WO2014209022A1

WO2014209022A1 - Chewable tablet formulation comprising tadalafil or a pharmaceutically acceptable salt thereof

Info

Publication number: WO2014209022A1
Application number: PCT/KR2014/005653
Authority: WO
Inventors: Caleb Hyungmin PARK; Yoeng Jin Kwon; Seung Jun Lee; Yong Il Kim; Jae Hyun Park; Jong Soo Woo
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2013-06-28
Filing date: 2014-06-25
Publication date: 2014-12-31
Also published as: TW201534355A; KR102239291B1; AR096725A1; TWI663990B; KR20150002453A

Abstract

The present invention relates to a chewable tablet comprising granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; granules having a specific particle size and density prepared by a wet granulation; at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate; and a pharmaceutically acceptable additive. The chewable tablet according to the present invention exhibits excellent dissolution rate, causes little foreign body sensation in the oral cavity, and does not cause unpleasant feelings when disintegrated in the oral cavity due to improved taste and flavor. Also, the chewable tablet can be chewed without water to improve compliance rate of patients who do not have difficulty in swallowing. Therefore, the inventive formulation can improve efficacy of PDE-5 inhibitors, and thus can be useful in the treatment of ED and pulmonary arterial hypertension.

Description

CHEWABLE TABLET FORMULATION COMPRISING

TADALAFIL OR A PHARMACEUTICALLY ACCEPTABLE SALT

THEREOF

FIELD OF THE INVENTION

The present invention relates to a chewable tablet comprising tadalafil or a pharmaceutically acceptable salt thereof, which can be taken without water.

BACKGROUND OF THE INVENTION

A phosphodiesterase-5 inhibitor (hereinafter, "PDE-5") is a selective inhibitor of cyclic guanosine 3 ',5 '-monophosphate phosphodiesterase type 5 (cGMP PDE-5), which is used for the treatment of erectile dysfunction; and a number of PDE-5 inhibitor drugs has been developed and are currently commercially available.

Tadalafil ((6R-tr<3/i5)-6-(l,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro- 2-methyl-pyrazino[ ,2' : l,6]pyrido[3,4-b]indole-l,4-dione), one of the PDE-5 inhibitors, is sold under the name of Cialis^® by Eli Lilly. This drug is known as useful for treating erectile dysfunction (ED) and benign prostatic hyperplasia (BPH), or patients with combined ED and BPH (Korean Patent No. 0577057).

Meanwhile, drugs may be formulated in various dosage forms including tablets, capsules, liquids, cataplasmas, injections, and the like. Among these dosage forms, a large portion of drugs are prepared and distributed in the form of solid tablets. Since solid tablets are usually prepared by compressing dry powders, solid tablets have advantages over liquid products in terms of easy packaging, easy management (e.g., distribution and storage due to their small volume), and long-term stability. Tablets can be classified in accordance with their functional and morphological characteristics. Functionally, tablets can be categorized as a regular tablet, an orally disintegrating tablet, and a chewable tablet. They can also be categorized according to their disintegration patterns: a fast-dissolving tablet, a sustained-release tablet, and a regular tablet. In most cases, however, as patients take these tablets voluntarily so as to treat their conditions; and it is required to improve patient drug compliance in order to obtain the desired effect of the drug. In case of a medicine that is prescribed to be taken three times a day, for example, it is the most effective to take the medicine in every 8 hours. However, patients are often advised to take their medication after eating their meals, because taking the medication itself is more important than keeping the time interval between each administration for optimal efficacy. As such, patient compliance is one of the most important factors in medication treatment.

In case of PDE-5 inhibitors, many attempts have been made for improving patient compliance including an effervescent tablet (Korean Patent Laid-open Publication No. 2001-0036527), an orally disintegrating tablet comprising sildenafil free base to improve its bite taste (Korean Patent Laid-open Publication No. 1999-0088249), and a regular film coating tablet, and the like; but no attempt has been made to prepare a chewable tablet comprising tadalafil which can be taken without water.

