Patent Description:
Erectile dysfunction and benign prostatic hyperplasia are diseases common to males in their <NUM>'s or older. Erectile dysfunction is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance due to various causes including cardiovascular diseases, diabetes, hormonal deficiency, etc. Benign prostatic hyperplasia is an increase in size of the prostate which causes dysuresia, with the concomitant or consequent onset of complications such as urinary infection, urolithiasis, hematuria, renal failure, etc..

Tadalafil is a substance belonging to phosphodiesterase <NUM> (PDE <NUM>) inhibitors such as sildenafil and vardenafil. Tadalafil has a half life at least <NUM> times longer than sildenafil and vardenafil. Tadalafil was originally developed by Icos Corporation. Eli Lilly and Company currently offers Cialis®, a treatment for erectile dysfunction containing tadalafil, and Adcirca®, a treatment for pulmonary arterial hypertension, on the market. Cialis® was approved in <NUM> by the FDA as a treatment for benign prostatic hyperplasia.

Tamsulosin is an α1a blocker effective in the treatment of symptoms of benign prostatic hyperplasia, chronic prostatitis, and chronic abdominal pain. In addition, tamsulosin is also effective in the treatment of urolithiasis via the skeletal muscle relaxation mechanism by blocking α1a. Tamsulosin was first developed by Yamanouchi Pharmaceutical Co. in <NUM>, and various products containing tamsulosin hydrochloride are known (<CIT>, etc.).

Erectile dysfunction and benign prostatic hyperplasia may occur alone and independent of each other. However, erectile dysfunction and benign prostatic hyperplasia are likely to occur in the same patient, and, according to a study, <NUM> patients out of <NUM> erectile dysfunction patients in Korea also had prostate gland diseases. Accordingly, there is a need for the development of a therapeutic method to treat the two diseases simultaneously with excellent stability and efficacy.

In particular, although the action mechanism of tadalafil differs from that of tamsulosin, they are both effective in the treatment of benign prostatic hyperplasia. Therefore, a more excellent therapeutic effect may be obtained by administering both tadalafil and tamsulosin simultaneously or at intervals as a combined therapy, and also adverse effects due to long term administration may be alleviated by reducing the dosage of each individual drug. However, the combined therapy, which requires administration of at least two drugs as individual units may deteriorate drug compliance, and thus may cause much inconvenience to patients who are under continuous medication. In addition, the combined therapy also causes much inconvenience to patients who continuously manage their social activities by requiring them to carry with them and administer several individual drug units.

Accordingly, there is an urgent need for the development of a composite formulation (also called as a combination drug) containing at least two active ingredients necessitating a combined therapy. However, the development of a composite formulation containing at least two active ingredients raises problems as follows. First, the composite formulation requires that the different active ingredients to be used therein be easily and freely combined but unexpected difficulties may occur due to various problems caused by the pharmacokinetic and pharmaceutical characteristics of the drugs. Second, the amount of a composition containing the active ingredients and a pharmaceutically acceptable excipient should be in the range suitable as a medicine. Therefore, when the amount of active ingredients to be combined is excessive or too little it may be difficult to prepare them into a composition with an appropriate mass. Third, in manufacturing a combination drug, the dissolution rate and stability of the composite formulation may be deteriorated by the interaction between the different active ingredients of the composite formulation, thus making it difficult to develop a fixed composite formulation for administration in a physicochemically stable form. The composite formulation may be manufactured in the form of a double-layered or a triple-layered tablet to separate each active ingredient into each separate layer. However, the above method will require a special manufacturing facility such as a tableting machine for preparing double-layered or triple-layered tablets, and also interactions may occur among the ingredients in neighboring regions of the tablets. In the contemporary art, it has not been possible to establish a perfect separation between ingredients.

<CIT> discloses a method for treating the symptoms of benign prostatic hyperplasia.

<CIT> discloses a hard capsule composite formulation comprising one or more tablets encapsulated in the capsule, wherein the tablet or the tablets as a whole have a shape conforming to the internal space of the capsule.

EPO non-patent literature reference number XP055872455 is a press release regarding a phase III clinical trial evaluating administration of Cialis in parallel with tamsulosin to men with signs and symptoms suggestive of benign prostatic hyperplasia.

<NPL> discusses treatment of benign prostatic hyperplasia in hypertensive men.

EPO non-patent literature reference number XP055872454 discloses prescribing information for Cialis.

EPO non-patent literature reference number XP055664689 discloses prescribing information for Flomax (tamsulosin hydrochloride).

Accordingly, there has been a need for the development of a novel composite formulation with excellent medication convenience and stability, while being capable of providing the effects of preventing and treating erectile dysfunction and benign prostatic hyperplasia.

Accordingly, an object of the present invention is to provide a composite formulation with excellent medication convenience, dissolution rate and stability, while being capable of providing the effects of preventing and treating both erectile dysfunction and benign prostatic hyperplasia.

In order to accomplish the above object(s), the present invention provides a capsule composite formulation comprising: an independent part of tadalafil containing tadalafil or a pharmaceutically acceptable salt thereof; and an independent part of tamsulosin containing tamsulosin or a pharmaceutically acceptable salt thereof, in a separate state. The independent part of tadalafil is in the form of a tablet, and the independent part of tamsulosin is in the form of granules. The independent part of tamsulosin is coated with a coating material selected from the group consisting of povidone, propylene glycol, polyvinyl acetate, methacrylate-ethyl acrylate copolymer, triacetin, and a mixture thereof. The capsule composite formulation is filled into a hard capsule that has an internal capacity of <NUM>, and the coating material is used in the amount of <NUM> to <NUM> wt% relative to the total weight of the independent part of tamsulosin.

