KR20130018474A - Novel granule formulation containing sildenafil or pharmaceutically acceptable salts thereof as an active ingredient - Google Patents

Abstract

PURPOSE: A fast dissolving granule which is quickly dissolved in the oral cavity is provided to quickly and cheaply implement a high efficiency process. CONSTITUTION: A fast dissolving granule is prepared by assembling sildenafil or a pharmaceutically acceptable salt thereof with a fast dissolving carrier of sugar or sugar alcohol. The granule is dissolved in the oral cavity within 20 seconds. The sugar and sugar alcohol is xylitol, mannitol, isomalt, sorbitol, maltitol, lactose, inositol, erythritol, crystal fructose, trehalose, arabitol, galactitol, lactitol, or maltotritol.

Description

Novel GRANULE FORMULATION CONTAINING SILDENAFIL OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS AN ACTIVE INGREDIENT}

The present invention relates to a fast dissolving granule formulation containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and rapidly dissolving in the oral cavity. Specifically, the present invention is a fast-soluble granule formulation containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and rapidly dissolving in the oral cavity within 20 seconds upon oral administration, and having no foreign matter and residual feeling. It is about. More specifically, the present invention relates to a novel fast dissolving granule formulation containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and obtained by assembling a fast dissolving carrier that satisfies specific conditions, and dissolving the active ingredient. And a novel fast dissolving granule formulation in which absorption is promoted and at the same time, the maximum blood concentration (Tmax) is within 1 hour, and foreign body and residual feeling in the oral cavity are removed and a refreshing feeling is imparted. More specifically, the present invention is to reduce the variation in Tmax expressed between individuals when the present formulation is administered, specifically, a novel fast-soluble solution wherein R ( _{Tmax , 1h} ) is 80% or more and the bitter taste is removed. It relates to a granule formulation.

Sildenafil or a pharmaceutically acceptable salt thereof (collectively referred to herein as sildenafil and separately indicated only when it is necessary to distinguish sildenafil and its salts separately) is disclosed in Korean Patent No. 78931 and Korean Patent No. 262926. Its chemical structure, preparation method, and medical use are described, and it is a drug used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil is known to have a therapeutic effect of erectile dysfunction by selectively inhibiting cGMP phosphodiesterase subtype V (cGMP PDEv) to delay the breakdown of cGMP to regulate the amount of blood flowing into the penis. Since its commercialization in March, it has been used as the first choice drug for erectile dysfunction treatment and is administered about 1 to 4 hours before sexual activity.

Since sildenafil is a drug that is administered at irregular intervals before sexual activity, it is preferable that the faster the expression time of the drug is improved while improving the convenience of taking the drug, and as an oral dosage form, the dosage form can shorten the expression time of the drug. Research has been conducted.

In general, in order to speed up the expression time of the drug, it is possible to disintegrate rapidly in the stomach after oral administration so that the active ingredient is rapidly absorbed. In addition, for rapid disintegration of the dosage form, it is designed to disintegrate easily in the oral cavity before reaching the gastrointestinal tract (intraoral disintegrating tablet), or adhered or unattached to the intraoral mucosa so that the film disintegrates in the oral cavity. It is possible to design in a film form (strip formulation) for fast absorption.

However, in the case of oral disintegrating tablets, it usually takes at least 30 seconds or more to completely disintegrate and dissolve in the oral cavity, and in particular, until disintegration is completed, a severe foreign body may be felt in the oral cavity and thus may be taken without water. However, it did not significantly increase the ease of taking patients. In addition, if the active ingredient has a bitter taste, there is also a problem such as applying a separate high-tech concealment technology, Sildenafil is a drug with a bitter taste, so it is difficult to say that the ease of taking when the oral disintegrating tablets. In particular, attempts have been made to include free bases of sildenafil in oral disintegrating tablets or strip formulations to improve the bitter taste of sildenafil, but due to the nature of these formulations, the formulation remains at a specific site while in the oral cavity. The concentration of sildenafil increases, which causes the patient to still feel bitter taste. Accordingly, further technical considerations regarding bitumen concealment must be made.

In the case of a strip formulation, the formulation is prepared by mounting the active ingredient on a film-like strip, and has been used as an oral cleaner, but there is a limit to the amount of the active ingredient to be loaded into the formulation. Since the polymer is tacky, there is discomfort caused by foreign body residue and residues in the oral cavity, causing inconvenience to the patient. In addition, like oral disintegrating tablets, in the case of an active ingredient having a bitter taste, such as sildenafil, it is difficult to form a satisfactory formulation unless a separate high bite concealment technology is applied, and as mentioned above, Even when free base of sildenafil is used, it is not possible to completely remove the bitter rice due to the increase in concentration of sildenafil at a specific site in the oral cavity in which the formulation is located.

Korean Patent No. 435514 discloses a fast-acting form of sildenafil lactate, and discloses sugars, disintegrants, binders, excipients or glidants commonly used in the art as pharmaceutically acceptable carriers. Examples of the sugars that can be used include lactose, mannitol, sorbitol, xylitol (xylitol), erythritol, dextrose, sucrose, fructose, levose, maltodextrin, partinose, and the like. It is disclosed that it is preferable to use a porous material by, for example, since it can increase solubility in the oral cavity.

In addition, Korean Patent Laid-Open No. 2001-0036527 discloses a formulation for oral administration containing sildenafil citrate. In particular, it addresses the need for the development of a new dosage form that further improves the dosage and exhibits rapid drug expression, and discloses oral dosage preparations prepared in the form of liquids, effervescent tablets, chewing gum and chocolate. In addition, sildenafil preparations, especially viagra tablets, usually require 60 to 90 minutes for the highest blood concentration (Tmax), so the drug expression time should be kept in mind before the patient has sex. Although it is much simpler, it is mentioned that it is an oral tablet and must be taken with water. However, liquid formulations are difficult to apply when the main ingredient is poor in water stability, and foamed tablets must be added after foaming due to their properties. Chewing gum should be chewed until the active ingredient is absorbed, but the time is not clear. It does not, depending on the degree of chewing, even if not easily eluted from the gum base, there is a problem that chocolate is very susceptible to heat. Therefore, it is understood that it is difficult to say that the dosage convenience is increased.