In particular, considering its onset time, tadalafil needs to be taken with water about 30 minutes in advance of intercourse. Due to this irregular administration, patients often experienced great inconvenience.

Therefore, the present inventors have endeavored to prepare a tadalafil formulation with improved drug compliance and have accomplished the present invention by discovering a chewable tablet formulation, which can be taken easily without water. SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide an orally administratable formulation comprising tadalafil, which can be easily taken without water.

It is another object of the present invention to provide a method for manufacturing the formulation.

In accordance with one aspect of the present invention, there is provided a chewable tablet comprising:

granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient;

at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate; and

a pharmaceutically acceptable additive.

In accordance with another aspect of the present invention, there is provided a method for manufacturing a chewable tablet comprising the steps of:

(1) preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient;

(2) mixing the granules prepared in step (1) with at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate, and a pharmaceutically acceptable additive; and

(3) tableting the mixture obtained in step (2).

The chewable tablet in accordance with the present invention exhibits an excellent dissolution rate of tadalafil and causes little foreign body sensation in the oral cavity. The chewable tablet has improved taste and flavor, so it does not cause unpleasant feelings when disintegrated in the oral cavity. Also, the chewable tablet can be taken without water to improve compliance rate of patients who do not have difficulty in swallowing. Therefore, the chewable tablet can improve efficacy of PDE-5 inhibitors, and thus can be useful in the treatment of ED and pulmonary arterial hypertension.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph showing the dissolution rates of tadalafil released from the formulations of Examples 1 to 6 and Comparative Examples 1 to 3. Fig. 2 is a graph showing the tadalafil concentration versus time when the formulations of Examples 1 and 4 and Comparative Example 3 were orally administered to rats (n=6). DETAILED DESCRIPTION OF THE INVENTION

A chewable tablet in accordance with the present invention comprises: granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate; and a pharmaceutically acceptable additive.

In a preferred embodiment of the present invention, the chewable tablet comprises: granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient, and a non-hydrophilic binder selected from the group consisting of pregelatinized starch, acacia gum, gelatin, ethyl cellulose, and a mixture thereof; at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate; and a pharmaceutically acceptable additive. The chewable tablet formulation of the present invention comprises granules containing tadalafil or a pharmaceutically acceptable salt thereof.

The granules may be prepared by allowing granules to absorb tadalafil or a pharmaceutically acceptable salt thereof so as to give adhesive property to the granules, and then drying aggregated granules thus obtained. The granules contain tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient.

Tadalafil or a pharmaceutically acceptable salt thereof, which is an active ingredient for treating ED and BPH, is the main ingredient of commercially available Cialis^® in the form of a regular tablet which needs to be taken with water. However, the patient compliance can be improved if tadalafil or its pharmaceutically acceptable salt is formulated into a chewable tablet of the present invention, which can be taken without water. Tadalafil or its pharmaceutically acceptable salt may be comprised in an amount of 5 to 100 mg per unit dose, and 1 to 15% by weight, preferably 3 to 10% by weight, based on the total weight of the tablet.

The granules may further comprise a pharmaceutically acceptable additive, e.g., an excipient, a binder, etc. The granules may be comprised in an amount of 45 to 65% by weight, preferably 47 to 63% by weight, based on the total weight of the tablet.

In one embodiment of the present invention, the granules may contain a hydrophilic binder. The granules containing the hydrophilic binder in the present invention have a particle size of at least 500 μηι, preferably 500 to 850 μπι, which are comprised in an amount of at least 10% by weight, preferably 10 to 25% by weight, based on the total weight of granules, and the average particle size of the granules is at least 150 μιη, preferably 150 to 300 μπι. More preferably, the granules having a particle size of 500 to 850 μπι are comprised in an amount of 15 to 25% by weight, based on the total weight of granules, and the average particle size of the granules is 170 to 270 μπι.

