KR101778688B1 - Pharmaceutical combination preparation comprising phosphodiesterase―5 inhibitors - Google Patents

Abstract

The present invention relates to a pharmaceutical combination preparation comprising two or more types of phosphodiesterase-5 (PDE-5) inhibitors. Specifically, the present invention relates to a combination preparation for treating erectile dysfunction comprising: tadalafil as a first active component, whose particle size is controlled, and which has excellent solubility and release rate by using a surfactant, is pharmaceutically stable, and has improved bioavailability; and as a second active component, one or more types of PDE-5 inhibitors selected from the group consisting of sildenafil, vardenafil, udenafil, rodenafil, mirodenafil, and avanafil. Due to having significantly improved solubility and release rate of the first active component, tadalafil, and comprising more than one types of PDE-5 inhibitors selected from the group consisting of sildenafil, vardenafil, udenafil, rodenafil, mirodenafil, and avanafil in a single administration form, the pharmaceutical combination preparation of the present invention shows superior effects in terms of an early onset time of effect, longer drug persistence, and significantly reduced occurrence of side effects, thereby creating a synergistic effect in the treatment of erectile dysfunction. Thus, the pharmaceutical combination preparation of the present invention can serve as an alternative to pre-existing single-component erectile dysfunction medications such as Viagra and Cialis, and can be beneficially used in the treatment and alleviation of erectile dysfunction.

Description

[0001] The present invention relates to a pharmaceutical combination preparation containing phosphodiesterase-5 inhibitors which comprises a phosphodiesterase-

The present invention relates to a pharmaceutical combination comprising two or more phosphodiesterase-5 inhibitors, and more particularly to a pharmaceutical combination comprising at least two phosphodiesterase-5 inhibitors, And at least one PDE selected from the group consisting of sildenafil, vardenafil, idenafil, roodenafil, mirodenapil, and avanapil as the second active ingredient, which is excellent in solubility and dissolution rate, stable in formulation and improved in bioavailability, -5 < / RTI > inhibitor for the treatment of erectile dysfunction.

Male sexual dysfunction refers to sexual life related disorders including loss of libido and penile curvature, and erectile dysfunction is a major disease. Erectile dysfunction refers to a state in which erection induction or erectile state is difficult to maintain for sexual intercourse, and ejaculatory disorders such as premature ejaculation, seizure, and extreme feeling can not be carried out. Specifically, the supply of blood to the penile corpus cavernosum is not smooth due to cardiovascular disease, diabetes, and hormone deficiency, or even if the blood flow is supplied, the corpus cavernosum does not block, Time is not maintained, and both men and women are not satisfied with sexual life. The worldwide prevalence of erectile dysfunction is 35 to 50%. The prevalence in Korea is estimated to be about 40% in men over 40 years of age, and the estimated number is about 2 million.

The erection is accomplished by releasing nitric oxide (NO) in the cavernosal body of the penis and then relaxing the smooth muscle through the synthesis of cyclic guanosine 3 ', 5'-monophosphate (cGMP), where cGMP is released from phosphodiesterase 5 (PDE-5, phosphodiesterase-5). PDE-5 inhibitors known as erectile dysfunction drugs include sildenafil, which is a selective inhibitor of cyclic guanosine 3 ', 5'-monophosphate phosphodysterase type 5 (cGMP PDE-5) C ₂₂ H ₃₀ N ₆ O ₄ S), Vardenafil (C ₂₃ H ₃₂ N ₆ O ₄ S), Tadalafil (C ₂₂ H ₁₉ N ₃ O ₄ ), Udenafil, C _{25 H 36 N 6 O 4 S)} , in Gardena field _{(Lodenafil, C 23 H 32 N} 6 O 5 S), mirodenafil _{(Mirodenafil, C 26 H 37 N} 5 O 5 S) , and Havana Peel (Avanafil, C ₂₃ H ₂₆ C ₁ N ₇ O ₃ ) have been developed.

PDE-5 inhibitors are important for PDE-5 enzyme selectivity and time of action, and sildenafil, vardenafil, and udenafil may exhibit transient visual impairment on dosing because their selectivity to PDE-6 is about 10-fold and their selectivity is weak. Therefore, side effects such as headache, facial flushing, rhinitis symptoms, and digestive disorders have been reported upon oral administration of a tablet containing a PDE-5 inhibitor. Clinical efficacy and safety of PDE-5 inhibitors for erectile dysfunction and patient preference studies showed that when administered at the maximum dose in clinical trials using sildenafil, vardenafil and tadalafil commercial oral formulations, side effects The incidence of adverse drug reactions has been reported to be about 1/5 of the test group, and the difference in drug side effects ratio is not large (Korean Urology Journal , 2007, Vol. 48, No. 2, p.219-225). Specifically, Pfizer's "Viagra Tablets", a commercial drug of sildenafil citrate salt, reports side effects such as flushing, headache, dyspepsia, dizziness, palpitations, eyeball redness, and visual anomalies. In addition, side effects such as facial flushing, headache, fever, chest discomfort, eye irritation, nasal congestion, and indigestion have been reported in Donga Pharmaceutical's "Zydena Chung", a commercial oral formulation of Udenapil. When using high-dose formulations, the side effects may be more severe.

In the case of the action time, the time to reach the highest blood concentration (T _max ) and the half-life (T _1/2 ), which is the time required for the amount of drug absorbed in the body, to be reduced to half are important. When _Tmax is fast, the time required for the drug to reach the effective concentration is short, so that the time for the efficacy is fast. If the half-life is long, the action time of the erectile drug may be prolonged if the sexual stimulation is given. Of PED-5 inhibitor, sildenafil, T _max and half-life are each an hour and 4 hours, T _max and the half-life of vardenafil 0.7 hours, respectively, with 4-5 hours, T _max and the half-life of tadalafil 2 hours and 17.5 hours, respectively, The T _max and half-life of idenafil are 1.2 hours and 10 hours, respectively. The T _max and half-life of Mirobenfil are 35 hours and 2.5 hours respectively, and the T _max and half-life of avanapyr are 0.5 hours and 10 hours, respectively. Sildenafil, vardenafil and avanafil can be expected to exhibit fast drug efficacy within 1 hour on the basis of the above-mentioned T _max and half-life. However, in the case of tadalafil and udenafil, it is expected to have a long half- have. On the other hand, it is known that, in the case of udenafil, the duration of action is relatively short compared with that of tadalafil, even though it is a drug having a relatively long half-life. To overcome this shortcoming, the sustained-release formulation is disclosed in Korean Patent No. 1004205 . In the case of tadalafil, the medicinal effective duration is known to be about 36 hours, and it is disclosed in Korean Patent Registration No. 0577057 concerning daily dosing of 1 to 20 mg.

Therefore, in the case of tadalafil, it can be judged as an ideal daily therapy for erectile dysfunction because it is clinically proven to have a prostate disease, which is a coexisting disease, as a long-acting erectile dysfunction agent having the longest action time of PED-5 inhibitor have. However, there is a disadvantage that the onset time is long due to a long T _max . In addition, there is a disadvantage in that the administration time of the medicinal effect of tadalafil is at least 30 minutes, and the drug should be taken in advance in consideration of the efficacy time of the medicinal effect at the time of sexual intercourse, and sufficient PDE-5 inhibitory effect can not be expected at a low dose, It may be difficult to expect. It is known that tadalafil is a very poorly soluble drug and has a low solubility of 2 μg / ml (see US Pat. No. 6,841,167) and is known to be insoluble in some organic solvents such as ethanol and methanol. In order to enhance the drug efficacy of tadalafil, Is required.

Therefore, the development of erectile dysfunction treatment that has a long duration of pharmacological efficacy, a long duration of pharmacological effect and a reduced side effect has not been developed yet, and therefore, it is necessary to develop such a product. Accordingly, the present inventors have made efforts to develop a combination preparation using tadalafil as an alternative to the conventional erectile dysfunction treatment.

Combination preparations can be expected to reduce the side effects that may be caused by long-term drug use by reducing the use of a single drug. However, the development of complex preparations for two or more PDE-5 inhibitors has the following difficulties.

First, the combination of different active ingredients to be used in the combination preparation should be easy and free, and unexpected difficulties may arise due to various problems arising from the pharmacokinetic and pharmacodynamic properties of the drugs. Second, the mass of the composition comprising the active ingredient and the pharmaceutically acceptable excipient should be of a reasonable size without difficulty in administration, but if the drug content to be compounded is too much or too small, mass control with a suitable composition may be difficult . Third, the dissolution rate and stability of the drug may be lowered due to the mutual reaction between the different active ingredients in the preparation of the combined preparation. In this case, it is difficult to develop a fixed combination combination in a physico-chemically stable form.

Under these circumstances, the inventors of the present invention have made extensive efforts to develop a combined preparation having superior effects to replace conventional erectile dysfunction therapies by using tadalafil. As a result, it has been found that the disadvantages of the PDE-5 inhibitor single agent are improved, The present inventors have completed the present invention by developing a combined preparation containing the above PDE-5 inhibitor.

Korea Patent No. 1004205 Korean Patent No. 0577057 US Patent No. 6841167

Korean Journal of Urology, 2007, Vol. 48, No. 2, p.219-225

It is an object of the present invention to provide a pharmaceutical composition comprising tadalafil or a pharmaceutically acceptable salt thereof as a first active ingredient; The second active ingredient is selected from the group consisting of sildenafil, vardenafil, udenafil, lodenafil, mirodenafil, avanafil and their pharmaceutically acceptable salts One or more PDE-5 (phosphodiesterase-5) inhibitors selected from the group consisting of: And a surfactant. The present invention also provides a combination preparation for erectile dysfunction.