On the other hand, although the formulation is not used for the purpose of shortening the expression time of the drug, there are granules in the oral dosage form. In connection with such granules, there is an example in which herbal extracts are used as granules, but since they are not formulations that dissolve immediately in the oral cavity immediately after administration, they must be taken with water and the patient has a considerable sense of foreign body in the oral cavity. It has been considered as a formulation far from improving the convenience of taking. In addition, the existing granules have been considered to be suitable for use in mixing with beverages or taken with foods, and very few have been considered as an independent alternative oral alternative to tablets or capsules. In the art, it was common to see granules as intermediates for filling tablets or intermediates for filling capsules. Therefore, it is difficult to find an example of increasing the ease of taking or improving the body dynamics of the active ingredient by using granules as an independent dosage form.

For example, U. S. Patent Application Publication No. US2011 / 0027377 discloses a granule formulation in which the solubility is increased by granulating a poorly soluble drug belonging to class II or class IV by BCS, wherein the above formulation has a maltodextrin and a specific molecular weight. After mixing together with the active ingredient using a polyethylene glycol having, and extruded by a screw extruder (screw extruder) to granulate, the granule size reaches 100 to 2500㎛, which is dissolved in water and administered to animals or used It is difficult to say that the formulation of granules as an independent formulation is difficult to disclose, as related to the manufacture of tablets by tableting (tableting granules, etc.) or to be used in capsules. There is nothing.

US 2011/0117193 discloses a formulation of granulated antiretroviral agents for the treatment of children exposed to HIV / AIDS. Herein, a rapidly dissolving granule form is disclosed. Granules are prepared using saccharin as a sweetening agent and LUDIFLASH, croscarmellose sodium and Kollidon as a disintegrant, but the final dosage form is By describing that granules can be mixed with water and administered as a suspension, it does not disclose granule formulations that can be taken without water.

Korean Laid-Open Patent Publication No. 10-2007-0062978 discloses paracetamol, NSAID and sugar alcohol-containing granules prepared by melt extrusion, and includes alcohol, paracetamol and NSAID salts with other excipients which may optionally be present in the granular component. After drying together, the mixture is heated to a temperature of 100-165 ° C. in the extruder to completely melt the sugar alcohol, thereby mixing the molten sugar alcohol with unmelted NSAID salts, paracetamol and other optional excipients, and melting The granulated mass is poured onto a cooled stainless steel tray or cooled movable belt at 10 ° C., cooled, and then the solidified molten mixture is milled to prepare granules, but here too, the use of granules as an intermediate for preparing tablets. It only discloses the technical idea of making the granule itself as a final dosage form, In addition, since the process of melting the sugar alcohol to a high temperature and mixing it with the active ingredients, and then cooling it again, a special consideration for the high manufacturing cost and equipment was needed.

Korean Patent Laid-Open Publication No. 10-2009-0086469 discloses a powder formulation for a published cyclovir, and the formulation discloses a powder formulation including a published cyclovir, povidone, fumaric acid, benzoate sodium, saccharin, and mannitol. This formulation is also based on the premise of administration in admixture with a separate solution, and thus the final dosage form is a liquid rather than a granule.

In addition, U.S. Patent No. 5169643 discloses a granule formulation containing thiol carbamate, and U.S. Patent No. 5532209 discloses a granule formulation containing propanyl, but these are for pharmaceuticals administered to humans. No consideration was given to rapid dissolution or ease of taking.

From the foregoing prior art, many attempts have been made in the art to shorten the expression time of drug efficacy while containing sildenafil as an active ingredient, while reducing the expression time of drug efficacy while making granules the final dosage form. However, there is no attempt to improve the convenience of taking by removing bitterness while eliminating residual feeling. In particular, as a granule formulation containing sildenafil as an active ingredient, it dissolves quickly in the oral cavity and shortens the expression time of the drug, and also reduces the variation among individuals related to the drug expression time, and at the same time, a sense of foreign body and residual feeling in the oral cavity. It is thought that the granule formulation which removed and gave a refreshing feeling was not performed especially.

Korean Patent No. 78931 Korean Patent No. 262926 Korean Patent No. 435514 Korean Laid-Open Patent No. 2001-36527 U.S. Patent Publication No. US2011 / 0117193 United States Patent Application Publication No. US2011 / 0027377 Korean Patent Publication No. 10-2007-0062978 Korean Patent Publication No. 10-2009-0086469

Accordingly, the present invention is an oral dosage form containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, which is rapidly dissolved in the oral cavity, can be taken without water, and has a final dosage form in the form of granules. To provide a task to solve. Specifically, the formulation of the present invention is to solve the problem to provide a novel fast-dissolving granules that are rapidly dissolved within 20 seconds in the oral cavity during oral administration, there is no foreign body and no residual feeling, and is given a refreshing feeling. Furthermore, the present invention is a novel fast-dissolving granule form prepared by mixing sildenafil or a pharmaceutically acceptable salt thereof with sugars satisfying specific conditions, which accelerates dissolution and absorption of active ingredients and shortens Tmax. It is an object of the present invention to provide a novel fast-dissolving granule formulation in which the variation in Tmax expressed in the liver is small, the foreign body and residual feeling in the oral cavity are removed, and the bitter taste is removed.

To this end, the present invention provides the following solutions.

It is obtained by assembling a fast dissolving carrier selected from the group consisting of sildenafil or a pharmaceutically acceptable salt thereof, sugar and sugar alcohol, and provides a fast dissolving granule form, which is rapidly dissolved in the oral cavity during oral administration. .

In addition, in the rapid dissolving granules, the granules are provided in a quick dissolving granules, characterized in that dissolved within 20 seconds in the oral cavity.

In the fast dissolving granules, the sugar and sugar alcohol may be xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, fructose, trehalose, ribitol, arabitol, galactitol, There is provided a fast dissolving granule form, which is selected from the group consisting of lactitol and maltotritol and mixtures thereof.

In addition, in the fast dissolving granules, the formulation is a final dosage form, there is provided a fast dissolving granules, characterized in that there is no foreign matter and no residual feeling even when taken without water.

Further, in the rapid dissolving granule formulation, the rapid dissolving granule is provided with the rapid dissolving granule, characterized in that the rapid dissolving carrier satisfies the following conditions (1), (2) and (3).

(1) Instantaneous solubility is 30mg / ml or more

(2) 5 minutes solubility is 50 mg / ml or more

(3) Instant solubility is not more than 90% of maximum solubility

Further, in the quick dissolving granules, a quick dissolving granules is provided, characterized in that the Tmax of the quick dissolving granules is within 1 hour.

In the fast dissolving granules, the fast dissolving granules is provided with a fast dissolving granules, wherein R ( _{Tmax , 1h} ) is 80% or more.

