KR20140077658A - Chewable tablet comprising a phosphodiesterase-5 inhibitor - Google Patents

Abstract

The present invention relates to a quinquer comprising a phosphodiesterase-5 (PDE-5) inhibitor and a disintegrant having an expansion coefficient of from 4 to 8 L / kg, And it is useful as a therapeutic agent for erectile dysfunction in men because it is possible to increase the patient's compliance with medication and satisfaction of medication,

Description

[0002] CHEWABLE TABLET COMPRISING A PHOSPHODIESTERASE-5 INHIBITOR,

The present invention relates to a phosphodiesterase-5 (PDE-5) inhibitor or a pharmaceutically acceptable salt thereof; And a disintegration in which the expansion coefficient is adjusted.

Erectile dysfunction is caused by a variety of causes, such as malnutrition of male blood flow to the corpus cavernosum or blood supply to the corpuscle is not blocked by the blood flow to the venous outflow due to the corpuscular pressure is not rising because the erection is maintained for a certain time And it is said that the case where the sex life is not satisfactory enough for both sexes is more than 25% of the total sex life. Erectile dysfunction is a common disease that can occur in all age groups, especially in older people aged 55 years or older. In general, about 5% to 10% of men are known to have impotence.

PDE-5 inhibitors, commonly known as erectile dysfunction agents, include Vardenafil, 1- [5-aminopyrimidin-5-yl] Propyl imidazo [5,1-f] [1,2,4] triazin-2-yl) -4-ethoxy-4- ethoxyphenyl] sulfonyl] _{-4-ethyl, C 23 H 32 N 6 O} 4 S), sildenafil (sildenafil, 1 - [[3- (6,7- dihydro-1-methyl-7-oxo-3 profile -1H- pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] _{-4-methylpiperazine, C 22 H 30 N 6 O} 4 S), the other changes Methyl-pyrazino [1 ', 5 ' , 2 ': 1,6] pyrido [3,4-b] _{indole-1,4-dione, C 22 H 19 N 3 O} 4), Udenafil _{(Udenafil, C 25 H 36 N} 6 O 4 S) have been developed. It is disclosed that vardenafil is used in Korean Patent No. 0430355, sildenafil is used in Korean Patent No. 0262926, tadalafil is used in Korean Patent No. 0357411, and Udenapil is used in Korean Patent No. 0353014 as an erectile dysfunction agent.

These PDE-5 inhibitors are mostly used in the form of oral tablets, and vardenafil is marketed by Bayer under the name Levitra, sildenafil is marketed under the name Viagra by Pfizer, and tadalafil is marketed by Lilly And is commercially available. Yudenapil is also sold under the brand name Zydena in Dong-A Pharm. Because these drugs take about 60 to 90 minutes to express the drug, they have to take drugs in advance in consideration of the efficacy of the drug during sexual intercourse. In addition, there are inconveniences caused by the fact that they should be taken with water when they are used in general tablets. Therefore, there is a desperate need for the development of a PDE-5 inhibitor formulation that can be taken without water and capable of rapid absorption in the oral cavity.

In addition, the PDE-5 inhibitor used as a treatment for erectile dysfunction in men is a drug called "Happy Drug" which improves the quality of life of the patient. It also includes factors such as drug efficacy, convenience of medication and satisfaction with medication. It should be considered important. Conventional oral disintegration and quinqueride disintegration in the oral cavity is fast, but it is difficult to completely solve the impression of feeling that the sand remains in the oral cavity after taking it.

Accordingly, the present inventors have conducted research to develop a PDE-5 inhibitor formulation that improves compliance with medicines, increases medication satisfaction, can be taken without water, and has a quick disintegration after oral administration, Respectively.

[Patent Document 1] Korean Patent No. 0430355

[Patent Document 2] Korean Patent No. 0262926

[Patent Document 3] Korean Patent No. 0357411

[Patent Document 4] Korean Patent No. 0353014

Accordingly, an object of the present invention is to provide a PDE-5 inhibitor-containing toothpaste which can be easily disintegrated in the oral cavity without remaining in the mouth.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising a PDE-5 inhibitor or a pharmaceutically acceptable salt thereof; And a disintegration with an expansion coefficient of 4 to 8 L / kg.

