.0 mg of Opadry II, making the total amount 180 mg.

In Example 7, based on Example 6, the remaining excipients except the main ingredient were reduced in a similar ratio to prepare tadalafil 2.5 mg tablets with a total amount of 125 mg.

Comparative Examples 1 to 3: Preparation of tablets from tadalafil granules

Comparative Example 1 was performed with the same composition as Example 4, but was post-mixed and tableted using granules sized through a 20 mesh sieve in the sizing step.

Comparative Example 2 was performed with the same composition as Example 4, but was post-mixed and tableted using granules sized through a 60 mesh sieve in the sizing step.

Comparative Example 3 was performed with the same composition as Example 4, but was post-mixed and tableted using granules sized through a 100 mesh sieve in the sizing step.

Example 8: Preparation of tablets from tadalafil granules

Example 8 was prepared in the same manner as Example 6, except that hydroxypropyl cellulose (HPC-L) was used as a binder instead of hydroxypropyl cellulose (HPC-EXF).

Test Example 1: Particle size analysis

(1) Mesh Profile

In order to confirm the particle size of the granules obtained in the manufacturing process of Examples 1 to 5, Example 7, and Comparative Examples 1 to 3, they were measured using a particle size analyzer to obtain a mesh profile.

In detail about the above test method, after overlapping circular sieves of 20mesh, 35mesh, 60mesh, 100mesh, and 200mesh in that order, an appropriate amount of granules was injected into the uppermost 20mesh sieve. After separating the granules by size using a sieve shaker for 5 minutes, the mass of the granules remaining on each round body was measured and the weight percentage was calculated.

Figure 1 shows mesh profiles according to particle size analysis for the granules prepared in Examples 1 to 4. In this specification, #n passing represents the granules that passed when sieved through an n mesh sieve, and #n remaining amount represents the granules remaining on the sieve when sieved through an n mesh sieve. In Figure 1, for example, #200 passage indicates the granules that passed when sieved with a 200 mesh round sieve, and #200 remaining indicates granules remaining on the 200 mesh round sieve. In this specification, 200mesh, 100mesh, 60mesh, 35mesh, and 20mesh correspond to 75㎛, 150㎛, 250㎛, 450㎛, and 850㎛, respectively.

Figure 2 shows mesh profiles according to particle size analysis for granules prepared in Comparative Examples 1 to 3, Examples 4 to 5, and Example 7.

(2) Particle size distribution

Based on the results obtained by measuring with a particle size analyzer for Examples 1 to 5, Example 7 and Comparative Examples 1 to 3, the weight (%) of the granules by particle size was calculated and shown in Table 2 below.

[Table 2]

As shown in Table 2 and Figures 1 and 2, the granules prepared in Examples 1 to 5 and Example 7 according to the present invention contain 10 to 40% by weight of particles having a particle diameter of 250 to 450 ㎛ (60 to 35 mesh). , a particle size distribution was shown in which particles with a particle size of 75-150㎛ (200-100mesh) were present in less than 18% by weight.

It was confirmed that there was no significant difference in particle size distribution between Examples 1 and 2, which were manufactured on a scale of 1,000 T or 5,000 T, and Examples 4 and 5, which were manufactured on a scale of 30,000 T or 100,000 T, considering actual production. . In addition, Example 7 at a dose of 2.5 mg also showed a profile similar to the particle size distribution of Examples 4 and 5 at a dose of 5 mg.

In comparison, the granules of Comparative Example 1 showed a relatively large particle size, with more than 40% by weight of particles having a particle diameter of 250 to 450㎛ and more than 30% by weight of granules having a particle diameter of 450㎛ or more, and Comparative Example 2 had a relatively large particle size. In Comparative Example 3, granules with a particle diameter of 250 to 450 ㎛ are less than 20% by weight, and granules with a particle diameter of 75 to 150 ㎛ are more than 18% by weight. In Comparative Example 3, granules with a particle diameter of 250 to 450 ㎛ are less than 10% by weight, 75 The particle size distribution showed that granules with a particle diameter of ~150㎛ were present in more than 70% by weight. The granules of Comparative Examples 1 to 3 have the particle size distribution range of the granules prepared in Examples 1 to 5 and Example 7 (10 to 40% by weight of particles with a particle size of 250 to 450 ㎛ (60 to 35 mesh), and 75% by weight. It was confirmed that the particles of ~150㎛ (200~100mesh) were less than 18% by weight.