In addition, the rapid dissolving granules is provided with a quick dissolving granules, characterized in that the oral residual amount of sildenafil after 30 seconds of administration is 10% or less of the total amount of sildenafil contained in the formulation.

In the fast dissolving granules, the active ingredient is a sildenafil free base, and a fast dissolving granules is provided, wherein the bitter taste is removed.

Unlike the conventional oral granules, the novel fast-dissolving granules of the present invention, while dissolving rapidly in the oral cavity during oral administration, completely removes foreign body feelings and residual feelings and at the same time, refreshing feeling is greatly improved. Can be. In addition, since the Tmax is shortened and the variation of the Tmax between the individuals is small and the bitter taste is removed, it is very suitable as an oral dosage form of sildenafil that can be taken without water. Furthermore, the novel fast dissolving granules of the present invention have a relatively simple manufacturing process and are greatly advantageous in terms of cost for the effect.

In the present specification, the sildenafil is used as a generic term including all of the sildenafil free base or pharmaceutically acceptable salts thereof, but when it is necessary to distinguish them, they are respectively used as sildenafil free base or specific salts. It is specifically used as a name, for example, sildenafil citrate.

In the present specification, the granule is used as a generic term including all powders, fine grains, and granules defined in the Korean Pharmacopoeia, and refers to granular formulations of small fine or general particles. As a process for producing granules, a dry method of mixing an active ingredient, an excipient, and a binder to form a slug or a sheet-like substance to granulate, and a wet method of mixing, granulating and drying with a softener by adding a binder solution to a mixture of the active ingredient or an active ingredient and an excipient. In the wet method, a fluidized bed granulation method is used in which a raw material powder is a fluidized bed using airflow, and then sprayed and assembled with a binder solution, which is advantageous in that mixing, granulation, and drying processes are performed in one machine. Do. The method of producing the granules of the present invention is not particularly limited, but it is preferable to use a fluidized bed granulator.

In the present specification, the sense of foreign body refers to a feeling of causing discomfort due to the recognition of the administered medicine as a foreign substance different from a substance which is normally taken by the patient after administration of the medicine in the oral cavity, for example, This may include a feeling of stickiness, such as sand, or irritating feeling on the oral mucosa or tongue, and also a sticky feeling, such as mucus.

In the present specification, the feeling of retention means that even after a considerable time has passed after administration of the dosage form, for example, about 20 seconds after oral administration, the dosage form containing the active ingredient is dissolved and absorbed, The sense of staying in the oral cavity or the sense associated with traces of the dosage form of the formulation, such as not removing the taste or feel of the formulation in the oral cavity, is retained in the oral cavity, which is not enough to cause foreign body feeling but may cause discomfort in some patients. Means. If there is such a residual feeling, it may cause a desire to drink water or beverage additionally, and in this case, the characteristics of the preparation to be taken without water are not exhibited, so it must be considered together with the foreign body for the improvement of the quality of the preparation. It should be an element.

In the present specification, the refreshing feeling refers to a cool and refreshing feeling that is felt in the local area of the mouth and the entire mouth when the dosage form is administered, which is due to the endothermic reaction when the dosage form is dissolved in saliva. It is expressed by the correlation of the heat of dissolution, dissociation energy and rapidity of dissolution rate of the substances constituting the formulation.

In the present invention, the bitter taste refers to the bitter taste of sildenafil, and in the case of general tablets or capsules that are swallowed immediately after administration, it does not cause great discomfort in taking, but it remains in the mouth while remaining in the mouth to some extent. Disintegrating and dissolving formulations, such as buccal disintegrating tablets, strip formulations or granule formulations like the present invention, are important factors to be considered during formulation design.

In the present specification, "solubility in water" is a concept defined in the present invention in order to determine a pattern that dissolves at the same time as the dosage form of the present invention is administered orally, and it is a rapid solution in 250 ml of purified water at a temperature of 37 ± 0.5 ° C. 20.0 g of sieve was added and the paddle speed was set at 50 rpm, and the solubility (mg number of the dissolved solubilizer per ml, equal to or less) per 1 minute, 3 minutes, 5 minutes, 10 minutes and 15 minutes was obtained. After plotting the solubility at, 3 and 5 minutes, find the linear regression curve according to the least-squares method and extrapolate it to the intercept that meets the y-axis, that is, theoretically, the instantaneous solubility when time approaches zero. it means. Instantaneous solubility is a formulation in which the formulation of the present invention dissolves quickly or simultaneously with oral administration, and thus, the rapid dissolution effect of the formulation according to dissolution behavior including a change in the dissolution rate of the carrier at the microscopic level and It is the concept which the present inventors derived based on the novel knowledge that a foreign material sense and a residual feeling change.

In the present invention, the solubility for 5 minutes means the solubility in 5 minutes when 20.0 g of the fast solution is added to 250 ml of purified water at a temperature of 37 ± 0.5 ° C. and the paddle speed is 50 rpm. Is a formulation that dissolves rapidly at about the same time as oral administration, and is based on the novel knowledge that rapid dissolution effect, foreign body feeling and residual feeling change according to dissolution behavior including the change of dissolution rate of carrier at micro level. Solubility is defined to determine over time parameters to determine the dissolution behavior in the oral cavity of the rapid carrier at the microscopic level along with the instantaneous solubility.

In the present invention, the maximum solubility means the maximum value that can be dissolved when 20.0 g of the fast solution is added to 250 ml of purified water at a temperature of 37 ± 0.5 ° C. and the paddle speed is 50 rpm, that is, 80 mg / ml. . In the present invention, the maximum solubility is defined as the fast dissolving agent of the present invention is a formulation that dissolves at the same time as intraoral administration. Therefore, it is expected that the higher the instantaneous solubility, the higher the solubility. It was found that there is a case that is not good, and accordingly, it is to set the conditions of the fast-soluble carrier that can dissolve in the oral cavity and remove foreign feelings and residual feelings through the correlation between maximum solubility and instantaneous solubility.

In the present invention, Tmax means the time when the drug concentration in the blood reaches the maximum when the drug is administered, that is, the time it takes for the blood drug concentration to reach the highest concentration. The Tmax is obtained through actual clinical trials. Specifically, Tmax is obtained by taking blood at a specific time after obtaining a drug for a plurality of subjects to obtain blood concentrations. Therefore, the blood concentration values obtained from each subject are obtained. Since there is some difference between them, Tmax is calculated by calculating the average of the values obtained from them.