Further, the present invention provides a quartz crystal further comprising saccharides, sugar alcohols or a mixture thereof in the quartz crystal.

The chew containing the PDE-5 inhibitor according to the present invention can be taken without water and does not leave a residue in the oral cavity, thereby improving the patient's compliance with medication compliance and medicinal satisfaction, and having excellent oral solubility, It is useful as a remedy for male erectile dysfunction.

The chewing tablet of the present invention contains PDE-5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient together with a disintegrant with controlled expansion coefficient, thereby rapidly disintegrating in the oral cavity, The expression of the gene is rapidly promoted.

The active ingredient of the present invention may be PDE-5 inhibitors vardenafil, sildenafil, tadalafil, idenapil or pharmaceutically acceptable salts thereof, preferably sildenafil free base.

The PDE-5 inhibitor or pharmaceutically acceptable salt thereof may be contained in an amount of 5 to 100 mg per tablet and may be contained in an amount of 0.1 to 80% by weight, preferably 1 to 70% by weight, based on the total weight of the preparation It is good.

The disintegrant is an important component for the rapid disintegration of the quench according to the present invention, and it is preferably contained in an amount of 1.5 to 15% by weight based on the total weight of the preparation. If the content of the disintegrant exceeds 15% by weight, the tabletability may deteriorate and the form of the preparation may not be maintained. If the content of the disintegrant is less than 1.5% by weight, the disintegration of the tablets may be delayed.

Disintegration disintegrates tablets in three major ways: first, when the tablet is exposed to a liquid such as saliva, the disintegrant expands rapidly to disintegrate the tablet, and this type of excipient may be croscarmellose Cellulose sodium, starch glycolic acid sodium, pregelatinized starch, and the like; Secondly, when the tablet is exposed to a liquid such as saliva, the tablet is disintegrated by introducing moisture into the tablet by the capillary action of the disintegrant. Examples of this type of excipient include corn starch, sodium alginate and the like; Third, when the tablet is exposed to a liquid such as saliva, the disintegrant disintegrates by rapidly returning to its pre-compression form. Examples of this type of excipient include crospovidone, starch grain, etc. (John C. Carter, The role of disintegrants in solid oral dosage manufacturing, Carter Pharmaceutical Consulting, Inc.).

Since the disintegrants are usually water-insoluble, when disintegrating by mouth, the disintegrant does not melt and remains the main cause of residual perspiration in the mouth. Therefore, the particle diameter and the expansion coefficient of the disintegrant are very important factors for determining the restitution of the mouth. The greater the particle size of the disintegrant, the larger the feeling of mouth retention. The larger the expansion coefficient of the disintegrant, the greater the degree of swelling of the particle upon administration. However, if the expansion coefficient is too small, the disintegrating function will not be achieved, and large particles will remain in the mouth, resulting in a large residual in the mouth. When using a disintegrant having an appropriate range of particle size and expansion coefficient, it is possible to manufacture a quartz having a good disintegration force and a small mouthwash.

The disintegrant which can be used in the present invention may have an expansion coefficient of from 2 to 12 L / kg and preferably from 4 to 8 L / kg. Further, the particle size of the disintegrant can be variously determined in consideration of the expansion coefficient, and can be selected within a range of, for example, 5 to 250 탆.

According to one embodiment of the present invention, disintegrants having a coefficient of expansion within the above range can be used, illustratively, as follows: Polyplasdone XL-10 5.4 L / kg, Polypladone XL 5.8 (Kollidon CL) 4.3 L / kg, Crospovidone (Kollidon CL-M) 7.2 L / kg, Ac-Di-Sol 13.5 L / kg, StarCap 1500 ) 1.8 L / kg.

The disintegrant usable in the present invention is not limited to the disintegrant, and any disintegrant having an appropriate particle diameter and expansion coefficient may be used.

