KR101304343B1 - Fast dissolving oral formulation of pde-5 inhibitors - Google Patents

Abstract

The present invention relates to fast-acting forms of phosphodiesterase-5 (Phosphodiesterase-5, PDE-5) inhibitors, and more specifically, solubilizing vardenafil, sildenafil, tadalafil or udenafil, which are therapeutic agents for erectile dysfunction. It is a fast-solvent type of PDE-5 inhibitor that can be rapidly dissolved in the oral cavity by making it into a fast-solvent type that can be easily dissolved in the oral cavity. It is about.

PDE-5 Inhibitor, Vardenafil, Rapid Solvent

Description

FAST DISSOLVING ORAL FORMULATION OF PDE-5 INHIBITORS}

Figure 1 shows the differential scanning calorimetry (DSC) of the vardenafil solid dispersion and vardenafil raw material prepared in Examples 1 to 3 according to the present invention,

Figure 2 shows the erection state of the rabbit before and during administration of the vardenafil fast-acting tablet prepared according to the present invention,

Figure 3 is a photograph of the vardenafil melt-bonded fast dissolving prepared in Example 9 according to the present invention,

4 is a surface photograph of the vardenafil porous pore inner tablet prepared in Example 14 according to the present invention,

Figure 5 is a cross-sectional photograph of the vardenafil porous pore inner tablet prepared in Example 14 in accordance with the present invention.

The present invention relates to a fast-acting form of phosphodiesterase-5 (Phosphodiesterase-5, PDE-5) inhibitors, and more specifically to the erectile dysfunction treatment agent vardenafil, sildenafil, tadalafil and udenafil PDE-5 inhibitors that can be rapidly dissolved in the oral cavity by being contained in a solubilized form, so that the dosage can be easily taken and the medication compliance can be increased and the solubility in the oral cavity can be quickly expressed. It is about the solvent type of.

Phosphodiesterase-5 inhibitors commonly known as therapeutic agents for erectile dysfunction include vardenafil as a selective inhibitor of cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase type 5 (cGMP PDE-5). , 1-[[3- (1,4-Dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethyl, C ₂₃ H ₃₂ N ₆ O ₄ S, CAS no.224785-90-4), sildenafil, 1-[[3- (6,7- Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine, C ₂₂ H ₃ 0N ₆ O ₄ S, CAS no. 171599-83-0), tadalafil, (6R, 12aR) -6- (1,3-benzodioxol-5-yl) -2, 3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1 ', 2': 1,6] pyrido [3,4-b] indole-1,4-dione, C ₂₂ Drugs such as H ₁₉ N ₃ O ₄ , CAS no. 171596-29-5) and udenafil (Udenafil, C ₂₅ H ₃₆ N ₆ O ₄ S, CAS no. 268203-93-6) 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.

PDE-5 inhibitors are commercially available as oral erectile dysfunction agents in the form of tablets prepared using their water soluble salts to ensure rapid absorption and good bioavailability in formulation. Vardenafil hydrochloride is commercially available from Bayer under the trade name Levitra, and sildenafil is commercially available from Pfizer under the trade name Viagra. However, commercially available vardenafil hydrochloride has a very low water solubility of 0.11 mg / ml (Physicians desk reference, PDR, 2006, p3048-3053), and the water solubility of sildenafil citrate is 3.5 mg. / Ml (PDR 2006, p2552-2556), which is higher than vardenafil hydrochloride, but both of these substances require about 60 minutes of drug efficacy even when formulated in water-soluble salt form (PDR 2006, p2552-2556 and p3048-3053). It is uncomfortable to take it in consideration of the drug expression time during sex. In addition, since it should be taken with water even when taken as a regular tablet, in view of sexual partner care and compliance with medications, it is possible to dissolve and absorb rapidly without water in the oral cavity, so that various fast-acting preparations can have the desired effect. Research is urgently needed.

In Korean Patent Laid-Open No. 2001-36527, sildenafil, another PDE-5 inhibitor, was configured to have a fast solubility using a technique such as effervescent tablets. However, the citrate used in this formulation is a water-soluble salt, but a desired degree of water solubility ( 3.5 mg / ml, PDR 2006, p2552-2556), not only dissolve in the oral cavity, but also have a bitter taste that cannot be eaten. In order to improve the bitter taste of sildenafil citrate, an example of using a free base of sildenafil without a bitter taste in place of sildenafil citrate is disclosed in Korean Patent Publication No. 1999-0088249. However, the formulation using the free base of sildenafil can also reduce bitter taste in the oral cavity, but it has a disadvantage in that its solubility is so low that it has a limit in showing rapid and good bioavailability, which is its original purpose. Insoluble materials with extremely low solubility, however applied to the preparations of the rapidly disintegrating form in the oral cavity, are swallowed in the undissolved state and reach the digestive tract, and thus do not show a big difference from the general tablets administered orally.