Another object of the present invention is to provide a method for preparing a solid dispersion containing tadalafil free base.

Still another object of the present invention is to provide a free-radical dispersion of tadalafil free base prepared by the above method as the first active component; And a second active ingredient selected from the group consisting of sildenafil, vardenafil, udenafil, lodenafil, mirodenafil, avanafil and their pharmaceutically acceptable (PDE-5) inhibitor selected from the group consisting of a pharmaceutically acceptable salt, a prodrug, a salt thereof, and the like.

In one aspect to achieve the above object, the present invention provides a pharmaceutical composition comprising tadalafil or a pharmaceutically acceptable salt thereof as a first active ingredient; The second active ingredient is selected from the group consisting of sildenafil, vardenafil, udenafil, lodenafil, mirodenafil, avanafil and their pharmaceutically acceptable salts One or more PDE-5 (phosphodiesterase-5) inhibitors selected from the group consisting of: And a surfactant. The present invention also provides a combination preparation for erectile dysfunction.

The tadalafil used as the first active ingredient in the combination preparation of the present invention can be used in the form of tadalafil or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of tadalafil include hydrobromic acid salts, phosphates, sulfates, hydrochlorides, malates, fumarates, lactates, tartrates, citrates, besylates, camsylates and gluconates, But is not limited to, a tadalafil free base, for example, Cialis ^® tadalafil free base (Lilly ICOS).

In the combination preparation of the present invention, the above-mentioned tadalafil or pharmaceutically acceptable salt thereof may be prepared by mixing particles such as a Z-mill, a hammer mill, a ball mill, a fluid energy mill, It can be pulverized using a conventional mill which can be pulverized. In addition, the particle size of the tadalafil or pharmaceutically acceptable salt thereof can be subdivided by using a sieve method or a size classification method such as air current classification have. Methods for adjusting the desired particle size are well known in the art.

In the combined preparation of the present invention, the particle size (d _(0.9) ) of 90% or more of the particles of tadalafil or pharmaceutically acceptable salt thereof may be 1 탆 to 100 탆, preferably 1 탆 to 50 탆 And even more preferably from 1 [mu] m to 30 [mu] m, but is not limited thereto. The particle size of tadalafil plays an important role in drug release and bioavailability and achieves an improved dissolution rate when tadalafil or a pharmaceutically acceptable salt thereof having a d _(0.9) of less than 50 [mu] m is used in the combination preparation of the present invention (See Test Example 2 and Test Example 3).

In the present invention, the particle size is also expressed on the basis of a particle size distribution such as d _{( 0.X )} = Y (where X and Y are positive numbers). d _{( 0.X )} = Y represents the cumulative distribution of the particle size distribution of the drug obtained by measuring the particle diameter of the drug in the preparation, and X% (% ) Is Y. In other words, For example, d _(0.1) is the diameter of the particle at 10% by accumulating the particle size of the drug in small order, d _(0.5) is the particle size at 50% And d _(0.9) represents the diameter of the particle at 90% by accumulating the drug particle size in small order.

The _{extent to which the} particle size distribution d _{( 0.X )} represents the percentage of the total cumulative particle, based on any of the number, volume, or weight, will depend on the method used to determine the particle size distribution. Methods of measuring particle size distribution and the types of% associated therewith are known in the art. For example, when the particle size distribution is measured by a well-known laser diffraction method, the X value in d _(0.X) represents the percentage calculated by the volume average. Those skilled in the art are well aware that the results of particle size distribution measurements obtained by a particular method may be correlated with those obtained from other techniques based on experience with conventional experiments. For example, laser diffraction methods respond to the volume of particles to provide volume average particle size, which corresponds to weight average particle size when the density is constant.

In the present invention, measurement of the average particle size and particle size distribution of the particles of tadalafil or a pharmaceutically acceptable salt thereof can be carried out using a commercially available apparatus based on the laser diffraction / scattering method based on the Mie theory. For example, it can be measured using a commercially available apparatus such as a Helium-Neon-Laser Optical System (HELOS) optical diffraction particle size analyzer of Sympatec.

The PDE-5 (phosphodiesterase-5) inhibitors used as the second active ingredient in the combination preparation of the present invention are sildenafil, vardenafil, udenafil, lodenafil, and at least one PDE-5 inhibitor selected from the group consisting of mirodenafil, avanafil, and pharmaceutically acceptable salts thereof. Examples of pharmaceutically acceptable salts of the PDE-5 inhibitors include, but are not limited to, hydrobromide, phosphate, sulfate, hydrochloride, maleate, fumarate, lactate, tartrate, citrate, besylate, camsylate, gluconate, can, preferably sildenafil citrate salt and (sildenafil citrate, for example, Viagra ^® sildenafil citrate; Pfizer), vardenafil hydrochloride (vardenafil hydrochloride, for ^{example, Levitra ® vardenafil HCl; Schering-} Plough), Udenafil glass But are not limited to, udenafil free base, lodenafil carbonate, mirodenafil hydrochloride, and avanafil free base.

Since tadalafil, which is used as the first active ingredient in the combination preparation of the present invention, exhibits rapid release and improved solubility due to its small particle size, it forms large undesired particles due to agglomeration among the drugs, and bimodal elution There is a possibility to happen. Accordingly, the combined preparation of the present invention is characterized by minimizing aggregation of the particles by using a surfactant. Surfactants that may be used in the combination preparation of the present invention include sodium lauryl sulfate or sodium dioctylsulfosuccinate, reaction products of natural or hydrogenated vegetable oils with ethylene glycol (polyoxyethylene glycated natural or hydrogenated castor oil (Chremophor, BASF), polyoxyethylene sorbitan fatty acid esters (mono or trirauryl, esters of stearyl or oleyl (Tween)), polyoxyethylene-polyoxypropylene copolymers poloxamers), sorbitan fatty acid esters (sorbitan monolauryl, sorbitan monopalmityl, sorbitan monostearyl (product name: Span, Croda)), polyoxyethylene esters (product name: Myrj, Uniquema) Mono-and di-ester of serol, or free polyethylene glycol (product name: Gelucire, Gattefosse). have. But are not limited to, at least one member selected from the group consisting of sodium lauryl sulfate, polyoxyethylene glycated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene-polyoxypropylene copolymer , And more preferably sodium lauryl sulfate can be used. The surfactant may be contained in an amount of preferably 0.1% by weight to 30.0% by weight based on the total weight of the combined preparation.

The combined preparation according to the present invention may further comprise at least one additive selected from the group consisting of pharmaceutically acceptable disintegrants, diluents, binders and glidants.

The disintegrant serves to help dissolve the drug in the digestive juices. However, it is very important to select an appropriate disintegrant because the dissolution rate of the drug varies depending on the type of disintegrant. Therefore, in the combination preparation according to the present invention, in order to achieve an excellent dissolution rate, it is possible to use one kind selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, starch, alginic acid and sodium alginate The above disintegrants may be used. The disintegrant may be contained in an amount of 1.0 wt% to 30.0 wt%, preferably 2.0 wt% to 15.0 wt%, based on the total weight of the combined preparation.

The diluent may be, but is not limited to, one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch and calcium dihydrogenphosphate. The diluent may be contained in an amount of 1.0 wt% to 99.0 wt%, preferably 5.0 wt% to 90.0 wt%, based on the total weight of the combined preparation.

In addition, although the binder is not limited thereto, at least one binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and povidone may be used. The binder may be contained in an amount of 1.0 to 30.0% by weight, preferably 2.0 to 15% by weight, based on the total weight of the composite preparation.

The lubricant may also include, but is not limited to, stearic acid metal salts, stearic acid metal salts such as calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, waxes, glyceryl fatty acid esters, And glycerol dibehenate may be used. The lubricant may be contained in an amount of 0.2 wt% to 5.0 wt%, preferably 0.3 wt% to 3.0 wt% based on the total weight of the composite preparation.

The combined preparation according to the present invention may contain at least one active ingredient selected from the group consisting of PDE-5 inhibitors sildenafil, vardenafil, udenafil, The second active ingredient, which may be selected from one or more of the group consisting of mylordenafil and avanafil, elutes over 80% within 15 minutes.

Specifically, in one embodiment of the present invention, pulverization is carried out using an air jet mill to prepare an undifferentiated tadalafil free base having a d _(0.9) value of 32.2 탆 (Example 1) (Example 9), and the dissolution rate of tadalafil and sildenafil was analyzed. As a result, it was found that both of tadalafil and sildenafil started to elute It was confirmed that a high dissolution rate of 85% or more was reached within 5 minutes (Test Example 3, Fig. 3 and Fig. 4).

From these results, it was confirmed that an improved dissolution rate and dissolution rate can be achieved by using the combined preparation of tadalafil and sildarapril of the present invention prepared by micronization of the poorly soluble drug, tadalafil.

In addition, the combination preparation according to the present invention has excellent erectile dysfunction treatment effect as a substitute for existing erectile dysfunction treatment agents such as Viagra tablets and cialis tablets through the technical features described above.

The present invention also relates to a composition comprising tadalafil or a pharmaceutically acceptable salt thereof as the first active ingredient; At least one PDE-5 inhibitor selected from the group consisting of sildenafil, vardenafil, yudenapil, rodenavir, mirodenapil, avanapil and pharmaceutically acceptable salts thereof as the second active ingredient; And a surfactant in a therapeutically effective amount to provide a method of treating erectile dysfunction or a method of improving erectile dysfunction of the penis.

The term "therapeutically effective amount " as used herein refers to the amount of the combination preparation of the present invention effective in a method for treating erectile dysfunction or a method for improving erectile dysfunction of the penis.

