KR102239291B1 - Chewable tablet formulation comprising tadalafil or a pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention is a granule containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; Granules of specific particle size and density produced through wet processing; At least one disintegrant selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate; And it provides a tadalafil chewable tablet comprising a pharmaceutically acceptable additive. The chewable tablet of tadalafil of the present invention not only has excellent dissolution rate of tadalafil, has a low sense of foreign body in the oral cavity, has no discomfort even if it is disintegrated in the oral cavity with an improved taste and aroma, and can be chewed without water, so it is difficult to swallow in the oral cavity. As a drug that has improved adherence to patients who do not have the disease, it may exhibit improved efficacy of a PDE-5 inhibitor, and thus may be usefully used in the treatment of patients with erectile dysfunction and pulmonary arterial hypertension.

Description

Chewable tablet formulation containing tadalafil or a pharmaceutically acceptable salt thereof {CHEWABLE TABLET FORMULATION COMPRISING TADALAFIL OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF}

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

Phosphodiesterase-5 inhibitors (hereinafter referred to as'PDE-5') are generally selective inhibitors of cyclic guanosine 3′, 5′-monophosphate phosphodiesterase type 5 (cGMP PDE-5). It is used as a treatment for erectile dysfunction and is currently being developed as a drug and sold commercially.

Tadalafil ((6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, one of the PDE-5 inhibitors Pirazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione) is being sold under the brand name " ^{Cialis ® Tablet" by Lilly, and has erectile dysfunction.} And it is known that it can be used for the treatment of benign prostatic hyperplasia, or for the treatment of patients with erectile dysfunction and benign prostatic hyperplasia (Korea Patent No. 0577057).

Meanwhile, pharmaceuticals are used in various forms such as tablets, capsules, liquids, cataplasmas, and injections. Among them, a large proportion of pharmaceuticals are produced and distributed as solid tablets, and since such solid tablets are usually in the form of compressed dried powder, additional packaging is simple and the volume is small, so management of distribution and storage is easy. It has superior advantages over liquid products in terms of long-term stability. Tablets can be classified according to various functional and morphological criteria. Functionally, they are classified into general tablets, oral disintegrants or chewing agents, and fast-release tablets, sustained-release tablets, or general disintegrating tablets depending on the disintegration pattern. However, in most cases, the patient himself/herself voluntarily takes these tablets to treat diseases, but there is a problem in that individual patient adherence to medication must be increased in order to obtain the correct effect. For example, in the case of a drug that is taken three times a day, it is best to take it at 8-hour intervals, but instructing you to take it at meals is because the dose itself is more important than the interval. As such, patient compliance is one of the important points in drug treatment.

For PDE-5 inhibitors, effervescent tablets (Korean Patent Application Publication No. 2001-0036527), oral disintegrating tablets using sildenafil free base for improving bitter taste (Korean Patent Application Publication No. 1999-0088249), and general film coating definitions Various attempts have been made to increase medication compliance, such as studies of forms. However, in the case of tadalafil, tablets that can be chewed orally taken without water have not been studied.

In particular, tadalafil should be taken with water about 30 minutes before taking into account the drug onset time during sexual intercourse, but due to this dosage method having irregular intervals, there was a lot of inconvenience to the patient.

Accordingly, the present inventors have completed the present invention by developing a chewable tablet that can be easily taken by chewing in the oral cavity without water as a result of trying to develop a tadalafil formulation with improved medication compliance.

Korean Patent No. 0577057 Korean Patent Application Publication No. 2001-0036527 Korean Patent Application Publication No. 1999-0088249

An object of the present invention is to provide a formulation for oral administration of tadalafil that can be conveniently taken without water.

Another object of the present invention is to provide a method for preparing the formulation.

The present invention is a granule 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, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate; And it provides a tadalafil chewable tablet containing a pharmaceutically acceptable additive.

The present invention also includes the steps of (1) preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; (2) Mixing one or more disintegrants and pharmaceutically acceptable additives selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid and sodium alginate to the granules prepared in step (1) above. step; And (3) tableting the mixture obtained in step (2).