In the present invention, R ( _{Tmax , 1h} ) is, when the dosage form of the present invention is administered to a plurality of subjects in the range that can ensure statistically meaningful reliability, the total of the subjects of Tmax less than 1 hour Means percentage. This is a concept defined by the inventor in consideration of the fact that one of the main technical features of the formulation of the present invention is to reduce the variation in Tmax expressed between individuals. Originally, Tmax may be expressed differently depending on the person taking the drug, and therefore, Tmax calculated in the clinical trial means a statistical value. However, if the deviation of the Tmax expressed by each individual is large, this means that the expression time of the drug effect varies greatly depending on each individual. By the way, in the case of drugs that are regularly administered or drugs that do not have a significant difference in the expression time of the drug, the deviation of Tmax may not be a big problem, but in the case of sildenafil, which is an active ingredient of the present invention, to be administered before sexual activity Therefore, the expression time of the drug has a very important meaning. Currently, the commercially available Viagra tablets show Tmax 1 hour after administration, which in some cases has a Tmax of 4 hours, which indicates that there is a large variation in the expression time of the drug. will be. Accordingly, the present inventors have found that when the sildenafil is included in the formulation of the present invention, surprisingly, the Tmax and the variation of the Tmax between the individuals can be reduced. The main technical component of keeping the ratio above a certain ratio was defined and a new parameter called R ( _{Tmax , 1h} ) was defined.

In the present invention, the solute carrier is a carrier constituting the present formulation, which dissolves rapidly upon oral administration, has no foreign matter, no residual feeling, and can impart a refreshing feeling. In particular, the rapid-carrier for achieving the effect of the present invention should be instantaneous solubility and 5 minutes solubility of 30 mg / ml and 50 mg / ml or more, respectively, instantaneous solubility is 90% or less of the maximum solubility, It is preferable that it is -4 Kcal / g or less. Such rapid solubilizers are not particularly limited as long as they are rapidly soluble in the oral cavity as a pharmaceutically acceptable carrier and have no foreign body, no residual feeling, and can provide a refreshing feeling. Preferably used. Examples of such solute carriers include, but are not limited to, xylitol, mannitol, isomalt, sorbitol, maltitol, purified white sugar, lactose, inositol, erythritol, fructose, trehalose, ribitol, arabitol, galactitol, lactitol And pharmaceutically acceptable sugars or sugar alcohols and mixtures thereof, such as maltotritol, and any of these sugars or sugar alcohols satisfying the conditions defined in the present invention, based on compatibility with the active ingredient and other pharmaceutical considerations. It can be used without limitation. Hereinafter, the present invention will be described in detail.

The present invention greatly increases the ease of taking the drug by using sildenafil as an active ingredient, which can be taken without water, and solves the inconvenience of oral disintegrating tablets and strip formulations, which were previously available without water. will be.

The most preferred dosage form as a conventional oral dosage form is a tablet or capsule taken with water, but like sildenafil, it can be taken without water while carrying it at regular intervals and when a rapid drug expression time is required. Preferred formulations are preferred, and research and development of intraoral disintegrating tablets or strip formulations containing sildenafil as an active ingredient is in progress. However, in the case of intraoral disintegrating tablets, contrary to the expectation that it will disintegrate quickly in the oral cavity, it is necessary to hold tablets in the mouth for a considerable amount of time, and foreign body feelings cannot be avoided during that time, and even after dissolution in the oral cavity. It is true that many patients take a drink later or take it with water from the beginning unlike the original development intention. In addition, according to the research of the present inventors, when the sildenafil is composed of orally disintegrating tablets, it was found that the expression time of the drug was delayed rather than the conventional tablet, and therefore, it was found that the formulation was not suitable for sildenafil. Got it.

Furthermore, since the basic idea of manufacturing orally disintegrating tablets is to tablet at low pressure using a rapidly disintegrating excipient, breakage of the tablet often occurs during storage or distribution, and for this purpose, a separate packaging must be considered. It was also undesirable in terms of cost-effectiveness. In particular, sildenafil is a drug that exhibits bitter taste, so it is not an essential component for intraoral disintegrating tablets, and sildenafil in the oral cavity in which oral disintegrating tablets are placed even if sildenafil free base is used to suppress bitter taste. The concentration is bound to be high, which makes the patient feel bitter, so it is practically difficult for the patient to completely feel the bitter taste.

On the other hand, in the case of the strip formulation, another representative formulation that can be taken without water, the active ingredient is loaded into the film-like strip formulation using the film-forming polymer, and the dissolution rate is faster than the intraoral disintegrating tablet. However, there is a fundamental limitation on the amount of active ingredient loaded into the strip formulation, since sildenafil has a typical dosage of 50 mg or 100 mg, and there are technical limitations to loading it into the strip formulation, which is also sensitive to humidity. Therefore, since there is a possibility that the form of the formulation may be greatly distorted or deformed during storage after manufacture, special consideration should be given to the packaging. In addition, in the case of fast disintegrating tablets in the oral cavity, in the case of a drug having a bitter taste such as sildenafil, there is a technical difficulty in that a separate means for shielding it is required. In addition, when using the free base of sildenafil for the purpose of suppressing bitter taste, the bitter taste is eliminated to some extent, but once the formulation is positioned on the tongue, it is maintained until it dissolves in place, so that the specific in the oral cavity As the sildenafil is dissolved at the site, the concentration of the sildenafil at the site is concentrated, and thus it is understood that the formulation still has a bitter taste in the patient's position.

In addition, since the strip formulation uses sticky film-forming polymers, it feels foreign matter such as the stickiness of the mucous substance in the oral cavity when taking it, and also when it is stuck to the palate, which is not originally intended at the time of administration. Since it is difficult to change, it could not greatly improve the ease of taking.

On the other hand, in the case of conventional conventional granules, the majority of the formulations are taken by dissolving or suspending them in beverages or water, and thus, it is difficult to classify them into formulations that can be taken without water, and then mixed with beverages or water. In the case of granules that are not taken, when taken together with water, the patient feels severe foreign body residue and residual feeling in the oral cavity.

Accordingly, the present inventors have developed a novel fast-dissolving granule formulation which overcomes all the disadvantages of oral disintegrating tablets, strip formulations and conventional granule formulations, as a pharmaceutical formulation comprising sildenafil as an active ingredient. In the case of using a fast-carrier that satisfies the above, foreign body feelings and residual feelings are removed, and while the Tmax is shortened compared with the intraoral disintegrating tablet or the strip formulation, new knowledge is obtained that the variation between individuals is small. .