Therefore, there is an urgent need to develop a new formulation of a PDE-5 inhibitor that overcomes these shortcomings and exhibits high bioavailability while exerting a rapid effect.

Thus, the present inventors have solved the above problems, solid dispersion using a solid dispersion or a polymer or a sugar containing a PDE-5 inhibitor such as vardenafil, sildenafil, tadalafil or udenafil with cyclodextrin in order to solve the above problems The present invention was completed by preparing a high-shielding solubilized form using a method of forming a dispersion, and then preparing the vardenafil solid dispersion into a porous tablet and dissolving it in a fast dissolving form in the oral cavity.

Accordingly, it is an object of the present invention to provide a fast-acting form of a PDE-5 inhibitor which can be easily taken without water to increase medication compliance and can quickly express the medicament with good solubility in the oral cavity.

The present invention provides an oral fast-acting composition of a PDE-5 inhibitor containing as an active ingredient a PDE-5 inhibitor selected from the group consisting of vardenafil, sildenafil, tadalafil, udenafil, and pharmaceutically acceptable salts thereof. It is characterized by.

When the present invention as described above in more detail according to the components thereof are as follows.

First, according to the above object, the present invention provides a solid dispersion comprising a PDE-5 inhibitor and optionally substituted cyclodextrin derivative for solubilization and bitterness masking. The solid dispersion of the present invention may further include a surfactant, a water-soluble polymer or a pharmaceutical additive as necessary.

Hereinafter, the components of the solid dispersion of the present invention containing the PDE-5 inhibitor will be described in detail.

(1) active ingredient

The composition of the present invention contains a component selected from the group consisting of vardenafil, sildenafil, tadalafil, udenafil, and pharmaceutically acceptable salts thereof, which are PDE-5 inhibitors having an erectile dysfunction treatment effect, as an active ingredient. Preferably, it is possible to use vardenafil or hydrochloride of vardenafil.

(2) a cyclodextrin derivative represented by the following formula (1)

Cyclodextrin derivatives of Formula 1 are components used to mask the bitter taste of PDE-5 inhibitors and to form a complete amorphous solid dispersion with increased solubility of the drug. As the cyclodextrin derivative of the general formula (1) , preferably, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutyl ether-7-β-cyclodextrin, 2-hydroxy Hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy) propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin or 2-hydroxypropyl-γ-cyclodextrin can be used, more preferably Preferably 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin can be used. The cyclodextrin derivatives may be used alone or in the form of mixtures thereof.

Where

n is 6, 7 or 8,

R is a C _1-6 alkyl, hydroxy C _1-6 alkyl, carboxy C _1-6 alkyl or sulfoalkyl C _1-4 ether group.

(3) Optional additives

The solid dispersion of the present invention may further comprise a component selected from the group consisting of surfactants, water soluble polymers, pharmaceutical additives and mixtures thereof, and such optional additives may be included in the inclusion body by increasing the wetting of the solid dispersion. It improves the dissolution rate or bioavailability of oral induces rapid drug expression, and contributes to improving the flow and physical properties of the solid dispersion. The surfactant, the water-soluble polymer and the pharmaceutical additives will be described in detail as follows.

Iii) surfactants

① Polyoxyethylene-sorbitan-fatty acid esters:

Esters of mono or trilauryl, palmityl, stearyl or oleyl (trade names: Tween, Uniquema);

② sorbitan fatty acid esters:

Sorbitan monolauryl, sorbitan monopalmityl, sorbitan monostearyl (trade name: Span, Uniquema);

③ polyoxyethylene-polyoxypropylene block copolymer (Poloxamers);

④ Reaction products of natural or hydrogenated vegetable oils with ethylene glycol:

Polyoxyethylene glycolated natural or hydrogenated castor oil (trade name: Cremophor, BASF);

⑤ Polyoxyethylene fatty acid esters:

Polyoxyethylene stearic acid ester (trade name: Myrj, Uniquema);

⑥ sodium dioctylsulfosuccinate or sodium lauryl sulfate; And

⑦ mixtures of mono-, di- and tri-esters of glycerol, mono- and di-esters or free polyethylene glycols of polyethylene glycol (trade names: Gelucire, Gattefosse)

Among the surfactants listed above, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene fatty acid esters, mixtures of mono-, di- and tri-esters of glycerol, mono- and dies of polyethylene glycol Preference is given to ester or free polyethylene glycols, sodium dioctylsulfosuccinate or sodium lauryl sulfate, more preferably polyoxyethylene-polyoxypropylene block copolymers.