Test Example 2: Observation of capping and sticking phenomenon

The quality of the tablets prepared in Examples 4, 7, and Comparative Examples 1 to 3 was confirmed by visual observation. Figure 3 is a photograph observing whether capping and sticking occurred in tablets prepared in (a) Example 4 and (b) Comparative Example 3, respectively.

In addition, a total of 100 tablets were taken, and the number of tablets in which capping and sticking phenomenon occurred was measured and shown in Table 3 below.

[Table 3]

As shown in Table 3 and Figure 3, capping and sticking did not occur at all in the tablet of Example 4 according to the present invention. In addition, Example 7, which was a dose of 2.5 mg of tadalafil in which excipients excluding the main ingredient were reduced at the same rate, also did not cause problems with productivity.

In comparison, in the case of the tablets of Comparative Examples 1 and 2, where the particle size was adjusted differently from the present invention, capping and sticking phenomena occurred, and in Comparative Example 3, the frequency of occurrence was particularly high, and capping and sticking were more severe.

Test Example 3: Content uniformity test

The content of each of 10 tablets prepared in Examples 4, 7, and Comparative Examples 1 to 3 was measured by HPLC (Agilent, 5000 series), and the Korean Pharmacopoeia content uniformity test criteria (judgment value: 15%) The decision was made according to the following).

Specifically, the content uniformity of the tablets prepared in Examples 4, 7, and Comparative Examples 1 to 3 was measured using an extraction solvent in which acetonitrile and purified water were mixed at 50:50 (v/v). , the results are shown in Table 4.

[Table 4]

As shown in Table 4, the tablets of Examples 4 and 7 and Comparative Examples 2 and 3 satisfied a judgment value of less than 15%.

In comparison, in the case of the tablet of Comparative Example 1, the judgment value, which is the standard specified in the Korean Pharmacopoeia, far exceeded 15%, confirming that the content uniformity was poor and the quality of the product was low.

Test Example 4: Dissolution test when particle size was different (1)

A dissolution test was performed on 6 tablets of each of the formulations prepared in Examples 4 and 5 and Comparative Examples 1 and 3, and analyzed by HPLC (Agilent, 5000 series).

Specifically, six tablets each of Examples 4 and 5 and Comparative Examples 1 and 3 were prepared, and an elutor (rotating Speed: 50 rpm) was filled with 900 mL purified water, samples were sampled and analyzed at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, and 120 minutes, and the results are shown in Figures 4 and It is shown in Table 5.

Figure 4 shows the dissolution rate (%) according to the dissolution test for the tablets prepared in Examples 4 and 5 and Comparative Examples 1 and 3.

[Table 5]

As shown in Figure 4 and Table 5, Comparative Example 1 showed a dissolution rate that was about 3 to 5% lower than Examples 4 and 5. Additionally, Comparative Example 3 showed a dissolution rate that was about 2 to 5% higher than that of Examples 4 and 5. Since Examples 4 and 5 show an increased dissolution rate of tadalafil, which is poorly water-soluble, compared to Comparative Examples 1 or 3, it can be seen that they will improve bioavailability and exhibit excellent pharmacokinetic indices when applied in the human body. In addition, when the dissolution profile of Example 4 or 5 is shown, it can be seen that it is advantageous to exert an effective drug effect in the human body.

Test Example 5: Dissolution test when binding solutions are different (2)

A dissolution test was performed on each tablet of the formulation prepared in Examples 6 and 8, and analyzed by HPLC (Agilent, 5000 series).

In Example 6, hydroxypropyl cellulose-E extra fine (HPC-EXF) (molecular weight 80,000 Da, viscosity 300-600 mPas in 25°C/10% aqueous solution) was used as a binder.

In Example 8, hydroxypropyl cellulose-L (HPC-L) (molecular weight: 140,000 Da, viscosity: 6 to 10 mPas in 20°C/2% aqueous solution) was used as a binder.

(1) Measurement of viscosity of binding liquid

To measure the difference in viscosity between the two binders when using hydroxypropyl cellulose of HPC-EXF grade or HPC-L grade, respectively, a 4.5% aqueous solution containing HPC-EXF or HPC-L was used. SLS was added and the viscosity was measured using an RVDV-II+TPro viscometer (Brookfield) at 25°C. As a result, the HPC-L grade solution showed a viscosity of 60~80 mPas, and the HPC-EXF grade solution showed a viscosity of 30~50 mPas.