The chewing gum of the present invention may further comprise saccharides, sugar alcohols or a mixture thereof. These saccharides, sugar alcohols, or their mixtures are important ingredients that affect the sweetness, solubility, and tactile properties in the oral cavity of Cheongju. In order to exhibit such effects, sweetness and water solubility should be good. Usable saccharides include lactose, glucose, sucrose, fructose, levulose, maltodextrin and parathinose, and sugar alcohols include mannitol, sorbitol, xylitol, and erythritol. Particularly, it is preferable to use the above-mentioned saccharides or sugar alcohols which have been multiply repelled by spray drying or the like because they can increase the solubility in the oral cavity. Spray-dried mannitol (Mannitol SD200) may be used according to one embodiment of the present invention. The saccharides, sugar alcohols or their mixture may be contained in an amount of 10 to 98% by weight, preferably 20 to 95% by weight, based on the total weight of the preparation. If the content of the above-mentioned saccharides, sugar alcohols, or a mixture thereof is less than 10% by weight, there is a problem that the sweetness of the sweet taste and the feeling in the oral cavity are poor.

In addition to the above components, the composition of the present invention may further comprise at least one selected from the group consisting of pharmaceutically acceptable additives such as flavorings, colorants, sweeteners and glidants.

The flavoring agent is a flavor-enhancing additive which has the function of improving the sensation and taste in the oral cavity. Specific examples thereof include peppermint flavor, spearmint flavor, various fruit flavor and the like.

The coloring agent is selected from the group consisting of green 3, red 2, red 3, blue 1, blue 2, yellow 4, yellow 5, caramel, titanium oxide, Coloring matter, etc. may be used.

The sweetener has a function of improving the adherence and compliance of medicines by softening the tastes in the oral cavity when taking a quercetin. Specific examples thereof include stevioside, xylitol, sucralose, aspartame, acesulfame potassium, sucrose , Erythritol, and mixtures thereof.

Specific examples of the lubricant include stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, high melting point wax, glyceryl fatty acid esters, glycerol dibehenate And mixtures thereof.

It is preferred that the chew of the present invention should have a controlled hardness for rapid intraoral disintegration, preferably an average hardness in the range of 2 kp to 17 kp. For example, the chewing gum according to the present invention may have an average hardness in the range of 2 to 15 kp, and more preferably 8 to 15 kp. When the hardness is less than 2 kp, the chewing easily breaks and it is difficult to pack and distribute. When the hardness exceeds 17 kp, the chewing gum can not be disintegrated quickly in the oral cavity, so that the improvement in compliance can not be expected.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Reference example: Determination of expansion coefficient of disintegrant

(Kollidon CL, BASF, Germany), crospovidone (Kollidon CL-M, BASF, Germany), crospovidone (Polyplasone XL- ), Croscarmellose sodium cellulose (Ac-Di-Sol, DFE, Germany), and corn starch (StarCap 1500, ROQUETTE, France) were placed in a 100 mL volumetric flask in an amount of 10 g each, (Anisul Q. et al., A comparative study of current superdisintegrants, Pharmaceutical technology 2006). The expansion coefficient of the disintegrant was as follows: 5.4 L / kg of Polyplasdone XL-10, 5.8 L / kg of Polypladone XL, 4.3 L / kg of Crospovidone, Kollidon CL -M) 7.2 L / kg, 13.5 L / kg of croscarmokylmethylcellulose sodium (Ac-Di-Sol), 1.8 L / kg of corn starch (StarCap 1500).

EXAMPLE 1 and COMPARATIVE EXAMPLES 1 and 2: Preparation of a specimen having different types of disintegrant

(ROQUETTE, France), crospovidone (particle diameter 30-50 μm, Polyplasdone XL-10, ISP Company, USA), enzyme-treated Stevia (Korea), Blue No.2 Aluminum Lake (Borac, Korea), and Magnesium Stearate (NOF, Japan) were used to prepare quinqueradiene containing sildenafil as an active ingredient. Specifically, each of the compositions shown in Table 1 was mixed, and a quartz having a hardness of about 15 kp was prepared by using a refiner (MRC-45, Sejong Pharmatech, Korea) and tumbling to apply a force of about 5 kN.