The tadalafil chewable tablet of the present invention not only has excellent dissolution rate of tadalafil, but also has little feeling of foreign body in the oral cavity. In addition, it has improved taste and aroma without discomfort even if it is disintegrated in the oral cavity, and can be chewed without water, so there is no problem of difficulty swallowing in the oral cavity, and the patient's medication compliance is improved. Therefore, since the PDE-5 inhibitor can exhibit improved efficacy, it can be usefully used in the treatment of patients with erectile dysfunction and pulmonary arterial hypertension.

1 is a graph showing the dissolution rate of tadalafil of tablets of Examples 1 to 6 and Comparative Examples 1 to 3;
2 is a graph showing the concentration of tadalafil in blood over time after oral administration of the tablets of Examples 1 and 4 and Comparative Example 3 to rats (Rat, n=6).

Tadalafil chewable tablets of the present invention include granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; A disintegrant selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate; And pharmaceutically acceptable additives.

According to a preferred embodiment of the present invention, the chewable tablet of tadalafil of the present invention is selected from the group consisting of tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient, and pregelatinized starch, acacia gum, gelatin, ethylcellulose, and mixtures thereof. Granules containing a non-hydrophilic binder; A disintegrant selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate; And pharmaceutically acceptable additives.

The chewable tablet of tadalafil of the present invention includes granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient.

The granules are made by making tadalafil or a pharmaceutically acceptable salt thereof in a moisture-absorbed state so as to have adhesiveness, and accordingly, the agglomerated powder particles are re-dried. The granules contain tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient.

The tadalafil or a pharmaceutically acceptable salt thereof is a pharmacologically active ingredient having efficacy for treating erectile dysfunction and benign prostate in men, and is the main ingredient of the currently marketed product name Cialis in the form of a general tablet taken with water. In the same way, if it is manufactured as a chewable tablet that can be chewed in the mouth without water, it can increase patient compliance. The tadalafil or a pharmaceutically acceptable salt thereof may be contained in an amount of 5 to 100 mg per tablet, and is preferably contained in an amount of 1 to 15% by weight, preferably 3 to 10% by weight, based on the total weight of the tablet. .

The granules may further contain pharmaceutically acceptable additives, such as excipients and binders. The granules may be contained in an amount of 45 to 65% by weight, preferably 47 to 63% by weight, based on the total weight of the tablet.

According to an embodiment of the present invention, the granules may contain a hydrophilic binder, and the granules of the present invention including a hydrophilic binder have a particle size (particle size) of 500 μm or more, preferably 500 μm to 850 μm. It is present in an amount of 10 wt% or more, preferably 10 wt% to 25 wt%, and an average particle size of 150 µm or more, preferably 150 µm to 300 µm. More preferably, granules having a particle size of 500 µm to 850 µm are present in 15% to 25% by weight, and an average particle size may be 170 µm to 270 µm.

According to another embodiment of the present invention, the granules may contain a non-hydrophilic binder, and the granules of the present invention including the non-hydrophilic binder have a particle size (particle size) of 70 μm or more, preferably 70 μm to 150 μm. The particles may be present in an amount of 20% by weight or more, preferably 20% by weight to 45% by weight, and an average particle size of 100 µm or more, preferably 100 µm to 200 µm. More preferably, granules having a particle size of 70 µm to 150 µm are present in an amount of 25 to 40 wt%, and an average particle size may be 100 µm to 150 µm.

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 a tapped density of 0.40 to 0.70 g/mL, preferably 0.45. To 0.65 g/mL.

According to an embodiment of the present invention, the granules of the present invention comprising a non-hydrophilic binder may have an apparent density of 0.30 to 0.55 g/mL, preferably 0.40 to 0.50 g/mL, and a compressive density of 0.40 to 0.70 g. /mL, preferably 0.45 to 0.65 g/mL.

According to another embodiment of the present invention, the granules of the present invention comprising a hydrophilic binder may have an apparent density of 0.35 to 0.48 g/mL, preferably 0.40 to 0.47 g/mL, and a compressive density of 0.50 to 0.60 g/mL. mL, preferably 0.52 to 0.58 g/mL.