The combined preparation according to the present invention may be prepared in various formulations and may be formulated into tablets, powders, granules, capsules or the like such as tablets, film-coated tablets, unilamellar tablets, It can be changed.

The tadalafil used as the first active ingredient in the combination preparation of the present invention is 1.0 to 80.0 mg, preferably 2.5 to 20.0 mg, and more preferably 2.5 to 20.0 mg, based on the unit dosage form (granule, capsule or tablet) of the combination preparation according to the present invention, And even more preferably from 5.0 mg to 10.0 mg. The above-mentioned content means an amount based on tadalafil in free form.

The PDE-1 inhibitor used as the second active ingredient selected from the group consisting of sildenafil, vedenapil, idenafil, rodenavir, mirodenafil, avanapil, and pharmaceutically acceptable salts thereof in the combination preparation of the present invention, 5 inhibitor is present in an amount of from 2.5 mg to 200.0 mg, preferably from 2.5 mg to 150.0 mg, even more preferably from 5.0 mg to 150.0 mg, based on the unit dosage form (granule, capsule or tablet) of the combination preparation according to the invention .

Specifically, sildenafil is not limited thereto, but may be added in an amount of 10.0 mg to 100.0 mg, preferably 20.0 mg to 80.0 mg, more preferably 25.0 mg to 50.0 mg based on the unit dosage form of the combination preparation according to the present invention . The amounts described above refer to amounts based on the free-form siladropyl.

In addition, vardenafil may be used in an amount of 2.5 mg to 20.0 mg, preferably 5.0 mg to 10.0 mg, based on the unit dosage form of the combination preparation according to the present invention, although it is not limited thereto. The amounts described above refer to amounts based on vardenafil in free form.

In addition, the udenafil may be used in an amount of 25.0 mg to 200.0 mg, preferably 50.0 mg to 150.0 mg, based on the unit dosage form of the combination preparation according to the present invention, although it is not limited thereto. The amounts described above refer to amounts based on the free form of udenafil.

In addition, the rotenizil may be used in an amount of 10.0 mg to 80.0 mg, preferably 20.0 mg to 40.0 mg, based on the unit dosage form of the combination preparation according to the present invention, although it is not limited thereto. The amounts described above refer to amounts based on the free form of rhodamine.

In addition, the moloenafil may be used in an amount of 10.0 mg to 100.0 mg, preferably 25.0 mg to 50.0 mg, based on the unit dosage form of the combination preparation according to the present invention, though it is not limited thereto. The amounts described above refer to amounts based on the free form of mirodinafil.

In addition, the avanophil may be used in an amount of 25.0 mg to 200.0 mg, preferably 50.0 mg to 100.0 mg, based on the unit dosage form of the combination preparation according to the present invention, though not limited thereto. The amounts described above refer to amounts based on avanafil in free form.

In another aspect, the present invention provides a composition comprising: a) a tadalafil free base; A water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, polyvinyl alcohol, hydroxyethylcellulose, polyvinylpyrrolidone, and mixtures thereof; A surfactant selected from the group consisting of sodium lauryl sulfate, polyoxyethylene glycated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene-polyoxypropylene copolymer; And preparing a solution in which a pharmaceutically acceptable carrier is dissolved; And b) drying the solution of step a) to prepare a solid dispersion. The solidarity dispersion of tadalafil free base comprises the steps of:

The term "solid dispersion " in the present invention means a solid state in which a drug is homogeneously dispersed together with a polymer to form a physicochemical bond. The solid dispersion preparation technique is a technique in which a drug is dispersed in a small size Or disperse through intermolecular interactions to increase the solubility of the drug by reducing the crystallinity and improving the surface area of the drug.

That is, in the present invention, the "tadalafil free base-containing solid dispersion" is a form in which tadalafil is uniformly dispersed with a water-soluble polymer and a surfactant and is intermolecularly physicochemically bonded thereto. The particle size (d _(0.9) ) of the particles may be 1 to 100 mu m, preferably 1 to 50 mu m, and more preferably 1 to 30 mu m. The particle size of tadalafil plays a very important role in drug release and bioavailability, and the solid dispersion according to the present invention can increase the wettability of tadalafil, which is a poorly soluble drug, so that the solubility of tadalafil can be improved See example 1).

The water-soluble polymer has a uniform distribution with tadalafil while enhancing solubility by imparting hydrophilicity to tadalafil and minimizing deformation of tadalafil due to external temperature and moisture, thereby securing stability. Hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, and mixtures thereof. Preferably, hydroxypropyl methylcellulose can be used.

Surfactants that can be used in the preparation of the above-described tadalafil free base-containing solid dispersion include sodium lauryl sulfate or sodium dioctylsulfosuccinate, reaction products of natural or hydrogenated vegetable oils with ethylene glycol (polyoxyethylene glycolated natural or hydrogenated Polyoxyethylene sorbitan fatty acid esters (mono or trirauryl, esters of stearyl or oleyl (product name: Tween)), polyoxyethylene-polyoxypropylene (A product name: Myrj, Uniquema (trade name), manufactured by Mitsubishi Chemical Co., Ltd.), a polyoxyethylene ester (trade name: Myrj, Uniquema ) And mono-and di-esters of glycerol or free polyethylene glycols (product name: Gelucire, Gattefosse) It can be used a slow one. But are not limited to, at least one member selected from the group consisting of sodium lauryl sulfate, polyoxyethylene glycated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene-polyoxypropylene copolymer , And more preferably sodium lauryl sulfate can be used.

The solid dispersion of the present invention includes a pharmaceutically acceptable carrier (additive) in addition to the water-soluble polymer and the surfactant in order to improve the flowability (fluidity), physical properties, ease of handling and stability of the solid dispersion, The pharmaceutically acceptable carrier includes, but is not limited to, light anhydrous silicic acid, hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, titanium dioxide, aluminum silicate, calcium silicate, magnesium aluminum metasilicate, bentonite, And mixtures thereof. More preferably, light anhydrous silicic acid may be used.

Solvents which may be used to prepare the solution of step a) in the preparation of the solid dispersion containing tadalafil free base according to the present invention include, but are not limited to, water, ethanol, methylene chloride, acetone, acetonitrile, isopropyl Alcohols and mixtures thereof, and more preferably one or more selected from the group consisting of water, ethanol, acetone, methylene chloride, and mixtures thereof can be selected and used.

Drying methods that can be used in step b) to remove the solvent of the solution prepared in step a), when preparing the solid dispersion containing tadalafil free base according to the present invention, include, but are not limited to, The solvent may be removed from the solution by a spray drying method, a roller drying method, a solvent precipitation method, or a freeze drying method. The spray drying method is most preferable, and a fluidized bed granulator, a spray dryer, a C / F granulator and the like can be used for spray drying.

In yet another aspect, the present invention provides a tablet comprising a tadalafil free base-containing solid dispersion prepared by the above method as a first active ingredient; And a second active ingredient selected from the group consisting of sildenafil, vardenafil, udenafil, lodenafil, mirodenafil, avanafil and their pharmaceutically acceptable (PDE-5) inhibitor selected from the group consisting of a pharmaceutically acceptable salt, a hydrate, and a salt thereof.

The particle size (d _(0.9) ) of 90% or more of the particles of the tadalafil free base-containing solid dispersion used as the first active ingredient in the combined preparation may be 1 탆 to 100 탆, But may be 1 [mu] m to 50 [mu] m, and more preferably 1 [mu] m to 30 [mu] m. The particle size of tadalafil plays an important role in drug release and bioavailability, and an improved dissolution rate can be achieved when a tadalafil free base-containing solid dispersion having a d _(0.9) of less than 50 탆 is used in the combination preparation of the present invention (See Test Example 2 and Test Example 3).

In the present invention, the particle average particle size and particle size distribution of the solid dispersion containing the tadalafil free base can be measured using a commercially available apparatus based on the laser diffraction and scattering method based on the Mie theory as described above. For example, it can be measured using a commercially available apparatus such as a Helium-Neon-Laser Optical System (HELOS) optical diffraction particle size analyzer of Sympatec.

In addition, the PDE-5 (phosphodiesterase-5) inhibitor used as the second active ingredient in the combination preparation may be sildenafil, vardenafil, udenafil, lodenafil, and at least one PDE-5 inhibitor selected from the group consisting of mirodenafil, avanafil, and pharmaceutically acceptable salts thereof. Examples of pharmaceutically acceptable salts of the PDE-5 inhibitors include, but are not limited to, hydrobromide, phosphate, sulfate, hydrochloride, maleate, fumarate, lactate, tartrate, citrate, besylate, camsylate, gluconate, can, preferably sildenafil citrate salt and (sildenafil citrate, for example, Viagra ^® sildenafil citrate; Pfizer), vardenafil hydrochloride (vardenafil hydrochloride, for ^{example, Levitra ® vardenafil HCl; Schering-} Plough), Udenafil glass But are not limited to, udenafil free base, lodenafil carbonate, mirodenafil hydrochloride, and avanafil free base.

A tadalafil free base-containing solid dispersion as a first active ingredient; And at least one PDE-5 inhibitor selected from the group consisting of sildenafil, vardenafil, yudenapil, rodenavil, mirodenapil, avanapil, and pharmaceutically acceptable salts thereof as the second active ingredient. The formulation may further comprise at least one additive selected from the group consisting of pharmaceutically acceptable disintegrants, diluents, binders and glidants.

The disintegrant may be, but is not limited to, one or more disintegrants selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, starch, alginic acid, and sodium alginate.

The diluent may be, but is not limited to, one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch and calcium dihydrogenphosphate.

In addition, although the binder is not limited thereto, at least one binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and povidone may be used.

The lubricant may also include, but is not limited to, stearic acid metal salts, stearic acid metal salts such as calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, waxes, glyceryl fatty acid esters, And glycerol dibehenate may be used.