As Comparative Examples 1 and 2, using croscarmokylmethylcellulose sodium (particle diameter: 45 to 74 mu m, DFE, Germany) or corn starch (particle diameter: 74 to 125 mu m, ROQUETTE, France) instead of crospovidone, .

EXAMPLES 1 to 4: Preparation of chewing gum with different diameters of crospovidone

Polyplasdone XL (particle diameter 100 to 130 탆, ISP Company, USA) and cololidone (manufactured by Kollidon Corporation) were prepared in the same manner as in Example 1, ) CL (particle diameter 50 to 250 탆, BASF, Germany) and Kollidon CL-M (particle diameter 5 to 15 탆, BASF, Germany).

Examples 1, 5 to 7 and Comparative Examples 3 and 4: Preparation of chewing gum with varying amounts of crospovidone

Were prepared in the same manner as in Example 1 except that the amount of crospovidone was changed.

Examples 1 and 8 and Comparative Examples 5 and 6: Manufacture of different types of excipients

(DFE, Germany), microcrystalline cellulose (MINGTAI, Taiwan) or anhydrous calcium hydrogen phosphate (INNOPHOS, USA) instead of spray-dried mannitol was prepared in the same manner as in Example 1, Quenched.

Test Example : Definition  Oral Residual feeling  Testing and Disintegration test

(1) Oral residual test

The intraoral retention was measured and quantified by taking the sildenafil containing tinctures obtained in Examples 1 to 8 and Comparative Examples 1 to 6, and the results are shown in Tables 5, 7, 9 and 11.

The study was conducted on 10 healthy volunteers in 20 male volunteers. In order to minimize the error between the test subjects, the following dosing regimens were tested: 1) To prevent dry mouth, wet the mouth with 20 mL of water before dosing ; 2) When chewing tablets after medication, use the teeth near the front teeth as much as possible so that the molars do not get any drugs, and chew them all within 20 seconds; 3) Evaluate the residue in the mouth while rubbing the drug against the tongue and palate. The results are digitized from 0 to 5 (1: the residue disappears within 15 seconds, 2: the residue disappears within 30 seconds, 3: the residue disappears within 45 seconds, 4: the residue disappears within 60 seconds , 5: persistence persists for more than 60 seconds and is difficult to swallow).

(2) Deflection test

Disintegration times were measured for the sildenafil containing tinctures obtained in Examples 1 to 8 and Comparative Examples 1 to 6, and the results are shown in Tables 6, 8, 10 and 12. The disintegration test was conducted based on the disintegration test method described in Korean Pharmacopoeia. The disintegration time was defined as the time at which the tablets disappeared completely from the bottom of the disintegration device.

(3) Results and discussion

The results of the retention test and the disintegration test in the oral cavity of Example 1 and Comparative Examples 1 and 2 prepared by different kinds of disintegration are shown in Tables 5 and 6, respectively.

Example 1 Comparative Example 1 Comparative Example 2 Subject 1 One 4 3 Subject 2 One 5 4 Subject 3 0 3 2 Subject 4 0 4 2 Subject 5 One 4 3 Subject 6 One 5 3 Subject 7 One 4 2 Subject 8 2 5 3 Subject 9 One 4 3 Subject 10 One 5 4 Average 0.9 4.3 2.9

Example 1 Comparative Example 1 Comparative Example 2 One 12 10 32 2 11 10 31 3 12 11 33 4 13 10 29 5 10 12 30 6 13 12 27 Average (seconds) 11.8 10.8 30.3

As can be seen from the above Table 5, the residual sensation in the oral cavity of Example 1 using crospovidone was high at 0.9, but the residual in oral cavity of Comparative Examples 1 and 2 using croscarmellose methylcellulose sodium and corn starch The feeling was 4.3 and 2.9, which means that the feeling of staying was very high and satisfaction was low. This is because the crospovidone used has a particle size of 30 to 50 占 퐉 and does not significantly expand even when brought into contact with water, so that the residual in the mouth is small, but the croscarmex sodium cellulose has a particle size of 45 to 74 占 퐉, And the corn starch has a grain size of 74 to 125 탆 but the disintegration force is low, so that there is a feeling of residual feeling of remaining sand in the oral cavity after taking it. Therefore, the most preferred disintegrant for the quinquer of the present invention is judged to be crospovidone.