In another embodiment of the present invention, the granules may contain a non-hydrophilic binder. The granules containing the non-hydrophilic binder in the present invention have a particle size of at least 70 μιη, preferably 70 to 150 μπι, which are comprised in an amount of at least 20% by weight, preferably 20 to 45% by weight, based on the total weight of granules, and the average particle size of the granules is at least 100 μηι, preferably 100 to 200 μπι. More preferably, the granules having a particle size of 70 to 150 μπι are comprised in an amount of 25 to 40% by weight, based on the total weight of granules, and the average particle size thereof is 100 to 150 μπι.

The granules of the present invention may have a bulk density of 0.30 to 0.55 g/mL, preferably 0.35 to 0.50 g/mL, and have a tapped density of 0.40 to 0.70 g/mL, preferably 0.45 to 0.65 g/mL.

In one embodiment of the present invention, the granules having the non- hydrophilic binder have a bulk density of 0.30 to 0.55 g/mL, preferably 0.40 to 0.50 g/mL, and have a tapped density of 0.40 to 0.70 g/mL, preferably 0.45 to 0.65 g/mL. In another embodiment of the present invention, the granules having the hydrophilic binder have a bulk density of 0.35 to 0.48 g/mL, preferably 0.40 to 0.47 g/mL, and have a tapped density of 0.50 to 0.60 g/mL, preferably 0.52 to 0.58 g/mL.

The chewable tablet of the present invention comprises a disintegrant. Since a chewable tablet formulation releases its pharmaceutically active ingredient by the masticatory force in the mouth and the disintegrating force which is exerted by the tablet itself, the tablet requires a disintegrant as a pharmaceutically acceptable additive. Also, it is important to select a suitable disintegrant because a chewable tablet is masticated by the teeth in the oral cavity. For example, use of a disintegrant having with poor dissolution rate results in greater foreign body sensations, causing patients to drink additional water and, eventually, lowers the patient compliance.

The disintegrant is at least one selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, sodium alginate, and a mixture thereof. The disintegrant is dissolved wholly or partially in saliva of the oral cavity and, thus, can minimize foreign body sensation caused by the chewable tablet. In the present invention, the disintegrant may be used in an amount of 1 to 10% by weight, preferably 3 to 7% by weight, based on the total weight of the tablet.

The chewable tablet of the present invention may contain a binder. In the present invention, the binder is used to make the tableting process easy, and the binder may be contained in the granules having tadalafil, or in the disintegrant, or both.

The binder used in the present invention may be a hydrophilic binder or a non-hydrophilic binder. The hydrophilic binder may be selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, light anhydrous silicylic acid, silicate salt derivatives including synthetic aluminum silicate or calcium silicate, phosphate salts including calcium hydrogen phosphate, carbonate salts including calcium carbonate, and a mixture thereof. The non- hydrophilic binder may be selected from the group consisting of pregelatinized starch, gum such as acacia gum, gelatin, cellulose derivatives such as ethyl cellulose, and a mixture thereof.

In one specific embodiment of the present invention, the binder is a non- hydrophilic binder. The non-hydrophilic binder is not readily dissolved in water, and thus can minimize foreign body sensation caused by the chewable tablet formulation when administered orally.

The binder is comprised in an amount which minimizes its effect on the taste of the formulation, e.g., 0.1 to 10% by weight, preferably 0.2 to 7% by weight, based on the total weight of the tablet.

The chewable tablet of the present invention contains a pharmaceutically acceptable additive.

The pharmaceutically acceptable additive may be contained in the granules comprising tadalafil, or mixed with the disintegrant, or used in both. The pharmaceutically acceptable additive used in the present invention may be, for example, selected from the group of a diluent, a flavoring agent, a sweetener, a lubricant, and a mixture thereof. The chewable tablet may further comprise an additional additive known in the art so as to improve processability, fluidity, stability, or tabletability of the unit dose formulation.