A tadalafil free base-containing solid dispersion as a first active ingredient; And at least one PDE-5 inhibitor selected from the group consisting of sildenafil, vardenafil, yudenapil, rodenavil, mirodenapil, avanapil, and pharmaceutically acceptable salts thereof as the second active ingredient. According to the particle size control of the tadalafil free base-containing solid dispersion which is the first active ingredient, the first active ingredient in which the water-soluble polymer, the surfactant and the tadalafil are uniformly dispersed and intermolecularly bonded, both the first active ingredient and the second active ingredient It is eluted by more than 80% within 15 minutes.

Specifically, in one embodiment of the present invention, in order to improve the solubility of tadalafil, which is a poorly soluble drug, and to improve the dissolution rate, tadalafil free base-containing solid dispersion was prepared using sodium laurylsulfate as a water-soluble polymer and a surfactant (Example 2-1), a composite preparation containing the above-mentioned tadalafil free base-containing solid dispersion having a d _(0.9) value of 29.8 占 퐉 as the first active ingredient and a sildenafil citrate salt as the second active ingredient was prepared ), The dissolution rate of tadalafil and sildenafil was analyzed. As a result, it was confirmed that both of tadalafil and sildenafil reached a high dissolution rate of 85% or more within 5 minutes after the start of elution (Test Example 3, FIG. 3 and FIG.

In addition, by measuring the time and efficacy duration of the efficacy of the combined preparation of tadalafil and sildenafil by using the albino rabbit, it was found that the onset time (effective onset time) of the sildenafil citrate (product of sildenafil citrate) ) Was much shorter and the erection duration was also significantly increased (Test Example 4 and Fig. 5).

In addition, the results of evaluating the side effects of the combined preparations containing tadalafil and sildenafil for the adult male patients over 20 years of age showed that compared to the volunteers who received Viagra and Pamela's Cialis tablets, , And side effects such as indigestion were scarcely caused (Test Example 5 and Table 21).

From these results, it is possible to achieve an improved dissolution rate and dissolution rate using the combined preparation of tadalafil and sildenafil of the present invention prepared by micronizing tadalafil, which is a poorly soluble drug, in the form of a solid dispersion, It is possible to effectively use it as an erectile dysfunction treatment agent because it not only has a superior effect of substituting for a therapeutic agent but also remarkably reduces side effects.

That is, as a first active ingredient, a tadalafil free base-containing solid dispersion; And at least one PDE-5 inhibitor selected from the group consisting of sildenafil, vardenafil, yudenapil, rodenavil, mirodenapil, avanapil, and pharmaceutically acceptable salts thereof as the second active ingredient. The above-described technical features of the preparation have an excellent erectile dysfunction therapeutic effect that can replace the existing erectile dysfunction treatment such as Viagra tablets and Cialis tablets.

The amount of each active ingredient can be reduced by lowering the minimum effective concentration (MEC) showing the PDE-5 inhibitory effect by causing the active ingredients to rapidly dissolve and being absorbed into the body, 5 suppresses the onset time through the synergistic effect of the inhibitory effect. Therefore, it is expected that the drug efficacy can be anticipated immediately after the administration of the combination preparation. In addition, the PDE- The above-mentioned effects can be expected to be sustained. Also, by reducing the amount of single active ingredient used, a reduction in the side effects seen with high dose, single component PDE-5 inhibitors can be expected.

The present invention also relates to a solid dispersion comprising a tadalafil free base as a first active ingredient; And at least one PDE-5 inhibitor selected from the group consisting of sildenafil, vardenafil, yudenapil, rodenavil, mirodenapil, avanapil, and pharmaceutically acceptable salts thereof as the second active ingredient. The present invention provides a method for treating a penile erectile dysfunction or a method for improving a penile erectile dysfunction by administering a therapeutically effective amount of the agent.

The term "therapeutically effective amount " as used herein refers to the amount of the combination preparation of the present invention effective in a method for treating erectile dysfunction or a method for improving erectile dysfunction of the penis.

Further, as a first active ingredient, a tadalafil free base-containing solid dispersion; And at least one PDE-5 inhibitor selected from the group consisting of sildenafil, vardenafil, yudenapil, rodenavil, mirodenapil, avanapil, and pharmaceutically acceptable salts thereof as the second active ingredient. The preparation can be prepared in various formulations and can be formulated into tablets, powders, granules, capsules or the like such as tablets, film-coated tablets, monolayer tablets, bi-layer tablets, multilayer tablets or trophic tablets.

The tadalafil free base-containing solid dispersion to be used as the first active ingredient in the combined preparation is 1.0 mg to 80.0 mg, preferably 2.5 mg, based on the unit dosage form (granule, capsule or tablet) of the combination preparation according to the present invention To 20.0 mg, and even more preferably from 5.0 mg to 10.0 mg. The above-mentioned content means an amount based on tadalafil in free form.

In the combined preparation, tadalafil as a first active ingredient may be administered in combination with a relatively small amount of 1.0 mg to 80.0 mg, preferably 2.5 mg to 20.0 mg, even more preferably 5.0 mg to 10.0 mg, It is easy to control the compounding ratio with the second active ingredient selected from the group consisting of sildenafil, vardenafil, idenafil, rodenavir, mirodenafil, avanapil and pharmaceutically acceptable salts thereof , And the size of the unit dosage form can be kept small. In addition, since tadalafil is more than 700 times more selective for PDE-6 than other PDE-5 inhibitors used as the second active ingredient, when used in a relatively small amount as described above, PDE- 6 side effects such as visual anomalies due to inhibition can be minimized.

A PDE-5 inhibitor used as a second active ingredient selected from the group consisting of sildenafil, vardenafil, yudenapil, rodenavir, mirodenapil, avanapil and their pharmaceutically acceptable salts in the combination preparation, Is used in an amount of from 2.5 mg to 200.0 mg, preferably from 2.5 mg to 150.0 mg, even more preferably from 5.0 mg to 150.0 mg, based on the unit dosage form (granule, capsule or tablet) of the combination preparation according to the invention .

Specifically, sildenafil is not limited thereto, but may be added in an amount of 10.0 mg to 100.0 mg, preferably 20.0 mg to 80.0 mg, more preferably 25.0 mg to 50.0 mg based on the unit dosage form of the combination preparation according to the present invention . The amounts described above refer to amounts based on the free-form siladropyl.

In addition, vardenafil may be used in an amount of 2.5 mg to 20.0 mg, preferably 5.0 mg to 10.0 mg, based on the unit dosage form of the combination preparation according to the present invention, although it is not limited thereto. The amounts described above refer to amounts based on vardenafil in free form.

In addition, the udenafil may be used in an amount of 25.0 mg to 200.0 mg, preferably 50.0 mg to 150.0 mg, based on the unit dosage form of the combination preparation according to the present invention, although it is not limited thereto. The amounts described above refer to amounts based on the free form of udenafil.

In addition, the rotenizil may be used in an amount of 10.0 mg to 80.0 mg, preferably 20.0 mg to 40.0 mg, based on the unit dosage form of the combination preparation according to the present invention, although it is not limited thereto. The amounts described above refer to amounts based on the free form of rhodamine.

In addition, the moloenafil may be used in an amount of 10.0 mg to 100.0 mg, preferably 25.0 mg to 50.0 mg, based on the unit dosage form of the combination preparation according to the present invention, though it is not limited thereto. The amounts described above refer to amounts based on the free form of mirodinafil.

In addition, the avanophil may be used in an amount of 25.0 mg to 200.0 mg, preferably 50.0 mg to 100.0 mg, based on the unit dosage form of the combination preparation according to the present invention, though not limited thereto. The amounts described above refer to amounts based on avanafil in free form.

The solubility and dissolution characteristics of tadalafil, which is an insoluble drug used as a first active ingredient of a pharmaceutical combination preparation containing two or more kinds of phosphodiesterase-5 inhibitors according to the present invention, By including one or more PDE-5 inhibitors selected from the group consisting of tadalafil and sildenafil, vadenapil, udenafil, rodeenafil, mirodenapil and avanafil in one single dosage form, the existing one, such as Viagra tablets and cialis tablets, Since it has a superior effect to replace the single-component erectile dysfunction treatment, that is, the onset time is fast, the duration of the effective effect is long, and the occurrence of side effect is also remarkably reduced, so that the erectile dysfunction treatment is synergistic. Can be usefully used for improvement.

1 is a graph showing solubility test results of tadalafil free base and tadalafil-containing solid dispersion of Examples 2-1 to 2-13, which were carried out according to Test Example 1 of the present invention.
Figure 2 shows the time course of tadalafil dissolution tests of a combination of a commercially available control formulation (Comparative Example 3; cialis tablet) and the combined preparations containing tadalafil and sildenafil prepared in Examples 4, 7 and 9, performed according to Test Example 2 of the present invention Fig.
FIG. 3 shows the results of a comparison between the control preparation (Comparative Example 1; combined preparation of tadalafil and sildenafil containing non-undifferentated tadalafil free base) and tadalafil prepared in Examples 4 and 9, The results are shown in Table 1. [Table 1] < tb >< TABLE >
Figure 4 shows the results of a comparison between the control formulation (Comparative Example 1; combined preparation of tadalafil and sildenafil containing non-micronized tadalafil free base) and tadalafil prepared in Examples 4 and 9, The results are shown in Table 1. [Table 1] < tb >< TABLE > Columns = 2 < tb >
FIG. 5 is a graph showing the results of a drug efficacy test showing the erectile state of albino rabbit, which was carried out according to Test Example 4 of the present invention, in which a commercially available control preparation (Comparative Example 2, Viagra tablets) and tadalafil and sildenafil containing preparations prepared in Example 4 FIG. 2 is a graph showing the increase in the length of the penis mucosa of a male albino rabbit over time after oral administration of the combination preparation. FIG.

