KR101418406B1 - Orally disintegrating tablet comprising sildenafil free base - Google Patents

Abstract

The present invention relates to a sildenafil free base; And at least two disintegrants selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone. The oral cavity disintegration tablet according to the present invention has a bitter taste And can be rapidly disintegrated within 30 seconds in the oral cavity without water. Therefore, it can be used for erectile dysfunction treatment because it can increase the patient's compliance with the medication.

Description

[0001] ORALLY DISINTEGRATING TABLET COMPRISING SILDENAFIL FREE BASE [0002]

The present invention relates to an oral debonding treatment for erectile dysfunction treatment which contains sildenafil free base as a pharmacologically active ingredient.

Erectile dysfunction is a state in which the supply of blood to the penile corpuscle of the male is not smooth or even if the blood flow is supplied, the erection is not maintained for a certain period of time because the pressure of the corpus cavernosus does not rise due to the flow of the corpuscle, It is said that when both men and women are not satisfied with sexual life 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 erectile dysfunction.

The causes of erectile dysfunction can be classified into psychogenic (mental cause) and temperamental (physical cause). In the case of substrateability, there is a method of inserting a support into the penis, a method of injecting a drug into the urethra, or a method of self-injecting a penis. However, the above method is not widely used because of inconvenience such as having to perform surgery or injecting the patient himself.

As a product that improves these inconveniences, a tablet (trade name: Viagra tablet) containing sildenafil citrate as a drug-effective ingredient is marketed by Pfizer, and sildenafil, which is a main ingredient of the tablet, is useful as an oral erectile dysfunction treatment agent in Korean Patent No. 262926 .

Sildenafil has the chemical name 1- [4-ethoxy-3- (6,7-dihydro-1 -methyl-7-oxo- Yl) -phenylsulfonyl] -4-methylpiperazine, which acts as a selective inhibitor of cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase type 5 (cGMP PDE-5). Sildenafil is used in the form of its water-soluble salt, citrate, to ensure rapid absorption during formulation and good bioavailability. However, since sildenafil citrate has a duration of about 60 minutes to 90 minutes, it has a disadvantage in that it is necessary to take the drug in advance in consideration of the time of administration of the drug when it is sexually active. In addition, there is the inconvenience that it should be taken with water when taking the tablet in general. Therefore, there is an urgent need for studies on sildenafil preparations that can be taken without water and capable of rapid absorption in the oral cavity.

In order to improve the patient's medication convenience and adherence to medicines, the medicinal properties that are essential are the guidelines issued by the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), "Orally Disintegrating Tablets (ODT) "recommends that the disintegration time be less than 30 seconds due to the properties of the oral disintegration tablet, so it is not easy for researchers in this industry to develop a tablet disintegration tablet that can be administered without water .

On the other hand, when the commercially available sildenafil citrate is used to prepare oral cavity disintegrating tablets, it is very difficult to expect improvement in compliance due to the very bitter taste of sildenafil citrate. Therefore, it is necessary to develop oral cavity disintegration definition which has pharmacokinetic characteristics equal to or more than that of commercially available Viagra tablets, and disintegrates within 30 seconds without water in the mouth and has no bitter taste and improves the convenience of medication.

Accordingly, the present inventors have completed the present invention by finding an oral cavity disintegrating tablet which can be easily taken by disintegrating within 30 seconds without water in the oral cavity by improving the adherence compliance of the tablet using the sildenafil free base.

Korean Patent No. 262926

Accordingly, an object of the present invention is to provide a mouth-shrinkage tablet containing sildenafil free base as a pharmacologically active ingredient.

In order to achieve the above object, the present invention provides a sildenafil free base; And at least two disintegrants selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone.

The sildenafil free base containing sildenafil free base according to the present invention has no bitter taste and can be rapidly disintegrated within 30 seconds in the oral cavity without water, thereby enhancing patient compliance.

The present invention relates to a sildenafil free base; And at least two disintegrants selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone.

The sildenafil free base used as a pharmacologically active ingredient in the present invention is a pharmacologically active ingredient having the effect of treating erectile dysfunction in male, unlike the currently available sildenafil citrate, has no salt and does not show any bitter taste. It is not bitter when disintegrated in the oral cavity, so patients' compliance with the medication can be improved.