The tadalafil chewable tablet of the present invention contains a disintegrant. Because chewable tablets elute pharmacologically active ingredients in the oral cavity by chewing power and disintegrating power of the tablet itself, it contains a disintegrant as an essential component as a pharmaceutically acceptable additive. In addition, since it is chewed by the teeth in the oral cavity, it is important to select an appropriate disintegrant.For example, if a disintegrant with poor solubility by saliva in the oral cavity is used, a foreign body sensation is felt. As a result, there is a fear that medication adherence may decrease.

The disintegrant may be any one selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate, or a mixture of two or more. The disintegrating agent is completely or partially dissolved by saliva in the oral cavity, and when taken, it is possible to minimize the feeling of foreign body caused by chewing tablets. 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 tadalafil of the present invention contains a binder. The binder is used to facilitate molding in the manufacture of granules, and may be included in the tadalafil-containing granules, may be mixed with a disintegrant, or may be used for both.

The binder may be a hydrophilic binder or a non-hydrophilic binder. The hydrophilic binder is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, light anhydrous silicic acid, synthetic aluminum silicate or silicate derivative containing calcium silicate, phosphate containing calcium hydrogen phosphate, carbonate containing calcium carbonate, and mixtures thereof. It may be selected from the group consisting of. The non-hydrophilic binder may be selected from the group consisting of pregelatinized starch, gums such as acacia gum, cellulose derivatives such as gelatin and ethyl cellulose, and mixtures thereof.

In one specific embodiment of the present invention, a non-hydrophilic binder is used as the binder. The non-hydrophilic binder is a binder that is used by dispersing because it is not well soluble in water, and can minimize the feeling of foreign body caused by chewing tablets when taken.

The binder should be an amount capable of minimizing the effect on the texture, and may be included in an amount of 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 tadalafil of the present invention contains a pharmaceutically acceptable additive.

The pharmaceutically acceptable additive may be included in tadalafil-containing granules, mixed with a disintegrant, or used in both. The pharmaceutically acceptable additive may be selected from the group consisting of, for example, a diluent, a flavoring agent, a sweetening agent, a lubricant, and a mixture thereof. In addition, any additives known in the pharmaceutical art to be useful for improving processability, flowability, stability or moldability of the unit dosage form may be further included.

The diluent is used for bulking. The diluent may be selected from the group consisting of mannitol, lactose, starch, microcrystalline cellulose, rudipress, calcium dihydrogen phosphate, and mixtures thereof. The diluent may be included 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 can increase medication compliance by emitting an appropriate scent when taking chewable tablets. The flavoring agent may be selected from the group consisting of peppermint flavor, spearmint flavor, fruit flavor (eg, apple flavor, cherry flavor, grape flavor, lemon flavor, strawberry flavor, etc.), and mixtures thereof. However, depending on the amount of the flavoring agent, the disintegration and stability of the chewable tablet may be affected, and if excessively used, an unpleasant scent and texture may be provided, and thus an appropriate amount of the flavoring agent is required. The flavoring agent may be included 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 improve preference and medication compliance by giving off a sweet taste in the oral cavity when taking the chewable tablet. The sweetener may be selected from the group consisting of saccharin, stevioside, sucralose, aspartame, and mixtures thereof. The sweetener may be included 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 used to increase the flowability of other materials. The lubricant is stearic acid, metal stearate salts (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 it may be selected from the group consisting of a mixture thereof. The lubricant may be included 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 can be prepared by a conventional pharmaceutical process.

The method for preparing tadalafil chewable tablets of the present invention includes the steps of: (1) preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; (2) Mixing one or more disintegrants and pharmaceutically acceptable additives selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid and sodium alginate to the granules prepared in step (1) above. step; And (3) tableting the mixture obtained in step (2).

According to a preferred embodiment of the present invention, the chewable tablet of the present invention is from the group consisting of (1) tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient, and pregelatinized starch, acacia gum, gelatin, ethylcellulose, and mixtures thereof. Preparing granules comprising the selected non-hydrophilic binder; (2) at least one disintegrant selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate in the granules prepared in step (1); And mixing a pharmaceutically acceptable additive; And (3) tableting the mixture obtained in step (2).