Also, as shown in Table 6, crospovidone and croscarmic carboxymethylcellulose sodium were excellent in disintegration, while the disintegration times of the chewiness of Example 1 and Comparative Example 1 were all within about 10 seconds, while the corn starch of Comparative Example 2 was superior You can see the damage is low.

On the other hand, the results of the retention test and the disintegration test in the oral cavity of Examples 1 to 4, which were prepared by varying the particle diameters of crospovidone, are shown in Tables 7 and 8, respectively.

Example 1 Example 2 Example 3 Example 4 Subject 1 One One One 2 Subject 2 One 2 2 2 Subject 3 0 One One 2 Subject 4 0 One One One Subject 5 One One One 2 Subject 6 One 2 2 3 Subject 7 One One One 2 Subject 8 2 2 One 3 Subject 9 One 2 One 3 Subject 10 One One One 2 Average 0.9 1.4 1.2 2.2

Example 1 Example 2 Example 3 Example 4 One 12 8 15 11 2 11 7 18 11 3 12 8 19 10 4 13 7 17 12 5 10 8 17 11 6 13 9 19 10 Average (seconds) 11.8 7.8 17.5 10.8

As can be seen from Table 7, the chews of Examples 1 to 4, in which crospovidone was used at different particle diameters, had a satisfactory degree of oral residual remission of 2.2 or less.

As can be seen from Table 8, although the disintegration time was slightly different depending on the expansion coefficient, the disintegration time of all the quenched samples of Examples 1 to 4 was fast.

Taking all the results of Tables 7 and 8 into consideration, when crospovidone having a particle size of 5 to 250 μm, which has a coefficient of expansion of 4 to 8 L / kg in the quench of the present invention, is used, Show time.

On the other hand, the results of the retention test and the disintegration test in the oral cavity of Examples 1, 5 to 7 and Comparative Examples 3 and 4 prepared by varying the amount of crospovidone are shown in Tables 9 and 10, respectively.

Comparative Example 3 Example 5 Example 1 Example 6 Example 7 Comparative Example 4 Subject 1 3 2 One 2 3 3 Subject 2 2 One One 2 3 4 Subject 3 One One 0 One 2 3 Subject 4 One 0 0 2 2 4 Subject 5 2 One One 2 3 4 Subject 6 2 2 One 2 3 4 Subject 7 3 0 One 2 3 3 Subject 8 2 One 2 3 3 4 Subject 9 2 One One 2 2 3 Subject 10 3 One One 3 3 4 Average 2.1 1.0 0.9 2.1 2.7 3.6

Comparative Example 3 Example 5 Example 1 Example 6 Example 7 Comparative Example 4 One 35 16 12 10 8 6 2 33 18 11 7 8 5 3 34 20 12 11 6 6 4 34 23 13 12 9 7 5 39 22 10 9 10 7 6 43 19 13 10 7 6 Average (seconds) 36.3 19.7 11.8 9.8 8.0 6.2

As can be seen from Table 9, the chewings of Comparative Example 3, which used crospovidone at 5 to 90 mg, and the chewings of Examples 1 and 5 to 7, were highly satisfied with the oral cavity residual feeling of 3 or less and the crospovidone content was 120 mg Weight%) of Comparative Example 4 had a relatively large residual feeling. The reason for this is that crospovidone is insoluble in water, so that the amount of crospovidone remaining in the mouth increases as the amount used increases.

Further, as shown in Table 10, the disintegration time was shortened as the content of crospovidone was increased. In Comparative Example 3 using the smallest amount of crospovidone, the disintegration time was 36.3 seconds, and the residual in the mouth due to the long disintegration time was also relatively large compared to the amount of crospovidone as shown in Table 9.

Based on the results of Tables 9 and 10, it is preferred that the crospovidone in the quench of the present invention is contained in an amount of 1.5 to 15% by weight based on the total weight of the preparation.