The diluent is used to increase the weight of the tablet. The diluent may be selected from the group consisting of mannitol, lactose, starch, microcrystalline cellulose, Ludipress, calcium hydrogen phosphate, and a mixture thereof. The diluent may be comprised in an amount of 1 to 99% by weight, preferably 35 to 90% by weight, based on the total weight of the tablet.

The flavoring agent helps improving the patient compliance by adding good aroma to the chewable tablet. The flavoring agent may be selected from the group consisting of peppermint flavor, spearmint flavor, fruit flavor (e.g..apple flavor, cherry flavor, grape flavor, lemon flavor, strawberry flavor, etc.), and a mixture thereof. However, the amount of the flavoring agent can affect disintegration and stability of the chewable tablet. The flavoring agent is preferably contained in a suitable amount because an excessive amount thereof may cause unpleasant flavor and sensation. The flavoring agent may be comprised in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the tablet.

The sweetener may be used to give a sweet flavor when administered orally, and thus improve patient acceptability and compliance. The sweetener may be selected from the group consisting of saccharin, stevioside, sucralose, aspartame, and a mixture thereof. The sweetener may be comprised in an amount of 0.5 to 10% by weight, preferably 1 to 5% by weight, based on the total weight of the tablet.

The lubricant may be employed to improve the fluidity of other materials. The lubricant may be selected from the group consisting of stearic acid, metallic stearate (e.g., calcium stearate, magnesium stearate, etc.), talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glyceryl fatty acid ester, glycerol dibehenate, and a mixture thereof. The lubricant may be comprised in an amount of 0.3 to 5% by weight, preferably 0.5 to 3% by weight, based on the total weight of the tablet.

The chewable tablet of the present invention may be manufacture by using a conventional pharmaceutical method known in the art.

The present invention provides a method for manufacturing the chewable tablet comprising the steps of: (1) preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; (2) mixing the granules prepared in step (1) with at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate, and a pharmaceutically acceptable additive; and (3) tableting the mixture obtained in step (2).

According to one preferred embodiment of the present invention, the chewable tablet of the present invention can be prepared by a method comprising the steps of: (1) preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient, and a non-hydrophilic binder selected from the group consisting of pregelatinized starch, acacia gum, gelatin, ethyl cellulose, and a mixture thereof; (2) mixing the granules prepared in step (1) with at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate, and a pharmaceutically acceptable additive; and (3) tableting the mixture obtained in step (2).

The chewable tablet of the present invention may be manufactured by any conventional methods well-known in the art.

The method for manufacturing the chewable tablet of the present invention comprises a step of preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient. Preferably, the method comprises a step of preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; and a binder. More preferably, the method comprises a step of preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; and a non-hydrophilic binder selected from the group consisting of pregelatinized starch, acacia gum, gelatin, ethyl cellulose, and a mixture thereof.

The granules containing the tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient may be prepared by a conventional granulation process. The granulation process allows granules to absorb tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient, allowing the granules to have an adhesive property. Then, the active ingredient having adhesiveness aggregates to form large particles, i.e., granules.

Preferably, the granulation process is a conventional wet granulation process using a binding solution. The binding solution used in the granulation process may be prepared by using a hydrophilic or non-hydrophilic binder as described above. During the preparation of the binding solution, a solubilizer may be further employed to increase dissolution or absorption of an active ingredient by reducing the interfacial tension between the particles of the active ingredient and a medium thereof. The solubilizer may comprise a surfactant such as sodium lauryl sulfate (SLS) or polyoxyethylene sorbitan fatty acid ester, etc. In one exemplary embodiment of the present invention, SLS may be used.