Various processes involved in the manufacture of chewable tablets according to the present invention can be performed based on conventional processes well known in the pharmaceutical field.

First, the method for preparing tadalafil chewable tablets of the present invention includes preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient. Preferably, tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; And preparing granules containing a binder. More preferably, tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient; And preparing granules comprising a non-hydrophilic binder selected from the group consisting of pregelatinized starch, gum acacia, gelatin, ethyl cellulose, and mixtures thereof.

Granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient may be prepared 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 solution. The binding solution can be prepared using a hydrophilic or non-hydrophilic binder as mentioned above. When preparing the binding solution, a solubilizing agent may be additionally added to help dissolve or absorb the active ingredient by reducing the interfacial tension between the particles of the active ingredient and the medium to be dissolved. The solubilizing agent may include a surfactant such as sodium lauryl sulfate (SLS) or polyoxyethylene sorbitan fatty acid ester, and sodium lauryl sulfate may be used as an embodiment of the present invention.

For example, hydroxypropylcellulose, hydroxypropylmethylcellulose, light anhydrous silicic acid, synthetic aluminum silicate or silicate derivatives containing calcium silicate, phosphates containing calcium hydrogen phosphate, carbonates containing calcium carbonate, and mixtures thereof A hydrophilic binder selected from the group consisting of; Alternatively, a non-hydrophilic binder selected from the group consisting of gums such as pregelatinized starch, gum acacia, cellulose derivatives such as gelatin, ethylcellulose, and mixtures thereof is used as an appropriate granulating solvent such as water, ethanol, isopropanol, and these It can be dissolved in a mixture of, etc. to prepare a binding solution.

A preferred embodiment of the wet granulation process includes the steps of: (a) blending tadalafil with a pharmaceutically acceptable additive; (b) adding a granulation solvent while maintaining the mixture obtained in step (a) under shear; (c) drying the resulting wettable material obtained in step (b); And (d) grinding or sieving the material obtained in step (c).

Pharmaceutically acceptable additives in step (a) of the wet granulation process are known in the pharmaceutical field as useful for improving processability, flowability, stability or moldability of excipients, diluents, binders, and other unit dosage forms. Can be any additive.

The granulation solvent in step (b) of the wet granulation process may include water, ethanol, isopropanol, and mixtures thereof. Other ingredients, such as binders, wetting agents, buffers, and the like, can be added to the granulation solvent as is known in the pharmaceutical art. The solvent may be applied by any technique known in the art, and preferred methods of applying the solvent while imparting shear include high shear granulation, low shear granulation, fluid bed granulation, and extrusion granulation.

The drying process in step (c) of the wet granulation process is air drying at a temperature not exceeding about 60°C, preferably not exceeding about 50°C, and more preferably not exceeding about 40°C. , Fluidized bed drying, oven drying or microwave drying.

Grinding or sieving in step (d) of the wet granulation process may be performed using a 20 mesh (about 841 μm) sieve.

The method for preparing tadalafil chewable tablets of the present invention comprises at least one disintegrant selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate in the granules prepared above, and a pharmaceutically acceptable additive. And mixing.

The mixing process includes at least one disintegrant selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate in granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceuticals. This is a process of post-mixing an acceptable additive.

In the post-mixing process, as a pharmaceutically acceptable additive, a component selected from the group consisting of the diluent, flavoring agent, sweetening agent, lubricant, and mixtures thereof may be appropriately selected and used as necessary.

The preparation method of tadalafil of the present invention includes tableting the mixture obtained in the step of mixing a disintegrant and a pharmaceutically acceptable additive in granules containing the tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient. In the above step, for example, by using a rotary tablet press to tablet, the mastication tablet can be manufactured.

The tadalafil chewable tablet of the present invention exhibits 45% or more of tadalafil dissolution within 10 minutes in the dissolution test according to the paddle method of the USP Dissolution test item, preferably within 5 minutes. The elution of 85% or more of tadalafil is shown within 15 minutes, preferably within 10 minutes.