Ii) water soluble polymer

In the present invention, one or more water-soluble polymers may be optionally added to improve the flowability and physical properties of the solid dispersion, and representative examples thereof include alkyl cellulose such as methyl cellulose; Hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; Hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; Carboxyalkyl celluloses such as carboxymethyl cellulose; Alkali metal salts of carboxyalkyl celluloses such as sodium carboxymethyl cellulose; Carboxyalkylalkyl celluloses such as carboxymethylethyl cellulose; Carboxyalkyl cellulose esters; Starch; Pectin, such as sodium carboxymethylamylopectin; Chitosan and chitin derivatives; Polysaccharides such as alginic acid, alkali metals and ammonium salts thereof, carrageenan, galactomannan, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum; Polyacrylic acid and salts thereof; Polymethacrylic acid and its salts, methacrylic acid copolymers and aminoalkyl methacrylic acid copolymers; Polyvinylacetate and diethylaminoacetate; Sugar-based surfactants such as sucrose distearate, sucrose monodistearate and sucrose monopalmitate; Polyvinyl alcohol; Polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone and vinyl acetate; Polyalkylene oxides such as polyethylene oxide and polypropylene oxide; And it may be selected from the group consisting of a copolymer of ethylene oxide and propylene oxide.

Among the water-soluble polymers listed above, alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses and polyvinylpyrrolidone are particularly preferred, and more preferably hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl Pyrrolidone can be used.

Iii) pharmaceutical additives

In the present invention, in order to improve the flowability and physical properties of the solid dispersion and to prepare the solid dispersion in an oral dosage form, one or more pharmaceutically acceptable excipients may be optionally added in addition to the active ingredient. For example, lactose, starch, starch sodium glycolate, crospovidone, croscarmellose sodium, maltodextrin, microcrystalline cellulose, calcium phosphate, calcium carbonate or crystalline cellulose can be added, and other stearic acid as lubricants. , Magnesium stearate, talc and the like can be added.

The solid dispersion of the amorphous PDE-5 inhibitor of the present invention comprises a substituted cyclodextrin derivative in a proportion of 30 parts by weight or less based on 1 part by weight of vardenafil as a pharmacologically active ingredient. Surfactants or pharmaceutical additives may be used in amounts of up to 20 parts by weight based on 1 part by weight of PDE-5 inhibitor. Preferably, the PDE-5 inhibitor-containing solid dispersion of the present invention comprises up to 10 parts by weight of substituted cyclodextrin derivatives relative to 1 part by weight of the PDE-5 inhibitor. In addition, the compositions of the invention illustrated in the following examples may be mentioned as preferred examples.

The solid dispersion of the PDE-5 inhibitor of the present invention comprises the steps of (1) dissolving or dispersing a substituted cyclodextrin derivative in a solvent with or without water, and (2) dissolving the PDE-5 inhibitor in a solvent. , And (3) combining the solutions obtained in the above steps into one and then removing the solvent therefrom.

In the above production method, one or more surfactants, water-soluble polymers, pharmaceutical additives or mixtures thereof may be further dissolved or dispersed in the solution of step (1), if necessary. In addition, as the solvent of steps (1) and (2), water, ethanol, isopropyl alcohol, acetone, acetonitrile, dichloromethane or a mixed solvent of one or more thereof may be used, but the scope thereof is not limited thereto. .

In step (3), a solid dispersion of amorphous vardenafil is obtained by removing the solvent from the solution using spray drying, roller drying, solvent precipitation and lyophilization, which are generally used as solvent removal methods in the preparation of the solid dispersion. .

The PDE-5 inhibitor used as an active ingredient is contained in an amount of 5 to 100 mg per tablet, and preferably 0.1 to 80% by weight, preferably 1 to 70% by weight in the total formulation.