That is, the present invention is a binder solution in which sildenafil and a fast carrier are mixed and wet granulated with a binder solution in which a pharmaceutically acceptable binder is dissolved, or a binder and sildenafil in which the pharmaceutically acceptable binder and sildenafil are dissolved / dispersed in the fast carrier. A novel fast dissolving granule formulation wet granulated is disclosed. The solubilizing agent of the present invention is preferably sugar or sugar alcohol, but is not limited thereto. Specifically, (1) instantaneous solubility is 30 mg / ml or more, (2) 5 minutes solubility is 50 mg / ml or more and ( 3) It is preferable to use sugar or sugar alcohol whose instantaneous solubility is 90% or less of the maximum solubility.

The instantaneous solubility of the present invention was determined by adding 20.0 g of the solute carrier to 250 ml of purified water at a temperature of 37 ± 0.5 ° C. and setting the paddle speed at 50 rpm to determine the solubility at 1, 3, 5, 10 and 15 minutes. After plotting the solubility at 1, 3, and 5 minutes, find the linear regression curve using the least-squares method, extrapolate it, and intercept the intersection with the y-axis, that is, theoretically, when time approaches zero Instantaneous solubility means, solubility in 5 minutes means solubility in 5 minutes, and maximum solubility means the maximum value that the solubilizing agent can dissolve under the same conditions as above.

The present inventors have found that when the instantaneous solubility is 30 mg / ml or more and the 5-minute solubility is 50 mg / ml or more, the granules dissolve rapidly in the oral cavity, and at the same time, foreign substances and residual feelings cannot be felt, resulting in an extremely high dose convenience. When the instant solubility and the 5-minute solubility satisfy the above conditions, when the instant solubility exceeds 90% based on the maximum solubility, the foreign substance and the residual feeling were not good. In particular, in the present invention, the introduction of the concept of instantaneous solubility must simultaneously satisfy two requirements, that the formulation of the present invention must be quickly dissolved and there should be no foreign matter and residual feeling, In other words, it has been found to be related to the change of the dissolution rate at the micro level (i.e., even if the solubility is high, if the dissolution rate at the micro level is slow or the change in the dissolution rate is slow, a foreign object or residual feeling is felt). Therefore, it was introduced according to the necessity of a parameter that simultaneously evaluates the dissolution rate and solubility reflecting the temporal factors at the micro level.

Therefore, even when the same type of carrier is used and the instant solubility and the 5 minute solubility of the present invention are not satisfied, the dissolution rate in the oral cavity may be slow or the dissolution rate in the oral cavity may be high, but there is a foreign body feeling and residual feeling. It should be noted that the effects of the invention cannot be achieved.

Although the specific fast-carrier used in the present invention is not limited, Preferably, sugar or sugar alcohol can be used. Specific examples thereof include pharmaceutically acceptable such as xylitol, mannitol, isomalt, sorbitol, maltitol, refined sugar, lactose, inositol, erythritol, fructose, trehalose, ribitol, arabitol, galactitol, lactitol and maltotritol. Sugars or sugar alcohols, and mixtures thereof, and foreign matters and residual feelings if the instant solubility is 30 mg / ml or more, 5 minutes or more, 50 mg / ml or more and the instant solubility is 90% or less of the maximum solubility. The absence of this can achieve the effects of the present invention. That is, if the instant solubility of the rapid carrier is less than 30 mg / ml, or if the 5-minute solubility is less than 50 mg / ml, or if the instant solubility exceeds 90% of the maximum solubility, it does not dissolve rapidly in the oral cavity. Or a sense of foreign body and / or residual feeling in the oral cavity. On the other hand, although the dissolution rate may change depending on the particle size, particle size distribution or specific surface area, the fast-carrier is, in the present invention, conditions of instant solubility and 5 minutes solubility, without particular limitations related to individual specific surface area or particle size. It should be noted that if it is satisfied, it can be used as a fast carrier. For example, sugar alcohols specially spray-dried to impart porosity have a small particle size, so that the instantaneous solubility is high but the instantaneous solubility exceeds 90% of the maximum solubility. May not be used as a preferred rapid carrier. That is, the conditions related to the instantaneous solubility and 5 minutes solubility of the present invention are different concepts from the specific surface area and particle size of the fast-carrier, and satisfy the conditions of the present invention even if the specific surface area is large or the particle size is small. If not, the effect of the present invention cannot be achieved. Therefore, it should be noted that the specific surface area of the carrier is increased to increase the dissolution rate and that it is clearly distinguished from the use of the fast dissolving carrier that satisfies the conditions of the present invention.

In addition, from the viewpoint of imparting a refreshing feeling, the formulation of the present invention preferably uses a fast dissolving carrier having a heat of dissolution of -4.0 kPa / g or less. For example, in the case of xylitol, -36.6 kPa / g of heat of dissolution Since it is, it is very preferable from a viewpoint of a refreshing feeling.

The fast carrier may be included in an amount of 40% to 98.75% by weight of the granule formulation of the present invention.

The active ingredient that may be included with the solute carrier of the present invention is sildenafil, and includes both sildenafil free base and pharmaceutically acceptable salts of sildenafil, but the type of salt is not limited. However, for the purpose of blocking the bitter taste, it is preferable to use free base of sildenafil. In particular, according to the research of the present inventors, even when using a sildenafil free base, in the case of using oral disintegrating tablets or strip formulations, the bitter taste is still felt, but when the sildenafil free base is included in the granules of the present invention The effect of removing the bitter taste is completely obtained, and therefore, it should be noted that combining the sildenafil free base with the granule formulation of the present invention to remove the bitter taste is one of the main technical features of the present invention.

When the sildenafil free base is included in the formulation of the present invention, the reason why the bitter taste is completely eliminated, unlike other formulations containing sildenafil, is a rapid intraoral dissolution rate and dissolution at a relatively large surface area, and It is assumed that the action by the sugar or sugar alcohol used is organically bonded to each other.

Particularly, sildenafil is a preferred active ingredient, so that the shorter the expression time of the drug is expected, the irregular administration is expected, and considering that it is a drug to be taken immediately when a situation requiring administration, the granule formulation of the present invention is very Suitable.

That is, in the case of sildenafil, it is often necessary to administer urgently in an unexpected situation, and even when there is no water around, it is frequently necessary to perform rapid administration, so it is possible to take it without water, and there is no foreign matter and residual feeling. It is possible to enjoy the advantages of the formulation of the invention to the fullest.