According to a preferred embodiment of the present invention, in the case of a chewable tablet containing a non-hydrophilic binder as a binder, the dissolution test according to the paddle method of the USP dissolution test item shows 70% or more of tadalafil dissolution within 5 minutes. In addition, 85% or more of tadalafil elution is shown within 10 minutes.

In addition, the chewable tablet of the present invention exhibits an equivalent or better bioavailability of tadalafil compared to general tablets that must be taken with water even when taken without water, so it has the effect of improving the bioavailability of tadalafil as well as the compliance of the patient. have.

Hereinafter, the present invention will be described in more detail by examples. However, these are merely exemplary, and the present invention is not intended to be limited thereto.

Example 1: Preparation of tadalafil chewable tablet 1

After mixing tadalafil (Dongwoo, Korea), mannitol, and pregelatinized starch in the composition shown in Table 1 below, the pregelatinized starch and sodium lauryl sulfate were combined with a binder solution dissolved in water, dried, and sieved through a 20 mesh sieve to wet Granules were prepared.

Tadalafil granules were prepared by adding microcrystalline cellulose, mannitol, sodium starch glycolate, sucralose, mint flavor, cherry flavor, aluminum lake (pigment), and magnesium stearate to the prepared granules and mixing them.

From the granules, a tablet containing 5 mg of tadalafil per tablet was prepared using a rotary tablet press (GRC-18; Sejong Machinery, Korea).

Example 2: Preparation of tadalafil chewable tablet 2

Tablets were prepared in the same composition and method as in Example 1, except that acacia gum was used instead of pregelatinized starch as a binder.

Example 3: Preparation of tadalafil chewable tablet 3

Tablets were prepared in the same composition and method as in Example 1, except that ethyl cellulose was used instead of pregelatinized starch as a binder.

Example 4: Preparation of tadalafil chewable tablet 4

Tablets were prepared in the same composition and method as in Example 1, except that hydroxypropylcellulose L-type (HPC-L), which is a hydrophilic binder, was used instead of pregelatinized starch as a binder.

Example 5: Preparation of tadalafil chewable tablet 5

Tablets were prepared in the same composition and method as in Example 1, except that calcium carboxymethylcellulose was used instead of sodium starch glycolate as a disintegrant.

Example 6: Preparation of tadalafil chewable tablet 6

Tablets were prepared in the same composition and method as in Example 4, except that calcium carboxymethylcellulose was used instead of sodium starch glycolate as a disintegrant.

Composition Content (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Primary
mix Tadalafil 5.0 5.0 5.0 5.0 5.0 5.0 Mannitol 39.8 39.8 39.8 39.8 39.8 39.8 Pregelatinized starch 2.7 - - - 2.7 - Acacia sword - 2.7 - - - - Ethyl cellulose - - 2.7 - - - HPC-L - - - 2.7 - 2.7 Binding liquid Pregelatinized starch 1.3 - - - 1.3 - Acacia sword - 1.3 - - - - Ethyl cellulose - - 1.3 - - - HPC-L - - - 0.5 - 0.5 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) Secondary
mix 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 - - Carboxymethylcellulose calcium - - - - 4.5 4.5 Sucralose 1.5 1.5 1.5 1.5 1.5 1.5 Peppermint 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
mix Magnesium stearate 1.0 1.0 1.0 1.0 1.0 1.0 Gross weight 88.2 88.2 88.2 87.4 88.2 87.4

Comparative Example 1: Preparation of tadalafil chewable tablet 7

Tablets were prepared in the same composition and method as in Example 4, except that a 35 mesh sieve was used instead of 20 mesh during sieving in the granule production process.

Comparative Example 2: Preparation of tadalafil chewable tablet 8

Tablets were prepared in the same composition and method as in Example 4, except that povidone was used instead of HPC-L as a binder.

Comparative Example 3: Preparation of tadalafil chewable tablet 9

Tablets were prepared in the same composition and method as in Example 4, except that granules were prepared using a Fitz Mill when sieved during the granulation production process.