For example, the binding solution may be prepared by dissolving in a suitable granulation solvent, e.g., water, ethanol, isopropanol, and a mixture thereof, a hydrophilic binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, light anhydrous silicylic acid, silicate salt derivatives including synthetic aluminum silicate or calcium silicate, phosphate salts including calcium hydrogen phosphate, carbonate salts including calcium carbonate, and a mixture thereof; or the non-hydrophilic binder selected from the group consisting of pregelatinized starch, gum such as acacia gum, gelatin, cellulose derivatives such as ethyl cellulose, and a mixture thereof.

In a preferred embodiment, the wet granulation comprises the steps of: (a) blending tadalafil with a pharmaceutically acceptable additive; (b) adding a granulation solvent to the mixture obtained in step (a) under shear conditions; (c) drying the material wetted in step (b); and (d) pulverizing or sieving the material obtained in step (c).

In step (a) of the wet granulation process, the pharmaceutically acceptable additive may include, but is not limited to, an excipient, a diluent, or any conventional additive commonly used in the pharmaceutical industry which is useful for improving process ability, fluidity, stability, or tabletability of the unit dose formulation.

In step (b) of the wet granulation process, examples of the granulation solvent may include, but is not limited to, water, ethanol, isopropanol, or a mixture thereof. Additionally, any conventional additive well-known in the art, e.g., a binder, a wetting agent, a buffer, etc., may be added to the granulation solvent. Also, any conventional technique well-known in the art may be used to add the solvent under shear. Preferably, shear techniques such as high shear granulation, low shear granulation, fluid bed granulation, extrusion granulation, etc. may be used to add the solvent.

In step (c) of the wet granulation process, the drying process may be conducted by air drying, fluidized bed drying, oven drying, or microwave drying at a temperature of about 60°C or less, preferably at a temperature of about 50°C or less, more preferably at a temperature of about 40°C or less.

In step (d) of the wet granulation process, the pulverizing or sieving step may be conducted by using a mesh screen having the size of 20 mesh (about 841 Hm).

The method for manufacturing the chewable tablet of the present invention comprises a step of mixing the granules with at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate, and a pharmaceutically acceptable additive.

The mixing step is conducted via a post-mixing process: adding at least one disintegrant selected from the group consisting of sodium starch glycolate, carboxymethyl cellulose calcium, starch, alginic acid, and sodium alginate, and a pharmaceutically acceptable additive to the granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient.

In the post-mixing process, an additional ingredient selected from the group consisting of a flavoring agent, a coloring agent, a sweetening agent and a lubricant may be used as a pharmaceutically acceptable additive, if necessary.

The method for manufacturing the chewable tablet of the present invention comprises a step of tableting a mixture obtained from the mixing step in which granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrant, and a pharmaceutically acceptable additive. The tableting process may be carried out, for example, by using a rotary tableting machine.

The chewable tablet of the present invention releases at least 45% of tadalafil within 10 minutes, preferably within 5 minutes, when tested according to the U.S.P Dissolution test (paddle method). Release of at least 85% of tadalafil is achieved within 15 minutes, preferably within 10 minutes.

According to one preferable embodiment, a chewable tablet having a non- hydrophilic binder as a binder releases at least 70% of tadalafil within 5 minutes, when tested according to the U.S.P Dissolution test (paddle method); and releases at least 85% of tadalafil within 10 minutes.

Further, the chewable tablet of the present invention, which can be taken without water, exhibits a similar or superior bioavailability of tadalafil as compared with a regular tablet; and thus can be used to improve patient compliance and bioavailability of tadalafil.

Hereinafter, the present invention is described more specifically by the following examples, but these are provided only for illustration purposes, and the present invention is not limited thereto.

Example 1: Preparation of chewable tablet 1

In accordance with the ingredients listed in Table 1 , tadalafil (Dong woo, Korea), mannitol, and pregelatinized starch were mixed. The mixture was combined with a binding solution prepared by dissolving pregelatinized starch and sodium lauryl sulfate in water, dried, and then sifted through a 20 mesh sieve to obtain wet granules.