Furthermore, the granules of the present invention have a shorter time (Tmax) to reach the maximum blood concentration after drug administration compared to other formulations containing the same amount of sildenafil, for example, general tablets or intraoral disintegrating tablets. This is a major component, which is a great advantage in consideration of the characteristics of sildenafil which requires urgent administration and rapid drug expression. In addition, the formulation of the present invention not only shortens Tmax, but also has an effect of reducing the variation among individuals of Tmax, which is one of the great technical features of the present invention.

That is, as described above, since Tmax is an average value of values obtained from various subjects, there is a standard deviation. The larger the standard deviation, the more the in-body dynamics of the drug are not uniform among the individuals. In the case of large, there is a difference in the time of onset of the drug depending on the patient, and in the case of a drug requiring rapid onset of the drug such as sildenafil, it may be universally applied to a plurality of individuals in determining the time of dosing. It is difficult to determine the exact time of administration.

However, according to the research of the present inventors, in the case of sildenafil, when prepared as a conventional tablet, the Tmax is at least about 1 hour or more, and the standard deviation is 0.9 hours, which is 4 hours depending on the individual. It also means to exist. For this reason, currently available commercially available sildenafil containing tablets have been set for a wide range of time periods from 1 hour to 4 hours before sexual activity. However, considering that the half-life of the sildenafil-containing tablet is about 2.2 hours, if the patient selects and administers any time during a wide range of dosing periods of 1 to 4 hours of sexual activity, a satisfactory drug may not be obtained. Therefore, there is an urgent need for the development of a formulation that reduces the difference between individuals while shortening Tmax.

By the way, the inventors have found that when sildenafil is applied to the formulation of the present invention, the Tmax is shortened to within 1 hour and the deviation between individuals associated with Tmax is minimized. That is, in the case of the formulation of the present invention, it was found that R ( _{Tmax , 1h} ) is 80% or more, and that R ( _{Tmax, 1h} ) is 80% or more, that is, the proportion of individuals expressing Tmax within 1 hour. More than 80% of this total subject means that the Tmax was within 1 hour in 80% or more of the subjects, which means that the dosage form of the present invention has very little difference in the time between expression of the individual. For this reason, the formulation of the present invention has the advantage of providing a universal dosing point for achieving a more satisfactory drug efficacy for most patients compared to conventional tablets in setting the dosing point.

On the other hand, sildenafil may be included in an amount of 1.25% by weight to 60% by weight of the granule formulation of the present invention.

In addition, another feature of the formulation of the present invention is that the amount of active ingredient remaining in the oral cavity after taking is significantly less than other rapid oral disintegrating formulations, that is, for example, the formulation of the present invention. The oral residual amount of sildenafil 30 seconds after administration of is 10% or less of the total amount of sildenafil included in the formulation. That is, in the case of sildenafil, oral disintegrating tablets and strip formulations are considered as fast dissolving formulations containing sildenafil in accordance with the finding that it is desirable to be able to take rapid drug efficacy and without water. However, when taking oral disintegrating tablets and strip formulations without water, there is a problem that the active ingredient remains in the oral cavity even after a considerable time passes. This means that in the case of intraoral disintegrating tablet or strip formulation, it disintegrates rapidly in the oral cavity, but in the case of not actually taking water, a considerable amount of the active ingredient remains in the oral cavity. There is a disadvantage that it is not expressed or the expression time of the drug is delayed. However, in the case of the formulation of the present invention, even when taken without water, after oral administration of the formulation, for example, 30 seconds after administration of the formulation, oral disintegrating tablets in which the residual amount of the active ingredient in the oral cavity contains the same content of the same active ingredient or Compared with the strip formulation, it is 10 to 20 times less, that is, the active ingredient contained in the formulation is characterized by rapid movement to the gastrointestinal tract. Therefore, the formulation of the present invention has a remarkably superior effect as compared to orally disintegrating tablets or strip formulations in terms of faithful expression of the drug and shortening of the drug expression time.

As a method of preparing the formulation of the present invention, the solubilizing agent and sildenafil are mixed, and separately, a pharmaceutically acceptable binder is dissolved in a solvent to prepare a binding solution, and the mixture of the gastric solubilizing agent and the active ingredient is added to a granulator. After the administration, and granulated while spraying the gastric binding solution, pharmaceutically acceptable excipients such as sweeteners and fragrances may be post-mixed to the granules thus prepared, and put into a wrapping paper to form a granule for single administration. Alternatively, a binder is prepared by mixing / suspending a pharmaceutically acceptable binder and sildenafil in a solvent, administering the solute carrier to the granulator, and granulating while spraying the above binding solution, and then sweetening and flavoring the granules thus prepared. A pharmaceutically acceptable excipient such as the above may be post-mixed and put into a packaging paper to prepare granules for single administration. Since the granules for single administration can be administered in one dose per unit, there is no foreign matter and residual feeling, so even when taken without water, no foreign feeling is felt, and there is no residual feeling and gives a refreshing feeling. There is no desire to drink water even after administration.

Granules according to the present invention can be provided in the form of a portable sachet and three-sided packaging (stick), but is not limited to this, such a packaging container can be carried in a wallet anytime and anywhere can be taken immediately. Has the advantage.

In the above production method, a binder commonly used to facilitate the formation of particles during the granulation process may be used. For example, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl Pharmaceutically acceptable binders and mixtures thereof, such as pyrrolidone (PVP) and hydroxyethyl cellulose, can be used, and can be dissolved in purified water and used in the form of a binder solution. The amount of these binders may be used in amounts of 0.05% to 15% by weight of the total formulation.

In the present invention, one or more flavoring agents may be used pharmaceutically to improve the flavor of the preparation and to increase the compliance. Acceptable flavors include orange, grape, apple, lemon, strawberry, cherry, pineapple, banana, tuttifruit, blueberry, peppermint, cocoa, peach and milk or pharmaceutical Acceptable flavoring agents and mixtures thereof can be used. Their amount may be included in 0.001% to 10% by weight of the total formulation.