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

After simply mixing the components of the same composition as in Example 4 in Table 1, the mixture was tableted with a rotary tablet press (GRC-18; Sejong Machinery, Korea) to prepare a tablet containing 5 mg of tadalafil per tablet. I did.

Comparative Example 5: Preparation of tadalafil chewable tablet 11

Tablets were prepared in the same composition and method as in Example 4, except that croscarmellose sodium was used instead of sodium starch glycolate as a disintegrant.

Comparative Example 6: Preparation of tadalafil chewable tablet 12

Tablets were prepared in the same composition and method as in Example 4, except that crospovidone was used instead of sodium starch glycolate as a disintegrant.

Test Example 1: Sensory evaluation (foreign body feeling and taste evaluation)

The tablets prepared according to Examples 1 and 4 to 6 and Comparative Examples 5 and 6 were taken without water to 10 subjects to perform a sensory test for foreign body sensation and sweet taste.

Each subject recorded scores (1-5 points) for each item as follows, and the scores were averaged and shown in Table 2 below:

Example 1 Example 4 Example 5 Example 6 Comparative Example 5 Comparative Example 6 Foreign body 1.1 1.4 1.4 1.5 4.2 4.0 sweetness 3.3 3.3 3.2 3.3 3.2 3.1 * Foreign body sensation: Very high: 5 points; Slightly more: 4 points; Moderate: 3 points; Slightly less: 2 points; And very little: 1 point
* Sweet: Not at all sweet: 1 point; Insignificant sweetness: 2 points; Moderate: 3 points; A little sweet: 4 points; And very sweet: 5 points

As a result of the evaluation, in the sweet taste item, the tablets of Examples 1 and 4 to 6 and the tablets of Comparative Examples 5 and 6 obtained similar scores, but in the foreign body sensation item, the tablets of Examples 1 and 4 to 6 were A score significantly lower than that of tablets was obtained.

From the above results, it was confirmed that the chewable tablets using sodium starch glycolate and calcium carboxymethylcellulose as disintegrants had very little foreign body sensation in the oral cavity.

Test Example 2: Comparative evaluation of particle size, density and dissolution rate

(1) particle size evaluation

The particle sizes of the tadalafil granules obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were measured using a sieve, and the ratio and average particle size of particles having sizes of 500 µm to 850 µm, and 70 µm to 150 µm are shown in the following table. It is shown in 3.

500 μm to 850 μm 70 μm to 150 μm Average particle size Example 1 1.8% by weight 33.3% by weight 115.3 μm Example 2 3.5% by weight 30.2% by weight 121.7 μm Example 3 2.4% by weight 31.8% by weight 119.2 μm Example 4 17.2% by weight 4.3% by weight 263.4 μm Example 5 2.9% by weight 30.0% by weight 124.4 μm Example 6 15.7% by weight 6.8% by weight 255.1 μm Comparative Example 1 9.7% by weight 10.8% by weight 192.9 μm Comparative Example 2 12.7% by weight 8.7% by weight 242.7 μm Comparative Example 3 0.0% by weight 12.8% by weight 145.8 μm

As can be seen in Table 3, the granules of Examples 4 and 6 using a hydrophilic binder showed a similar particle size distribution as the proportion of particles having a size of 500 µm to 850 µm was 15 to 18% by weight, and a non-hydrophilic binder In the granules of Examples 1 to 3 and 5 using, the proportion of particles having a size of 70 μm to 150 μm was 30 to 35% by weight, showing a similar distribution. The average particle size was lower in the granules of Examples 1 to 3 and 5 using the non-hydrophilic binder compared to the granules using the hydrophilic binder.

On the other hand, the granules of Comparative Example 1, which were sieved with a hydrophilic binder and sieved with 35 mesh, and the granules of Comparative Example 3, which were sieved with a pitted mill, had an average particle size lower than those of Examples 4 and 6 sieved with 20 mesh.

(2) density evaluation

The densities of the tadalafil granules obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were measured and shown in Table 4.