The sildenafil free base may be contained in an amount of 25 to 100 mg as sildenafil per tablet and may be contained in an amount of 3 to 50% by weight, preferably 5 to 30% by weight, based on the total weight of the tablets.

The oral cavity disintegration tablet of the present invention contains a disintegrant as an essential ingredient as a pharmaceutically acceptable additive, and the disintegrant facilitates the disintegration of the oral disintegration in the oral saliva, thereby facilitating the taking of the drug.

It is important to select the appropriate type of disintegrant and use the appropriate amount of disintegrant to improve the disintegration time in the mouth. For example, if the disintegration time in the oral cavity is delayed, the rate of disintegration can be improved by increasing the amount of disintegrant. However, if the disintegrant is used excessively, The tablet can not have a strong strength enough to hold it. Therefore, the selection of the appropriate type of disintegration and the setting of the dosage are very important.

The disintegrant usable in the present invention is a mixture of two or more selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, preferably a mixture of sodium starch glycolate and crospovidone, and starch glycolic acid sodium salt And croscarmellose sodium may be used. The disintegrant may be used in an amount of 2 to 30% by weight, preferably 5 to 20% by weight, based on the total weight of the tablet.

The combination use of two or more types of disintegrants among the disintegrants according to the present invention not only can show the oral disintegration time sufficient to improve the compliance of the patients with the oral disintegration tablet containing sildenafil free base, The amount of the disintegrant to be used in the present invention can be reduced and the accuracy can be improved .

According to one embodiment of the present invention, when crospovidone, croscarmellose sodium, or sodium starch glycolate is used alone in an excess amount, not only the disintegration time in oral cavity is significantly slower than the case where two or more kinds of them are used in combination, May not have sufficient compressive force to maintain the oral dosage form, and may have difficulty in the manufacturing process, such as increasing the degree of grinding.

The oral cavity disintegration tablet of the present invention may further comprise a pharmaceutically acceptable additive consisting of a diluent, a flavoring agent, a mating agent, a lubricant, and a mixture thereof.

The diluent usable in the present invention may be selected from the group consisting of mannitol, microcrystalline cellulose, lactose, starch, and mixtures thereof. The diluent may be used in an amount of 10 to 90% by weight, preferably 30 to 70% by weight, based on the total weight of the tablet.

The flavoring agent which can be used in the present invention is a flavor-enhancing additive which improves the sensation and taste in the oral cavity. Specific examples thereof include peppermint flavor, spearmint flavor, and various fruit flavor. The flavoring agent may be used in an amount of 0.3 to 5% by weight, preferably 0.5 to 2% by weight, based on the total weight of the tablet.

The mating agent which can be used in the present invention gives a sweet taste in the oral cavity when taken orally, and softens the touch, thereby improving the compliance with medication. Specific examples include stevioside, xylitol, sucralose, aspartame, acesulfame potassium, sucrose, erythritol, and mixtures thereof. The matting agent may be used in an amount of 0.3 to 5% by weight, preferably 0.5 to 2% by weight, based on the total weight of the tablet.

Lubricants usable in the present invention include, but are not limited to, stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, waxes of high melting point, glyceryl fatty acid esters, glycerol Dibehenate, and mixtures thereof may be used. The lubricant may be used in an amount ranging from 0.3 to 5% by weight, preferably 0.5 to 3% by weight, based on the total weight of the tablet.

The oral cavity disintegration tablet of the present invention preferably has a hardness controlled for rapid disintegration in the mouth, and preferably exhibits an average hardness in the range of 2 kp to 15 kp. If the hardness is less than 2 kp, the oral disintegration easily breaks, which makes it difficult to pack and distribute. When the hardness exceeds 15 kp, the disintegration of the oral disintegrating tablet can not be rapidly disintegrated in the oral cavity.

In addition, the disintegration time in oral cavity disintegration according to the present invention is very fast, which is 60 seconds or less, preferably 30 seconds or less, while the hardness of the tablet is about 5-6 kp and the degree of carcass is 0.3% or less. .