In the present invention, one or more sweeteners may be used to enhance the sweetness of the formulation and to increase dose compliance. The sweetener is an important factor in that it is directly related to the dosage convenience in the oral dosage form. In the present invention, since a sugar or a sugar alcohol is used, the fast carrier itself acts as a sweetener, but a natural sweetener and a synthetic sweetener are used as well. You can also use both. Examples of such sweeteners include, but are not limited to, natural sweeteners such as sugars such as sucrose, dextrose, fructose, glucose, liquid glucose and maltose, saccharin, cyclamate and aspartame, acesulfame K, sucralose Pharmaceutically acceptable synthetic sweeteners, such as synthetic sweeteners such as alitam and neotam. Sweeteners can be used in amounts of 0.05% to 20% by weight of the total formulation.

The present invention will be described through the following examples. However, the following examples are not intended to limit the scope of the present invention as an exemplary embodiment of the present invention, it should be noted that various modifications may exist within the spirit of the present invention.

Preparation Examples 1 to 33

The large crystals supplied for sugar and sugar alcohols (xylitol, sorbitol, maltitol, mannitol, isomalt, inositol, lactose, refined white sugar, fructose, trehalose, and erythritol) are pulverized to suit the intended use, and then made by apples. Examples 1 to 33 were used. Table 1 below shows the D50 values (unit μm) of the fast-carrier prepared in each preparation example.

[Table 1]

Test Example 1

In order to obtain the instantaneous solubility of the solute carriers prepared in Preparation Examples 1 to 33, 20.0 g of each sample was placed in a weighing dish, and slowly charged into 250 ml of purified water at a paddle speed of 50 rpm at 37 ± 0.5 ° C. Solubility in 1 minute, 3 minutes, 5 minutes, 10 minutes, 15 minutes was carried out under the same conditions as Table 2 and analyzed by the method shown in Table 3. Table 4 shows the solubility for each elution time.

[Table 2]

[Table 3]

[Table 4]

After plotting the solubility at 1 minute, 3 minutes, and 5 minutes shown in Table 4 on the graph, a linear regression curve was calculated according to the least squares method, and each y-intercept value was defined as instantaneous solubility. Instantaneous solubility and 5-minute solubility for each preparation example are shown in Table 5 below. Table 5 also shows whether instantaneous solubility of 30 mg / ml or more and 5 minutes of solubility of 50 mg / ml or more, which is the fast-carrier condition of the present invention, is also satisfied.

[Table 5]

Examples 1 to 33

Dissolve hypromellose and polyvinylpyrrolidone in purified water as shown in Tables 6 to 9, and then sprayed into the mixture of sildenafil and Preparation Examples 1 to 33 using a fluid bed granulator (Fluid Bed Granulator, Glatt, Germany), respectively. Got. The final granules were prepared by mixing sucralose and peppermint flavor to the prepared granules.

TABLE 6

[Table 7]

[Table 8]

Table 9

Example 34

As shown in Table 10, was prepared in the same manner as in Example 2, except that sildenafil citrate was used instead of sildenafil free base as the active ingredient of Example 2.

[Table 10]

Example 35

Sildenafil free base as an active ingredient in Example 2 was prepared in the same manner as in Example 2 except that granules were obtained by dispersing hypromellose and polyvinylpyrrolidone in a combined solution dissolved in purified water and then spraying on xylitol.

Example 36

In Example 35, the sildenafil free base was dispersed as an active ingredient in a binding solution of hypromellose and polyvinylpyrrolidone dissolved in 75% by weight of ethanol (75% by weight of ethanol, 25% by weight of purified water), followed by spraying on xylitol to form granules. Prepared in the same manner as in Example 35, except that obtained.

Comparative Example 1

As shown in Table 11, after the sildenafil free base, corn starch, crospovidone, hydroxypropyl cellulose, rudy flash, prosolve, citric hydrate with apple No. 26 (600 ㎛) apples and mixed, colloidal silicon oxide and stearyl Sodium fumarate was appled into No. 30 sieve (500 μm), and then mixed with the mixture to prepare a final mixture. The final mixture was compressed into tablets using a single tablet press (XENA-I, RAON, KOREA).

TABLE 11

Comparative Example 2

As shown in Table 12, instead of sildenafil free base,

It was prepared in the same manufacturing method as in Comparative Example 1 except that it was used.

[Table 12]

Comparative Example 3

A commercially available sildenafil citrate product Viagra tablet (50 mg (50 mg as sildenafil free base, Pfizer Korea, Australia)) was used as Comparative Example 3.

Comparative Example 4

In the same manner as in Preparation Example 4 in which the film forming degree, texture, and solubility of the preparation examples presented in Korean Patent Application Publication No. 10-2011-0041412 were found to be very good, as follows, sildenafil free base, crystalline cellulose, carrageenan gum, and polysorbate Oral disintegrating film was prepared using menthol, peppermint oil, aspartame, enzyme treatment stevia, glycerin, and hydroxypropyl cellulose.

Comparative Example 5

It was prepared in the same manner as in Comparative Example 4 except for using sildenafil citrate instead of sildenafil free base as shown in Table 13.

[Table 13]

Test Example 2

Sensory tests for oral dissolution rate, foreign body feeling and residual feeling were performed in six healthy adults with Examples 1 to 36 and Comparative Examples 1 to 4. The results are shown in Tables 15 to 17 according to the evaluation criteria in Table 14.

[Table 14]

TABLE 15

[Table 16]

TABLE 17

Test Example 3

Sensory tests on oral dissolution rate, foreign body feeling and residual feeling were carried out on six healthy adults with Examples 1 to 36 and Comparative Examples 1 to 5. The results are shown in Table 19 below according to the evaluation criteria in Table 18 below.

[Table 18]

TABLE 19

As described above, when the granule formulation is formed by using the fast dissolving agent that does not satisfy any one of the instantaneous solubility, the 5 minutes solubility, and the relationship between the instantaneous solubility and the maximum solubility, the effect of the present invention is large because the foreign substance and residual feeling are large. It can be seen that this is not achieved.

Test Example 4

The sensory test (Gyomi test) was compared and measured for 15 healthy adult males with Examples 1 to 36 and Comparative Examples 1 to 5. To evaluate according to the criteria of Table 20, the results are shown in Table 21 below.

TABLE 20

TABLE 21

When using the formulation of the present invention including the sildenafil free base as described above, the bitter taste could not be felt, but when the sildenafil citrate was included as an active ingredient, the bitter taste could be felt. On the other hand, in the case of oral disintegrating tablets and oral disintegrating film, even if the sildenafil free base as an active ingredient was able to feel the bitter taste, which is a bitter taste by the combination of the use of the sildenafil citrate and the formulation of the present invention as an active ingredient Suggests that it is removed.