Apparent density Compression density Example 1 0.46 g/mL 0.59 g/mL Example 2 0.45 g/mL 0.57 g/mL Example 3 0.46 g/mL 0.57 g/mL Example 4 0.43 g/mL 0.49 g/mL Example 5 0.46 g/mL 0.57 g/mL Example 6 0.43 g/mL 0.51 g/mL Comparative Example 1 0.44 g/mL 0.60 g/mL Comparative Example 2 0.48 g/mL 0.57 g/mL Comparative Example 3 0.51 g/mL 0.67 g/mL

As can be seen in Table 4, the granules of Examples 4 and 6 using a hydrophilic binder exhibited an apparent density of 0.43 g/mL and a compressive density of 0.49 to 0.51 g/mL, and Example 1 using a non-hydrophilic binder. Granules of to 3 and 5 exhibited an apparent density of 0.45 to 0.46 g/mL, and a compressive density of 0.57 to 0.59 g/mL.

On the other hand, the granules of Comparative Example 1 sieved with 35 mesh and Comparative Example 3 using Pittsmill showed higher density values than the granules of Example 4 sieved with 20 mesh.

(3) Evaluation of dissolution rate

Dissolution tests were performed on the tablets of Examples 1 to 6 and Comparative Examples 1 to 3 using 1000 ml of 0.5% SLS according to the paddle method of the USP Dissolution test. . Samples of the elution test solution were taken at 0, 5, 10, 15, 30, and 45 minutes after the start of the test, and liquid chromatography was performed under the following conditions, and the tadalafil dissolution rate was calculated, as shown in Table 5 and FIG. 1 below.

<Liquid chromatography conditions>

-Column: A column filled with octadecylsilylated silica gel for liquid chromatography with a particle diameter of 3.5 µm in a stainless tube with an inner diameter of about 4.6 mm and a length of 5 cm (Zorbax SB-C8, Agilent Zorbax)

-Column temperature: 40℃

-Sample injection volume: 50 μL

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

-Flow rate: 2.0 mL/min

-Detector: ultraviolet absorbance photometer (measurement wavelength 225 nm)

Elution time (minutes) 0 5 10 15 30 45 Dissolution rate (%) Example 1 0 76.1 89.8 97.1 97.5 97.8 Example 2 0 74.3 90.6 98.3 98.8 99.0 Example 3 0 72.5 87.7 95.8 97.1 97.9 Example 4 0 59.4 91.6 97.9 98.1 98.2 Example 5 0 70.8 89.2 95.4 97.7 98.5 Example 6 0 52.1 87.2 95.9 98.4 98.8 Comparative Example 1 0 45.2 82.2 92.3 98.0 98.6 Comparative Example 2 0 36.1 73.4 89.7 97.8 98.0 Comparative Example 3 0 27.8 59.5 79.2 98.0 98.5

As shown in Table 5 and FIG. 1, the tablets of Examples 1 to 6 quickly showed a high tadalafil dissolution rate. Specifically, the tablets of Examples 1 to 3 and 5 using the non-hydrophilic binder showed the highest initial dissolution of 70% or more within 5 minutes, and a dissolution rate of 95% or more within 15 minutes. In addition, the tablets of Examples 4 and 6 using the hydrophilic binder showed a dissolution rate of 50% or more within 5 minutes and 95% or more within 15 minutes.

On the other hand, the tablets of Comparative Example 1 with different particle sizes and densities and the tablets of Comparative Example 2 using povidone showed a dissolution rate of 95% or more only after 30 minutes, indicating that the chewable tablet according to the present invention exhibited an excellent dissolution rate.

Test Example 3: Comparative evaluation of pharmacokinetic parameters (PK parameters) in animals

The tablets obtained in Examples 1 and 4 and Comparative Example 3 were pulverized, dispersed in 10 ml of 0.5% carboxymethylcellulose (CMC) solution, and orally administered according to the weight of each of 6 rats, 0 and 0.25 , 0.5, 1, 2, 4, 8, 12, 24 and 48 hours, blood samples were collected and the area under the blood drug concentration-time curve (AUC), the highest blood concentration (C _max ), and the time to reach the highest blood concentration (T _The PK parameters including max) were measured for each PK profile, and are shown in Table 6 and FIG. 2 below.