Microcrystalline cellulose, mannitol, sodium starch glycolate, sucralose, peppermint flavor, cherry flavor, aluminum lake (pigment), and magnesium stearate were added to the granules thus obtained to obtain tadalafil granules.

The tadalafil granules were compressed into a tablet using a rotary tableting machine (GRC-18; Sejong, Korea) to prepare a chewable tablet containing 5 mg of tadalafil per unit dose.

Example 2: Preparation of chewable tablet 2 A chewable tablet was prepared by using the same ingredients and the same procedure of Example 1, except for using acacia gum instead of pregelatinized starch as a binder.

Example 3: Preparation of chewable tablet 3

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 1, except for using ethyl cellulose instead of pregelatinized starch as a binder. Example 4: Preparation of chewable tablet 4

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 1, except for using a hydrophilic binder, hydroxypropyl cellulose L-type (HPC-L), instead of pregelatinized starch as a binder.

Example 5: Preparation of che able tablet 5

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 1, except for using carboxymethyl cellulose calcium instead of sodium starch glycolate as a disintegrant. Example 6: Preparation of chewable tablet 6

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 4, except for using carboxymethyl cellulose calcium instead of sodium starch glycolate as a disintegrant.

[Table 1]

Sodium lauryl sulfate (SLS) 0.3 0.3 0.3 0.3 0.3 0.3

Water (8.0) (8.0) (8.0) (8.0) (8.0) (8.0)

Microcrystalline cellulose 16.1 16.1 16.1 16.1 16.1 16.1

Mannitol 15.0 15.0 15.0 15.0 15.0 15.0

Sodium starch glycolate 4.5 4.5 4.5 4.5 - -

2^nd Carboxymethyl cellulose

- - - - 4.5 4.5 mixing calcium

Sucralose 1.5 1.5 1.5 1.5 1.5 1.5

Peppermint flavor 0.5 0.5 0.5 0.5 0.5 0.5

Cherry flavor 0.5 0.5 0.5 0.5 0.5 0.5

Final

Magnesium stearate 1.0 1.0 1.0 1.0 1.0 1.0 mixing

Total weight 88.2 88.2 88.2 87.4 88.2 87.4

Comparative Example 1: Preparation of chewable tablet 7

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 4, except that a 35 mesh sieve was used instead of a 20 mesh sieve during the granulation process.

Comparative Example 2: Preparation of chewable tablet 8

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 4, except for using povidone instead of HPC-L as a binder.

Comparative Example 3: Preparation of chewable tablet 9 A chewable tablet was prepared by using the same ingredients and the same procedure of Example 4, except for using a Fitz mill to prepare granules during the granulation process.

Comparative Example 4: Preparation of chewable tablet 10 (direct compression method)

A chewable tablet was prepared by simply mixing the same ingredients of Example 4 as listed in Table 1 above, and then compressing the mixture thus obtained by using a rotary tableting machine (GRC-18; Sejong, Korea) to prepare a chewable tablet containing 5 mg of tadalafil per unit dose.

Comparative Example 5: Preparation of chewable tablet 11

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 4, except for using croscarmellose sodium instead of sodium starch glycolate as a disintegrant.

Comparative Example 6: Preparation of chewable tablet 12

A chewable tablet was prepared by using the same ingredients and the same procedure of Example 4, except for using crospovidone instead of sodium starch glycolate as a disintegrant.

Experimental Example 1: Degree of foreign body sensation and taste test

The degrees of foreign body sensation and taste were evaluated when chewable tablets obtained in Examples 1 and 4 to 6, and Comparative Examples 5 and 6 were orally administered to 10 human subjects without water.

The results were evaluated on a scale of 1 to 5 for each category, and the average values of the result are shown in Table 2 below. [Table 2]

As a result, the tablets prepared in Examples 1 and 4 to 6 and Comparative Examples 5 and 6 have very similar sweet taste. However, the tablets prepared in Examples 1 and 4 to 6 have significantly low foreign body sensation as compared with the tablets prepared in Comparative Examples 5 and 6.