Hereinafter, the constitution and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example  1: undifferentiated Tadalafil  Produce

To improve the solubility of the poorly soluble drug tadalafil, micronized tadalafil was prepared. Specifically, 100 g of a pure tadalafil free base having a particle size of at least 90% of 231.5 탆 (d _(0.9) = 231.5 탆) was pulverized using an air jet mill, Gt; free base of tadalafil. The particle size of the undifferentiated tadalafil free base obtained was measured using a light diffraction particle size analyzer (HELOS system (Helium-Neon Laser Optical System) from Sympatec) under the conditions of using a 100 mm lens and pneumatic injection of 2.0 bar As a result, it was confirmed that the value of d _(0.9) was 32.2 탆.

Example  2: Tadalafil  contain Of the solid dispersion  Produce

To improve the solubility of tadalafil, which is a poorly soluble drug, and to improve the dissolution rate, tadalafil - containing solid dispersions were prepared using water - soluble polymers and various surfactants.

Example  2-1: Tadalafil  contain Of the solid dispersion  Manufacturing 1

1 g of a tadalafil free base, 1 g of hydroxypropyl methylcellulose 2910 (HPMC 2910) as a water-soluble polymer, 0.2 g of sodium lauryl sulfate as a surfactant, 0.8 g of light anhydrous silicic acid was dissolved in 50 ml of purified water and 150 < RTI ID = 0.0 > Ml < / RTI > of acetone. This was spray-dried using a spray drier (Buchi, Mini Spray Dryer, B-191) to obtain a fine solid dispersion. The spray drying conditions were an inlet temperature of 65 ° C and an outlet temperature of 45 to 50 ° C, followed by drying at 60 ° C for about 2 hours to remove residual organic solvent. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 29.8 탆.

Example  2-2: Tadalafil  contain Of the solid dispersion  Manufacturing 2

Except that 0.2 g of Tween-20 was used as the surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 31.5 탆.

Example  2-3: Tadalafil  contain Of the solid dispersion  Manufacturing 3

Except that 0.2 g of tween 80 (tween-80) was used as the surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 24.5 占 퐉.

Example  2-4: Tadalafil  contain Of the solid dispersion  Manufacturing 4

Except that 0.2 g of labrasol was used as a surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 26.8 탆.

Example  2-5: Tadalafil  contain Of the solid dispersion  Manufacturing 5

Except that 0.2 g of Aconon MC8-2 (acconon MC8-2) was used as a surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 34.5 占 퐉.

Example  2-6: Tadalafil  contain Of the solid dispersion  Manufacturing 6

Except that 0.2 g of cremophor EL was used as a surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 41.5 탆.

Example  2-7: Tadalafil  contain Of the solid dispersion  Manufacturing 7

Except that 0.2 g of cremophor ELP (surfactant) was used as the surfactant, The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 35.6 탆.

Example  2-8: Tadalafil  contain Of the solid dispersion  Manufacturing 8

Except that 0.2 g of cremophor RH40 (surfactant) was used as the surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 20.4 탆.

Example  2-9: Tadalafil  contain Of the solid dispersion  Manufacturing 9

Except that 0.2 g of Cremophor RH60 (surfactant) was used as the surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 37.5 탆.

Example  2-10: Tadalafil  contain Of the solid dispersion  Manufacturing 10

Except that 0.2 g of cremophor A25 was used as a surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 42.5 탆.

Example  2-11: Tadalafil  contain Of the solid dispersion  Manufacturing 11

Except that 0.2 g of Solutol HS15 (surfactant) was used as the surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 31.0 탆.

Example  2-12: Tadalafil  contain Of the solid dispersion  Manufacturing 12

Except that 0.2 g of plurol diisostearic was used as the surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle size of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 25.6 탆.

Example  2-13: Tadalafil  contain Of the solid dispersion  Manufacturing 13

Except that 0.2 g of floxamer 407 (poloxamer 407) was used as the surfactant. The same procedure and the same conditions as in Example 2-1 were repeated to prepare a tadaparax-containing solid dispersion. The average particle diameter of the prepared tadalafil-containing solid dispersion was measured in the same manner as in Example 1, and it was confirmed that the value of d _(0.9) was 38.5 탆.

In Example 2-1, sodium lauryl sulfate used as a surfactant was changed to another surfactant, and as shown in Examples 2-2 to 2-13, various dispersions of various tadalafil-containing solid dispersions The compositions of the tadalafil-containing solid dispersions prepared in Examples 2-1 to 2-13 were compared and summarized in Table 1 below.

Example  3: Tadalafil  ≪ RTI ID = 0.0 > 1 < / RTI >

30.0 mg (content corresponding to 10.0 mg as tadalafil free base) of the tadalafil solid dispersion prepared in Example 2-1 and 70.2 mg of sildenafil citrate (content corresponding to 50.0 mg as sildenafil free base ), 187.8 mg of mannitol, 80.0 mg of microcrystalline cellulose, 12.0 mg of hydroxypropyl methylcellulose (HPMC), 8.0 mg of sodium starch glycolate and 8.0 mg of crospovidone Were passed through a No. 20 sieve, placed in a V-type mixer, and mixed for 30 minutes. 4.0 mg of magnesium stearate was added as a lubricant and mixed for 5 minutes. The resultant mixture powder was tableted so that the hardness of the tablet was about 10 KP using a single-handed tableting machine (ERWEKA, EP-1) to prepare tadalafil and sildenafil Was prepared.

Compositions of the combined preparation of tadalafil and sildenafil prepared as described above are summarized in Table 2 below.

Mixing portion ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Mannitol (diluent) 187.8 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder) 12.0 mg Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  4: Tadalafil  ≪ RTI ID = 0.0 > 2 < / RTI &

30.0 mg (content corresponding to 10.0 mg as tadalafil free base) of the tadalafil solid dispersion prepared in Example 2-1 and 70.2 mg of sildenafil citrate (content corresponding to 50.0 mg as sildenafil free base ), Mannitol (187.8 mg), microcrystalline cellulose (80.0 mg), sodium starch glycolate (8.0 mg) and crospovidone (8.0 mg) were mixed and then 120.0 mg of hydroxypropylcellulose (hydroxypropyl methylcellulose, HPMC) dissolved in 12.0 ㎎ of water was used for wet granulation and then sieved with a No. 20 sieve. 4.0 mg of magnesium stearate was added as a lubricant and mixed for 5 minutes. The resultant mixture powder was tableted so that the hardness of the tablet was about 10 KP using a single-handed tableting machine (ERWEKA, EP-1) to prepare tadalafil and sildenafil Was prepared.

The composition of the combined preparation of tadalafil and sildenafil prepared as described above is summarized in Table 3 below.

Granules of tadalafil and sildenafil ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Mannitol (diluent) 187.8 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  5: Tadalafil  And preparation of a complex preparation containing sildenafil 3

The granules of tadalafil and sildenafil were prepared according to the composition ratios shown in Table 4 below.

Tadalafil granule part ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Mannitol (diluent) 100.0 mg Microcrystalline cellulose (diluent) 40.0 mg Hydroxypropylcellulose (binder)
(Purified water) 6.0 mg
(80.0 mg of purified water) Starch glycolate sodium (disintegrant) 4.0 mg Crospovidone (disintegrating) 4.0 mg Sildenafil granule part Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Mannitol (diluent) 87.8 mg Microcrystalline cellulose (diluent) 40.0 mg Hydroxypropylcellulose (binder)
(Purified water) 6.0 mg
(80.0 mg of purified water) Starch glycolate sodium (disintegrant) 4.0 mg Crospovidone (disintegrating) 4.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Specifically, as shown in Table 4, 6.0 mg of hydroxypropyl methylcellulose (HPMC) in a composition of tadalafil granules was dissolved in purified water (80.0 mg) to prepare a binding solution. Using the binding solution prepared as described above, A mixture of 30.0 mg of tadalafil solid dispersion prepared in Example 2-1 (content corresponding to 10.0 mg of tadalafil free base) and the remaining excipient was wet-granulated and then sieved with a No. 20 sieve and dried to prepare a tadalafil granule .

As shown in Table 4, 6.0 mg of hydroxypropyl methylcellulose (HPMC) in the composition of sildenafil granules was dissolved in 80.0 mg of purified water to prepare a binding solution. Using the binding solution prepared as described above, a sildenafil The mixture of sildenafil citrate (70.0 mg) (corresponding to 50.0 mg as sildenafil free base) and the remaining excipient was wet-granulated and then sieved with a No. 20 sieve and dried to prepare sildenafil granules separately.

Each of the granules thus prepared was placed in a V-type mixer and mixed for 30 minutes. 4.0 mg of magnesium stearate was added thereto as a lubricant and mixed for 5 minutes. The resultant mixture was stirred and mixed with a single-screw tabletting machine (ERWEKA , EP-1) was used to prepare a complex preparation containing tadalafil and sildenafil by tableting so that the hardness of the tablet was about 10 KP.

Example  6: Tadalafil  ≪ RTI ID = 0.0 > 4 < / RTI >

In the same manner as in Example 5, the final mixture prepared according to the contents of Table 4 was filled into No. 0 size hard capsules to prepare a combined preparation containing hard capsules of tadalafil and sildenafil.

Example  7: Tadalafil  ≪ RTI ID = 0.0 > 5 < / RTI >

The granules of tadalafil and sildenafil were each prepared in the same manner as in Example 5, and then 2.0 mg of magnesium stearate was added to each of granules To prepare a tadalafil mixed portion and a silnadevil mixed portion, respectively. A complex preparation containing two-layer tabadal form of tadalafil and sildenafil was prepared by using the prepared tadalafil mixed portion as a single layer and the sildenafil mixed portion as two layers.