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

Example 1: Preparation of oral disintegration

- Mixed part -

Sildenafil free base 100.0 mg

Mannitol 404.0 mg

Sodium starch glycolate 30.0 mg

Crospovidone 30.0 mg

Stevioside 12.0 mg

Peppermint fragrance powder 12.0 mg

- Lubricant -

Magnesium stearate 12.0 mg

Sildenafil free base, mannitol, sodium starch glycolate, crospovidone, stevioside, and peppermint flavor powder were passed through a No. 20 sieve, mixed in a V-type mixer, and mixed for 30 minutes. Magnesium stearate was added as a lubricant and mixed for 5 minutes. The resulting powder mixture was tableted so as to apply a force of about 5 kN using a rotary tablet machine (Sejong Pharmatech, MRC-45) to prepare a mouthwash containing sildenafil free base Bran solution.

The hardness and the degree of abrasion of the obtained oral cavity were measured using an Erweka hardness tester and a scratch measuring instrument (25 rpm, 100 free drops). The average hardness of the oral disintegration was 5.5 kp and the degree of grind was 0.1%.

Example 2: Preparation of oral disintegration

The same procedure as in Example 1 was carried out except that 30 mg of croscarmellose sodium was used instead of 30 mg of crospovidone to prepare a mouth-bone disintegrating tablet. The average hardness of the oral disintegration was 5.4 kp and the degree of grind was 0.0%.

Example 3: Oral disintegration definition preparation

The same procedure as in Example 1 was conducted except that 40 mg of sodium starch glycolate and 40 mg of crospovidone were used, respectively, to prepare an oral debuffing vessel. The average hardness of the oral disintegration was 5.2 kp and the degree of grind was 0.2%.

Example 4: Preparation of Oral Disintegration Definition

The procedure of Example 1 was repeated except that 40 mg of sodium starch glycolate was used and 40 mg of croscarmellose sodium was used instead of crospovidone. The average hardness of the oral disintegration was 5.1 kp and the muscle strength was 0.2%.

Example 5: Preparation of oral disintegration

The same procedure as in Example 1 was carried out except that 40 mg of croscarmellose sodium was used instead of sodium starch glycolate and 40 mg of crospovidone was used. The average hardness of the oral disintegration was 5.2 kp and the degree of grind was 0.2%.

Example 6: Preparation of oral disintegration

The same procedure as in Example 1 was conducted except that 40 mg of sodium starch glycolate and 40 mg of crospovidone were used, and 40 mg of croscarmellose sodium was further used to prepare a mouth-bone disintegrating tablet. The average hardness of the oral disintegration was 4.9 kp, and the degree of muscle fatigue was 0.3%.

Comparative Example 1: Preparation of oral disintegration

- Mixed part -

140.5 mg of sildenafil citrate (100.0 mg as sildenafil)

Mannitol 404.0 mg

Sodium starch glycolate 30.0 mg

Crospovidone 30.0 mg

Stevioside 12.0 mg

Peppermint fragrance powder 12.0 mg

- Lubricant -

Magnesium stearate 12.0 mg

According to the same composition as above, an oral cavity disintegrating tablet containing sildenafil citrate was prepared in the same manner as in Example 1. The average hardness of the oral disintegration was 5.2 kp and the degree of grind was 0.2%.

Comparative Example 2: Preparation of oral disintegration

- Mixed part -

Sildenafil free base 100.0 mg

Mannitol 404.0 mg

Sodium starch glycolate 50.0 mg

Stevioside 12.0 mg

Peppermint fragrance powder 12.0 mg

- Lubricant -

Magnesium stearate 12.0 mg

According to the same composition as above, an oral cavity disintegrating tablet containing sildenafil free base was prepared in the same manner as in Example 1. The average hardness of the oral disintegration was 5.0 kp and the degree of grind was 0.2%.

Comparative Example 3: Preparation of oral disintegration

The same procedure as in Comparative Example 2 was carried out except that sodium starch glycolate was used in an amount of 100 mg to prepare an oral debuffing vessel. The average hardness of the obtained oral disintegration was 1.8 kp and the degree of grind was 2.3%, which means that the hardness was not sufficient and the degree of grindability was poor.