Next, the fast dissolving composition of the present invention comprises a component consisting of sugars, binders, disintegrants, pore-forming substances, excipients, glidants and mixtures thereof commonly used in the art as pharmaceutically acceptable carriers for formulation. It may include.

The sugar is an important ingredient that affects sweetness, solubility, and touch in the mouth, and in order to exhibit such effects, it must have good sweetness and water solubility. Sugars that can be used include lactose, mannitol, sorbitol, xylitol, erythritol, glucose, sucrose, fructose, rebulose, maltodextrin, paratinose and the like. In particular, the saccharide is preferable because it can increase the solubility in the oral cavity to use a porous one by spray drying. The sugars may be contained in 10 to 98% by weight, preferably 20 to 95% by weight based on the total weight of the composition. If the content of the sugar is less than 10% by weight, there is a problem that the sweetness and the oral feel is poor.

The disintegrant component is an important component for rapid disintegration in the fast-solvent type according to the present invention, and generally crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl cellulose, starch sodium glycolate, calcium carboxymethyl cellulose, and the like. Can be used. The disintegrant component is preferably contained in less than 50% by weight, preferably 0.01 to 20% by weight based on the total weight of the composition. If the content exceeds the content of the disintegrant, there is a problem in that the tableting property is lowered and the form of the dosage form cannot be maintained.

The binder component is used to maintain the shape of the product when handling and storing the product as a component necessary to exhibit strength in the fast-solvent type according to the present invention, which can impart strength to the formulations commonly used in the art. Any of these may be used, such as polyethylene glycol, poloxamer, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gum arabic, tragacanta Gum, xanthan gum, sodium alginate, pectin, agar, water-dispersible starch and derivatives thereof may be used. Preferably, in the case of melt-bonded fast-soluble preparations, the melting point is 50 ° C to 80 ° C in polyethylene glycol and poloxamer. Phosphorus type is preferable and polyethylene glycol, polyvinylpyrrolidone or It is recommended to use a copolymer of nilpi pyrrolidone and vinyl acetate. The binder is preferably contained in 0.05 to 15% by weight, preferably 0.1 to 10% by weight based on the total weight of the composition. If the content of the binder is less than 0.01% by weight, there is a problem that the strength of the fast-acting formulation is weakened, and when the content of the binder exceeds 15% by weight, there is a problem of poor oral solubility.

The pore-forming material used in the case of a sublimable porous fast-acting tablet can be prepared in a porous formulation in order to create a porous pore so that it can be easily dissolved by saliva in the oral cavity during oral administration. The material may use one or more selected from a sublimable material that is sublimed at a relatively low temperature, ie menthol, camphor, thymol, organic acid, lower fatty acid and mixtures thereof, preferably menthol. The pore-forming material is sublimed through a simple drying process after compression compression with an active ingredient and a pharmaceutically acceptable carrier when formulated into a tablet and at this time generates a porous pore in the tablet. In addition, the pore-forming material should be readily sublimable at dry conditions of about 40 to 60 ℃.

For melt-bonded fast dissolving agents, polyethylene glycols 2000, 3000, 4000, 6000, 8000 and 20000 and poloxamers 188, 237, 338 and 407 having a melting point of 50 ° C. to 80 ° C. among poloxamers and polyethylene glycols. It is more preferable as a binder, and mixed with vardenafil or a solid dispersion thereof, the above-mentioned pharmaceutical additives such as sugars and binders, and applying a slight pressure to form a caking, and put into a packaging container that has already been molded, Heating to 80 ° C. or higher, preferably about 80 ° C., allows the binder component to melt to increase binding to form enhanced dosage forms. Alternatively, the mixture may be introduced into the packaging container in which the mold has already been molded, and then pressurized in order to preliminarily fix the form, and then packaged and warmed under the same conditions to form a final formulation. Among the packaging materials capable of molding the mold, polyvinyl chloride, polyvinylidene chloride, and the like may be deformed at the time of heating, thereby modifying the properties of the final product. In addition, the aluminum material can be molded to emboss or engraved letters on the tablet surface to prevent the patient or consumer from confusing the medicine, thereby preventing misuse of the medicine. There is an advantage.