The composition of the combined preparation of tadalafil and sildenafil prepared as described above is summarized in Table 5 below.

Tadalafil granule part ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Mannitol (diluent) 100.0 mg Microcrystalline cellulose (diluent) 40.0 mg Hydroxypropylcellulose (binder)
(Purified water) 6.0 mg
(80.0 mg of purified water) Starch glycolate sodium (disintegrant) 4.0 mg Crospovidone (disintegrating) 4.0 mg Final mixing Magnesium stearate (lubricant) 2.0 mg Sildenafil granule part Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Mannitol (diluent) 87.8 mg Microcrystalline cellulose (diluent) 40.0 mg Hydroxypropylcellulose (binder)
(Purified water) 6.0 mg
(80.0 mg of purified water) Starch glycolate sodium (disintegrant) 4.0 mg Crospovidone (disintegrating) 4.0 mg Final mixing Magnesium stearate (lubricant) 2.0 mg Total weight 400.0 mg / tablet

Example  8: Tadalafil  ≪ RTI ID = 0.0 > 6 < / RTI &

The granules of tadalafil were prepared in the same manner as in Example 5, and then mixed with sildenafil citrate as a sildenafil citrate and the remaining excipients in a V-type mixer according to the composition ratio shown in Table 6 below, followed by mixing for 30 minutes. Then, 4.0 mg of magnesium stearate was added as a lubricant, and the mixture was stirred for 5 minutes. Then, the resulting mixed powder was tableted so that the hardness of the tablet was about 10 KP using a single-screw tablet machine (ERWEKA, EP-1) And sildenafil were prepared.

Tadalafil granule part ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Mannitol (diluent) 100.0 mg Microcrystalline cellulose (diluent) 40.0 mg Hydroxypropylcellulose (binder)
(Purified water) 6.0 mg
(80.0 mg of purified water) Starch glycolate sodium (disintegrant) 4.0 mg Crospovidone (disintegrating) 4.0 mg Sildenafil mixed portion Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Mannitol (diluent) 87.8 mg Microcrystalline cellulose (diluent) 40.0 mg Hydroxypropylcellulose (binder) 6.0 mg Starch glycolate sodium (disintegrant) 4.0 mg Crospovidone (disintegrating) 4.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  9: Tadalafil  ≪ RTI ID = 0.0 > 7 < / RTI >

10.0 mg of undifferentiated tadalafil free base prepared in Example 1, 70.2 mg of sildenafil citrate (content corresponding to 50.0 mg as sildenafil free base), sodium lauryl sulfate sodium lauryl sulfate (1.0 mg), mannitol (206.8 mg), microcrystalline cellulose (80.0 mg), sodium starch glycolate (8.0 mg) and crospovidone (8.0 mg) And 12.0 mg of hydroxypropyl methylcellulose (HPMC), and the mixture was wet granulated and then sieved with a No. 20 sieve. 4.0 mg of magnesium stearate was added as a lubricant and mixed for 5 minutes. The resultant mixture powder was tableted so that the hardness of the tablet was about 10 KP using a single-handed tableting machine (ERWEKA, EP-1) to prepare tadalafil and sildenafil Was prepared.

The composition of the combined preparation of tadalafil and sildenafil prepared as described above is summarized in Table 7 below.

Granules of tadalafil and sildenafil ingredient Content (mg / 1 tablet) The undifferentiated tadalafil free base of Example 1 10.0 mg Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Sodium lauryl sulfate (surfactant) 1.0 mg Mannitol (diluent) 206.8 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  10: Tadalafil  ≪ RTI ID = 0.0 > 8 < / RTI >

15.0 mg (corresponding to 5.0 mg as tadalafil free base) of the tadalafil solid dispersion prepared in Example 2-1 and 70.2 mg of sildenafil citrate (content corresponding to 50.0 mg as sildenafil free base ), Mannitol (202.8 mg), microcrystalline cellulose (80.0 mg), sodium starch glycolate (8.0 mg) and crospovidone (8.0 mg) were mixed together and then 120.0 mg of hydroxypropylcellulose (hydroxypropyl methylcellulose, HPMC) dissolved in 12.0 ㎎ of water was used for wet granulation and then sieved with a No. 20 sieve. 4.0 mg of magnesium stearate was added as a lubricant and mixed for 5 minutes. The resultant mixture powder was tableted so that the hardness of the tablet was about 10 KP using a single-handed tableting machine (ERWEKA, EP-1) to prepare tadalafil and sildenafil Was prepared.

Compositions containing the prepared tadalafil and sildenafil were summarized in Table 8 below.

Granules of tadalafil and sildenafil ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 15.0 mg
(5.0 mg) Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Mannitol (diluent) 202.8 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  11: Tadalafil  ≪ RTI ID = 0.0 > 9 < / RTI >

A complex preparation containing 10.0 mg of tadalafil free base and 25.0 mg of sildenafil free base was prepared in the same manner as in Example 10, according to the composition ratio shown in Table 9 below.

Granules of tadalafil and sildenafil ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Sildenafil citrate salt
(As sildenafil free base) 35.1 mg
(25.0 mg) Mannitol (diluent) 222.9 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  12: Tadalafil  And Vardenafil  ≪ RTI ID = 0.0 > 10 &

A composite preparation containing 10.0 mg of tadalafil free base and 10.0 mg of vadapapil free base was prepared in the same manner as in Example 10, according to the composition ratio shown in Table 10 below.

Granules of tadalafil and vardenafil ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Vardenafil hydrochloride
(As vardenafil free base) 11.9 mg
(10.0 mg) Mannitol (diluent) 246.1 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  13: Tadalafil  And Vardenafil  ≪ RTI ID = 0.0 > 11 &

A complex formulation containing 5.0 mg of tadalafil free base and 10.0 mg of vadapadil free base was prepared in the same manner as in Example 10, according to the composition ratio shown in Table 11 below.

Granules of tadalafil and vardenafil ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 15.0 mg
(5.0 mg) Vardenafil hydrochloride
(As vardenafil free base) 11.9 mg
(10.0 mg) Mannitol (diluent) 261.1 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  14: Tadalafil  And Avana phil  ≪ RTI ID = 0.0 > 12 &

A complex formulation containing 10.0 mg of tadalafil free base and 100.0 mg of Avanafil free base was prepared in the same manner as in Example 10, according to the composition ratio shown in Table 12 below.

Granules of tadalafil and avanabel ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 30.0 mg
(10.0 mg) Avanafil free base 100.0 mg Mannitol (diluent) 158.0 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Example  15: Tadalafil  And Avana phil  ≪ RTI ID = 0.0 > 13 &

A complex preparation containing 5.0 mg of tadalafil free base and 100.0 mg of Avanafil free base was prepared in the same manner as in Example 10, according to the composition ratio shown in Table 13 below.

Granules of tadalafil and avanabel ingredient Content (mg / 1 tablet) The tadalafil solid dispersion of Example 2-1
(As tadalafil free base) 15.0 mg
(5.0 mg) Avanafil free base 100.0 mg Mannitol (diluent) 173.0 mg Microcrystalline cellulose (diluent) 80.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Crospovidone (disintegrating) 8.0 mg Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

The compositions and characteristics of the combined preparations prepared in Examples 3 to 15 are summarized in Table 14 below.

Comparative Example  One: Tadalafil  And preparation of a complex preparation containing sildenafil 14

10.0 mg of an undifferentiated tadalafil free base having a particle size of 90% or more of 231.5 占 퐉 (d _(0.9) = 231.5 占 퐉), 70.2 mg of sildenafil citrate (50.0 mg of sildenafil citrate as a sildenafil free base) Hydroxypropyl methylcellulose (HPMC) was added to purified water (120.0 mg), followed by the addition of 100 mg of lactose, 95.0 mg of lactose, 200.0 mg of microcrystalline cellulose, and 8.0 mg of sodium starch glycolate. 12.0 mg, and the mixture was wet granulated and then sieved with a No. 20 sieve. 4.0 mg of magnesium stearate was added as a lubricant and mixed for 5 minutes. The resultant mixture powder was tableted so that the hardness of the tablet was about 10 KP using a single-handed tableting machine (ERWEKA, EP-1) to prepare tadalafil and sildenafil Was prepared.

Compositions containing the prepared tadalafil and sildenafil were summarized in Table 15 below.

Granules of tadalafil and sildenafil ingredient Content (mg / 1 tablet) Undifferentiated tadalafil free base 10.0 mg Sildenafil citrate salt
(As sildenafil free base) 70.2 mg
(50.0 mg) Lactose (Thinner) 95.8 mg Microcrystalline cellulose (diluent) 200.0 mg Hydroxypropylcellulose (binder)
(Purified water) 12.0 mg
(Purified water 120.0 mg) Starch glycolate sodium (disintegrant) 8.0 mg Final mixing Magnesium stearate (lubricant) 4.0 mg Total weight 400.0 mg / tablet

Comparative Example  2: commercially available single formulation 1

Viagra tablets (50.0 mg / tablet as sildenafil free base, Pfizer, USA), a commercially available sildenafil citrate product, was used as a comparative example.

Comparative Example  3: commercially available formulations 2

A commercially available tadalafil product, cialis tablet (20.0 mg / tablet as tadalafil free base, Lilly, USA) was used as a comparative example.