(2) Dissolution test

Specifically, the tablets prepared in Examples 6 and 8 were prepared, and according to the Korean Pharmacopoeia Dissolution Test Method 2, the Paddle Method, an eluent (rotation speed: 50 rpm) with a constant temperature of 37°C was poured into 900 mL of purified water. After filling, the pH was adjusted to 4.0 and samples were sampled and analyzed at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, and 90 minutes, and the results are shown in Figure 5 below.

Figure 5 shows the dissolution rate (%) according to the dissolution test for the tablets prepared in Example 6 and Example 8.

As shown in Figure 5, it was confirmed that Example 6, which used an HPC-EXF grade binder, had an increased dissolution rate compared to Example 8, which used an HPC-L grade binder.

Claims (14)

Tadalafil or a pharmaceutically acceptable salt thereof, an excipient, a binder, a disintegrant, and a lubricant, and 15 to 38% by weight of particles with a particle size of 250 to 450 ㎛, and particles with a particle size of 75 to 150 ㎛. Contains 15% by weight or less,
Tadalafil or a pharmaceutically acceptable salt thereof is contained in the free form of tadalafil in a solid dosage form of 2.5 to 5 mg,
The excipient is any one selected from the group consisting of lactose monohydrate, microcrystalline cellulose, and mixtures thereof,
The binder is hydroxypropyl cellulose of the hydroxypropyl cellulose-E extra fine (HPC-EXF) grade,
The disintegrant is croscarmellose sodium,
The lubricant is any one selected from the group consisting of stearic acid, stearic acid metal salts, and mixtures thereof,
The excipients are included in 70 to 95% by weight based on the total weight of the solid formulation,
The binder is contained in an amount of 0.5 to 4% by weight based on the total weight of the solid formulation,
The disintegrant is contained in an amount of 3 to 10% by weight based on the total weight of the solid preparation,
A solid formulation in which the lubricant is contained in an amount of 0.1 to 2% by weight based on the total weight of the solid formulation. delete delete delete delete The solid formulation according to claim 1, wherein the binder is a hydroxypropyl cellulose solution having a viscosity of 300 to 600 mPas at 25°C when it is a 10% aqueous solution. The solid formulation of claim 6, wherein the solution further contains sodium lauryl sulfate (SLS). The solid preparation according to claim 1, wherein the solid preparation is for oral administration or parenteral administration. The method of claim 8, wherein the solid preparation is for oral administration selected from fine granules, granules, tablets, capsules, pills, pellets, and dry syrup, or any one selected from patches, injections, ointments, and suppositories. Solid preparation for parenteral administration. The method according to claim 1, wherein the solid formulation is in the form of granules manufactured through wet processing. (a) mixing tadalafil or a pharmaceutically acceptable salt thereof, excipients, and disintegrants;
(b) assembling the mixture by adding a binder solution to the mixture of step (a);
(c) sizing the granulated product of step (b) to obtain granules; and
(d) optionally comprising adding excipients, disintegrants, and lubricants to the granules of step (c) to formulate them;
Tadalafil or a pharmaceutically acceptable salt thereof is contained in the free form of tadalafil in a solid dosage form of 2.5 to 5 mg,
The excipient is any one selected from the group consisting of lactose monohydrate, microcrystalline cellulose, and mixtures thereof,
The binder is hydroxypropyl cellulose of the hydroxypropyl cellulose-E extra fine (HPC-EXF) grade,
The disintegrant is croscarmellose sodium,
The lubricant is any one selected from the group consisting of stearic acid, stearic acid metal salts, and mixtures thereof,
The excipients are included in 70 to 95% by weight based on the total weight of the solid formulation,
The binder is contained in an amount of 0.5 to 4% by weight based on the total weight of the solid formulation,
The disintegrant is contained in an amount of 3 to 10% by weight based on the total weight of the solid preparation,
The method for producing a solid formulation according to claim 1, wherein the lubricant is contained in an amount of 0.1 to 2% by weight based on the total weight of the solid formulation. The solid formulation according to claim 11, wherein the binder solution (b) is a hydroxypropyl cellulose solution having a viscosity of 300 to 600 mPas at 25°C when it is a 10% aqueous solution. The method for producing a solid formulation according to claim 11, wherein the step (c) of obtaining granules by sizing uses a mesh of 30 to 40. The method of claim 11, wherein the formulation step (d) is a tableting step.