On the other hand, the results of the retention test and disintegration test in the oral cavity of Examples 1 and 8 and Comparative Examples 5 and 6 prepared by different kinds of excipients are shown in Tables 11 and 12, respectively.

Example 1 Example 8 Comparative Example 5 Comparative Example 6 Subject 1 One One 3 4 Subject 2 One 2 4 4 Subject 3 0 One 3 3 Subject 4 0 One 3 3 Subject 5 One 2 3 4 Subject 6 One 2 4 4 Subject 7 One One 3 3 Subject 8 2 2 4 4 Subject 9 One One 3 3 Subject 10 One 2 3 4 Average 0.9 1.5 3.3 3.6

Example 1 Example 8 Comparative Example 5 Comparative Example 6 One 12 12 39 42 2 11 14 42 45 3 12 15 38 39 4 13 14 38 46 5 10 12 44 48 6 13 15 36 41 Average (seconds) 11.8 13.7 39.5 43.5

As can be seen from Table 11, in Examples 1 and 8 using spray-dried mannitol and lactose anhydrous, the satisfaction in the oral cavity remained in 0.9 to 1.5 was high, and in Comparative Example 5 using microcrystalline cellulose and anhydrous calcium hydrogen phosphate And 6, the residual sensation in the oral cavity was 3.3 to 3.6, and the feeling of staying in the chew information of the example was felt, but there was no inconvenience to taking. The reason for this difference in oral cavity residues is that spray-dried mannitol and anhydrous lactose have high solubility in water, and microcrystalline cellulose and anhydrous calcium hydrogen phosphate hardly dissolve in water. However, since the diameters of the microcrystalline cellulose and anhydrous calcium hydrogen phosphate used in Comparative Examples 5 and 6 were as small as 100 to 200 占 퐉, there was almost no discomfort due to the residual feeling.

Also, as shown in Table 12, the disintegration time was different depending on the solubility of the excipient. The disintegration times of the chews of Examples 1 and 8 using spray-dried mannitol and anhydrous lactose were rapidly disintegrated to 11.8 seconds and 13.7 seconds, respectively. The chewings of Comparative Examples 5 and 6 using microcrystalline cellulose and anhydrous calcium hydrogen phosphate had disintegration times It disintegrated relatively slowly at 39.5 seconds and 43.5 seconds.

As can be seen from the results of Tables 11 and 12, the excipients suitable for the quench of the present invention are spray-dried mannitol and anhydrous lactose, and spray-dried mannitol is most effective. This is because the spray-dried mannitol rapidly melts in the oral cavity due to the characteristics of the porous surface obtained through spray drying and the high solubility of mannitol itself.

Claims (11)

A PDE-5 inhibitor or a pharmaceutically acceptable salt thereof; And a disintegrant having an expansion coefficient of 4 to 8 L / kg. The method according to claim 1,
Wherein the PDE-5 inhibitor is a sildenafil free base. The method according to claim 1,
Wherein the chewing gum further comprises a saccharide, a sugar alcohol, or a mixture thereof. The method of claim 3,
Wherein the saccharide is selected from the group consisting of lactose, glucose, sucrose, fructose, levorphose, maltodextrin and paratinose, and the sugar alcohols are selected from the group consisting of mannitol, sorbitol, xylitol and erythritol. The method of claim 3,
Wherein the sugar alcohols are spray dried mannitol. The method of claim 3,
Wherein the saccharides, sugar alcohols or mixtures thereof are included in an amount of 10 to 98% by weight based on the total weight of the formulation. The method according to claim 1,
Wherein the disintegrant has a particle size of 5 to 250 占 퐉. The method according to claim 1,
Wherein the disintegrant is included in an amount of from 1.5 to 15% by weight based on the total weight of the formulation. The method according to claim 1,
Characterized in that the average roughness of the tooth is in the range of 2 to 17 kp. The method of claim 3,
Wherein the chew comprises sildenafil free base, spray dried mannitol and a disintegrant having an expansion coefficient of from 4 to 8 L / kg. The method according to claim 1,
Wherein the chewing gum further comprises at least one selected from the group consisting of sweeteners, flavors, colorants and glidants.