Comparative Example 4: Preparation of oral disintegration

The same procedure as in Comparative Example 2 was carried out except that 50 mg of sodium croscarmellose sodium was used instead of 50 mg of sodium starch glycolate to prepare a mouth-bone disintegrating tablet. The average hardness of the oral disintegration was 4.8 kp and the degree of grind was 0.3%.

Comparative Example 5: Preparation of oral disintegration

The same procedure as in Comparative Example 2 was carried out except that 50 mg of camelose calcium was used instead of 50 mg of sodium starch glycolate. The average hardness of the oral disintegration was 4.9 kp and the degree of grind was 0.3%.

Comparative Example 6: Preparation of oral disintegration

The same procedure as in Comparative Example 2 was carried out except that 30 mg of camelose calcium and 30 mg of corn starch were used instead of 50 mg of sodium starch glycolate to prepare an oral debuffing vessel. The average hardness of the oral disintegration was 5.3 kp and the degree of fatigue was 0.1%.

Comparative Example 7: Preparation of oral disintegration

Except that 40 mg of crospovidone and 40 mg of corn starch were used in place of 50 mg of sodium starch glycolate, to prepare an oral debuffing vessel. The average hardness of the oral disintegration was 4.2 kp and the muscle strength was 0.4%.

Comparative Example 8: Preparation of oral disintegration

Except that 40 mg of sodium croscarmellose sodium and 40 mg of corn starch were used in place of 50 mg of sodium starch glycolate, to prepare an oral cavity disintegrating tablet. The average hardness of the oral disintegration was 4.2 kp and the muscle strength was 0.4%.

The results are shown in Tables 1 and 2, respectively. The results are shown in Tables 1 and 2 below. In addition, the degree of bitter taste when tablets were disintegrated in the oral cavity was compared and shown in Tables 1 and 2 below.

As shown in the following Tables 1 and 2, when the sildenafil citrate was used (Comparative Example 1), the tablets had similar strengths, but the bitter taste in the mouth felt very strong when taken. Further, as compared with the purification using the combination of sodium starch glycolate or croscarmellose sodium alone, crospovidone and corn starch as a disintegrant, a combination of croscarmellose sodium and corn starch, the disintegrating starch glycolic acid Sodium citrate, crospovidone, and croscarmellose sodium were found to be excellent in tablet hardness and low in the degree of grindability.

Furtherance Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Disintegration rate (%) 10.0 10.0 12.9 12.9 12.9 18.1 Sildenafil free base 100 100 100 100 100 100 Sildenafil citrate - - - - - - Starch glycolate sodium 30 30 40 40 - 40 Crospovidone 30 - 40 - 40 40 Croscarmellose sodium - 30 - 40 40 40 Camelose calcium - - - - - - Corn starch - - - - - - Mannitol 404 404 404 404 404 404 Stevioside 12 12 12 12 12 12 Peppermint fragrance powder 12 12 12 12 12 12 Magnesium stearate 12 12 12 12 12 12 Gross weight (mg / tablet) 600 600 620 620 620 660 Purification hardness (kp) 5.5 5.4 5.2 5.1 5.2 4.9 Marson (%) 0.1 0.0 0.2 0.2 0.2 0.3 Bitter taste 0 0 0 0 0 0 Bitter taste: 0 (not used), + (slightly bitter), ++ (bitter bitter), +++ (bitter taste is very strong)

Furtherance Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Disintegration rate (%) 9.4 8.5 15.9 8.5 8.5 10.0 12.9 12.9 Sildenafil free base - 100 100 100 100 100 100 100 Sildenafil citrate 140.5 - - - - - - - Starch glycolate sodium 30 50 100 - - - - - Crospovidone 30 - - - - - 40 - Croscarmellose sodium - - - 50 - - - 40 Camelose calcium - - - - 50 30 - - Corn starch - - - - - 30 40 40 Mannitol 404 404 404 404 404 404 404 404 Stevioside 12 12 12 12 12 12 12 12 Peppermint fragrance powder 12 12 12 12 12 12 12 12 Magnesium stearate 12 12 12 12 12 12 12 12 Gross weight (mg / tablet) 640.5 590 630 590 590 600 620 620 Purification hardness (kp) 5.2 5.0 1.8 4.8 4.9 5.3 4.2 3.8 Marson (%) 0.2 0.2 2.3 0.3 0.3 0.1 0.4 0.5 Bitter taste +++ 0 0 0 0 0 0 0 Bitter taste: 0 (not used), + (slightly bitter), ++ (bitter bitter), +++ (bitter taste is very strong)