Thus, as can be seen from the result, it can be concluded that foreign body sensation of chewable tablets can be minimized when sodium starch glycolate or carboxymethyl cellulose calcium is used as a disintegrant.

Experimental Example 2: Comparison of particle size, density and dissolution rate

CI) Evaluation of particle size

Particle sizes of the tadalafil granules obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were measured by using a sieve. The average particle size and the ratio of granules having a particle size of 500 to 850 μπι or 70 to 150 μπι were illustrated in Table 3 below. [Table 3]

As' shown in Table 3 above, the granules of Examples 4 and 6, to which a hydrophilic binder was added, exhibited a similar distribution pattern and have a particle size of 500 to 850 μπι in an amount ranging from 15 to 18 wt%. The granules of Examples 1 to 3 and 5 containing a non-hydrophilic binder also exhibited a similar distribution pattern and have a particle size of 70 to 150 μπι in an amount ranging from 30 to 35 wt%. The granules of Examples 1 to 3 and 5 including a hydrophilic binder have lower average particle sizes than the granules with a non-hydrophilic binder.

Meanwhile, the granules of Comparative Example 1 prepared by using a hydrophilic binder which were sifted through a 35 mesh sieve, and the granules of Comparative Example 3 prepared by using a Fitz mill have a lower average particle size than the granules of Examples 4 and 6 which were sifted through a 20 mesh sieve.

(2) Evaluation of density

Densities of the tadalafil granules prepared in Examples 1 to 6 and Comparative Examples 1 to 3 were measured as indicated and recorded in Table 4 below. [Table 4]

As shown in Table 4 above, the granules of Examples 4 and 6 which were prepared by using a hydrophilic binder exhibited the bulk density of 0.43 g/mL, and a tapped density of 0.49 to 0.51 g/mL, whereas the granules of Examples 1 to 3, and 5 which were prepared by using a non-hydrophilic binder exhibited a bulk density of 0.45 to 0.46 g/mL, and a tapped density of 0.57 to 0.59 g/mL.

Meanwhile, the granules of Comparative Example 1 which were sifted through a 35 mesh sieve, and the granules of Comparative Example 3 prepared by using a Fitz mill have a higher density than the granules of Example 4 which were sifted through a 20 mesh sieve.

(3) Evaluation of dissolution rate Dissolution rates of the tablets prepared in Examples 1 to 6 and

Comparative Examples 1 to 3 were evaluated according to the USP dissolution test (paddle method) by using 1,000 niL of 0.5% SLS. Dissolution test samples were obtained 0, 5, 10, 15, 30, and 45 minutes after the initiation of the test, and a liquid chromatography was performed under the conditions described below. The results are shown in Table 5 and Fig. 1. <Liquid chromatography conditions>

- Column: stainless steel column filled with octadecylsilanized silica gel having a diameter of 3.5 μιη for liquid chromatography (Zorbax SB-C8, Agilent Zorbax, inner diameter 4.6 mm x length 5 cm)

- Temperature: 40°C

- Injection volume: 50 >L

- Mobile phase: water/methanol = 50/50 (v/v)

- Flow rate: 2.0 mL/min

- Detector: ultraviolet spectrophotometer (225 nm)

[Table 5]

As shown in Table 5 and Fig. 1, the tablets of Examples 1 to 6 rapidly released a large amount of tadalafil. Specifically, the tablets of Examples 1 to 3 and 5 containing a non-hydrophilic binder exhibited the highest initial dissolution rate by releasing at least 70% of tadalafil within 5 minutes, and at least 95% within 15 minutes. Also, the tablets of Examples 4 and 6 containing a hydrophilic binder released at least 50% of tadalafil within 5 minutes, and at least 95% within 15 minutes.

Meanwhile, the tablet of Comparative Example 1 having a different particle size and density and the tablet of Comparative Example 2 prepared by using povidone released at least 95% of tadalafil after 30 minutes. Thus, it can be concluded that the tablets of the present invention exhibited superior dissolution rates.