Test Example  One: Tadalafil  contain Of the solid dispersion  Solubility analysis

In order to improve the solubility of tadalafil, which is a poorly soluble drug, and to improve the dissolution rate, it is preferable that 90% or more of the particles prepared by using the water-soluble polymer and various surfactants in the above Examples 2-1 to 2-13 A solubility test was conducted on a tadalafil-containing solid dispersion having a particle size of less than 50.0 占 퐉 (d _(0.9) = 50.0 占 퐉). At this time, an undifferentiated tadalafil free base having a d _(0.9) value of 231.5 쨉 m was used as a control group.

Specifically, a non-undifferentiated tadalafil free base and each of the tadalafil-containing solid dispersions prepared in Examples 2-1 to 2-13 were dissolved in 1.5 ml of purified water in an amount of 10 mg as a tadalafil free base After the dose, the mixture was stirred at 25 캜 for 7 days. Seven days after the agitation, each purified water containing tadalafil was centrifuged (10,000 rpm, 10 minutes), and the supernatant obtained by centrifugation was filtered using a 0.45 μm pore size nylon filter. Under the analysis conditions shown in Table 16 below, the concentration of talarophil dissolved in the filtered solution was measured.

Analysis conditions of HPLC column A stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm was placed in a column packed with octadecyl silica gel for liquid chromatography having a particle diameter of 5 占 퐉 Mobile phase Methanol: purified water (50:50, v / v) Detector Ultraviolet absorption spectrophotometer (measuring wavelength 225 nm) Flow rate 2.0 ml / min Dose 50 μl

The solubility of each of the tadalafil-containing solid dispersions was analyzed by measuring the concentration of tadalafil dissolved in the filtered solution. As a result, it was found that the solubilities of the tadalafil-containing solid dispersions in Examples 2-1 to 2- It was confirmed that the solubility of the tadalafil-containing solid dispersion obtained in Example 13 was remarkably excellent. In particular, the tadalafil-containing solid dispersion obtained in Example 2-1 using sodium laurylsulfate as a surfactant had a solubility of about 1,600 占 퐂 / ml Indicating high water solubility. In contrast, unlabeled tadalafil free base exhibited low solubility of less than 1 g / ml (Fig. 1).

From the above results, it was found that the solubility of tadalafil, which is a poorly soluble drug, can be remarkably improved by preparing a solid dispersion containing tadalafil having a particle size of less than 50.0 쨉 m using a water-soluble polymer and various surfactants, , And the solubility of tadalafil-containing solid dispersion prepared using sodium lauryl sulfate as a surfactant was remarkably excellent.

Thus, in Examples 3 to 15, in order to improve the bioavailability and safety of the drug by improving the dissolution rate, the combination preparation exhibiting a remarkably excellent effect in erectile dysfunction treatment, The tadalafil-containing solid dispersion of Example 2-1 having a particle size of 29.8 占 퐉 and the PED-5 (phosphodiesterase-5) inhibitor exhibiting a solubility far superior to the undifferentiated tadalafil free base of Example 1, (Sildenafil, vardenafil, or avanafil), and the combination preparation was prepared in the form of preparations such as single-layer tablet, double-layer tablet, hard capsule, etc. (Table 14).

In the following Test Examples 2 to 5, the dissolution rate, the effect of the erectile dysfunction treatment, and side effects of the combined preparation of tadalafil and sildenafil prepared in Example 4, Example 7 and Example 9 were analyzed.

Test Example  2: Tadalafil  And sildenafil-containing combination preparation Tadalafil  Comparative analysis of dissolution rate

Comparative elution tests were conducted to investigate the increase in the release of tadalafil in the combination preparations containing tadalafil and sildenafil prepared in Examples 4, 7 and 9. At this time, cialis tablets (Comparative Example 3), a product of tadalafil available from Lilys, were used as a control agent.

Specifically, 30.0 mg (content equivalent to 10 mg of tadalafil free base) of the tadalafil solid dispersion of Example 2-1 and 70.2 mg of sildenafil citrate (content of sildenafil free base equivalent to 50.0 mg ), The combined preparation of Example 4 prepared in the form of a simultaneous granulation method and a single layer definition, 30.0 mg of the tadalafil solid dispersion of Example 2-1 (content corresponding to 10 mg as tadalafil free base) and sildenafil citrate The composite preparation of Example 7 prepared by the separate granulation method and the two-layered form including 70.2 mg of sildenafil citrate (corresponding to 50.0 mg of sildenafil free base), and the undifferentiated tadalafil free base of Example 1 10.0 mg and sildenafil citrate 70.2 mg (content equivalent to 50.0 mg as sildenafil free base) in a simultaneous granulation method and in a single layer definition Using a combined preparation of viscous Example 9 was compared to the dissolution rate of tadalafil in the purified water. Tadalafil elution conditions and tadalafil analysis conditions were performed as shown in Table 17 below.

Elution condition Eluent Purified water, 900 ml Device United States Pharmacopeia paddle method, 50 rpm Temperature 37 ℃ Analysis condition column A stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm was placed in a column packed with octadecyl silica gel for liquid chromatography having a particle diameter of 5 占 퐉 Mobile phase Methanol: purified water (50:50, v / v) Detector Ultraviolet absorption spectrophotometer (measuring wavelength 225 nm) Flow rate 2.0 ml / min Dose 50 μl

The dissolution rates of tadalafil in the complex preparations containing tadalafil and sildenafil obtained in Examples 4, 7 and 9 were compared and analyzed. As a result, the tadalafil-containing solid dispersion of Example 2-1 having a particle size of 29.8 탆 was included , And the combined preparation of Example 9, which was prepared with the undifferentiated tadalafil free base of Example 1 having a particle size of 32.2 占 퐉, had a cialis stage schedule (Comparative Example 3), and it was confirmed that the dissolution rate of tadalafil was higher than 70% at 60 minutes. In particular, the dissolution rate of tadalafil in the combination preparation of Example 4 and Example 7, which had been prepared with the tadalafil-containing solid dispersion of Example 2-1, showed a fast dissolution rate at a high dissolution rate of 85% or more at 15 minutes Respectively. On the contrary, it was confirmed that the schedule of the cialis stage of the control preparation maintained a low dissolution rate of only about 25% until 60 minutes (FIG. 2).

From the above results, it can be seen that the rate of dissolution of tadalafil in the combination preparation of tadalafil and silderafil of the present invention prepared by micronizing the poorly soluble drug particle of tadalafil to a level of 50 쨉 m or less is significantly higher than that of commercially available tadalafil there was.

Test Example  3: Tadalafil  And for sildenafil-containing combination preparations Tadalafil  And sildenafil

Comparative elution tests were conducted to examine the dissolution profiles of tadalafil and sildenafil in the combined preparation of tadalafil and sildenafil prepared in Examples 4 and 9 above. At this time, as the control agent, the combined preparation of tadalafil and sildenafil containing the non-undifferentiated tadalafil free base of particle size of 231.5 占 퐉 (d _(0.9) = 231.5 占 퐉) having a particle size of 90% or more was used .

Specifically, 30.0 mg (content equivalent to 10 mg of tadalafil free base) of the tadalafil solid dispersion of Example 2-1 and 70.2 mg of sildenafil citrate (content of sildenafil free base equivalent to 50.0 mg ), The combined preparation of Example 4 prepared in the form of a simultaneous granulation method and a single layer definition, and 10.0 mg of the undifferentiated tadalafil free base of Example 1 and 70.2 mg of sildenafil citrate as a sildenafil free base 50.0 mg), and the combined preparation of Example 9, which was prepared in the form of a single-layered formulation, using a single formulation of tadalafil and a single formulation of sildenafil (FDA (food and drug administration) dissolution method ), Respectively. The dissolution rates of tadalafil and sildenafil were analyzed according to the tadalafil elution conditions and tadalafil elution conditions and the sildenafil elution conditions and sildenafil elution conditions in Table 19 below, respectively.

Tadalafil elution condition Eluent 0.5% sodium lauryl sulfate solution, 1,000 ml Device United States Pharmacopeia paddle method, 50 rpm Temperature 37 ℃ Tadalafil assay conditions column A stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm was placed in a column packed with octadecyl silica gel for liquid chromatography having a particle diameter of 5 占 퐉 Mobile phase Methanol: purified water (50:50, v / v) Detector Ultraviolet absorption spectrophotometer (measuring wavelength 225 nm) Flow rate 2.0 ml / min Dose 50 μl

Sildenafil elution condition Eluent 0.01 M hydrochloric acid (HCl), 900 ml Device United States Pharmacopeia paddle method, 50 rpm Temperature 37 ℃ Sildenafil analysis conditions column A stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm was placed in a column packed with octadecyl silica gel for liquid chromatography having a particle diameter of 5 占 퐉 Mobile phase 0.05 M triethylamine (pH adjusted with phosphoric acid, pH 3.0): methanol: acetonitrile (580: 250: 170, v / v) Detector Ultraviolet absorption spectrophotometer (measurement wavelength: 290 nm) Flow rate 1.0 ml / min Dose 50 μl

The dissolution ratios of tadalafil and sildenafil to the combined preparations containing tadalafil and sildenafil prepared in Examples 4 and 9 were compared and compared to found that the tadalafil-containing solid dispersion of Example 2-1 having a particle size of 29.8 탆 contained , And the composite preparation of Example 9, which was prepared containing the undifferentiated tadalafil free base of Example 1 having a particle size of 32.2 占 퐉, were mixed with undiluted tadalafil free base used as a control preparation The dissolution rate of tadalafil and sildenafil was very fast and the dissolution rate was remarkably high as compared with the combined preparation of tadalafil and sildenafil prepared in Comparative Example 1, Furthermore, it was confirmed that both of tadalafil and sildenafil reached a high dissolution rate of 85% or more within 5 minutes after the start of elution in the combination preparation of Example 4 and Example 9. [ In contrast, the combination preparation of Comparative Example 1, which was a control preparation, exhibited a significantly lower dissolution rate than that of the combination preparations of Example 4 and Example 9, and it was also confirmed that the dissolution was not completed even after 60 minutes 3 and 4).