Test Example 5

In Example 2 and Comparative Example 3, dissolution test was performed by dissolution test at pH 1.2 (Korean Pharmacopoeia, artificial gastric juice) and pH 4.0 (Korean Pharmacopoeia, acetate buffer). The results are shown in Table 22 (Example 2) and Table 23 (Comparative Example 3).

Table 22

TABLE 23

As a result of the dissolution test, Example 2 showed a complete dissolution rate within 10 minutes after the start of dissolution, Comparative Example 3 showed a dissolution rate of about 90% only after about 30 minutes elapsed, it can be seen that the initial dissolution rate is significantly different after the start of dissolution have.

Test Example 6

In Example 2 and Comparative Example 3 was administered orally to 40 healthy adult males to determine the dynamics of sildenafil in the blood.

-Subjects: 40 healthy adult men (nothing except water after 8 pm the day before the experiment)

Test drug: Example 2, 1 packet (50 mg as sildenafil free base)

-Control drug: Comparative Example 3, 1 tablet (50 mg of Viagra tablet, 50 mg as sildenafil free base, Pfizer Pharmaceuticals, Australia)

-Method of administration: The test drug or control drug was orally taken. After the end of phase 1, the half-life was considered, and after 1 week, the phase 2 test was performed by crossing the test drug and the control drug (2 × 2, crossover).

-Blood collection method: Heparin-locked catheter was installed in the brachial vein area, and the blood was collected by 10mL at the following time.

Blood collection time: before (0 hours), after administration 0.25, 0.50, 0.75, 1, 1.25, 1.50, 2, 3, 4, 6, 8, 10, 12, 24 hours

-Sample storage: The collected blood is placed in a vacuum heparinized container (vacutainer), mixed and centrifuged for 10 minutes at 3,000 revolutions per minute (rpm) to take a supernatant (plasma) and placed in the container, and is set at -70 ° C. Stored in the freezer.

Results: The analysis results are shown in Table 24 below.

TABLE 24

As can be seen from the above table, it was found that the maximum blood concentration reaching time (Tmax) of Example 2 was shortened by 0.4 hours than the highest blood concentration reaching time (Tmax) of Comparative Example 3. In addition, while the standard deviation associated with Tmax of Comparative Example 3 is 0.9 hours, it can be confirmed that the standard deviation associated with Tmax of Example 2 is reduced by 2 times or more as 0.4 hours. This can be confirmed from the CV value related to Tmax, and the CV related to Tmax of Comparative Example 3 was 85.0, whereas the CV related to Tmax of Example 2 was 85.0, and the formulation of the present invention was compared to Tmax compared to general tablets. It can be seen that the deviations between related individuals have been greatly reduced.

On the other hand, Table 25 shows the Tmax of each of the total 40 subjects, and Table 26 shows the proportion of the subjects belonging to each Tmax.

TABLE 25

TABLE 26

From the above table, it can be seen that in Example 2, the proportion of the subjects whose Tmax is within 1 hour is more than 80%, that is, R ( _{Tmax, 1h} ) is 80% or more. This indicates that the inclusion of sildenafil in the formulation of the present invention reduces the variation in Tmax between individuals, thus indicating that the formulation of the present invention can provide a more universal dosing point.

Test Example 7 Oral Residue Analysis Test

Six healthy adult males were subjected to oral residual test with Example 2, Comparative Example 1 and Comparative Example 4 as follows.

30 seconds after taking Example 2, Comparative Example 1, or Comparative Example 4, respectively, or 1 tablet or 1 tablet (50 mg as sildenafil free base) without water, the intraoral residue was washed with 30 ml of water for 10 seconds. Rinse your mouth, collect in each beaker, then rinse once again with 30 ml of water for 10 seconds and collect in each beaker. (60 ml total) However, after rinsing the mouth, remove any residues in the mouth and analyze them together.

The above three test solutions (60 ml each) were placed in a 100 ml volumetric flask, and the content of sildenafil free base was analyzed according to the liquid chromatograph method using acetonitrile added to 100 ml as a sample solution. Table 27 shows the oral residual percentage of sildenafil in 30 seconds after dosing without water.

TABLE 27

From the above table, Example 1 can be said that the residual amount in the oral cavity is significantly less than Comparative Example 1 and Comparative Example 4. This shows that the effective drug can be administered within a short time when taken without water.

[Industrial applicability]

The fast dissolving granules of the present invention are granules having excellent foreign body feeling, residual feeling and refreshing feeling, and dissolve quickly in the oral cavity, have no foreign substances and residual feeling, and provide a fresh feeling. In particular, the formulation of the present invention can achieve the effects of the invention irrespective of the type of active ingredient, it is applicable to a variety of active ingredients. In addition, since the manufacturing process is relatively simple, a high efficiency process can be configured at low cost.

Claims (9)

A fast dissolving granule form obtained by assembling sildenafil or a fast-soluble carrier selected from the group consisting of pharmaceutically acceptable salts and sugars and sugar alcohols thereof, and rapidly dissolving in the oral cavity upon oral administration. The fast dissolving granules according to claim 1, wherein the granules are dissolved within 20 seconds in the oral cavity. According to claim 1 or 2, wherein the sugar and sugar alcohol is xylitol, mannitol, isomalt, sorbitol, maltitol, purified white sugar, lactose, inositol, erythritol, fructose, trehalose, ribitol, arabitol, galactitol, A fast dissolving granule formulation, characterized in that it is selected from the group consisting of lactitol and maltotritol and mixtures thereof. 4. The fast dissolving granules according to claim 3, wherein the dosage form is a final dosage form, and there is no foreign matter and residual feeling even when taken without water. The fast dissolving granule type according to claim 1, wherein the fast dissolving carrier is a fast dissolving carrier that satisfies the following conditions (1), (2) and (3).
(1) Instantaneous solubility is 30mg / ml or more
(2) 5 minutes solubility is 50 mg / ml or more
(3) Instant solubility is not more than 90% of maximum solubility The rapid dissolving granules according to claim 5, wherein the rapid dissolving granules has a Tmax of 1 hour or less. The rapid dissolving granules according to claim 6, wherein the rapid dissolving granules has R ( _{Tmax , 1h} ) of 80% or more. 8. The fast dissolving granules according to claim 7, wherein the rapid dissolving granules has an intraoral residual amount of sildenafil after 30 seconds of administration is 10% or less of the total amount of sildenafil included in the formulation. The quick dissolving granules according to claim 8, wherein the active ingredient is sildenafil free base and bitter taste is removed.