In addition, the fast-soluble composition according to the present invention, in addition to the above components in the range that does not impair the effects of the present invention, for example, lubricant components such as magnesium stearate, talc, silica, sodium stearyl fumarate, valine, aspartame, stevio Sweeteners such as side, and excipient components such as microcrystalline cellulose may be further included as pharmaceutical additives to aid in formulation. The lubricant and excipient are each contained in an amount of 0.01 to 20% by weight, preferably 0.1 to 10% by weight, based on the total weight of the composition. If the content of the lubricant is less than 0.01% by weight, there is a problem that tableting is not good, and if it exceeds 20% by weight, there is a problem that the oral solubility is poor.

Such components can be used to prepare the rapid solvent form of the PDE-5 inhibitor. The fast-solvent type is preferably in the form of a tablet or a hardened mold. In addition, the fast dissolving type can be easily administered by oral administration since it disintegrates and dissolves quickly by intraoral saliva without eating extra water.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1

4 g of 2-hydroxypropyl-β-cyclodextrin (Aldrich) and 2 g of vardenafil hydrochloride were mixed with a water / ethanol mixture and stirred until the solution became clear. The mixed solution was put in a spray dryer (Buchi, Mini Spray Dryer, B-191, Switzerland) and spray dried to prepare a vardenafil solid dispersion. At this time, the inlet temperature of the spray dryer was maintained at 60 ℃, outlet temperature 45 ~ 50 ℃.

Example 2

A vardenafil solid dispersion was prepared in the same manner as in Example 1, except that 4 g of methyl-β-cyclodextrin was used.

Example  3

4 g of 2-hydroxypropyl-β-cyclodextrin, 2 g of vardenafil hydrochloride and 0.5 g of poloxamer 188 (Lutrol F68, BASF) were mixed in a water / ethanol mixture and stirred until the solution became clear. The mixed solution was put in a spray dryer (Buchi, Mini Spray Dryer, B-191, Switzerland) and spray dried to prepare a vardenafil solid dispersion. At this time, the inlet temperature of the spray dryer was maintained at 60 ℃, the outlet temperature of 45 ~ 50 ℃.

The composition of the formulations prepared in Examples 1 to 3 is shown in Table 1 below.

Example 4

2 g of vardenafil hydrochloride, 20 g of xylitol as water-soluble sugars, and 1 g of polyethylene glycol 6000 as a binder were mixed homogeneously. From the mixture, 20 mg of vadenafil hydrochloride was taken as an equivalent, caking in a form having a low hardness enough to maintain its properties, and then placed in an aluminum PTP where a mold was formed. . It was again cooled to room temperature to prepare a vardenafil melt-bonded quick-release tablet that maintains its caked appearance.

Example 5

The vardenafil melt-bonded fast dissolving tablet was prepared in the same manner as in Example 4, except that 6 g of the vardenafil hydrochloride dispersion prepared in Example 1 was used as an active ingredient.

Example 6

A vardenafil melt-bonded fast dissolving tablet was prepared in the same manner as in Example 4, except that 6.5 g of the vardenafil hydrochloride dispersion prepared in Example 3 was used as an active ingredient.

Example 7

A vardenafil melt-bonded rapid tablet was prepared in the same manner as in Example 5, except that 20 g of mannitol was used as a water-soluble sugar.

Example 8

A vardenafil melt-bonded rapid tablet was prepared in the same manner as in Example 5, except that 1 g of poloxamer 407 was used.

Example 9

2 g of vardenafil hydrochloride, 20 g of xylitol as water-soluble sugars, and 1 g of polyethylene glycol 6000 as a binder were homogeneously mixed. From the mixture, 20 mg of equivalent amount of vardenafil hydrochloride is taken into an aluminum PTP in which a mold is formed, and the powder inside the mold is pressed with a force not to deform the mold, and the surface is flattened and then packaged. Warmed for minutes. It was again cooled to room temperature to prepare a vardenafil melt-bonded quick-release tablet that maintains its caked appearance.

Example 10

A vardenafil melt-bonded fast dissolving tablet was prepared in the same manner as in Example 9, except that 6 g of the vardenafil hydrochloride dispersion prepared in Example 1 was used as an active ingredient.

Example 11

A vardenafil melt-bonded quick-release tablet was prepared in the same manner as in Example 10, except that 2 g of polyvinylpyrrolidone cross-linked with a disintegrant (product name: Collidone CL, BASF, Germany) was added.

Example 12

A vardenafil melt-bonded quick-release tablet was prepared in the same manner as in Example 10, except that an aluminum mold having a negative grain identification was used.