AUC _0-48 (ng hr/mL) C _max (ng/mL) T _max (hr) Example 1 1784.3 ± 488.1 177.2 ± 47.7 3.4 ± 1.9 Example 4 1810.9 ± 516.2 183.5 ± 58.4 3.8 ± 2.7 Comparative Example 3 1287.8 ± 632.6 125.6 ± 125.3 6.3 ± 0.8

As can be seen in Table 6 and FIG. 2, the tablets of Example 1 prepared through a wet granulation process using a non-hydrophilic binder, and Example 4 prepared through a wet granulation process using a hydrophilic binder _{Showed a faster in vivo absorption and higher AUC and C max} values of tadalafil than the tablets of Comparative Example 3 prepared by simple mixing and direct compression.

Claims (16)

Granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient and a binder;
At least one disintegrant selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid, and sodium alginate; And
It contains a pharmaceutically acceptable additive,
The binder is a hydrophilic binder, the granules contain 10 to 25% by weight of particles having a particle size of 500 µm to 850 µm, and an average particle size of 150 to 300 µm, or
The binder is a non-hydrophilic binder, the granules contain 20 to 45% by weight of particles having a particle size of 70 µm to 150 µm, and an average particle size of 100 µm to 200 µm,
The hydrophilic binder is hydroxypropylcellulose, hydroxypropylmethylcellulose, light anhydrous silicic acid, synthetic aluminum silicate or silicate derivative containing calcium silicate, phosphate containing calcium hydrogen phosphate, carbonate containing calcium carbonate, and mixtures thereof. It is selected from the group consisting of,
The non-hydrophilic binder is selected from the group consisting of pregelatinized starch, gum acacia, gelatin, ethyl cellulose, and mixtures thereof.
delete delete The method of claim 1,
The binding agent is included in an amount of 0.1 to 10% by weight based on the total weight of the chewable tablet, tadalafil chewable tablet.
The method of claim 1,
The tadalafil or a pharmaceutically acceptable salt thereof is contained in an amount of 1 to 15% by weight based on the total weight of the chewable tablet, tadalafil chewable tablet.
The method of claim 1,
The granules are included in an amount of 45 to 65% by weight based on the total weight of the chewable tablet, tadalafil chewable tablet.
The method of claim 1,
The disintegrant is included in an amount of 1 to 10% by weight based on the total weight of the chewable tablet, tadalafil chewable tablet.
The method of claim 1,
The pharmaceutically acceptable additive is selected from the group consisting of diluents, flavoring agents, sweetening agents, lubricants, and mixtures thereof.
The method of claim 1,
The chewed tablets exhibit a dissolution rate of at least 45% tadalafil within 10 minutes.
The method of claim 1,
Tadalafil chewing tablets, wherein the chewed tablets exhibit a tadalafil dissolution rate of 85% or more within 15 minutes.
delete delete The method of claim 1,
Tadalafil chewable tablets having a bulk density of the granules of 0.30 to 0.55 g/mL and a tapped density of 0.40 to 0.70 g/mL.
(1) preparing granules containing tadalafil or a pharmaceutically acceptable salt thereof as an active ingredient;
(2) Mixing one or more disintegrants and pharmaceutically acceptable additives selected from the group consisting of sodium starch glycolate, calcium carboxymethylcellulose, starch, alginic acid and sodium alginate to the granules prepared in step (1) above. step; And
(3) tableting the mixture obtained in step (2),
The preparation of the granules in step (1) is carried out by a wet granulation process using a binder solution,
The binding solution is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, light anhydrous silicic acid, synthetic aluminum silicate or silicate derivative containing calcium silicate, phosphate containing calcium hydrogen phosphate, carbonate containing calcium carbonate, and mixtures thereof. A hydrophilic binder selected from the group consisting of; Or a non-hydrophilic binder selected from the group consisting of pregelatinized starch, acacia gum, gelatin, ethylcellulose, and mixtures thereof, prepared by dissolving in a solvent selected from the group consisting of water, ethanol, isopropanol, and mixtures thereof. Tadalafil chewing tablet manufacturing method. delete delete

Images