Test Example  1: oral cavity Disintegration definition Disintegration  exam

The disintegration time of the oral debinding tablets containing sildenafil free base and sildenafil citrate obtained in Examples 1 to 6 and Comparative Examples 1 to 8 was measured and the results are shown in Tables 3 and 4, respectively. The disintegration time was measured based on the disintegration test method described in the Korean Pharmacopoeia. The disintegration time was the time at which the disintegration of the oral cavity was completely disappeared at the bottom of the disintegrant.

Test Example 2: Oral disintegration Definition Oral disintegration test

The oral disintegration times of the oral debindases containing sildenafil free base and sildenafil citrate obtained in Examples 1 to 6 and Comparative Examples 1 to 8 were measured and the results are shown in Tables 3 and 4, respectively. The oral disintegration time was measured by placing the oral cavity on the tongue and then gently rolling it with the tongue to completely disappear the oral cavity.

Furtherance Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Disintegration time (sec) 12 11 13 12 12 10 Oral disintegration time (sec) 14 16 12 13 15 18

Furtherance Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Disintegration time (sec) 17 75 63 68 65 95 60 65 Oral disintegration time (sec) 21 65 68 72 116 135 63 67

As shown in Tables 3 and 4, in the case of the oral disintegration preparation prepared by combining two or more of the specific disintegrants of the present invention as in Examples 1 to 6 and Comparative Example 1 containing no sildenafil free base, the disintegration time The disintegration time of the oral disintegration of Comparative Examples 2 to 8 was 60 seconds or more, indicating that the disintegration time was significantly slower than that of the Examples.

In addition, the disintegration time in the oral cavity disintegration-defined oral cavity of Examples 1 to 6 and Comparative Example 1 containing no sildenafil free base was also rapidly disintegrated within 30 seconds, whereas the disintegration time of the oral cavity disintegrants of Comparative Examples 2 to 8 Showed a disintegration time in the mouth of 60 seconds or more, indicating that the disintegration time in the mouth was significantly slower than that in the examples.

Claims (14)

Sildenafil free base; And 5 to 6.5% by weight of a mixture of sodium starch glycolate and 5 to 6.5% by weight of crospovidone or 5 to 6.5% by weight of sodium starch glycolate and 5 to 6.5% by weight of croscarmellose sodium Of the oral cavity of the erectile dysfunction treatment. delete delete The method according to claim 1,
Wherein the disintegration time of the tablets in the oral cavity is 30 seconds or less. The method according to claim 1,
Wherein the degree of grindability of the tablet is 0.3% or less. The method according to claim 1,
Wherein the tablet further comprises a pharmaceutically acceptable additive selected from the group consisting of a diluent, a flavoring agent, a flavoring agent, a lubricant, and a mixture thereof. The method according to claim 6,
Wherein the diluent is a component selected from the group consisting of mannitol, microcrystalline cellulose, lactose, starch and a mixture thereof. 8. The method of claim 7,
Characterized in that the diluent is contained in an amount of 10 to 70% by weight, based on the total weight of the tablet. The method according to claim 6,
Wherein the flavoring agent is a component selected from the group consisting of peppermint flavor, spearmint flavor, fruit flavor, and a mixture thereof. 10. The method of claim 9,
Characterized in that the flavoring agent is present in an amount of 0.3 to 5% by weight, based on the total weight of the tablet. The method according to claim 6,
Wherein the mating agent is a component selected from the group consisting of stevioside, xylitol, sucralose, aspartame, acesulfame potassium, sucrose, erythritol, and mixtures thereof. 12. The method of claim 11,
Characterized in that the mating agent is included in an amount of 0.3 to 5% by weight based on the total weight of the tablet. The method according to claim 6,
The lubricant is a component selected from the group consisting of stearic acid, metal salts of stearic acid, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glyceryl fatty acid esters, glycerol dibehenate, To the mouth cavity. 14. The method of claim 13,
Characterized in that the lubricant is present in an amount of 0.3 to 5% by weight based on the total weight of the tablet.