Example 13

A vardenafil melt-bonded fast dissolving tablet was prepared in the same manner as in Example 10, except that 2 g of citric acid sildenafil was added as an active ingredient.

Example 14

Homogeneously mixes 2 g of vardenafil hydrochloride, 20 g of xylitol as water-soluble sugars, 1 g of polyethylene glycol 6000 as a binder, 3 g of menthol powder as a pore-forming substance, 1 g of aspartame as a sweetener and 0.1 g of magnesium stearate as a lubricant. It was. 20 mg of the corresponding amount was taken from the mixture as vardenafil hydrochloride, and then tableted using a tablet press. The obtained tablet was dried in a dryer at about 60 ° C. for 12 hours, and the sublimation was confirmed when the residual amount of menthol was less than 1 mg to obtain a vardenafil porous rapid tablet.

Example 15

The fast dissolving vardenafil porous tablet was prepared in the same manner as in Example 14, except that 6.5 g of the vardenafil hydrochloride dispersion prepared in Example 3 was used as an active ingredient.

Comparative Example 1

Commercially available Levitra tablet (20 mg as vardenafil hydrochloride, Bayer, Germany) was used as a comparative example.

Test Example 1: Crystal Form Analysis

The crystal form was analyzed by measuring the endothermic peak of the vardenafil solid dispersion prepared in Examples 1 to 3 and the raw material of vardenafil hydrochloride using a differential scanning calorimeter (DSC, Rheometric Science, UK).

As a result, as shown in Figure 1 , it was confirmed that the raw material of vardenafil hydrochloride is a crystalline material, whereas the vardenafil solid dispersion prepared in Examples 1 to 3 was formed of an amorphous material.

Test Example 2 Measurement of Oral Dissolution Time

The oral dissolution time of the vardenafil melt-bonded tablets of Examples 4 to 12, the porous dentin tablets of Examples 14 and 15 and the Levitra tablet of Comparative Example 1 were placed on the tongue in the oral cavity and gently rubbed to measure the intraoral dissolution time. It is shown in Table 2 below.

As shown in Table 2, in the case of melt-bonded fast dissolving tablets and porous fast dissolving tablets of vardenafil prepared according to the present invention, they are softly dissolved within 5 to 10 seconds in the oral cavity, and thus can be taken without water. It was confirmed. In addition, when the vardenafil hydrochloride was used as it is, the bitter taste was hardly felt in the case of inclusion with the substituted cyclodextrin, which showed better results. On the other hand, Levitra tablets used as a comparative group was a very hard coating tablets took more than 5 minutes to disintegrate in the oral cavity, and because of its strong bitter taste, it was not possible to use it as a rapid tablet.

Test Example 3 Measurement of Drug Expression Time Using Albino Rabbit

In order to measure the drug release time of the vardenafil fast dissolving tablet prepared according to the present invention, the vardenafil melt fast dispersing tablet of Example 6, the vardenafil porous fast dissolving tablet of Example 14, and the levitra tablet of Comparative Example 1 were used as shown below. Erection start time and duration were measured.

As the test animals, male SPF New Zealand albino rabbits (weight about 2.0 to 2.5 kg, 3 months of age, Samta Cosa, Korea) were used for each of three animals, and they were used in a certain amount for more than 4 days under the same conditions. It was bred while supplying solid feed and water for phosphorus rabbit. The rabbits were fasted for more than 48 hours and then used in the experiment, and when fasting, they were allowed to drink water freely.

The rabbit prepared as described above, the vardenafil melted fast dissolving tablet of Example 6, and the porous dissolving tablet of vardenafil of Example 14 were administered in the oral cavity as the amount of vardenafil per 10 mg per mouth and the spout was held by hand to prevent swallowing or spitting. On the other hand, Levitra tablets of Comparative Example 1 was orally administered as a 10 mg equivalent amount per vardenafil per horse. As described above, the erection start time and duration were measured and the results are shown in Table 3 below.

The photo before and after the erection of the rabbit according to administration is shown in FIG. 2 . The erection start time after administration began to erect about 5-10 minutes when the melt-bonded fast dissolving tablet of Example 6 was administered and about 5-10 minutes when the porous fast dissolving tablet of Example 14 was administered. When the Levitra tablet of Example 1 was administered, the erection started after about 15 to 30 minutes, and it was found that the onset time was much shorter in the case of the fast-acting tablet according to the present invention. The retention time of the erected state showed similar results of about 30 to 40 minutes for all three compositions.