From the above results, the dissolution rate and dissolution rate of tadalafil and sildenafil for the combined preparation of tadalafil and silderafil of the present invention prepared by micronizing the particle size of tadalafil, which is a poorly soluble drug, to the level of 50 m or less, (Comparative Example 1) containing tadalafil and sildenafil prepared with free base (Comparative Example 1).

Test Example  4: Albino Rabbit  The present invention Tadalafil  And sildenafil-containing combination preparation,

Through the above Test Example 2 and Test Example 3, 30.0 mg (content equivalent to 10 mg as tadaraic acid free base) of the tadalafil solid dispersion of Example 2-1 and 70.2 mg of sildenafil citrate (sildenafil free base , The rate of dissolution of tadalafil in the combination preparation of Example 4 prepared by the simultaneous granulation method and the monolayer-defined form including the amount corresponding to 50.0 mg was remarkably increased compared with commercial tadalafil products, and the dissolution rate and dissolution rate of tadalafil and sildenafil Was significantly increased compared to the combined preparation of tadalafil and sildenafil (Comparative Example 1), which was prepared containing non-undifferentiated tadalafil free base.

Based on the above results, the efficacy of the combination preparation of Example 4 of the present invention and the duration of the drug efficacy in vivo were measured. At this time, Viagra tablets (Comparative Example 2), a product of sildenafil citrate, commercially available from Pfizer Inc., was used as the control agent.

Specifically, as experimental animals, six male Sprague-Dawley male New Zealand albino rabbits (body weight: about 3.5 to 4.0 kg, Samutoco, Korea) were used per test group, and they were weighed in the same condition for 4 days or more, And solid feed and water. The rabbit was fasted for 48 hours or more and used for the test.

The combined preparation of Example 4 of the present invention was administered to the prepared rabbit in an amount of 5 mg as tadalafil free base and 25 mg as sildenafil free base in the oral cavity. On the other hand, the Viagra tablets of Comparative Example 2 were orally administered in an amount of 50 mg as sildenafil free base per mouse. The erection start time and duration were measured after administration.

As a result of measuring the erection start time and the duration time after the Viagra tablets were administered as described above and the combination preparation of Example 4 of the present invention as described above, as shown in the following Table 20 and FIG. 5, When the combination preparation of Example 4 of the present invention was administered, erection started about 2.5 to 5 minutes. When the Viagra tablet of Comparative Example 2 was administered, erection started about 5 to 7.5 minutes, Compared with Viagra, I found that the erectile start time was faster. In addition, when the combination preparation of Example 4 of the present invention was administered, the maximum erection was performed for about 10 minutes, whereas when the control preparation, Viagra, was administered, the maximum erection occurred about 20 minutes. Thus, it was found that the onset time of the pharmaceutical composition was much shorter when the combination preparation of Example 4 of the present invention was administered than when the Viagra tablets were administered.

When the combination preparation of Example 4 of the present invention was administered, the erectile state was maintained for about 360 minutes in the erection state, but no erection was observed after 120 minutes when the control preparation, Viagra, was administered I did. Thus, it was found that the erection holding time was much longer when the combination preparation of Example 4 of the present invention was administered, as compared with the case of administration of Viagra tablets, which is the reference preparation.

Evaluation items Example 4 Comparative Example 2 Dose Tadalafil (5 mg) and sildenafil (25 mg) / mari Sildenafil (50 mg) / grains Erection start time About 2.5 to 5 minutes About 5 to 7.5 minutes Maximum erection time 10 minutes 20 minutes Erection hold time 360 minutes 120 minutes

The above results show that the onset time of the combined preparation of tadalafil and sildenafil of the present invention against albino rabbits is much shorter than that of commercially available sildenafil citrate product Viagra tablets, The duration was also significantly increased. Accordingly, the combined preparation of tadalafil and sildenafil of the present invention prepared by micronizing the particle size of tadalafil, which is a poorly soluble drug, to a level of 50 쨉 m or less has an excellent effect to replace the conventional erectile dysfunction treatment, It can be seen that

Test Example  5: Tadalafil  And Side Effects of Sildenafil Combined Preparations

Through the above Test Example 4, 30.0 mg (corresponding to 10 mg of tadalafil free base) and 70.2 mg of sildenafil citrate (50.0 mg as sildenafil free base) of the tadalafil solid dispersion of Example 2-1 (Comparative Example 2), which is a commercially available erectile dysfunction treatment agent, was compared with that of the combination preparation of Example 4, which was prepared in the form of a simultaneous granulation method and a single layer definition, And the duration of erection was also significantly increased.

Based on these results, clinical trials were conducted using the combination preparation of Example 4 of the present invention to evaluate the side effects. At this time, Viagra tablets (Comparative Example 2), which is commercially available from Pfizer Inc., and Cialis Tablets (Comparative Example 3), which is commercially available from Lilly Co., Ltd., were used as a control agent for erectile dysfunction.

Specifically, the subjects were 30 healthy male adult applicants aged 20 years or older and randomly selected 10 persons for each group. The first group was administered with the combined preparation of Example 4 of the present invention (10 mg of tadalafil free base, And 50 mg of sildenafil free base), and as a single formulation of PDE-5 (phosphodiesterase-5) inhibitor, the second group consisted of Viagra tablets (100 mg as sildenafil free base; 50 mg of sildenafil free base (Comparative Example 2)) was orally administered. In Group 3, cialis tablets (20 mg as tadalafil free base (Comparative Example 3)) were orally administered to evaluate side effects. Adverse drug reactions were assessed by the percentage of adverse reactions occurring within 24 hours after each drug administration.

As shown in the following Table 21, in the group of the patients who received the combination preparation of Example 4 of the present invention, the rate of adverse reactions occurred within 24 hours after administration of the drugs, It was confirmed that the side effects did not occur except for the results showing temporal abnormalities. However, in the case of the applicants who received the Viagra tablets (Comparative Example 2), which is marketed by Pfizer Inc. as an erectile dysfunction treatment, and the cialis tablets (Comparative Example 3), which is commercially available from Lilys, there are cases of facial flushing, headache, chest pain, indigestion, , Diarrhea, eye irritation, visual impairment and nasal congestion were significantly higher than those of the group administered with the combination preparation of Example 4 of the present invention. In particular, the proportion of the candidates who showed facial flushing was very high . These results show that the combination preparation of Example 4 of the present invention reduces the incidence of any adverse medical effects compared with the single dosage form of PDE-5 inhibitor alone.

Test group Example 4 Comparative Example 2 (Viagra Tablet) Comparative Example 3 (Cialis tablet) Dose Tadalafil (10 mg) and sildenafil (50 mg) mg / person Sildenafil (100 mg) / person Tadalafil (20 mg) / person Side effect ratio (person / group) Facial flushing One 5 4 headache 0 2 2 Chest pain 0 3 3 Indigestion 0 2 2 Heart palpitations 0 2 One diarrhea 0 One 2 Ocular congestion 0 2 One Temporal time error One 3 One Necrotic 0 2 2

Through the results of the series of the above test examples, the combination preparation of two or more PDE-5 inhibitors such as tadalafil and sildenafil of the present invention prepared by micronizing the poorly soluble drug of tadalafil to a level of 50 쨉 m or less, It has not only excellent effect of replacing conventional erectile dysfunction drugs such as cilostazol, cilostazol, and cialis but also remarkably reduces side effects.

Claims (17)

delete delete delete delete delete delete delete delete a) tadalafil free base; A water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, polyvinyl alcohol, hydroxyethylcellulose, polyvinylpyrrolidone, and mixtures thereof; Sodium lauryl sulfate as a surfactant; And preparing a solution in which a pharmaceutically acceptable carrier is dissolved;
b) spray drying the solution of step a) to prepare a tadalafil free base-containing solid dispersion having a particle size (d _(0.9) ) of 25 to 35 탆 as a first active ingredient; And
c) preparing and wetting a wet granulation comprising the solid dispersion of step b), sildenafil and its pharmaceutically acceptable salts, diluents, disintegrants, binders and lubricants as a second active ingredient; Wherein the dissolution rate of the first active ingredient and the second active ingredient is 80% or more within 15 minutes.
10. The composition of claim 9, wherein the pharmaceutically acceptable carrier is selected from the group consisting of light anhydrous silicic acid, hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, titanium dioxide, aluminum silicate, calcium silicate, magnesium aluminum metasilicate, bentonite, Wherein the dissolution rate of the first active ingredient and the second active ingredient is 80% or more within 15 minutes.
A solid dispersion containing a tadalafil free base as a first active ingredient, a sildenafil and a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a binder and a lubricant as a second active ingredient, Wherein the dissolution rate of the first active ingredient and the second active ingredient is 80% or more within 15 minutes.
delete delete delete delete The pharmaceutical composition according to claim 11, wherein the first active ingredient is contained at 2.5 mg to 20.0 mg in the unit dosage form and the second active ingredient is contained at 2.5 mg to 200.0 mg in the unit dosage form. 2 The dissolution rate of the active ingredient is 80% or more within 15 minutes.
12. The composition of claim 11, wherein the disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, starch, alginic acid, and sodium alginate; Wherein the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch and calcium dihydrogenphosphate; Wherein the binding agent is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and povidone; Characterized in that the lubricant is selected from the group consisting of stearic acid, stearic acid metal salts, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, waxes, glyceryl fatty acid esters and glycerol dibehenate. Wherein the dissolution rate of the second active ingredient is 80% or more within 15 minutes.

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