Experimental Example 3: Comparison of PK parameters in animal

The tablets prepared in Examples 1 and 4 and Comparative Example 3 were pulverized, dissolved in 10 mL of 0.5% of carboxymethyl cellulose (CMC). Each sample was orally administered to 6 rats, according to the body weight of the tested animal, and then blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 hours after the oral administration. Pharmacokinetic parameters of each PK profile, including the area under the concentration time curve (AUC), maximum concentration observed (C_max), and time of maximum concentration observed (T_max), were analyzed and indicated in Table 6 and Fig. 2.

[Table 6]

As shown in Table 6 and Fig. 2, the tablet of Example 1 prepared by wet granulation using a non-hydrophilic binder, and the tablet of Example 4 prepared by wet granulation using a hydrophilic binder demonstrated superior bioavailabilities of tadalafil as well as higher AUC and C_max values as compared with the tablet of Comparative Example 3 prepared by simple mixing and direct compression method.

Claims

WHAT IS CLAIMED IS:

1. A chewable tablet comprising:

a pharmaceutically acceptable additive.

2. The chewable tablet of claim 1, wherein the granules further contain a binder.

3. The chewable tablet of claim 2, wherein the binder is a non- hydrophilic binder selected from the group consisting of pregelatinized starch, acacia gum, gelatin, ethyl cellulose, and a mixture thereof.

4. The chewable tablet of claim 2, wherein the binder is comprised in an amount of 0.1 to 10% by weight, based on the total weight of the tablet.

5. The chewable tablet of claim 1, wherein tadalafil or a pharmaceutically acceptable salt thereof is comprised in an amount of 1 to 15% by weight, based on the total weight of the tablet.

6. The chewable tablet of claim 1, wherein the granules are comprised in an amount of 45 to 65% by weight, based on the total weight of the tablet.

7. The chewable tablet of claim 1 , wherein the disintegrant is comprised in an amount of 1 to 10% by weight, based on the total weight of the tablet.

8. The chewable tablet of claim 1, wherein the pharmaceutically acceptable additive is selected from the group consisting of a diluent, a flavoring agent, a sweetener, a lubricant, and a mixture thereof.

9. The chewable tablet of claim 1, wherein the tablet releases at least 45% of tadalafil within 10 minutes.

10. The chewable tablet of claim 1, wherein the tablet releases at least 85% of tadalafil within 15 minutes.

11. The chewable tablet of claim 2, wherein the binder is a hydrophilic binder, and the granules having a particle size of 500 to 850 μπι are comprised in an amount of 10 to 25% by weight, and the average particle size of the granules is 150 to 300 μπι.

12. The chewable tablet of claim 2, wherein the binder is a non- hydrophilic binder, and the granules having a particle size of 70 to 150 μπι are comprised in an amount of 20 to 45% by weight, and the average particle size of the granules is 100 to 200 μπι.

13. The chewable tablet of claim 2, wherein the granules have a bulk density of 0.30 to 0.55 g/mL, and have a tapped density of 0.40 to 0.70 g/mL.

14. A method for manufacturing a chewable tablet comprising the steps of:

(3) tableting the mixture obtained in step (2).

15. The method of claim 14, wherein the step (1) is carried out by a wet granulation process using a binding solution.

16. The method of claim 15, wherein the binding solution is prepared by dissolving in a solvent selected from the group consisting of water, ethanol, isopropanol, and a mixture thereof, a hydrophilic binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, light anhydrous silicylic acid, silicate salt derivatives including synthetic aluminum silicate or calcium silicate, phosphate salts including calcium hydrogen phosphate, carbonate salts including calcium carbonate, and a mixture thereof; or a non- hydrophilic binder selected from the group consisting of pregelatinized starch, acacia gum, gelatin, ethyl cellulose and a mixture thereof.