The fast dissolving agent form of the PDE-5 inhibitor of the present invention is a fast dissolving tablet which dissolves rapidly in the oral cavity, and thus the manufacturing process is simple and easy to take, thereby increasing medication compliance and shortening the erection start time by rapid drug expression. Has

Claims (33)

PDE-5 inhibitors selected from the group consisting of vardenafil, sildenafil, tadalafil, udenafil and pharmaceutically acceptable salts thereof and cyclodextrins represented by the following formula (1): Oral quick-use compositions for PDE-5 inhibitors, comprising a solid dispersion comprising a derivative as an active ingredient: [Formula 1]

Where n is 6, 7 or 8, R is a C _1-6 alkyl, hydroxy C _1-6 alkyl, carboxy C _1-6 alkyl or sulfoalkyl C _1-4 ether group. The method of claim 1, The oral fast dissolving composition of the PDE-5 inhibitor, characterized in that the PDE-5 inhibitor is vardenafil, sildenafil or a pharmaceutically acceptable salt thereof. delete delete The method of claim 1, The cyclodextrin derivative is 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutylether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, PDE, characterized in that it is selected from the group consisting of (2-carboxymethoxy) propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, and mixtures thereof Orally fast-acting compositions of --5 inhibitors. The method of claim 1, The solid dispersion is a rapid dissolution composition for oral use of a PDE-5 inhibitor, characterized in that it further comprises an optional additive selected from the group consisting of surfactants, water-soluble polymers, pharmaceutical additives and mixtures thereof. The method of claim 1, Oral genus of PDE-5 inhibitors, characterized in that the composition further comprises a pharmaceutically acceptable carrier selected from the group consisting of sugars, binders, disintegrants, pore-forming substances, excipients, glidants and mixtures thereof. Aqueous composition. 8. The method of claim 7, Oral quick-soluble composition of the PDE-5 inhibitor, characterized in that the saccharide is contained in 10 to 98% by weight based on the total weight of the composition. 8. The method of claim 7, The fast-soluble oral composition of the PDE-5 inhibitor, characterized in that the binder is contained in 0.05 to 15% by weight based on the total weight of the composition. 8. The method of claim 7, The rapid dissolution composition of the PDE-5 inhibitor, characterized in that the disintegrant is contained in less than 50% by weight based on the total weight of the composition. 8. The method of claim 7, The excipient and the lubricant are contained in 0.01 to 20% by weight, respectively, based on the total weight of the composition, oral fast-soluble composition of the PDE-5 inhibitor. The method according to claim 6, The rapid dispersible composition for oral PDE-5 inhibitors, characterized in that the solid dispersion comprises 30 parts by weight or less of cyclodextrin derivatives and 20 parts by weight or less of optional additives based on 1 part by weight of PDE-5 inhibitors. A method for the preparation of an oral fast-soluble composition for oral use of the PDE-5 inhibitor according to claim 1, comprising the step of formulating the solid dispersion of the PDE-5 inhibitor with a pharmaceutically acceptable carrier. 14. The method of claim 13, The solid dispersion of the PDE-5 inhibitor 1) dissolving or dispersing the cyclodextrin derivative in a solvent with or without water; 2) dissolving the PDE-5 inhibitor in a solvent; And 3) formulating a method comprising the step of combining the solution obtained in steps 1) and 2) into one and then removing the solvent therefrom. 15. The method of claim 14, In step 1), a surfactant, water-soluble polymer, pharmaceutical additives or mixtures thereof are further added to dissolve or disperse. 15. The method of claim 14, Wherein the solvent in steps 1) and 2) is selected from the group consisting of water, ethanol, isopropyl alcohol, acetone, acetonitrile, dichloromethane and mixtures thereof. 14. The method of claim 13, The solid dispersion of the PDE-5 inhibitor is mixed with a pharmaceutically acceptable carrier sugars and a binder to form a caking and melt-bonded under heating to prepare a melt-bonded rapid dissolving agent. 14. The method of claim 13, Mixing the solid dispersion of the PDE-5 inhibitor with sugars, binders, pore-forming substances, excipients and glidants which are pharmaceutically acceptable carriers, and then compressing, compressing, warming and drying the same to prepare a porous fast-soluble preparation. Characterized in that the formulation method. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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