In order to accomplish another object, the present invention also provides a method of manufacturing the above capsule composite formulation as defined in claim <NUM>. The method comprises: a) mixing tadalafil or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive, and tableting the granules thus obtained into a tablet; b) mixing tamsulosin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive, and granulating the mixture; and c) filling into a hard capsule the tadalafil tablet prepared in step a), and the tamsulosin granules prepared in step b), in a separate state. Step b) includes coating the granules obtained from the granulation process with a coating material selected from the group consisting of povidone, propylene glycol, polyvinyl acetate, methacrylate-ethyl acrylate copolymer, triacetin, and a mixture thereof. The capsule composite formulation is filled into a hard capsule that has an internal capacity of <NUM>, and the coating material is used in the amount of <NUM> to <NUM> wt% relative to the total weight of the independent part of tamsulosin.

The capsule composite formulation of the present invention may be prepared by efficiently filling a pharmaceutical composition into the limited internal capacity of a capsule. Therefore, the capsule composite formulation of the present invention has advantages in that it can provide high-dose active ingredients into a small sized capsule, thereby having high productivity and providing patients with improved convenience in taking the medicine. Additionally, the capsule composite formulation of the present invention has an excellent dissolution rate because the pharmaceutically active ingredients within the capsule are separated, thus having a low impact on the dissolution rate between the pharmaceutically active ingredients. Furthermore, the capsule composite formulation of the present invention has minimal reactivity between active ingredients, thus providing excellent product stability over time and is capable of maximizing the therapeutic effect of the pharmaceutically active ingredients.

The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings:.

The present invention is described in further detail below.

The term, "a composite formulation" used herein, refers to a formulation which includes at least two kinds of drugs or active ingredients within a single dosage unit such as a table or capsule.

The capsule composite formulation of the present invention is as defined in claim <NUM> and comprises i) an independent part of tadalafil containing tadalafil or a pharmaceutically acceptable salt thereof; and ii) an independent part of tamsulosin containing tamsulosin or a pharmaceutically acceptable salt thereof, in a separate state.

<FIG> is a diagram illustrating the capsule composite formulation according to an exemplary embodiment of the present invention, in which the independent part of tadalafil and the independent part of tamsulosin respectively form a separate independent layer within the hard capsule to be filled. More specifically, in an exemplary embodiment, the capsule composite formulation may comprise i) an independent tadalafil layer containing tadalafil or a pharmaceutically acceptable salt thereof; and ii) an independent tamsulosin layer containing tamsulosin or a pharmaceutically acceptable salt thereof, in a separate state.

The capsule composite formulation of the present invention has a therapeutic effect of preventing or treating erectile dysfunction and benign prostatic hyperplasia.

The independent part of tadalafil and the independent part of tamsulosin may contain water in the range of <NUM>% or less, respectively.

The pharmaceutically acceptable salt of tamsulosin may be, for example, tamsulosin hydrochloride.

The capsule composite formulation comprises a tadalafil tablet and a tamsulosin granule filled into a hard capsule. A diagram of a capsule composite formulation according to an embodiment of the present invention which comprises a tadalafil tablet and a tamsulosin granule filled into a hard capsule is shown in <FIG>.

Tadalafil or a pharmaceutically acceptable salt thereof may be contained in the range of from <NUM> to <NUM> wt% relative to the total weight of the independent part of tadalafil. Preferably, tadalafil or a pharmaceutically acceptable salt thereof may be administered to an adult at about <NUM> daily.

Tamsulosin or a pharmaceutically acceptable salt thereof may be contained in the range of from <NUM> to <NUM> wt% relative to the total weight of the independent part of tamsulosin. Tamsulosin or a pharmaceutically acceptable salt thereof may be administered to an adult, for example, at about <NUM> or <NUM> daily.

In the capsule composite formulation of the present invention, the independent part of tadalafil and the independent part of tamsulosin may each independently contain a pharmaceutically acceptable additive, respectively, for example, a diluent, a disintegrating agent, a binder, a stabilizing agent, a lubricant, a coloring agent, or a mixture thereof.

Examples of the diluent may include microcrystalline cellulose, lactose, Ludipress, mannitol, monocalcium phosphate, starch, low-substituted hydroxypropylcellulose, and a mixture thereof. The diluent may be used in the amount of from about <NUM> to <NUM> wt% relative to the total weight of each independent part, and preferably from about <NUM> to <NUM> wt%.

Examples of the disintegrating agent may include crosspovidone, sodium starch glycolate, sodium crosscarmellose, low-substituted hydroxypropylcellulose, starch, alginic acid or a sodium salt thereof, and a mixture thereof, which can serve for stable disintegration of active ingredients. The disintegrating agent may be used in the amount of from about <NUM> to <NUM> wt% relative to the total weight of each independent part, and preferably from about <NUM> to <NUM> wt%.

Examples of the binder may include hydroxypropylcellulose, hydroxypropyl methylcellulose, hypromellose, polyvinyl acetate, polyvinyl pyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, synthetic aluminum silicate, a silicate derivative such as calcium silicate or magnesium metasilicate aluminate, phosphate such as calcium hydrogen phosphate, carbonate such as calcium carbonate, pregelatinized starch, gums such as acasia gum, gelatin, cellulose derivatives such as ethyl cellulose, and a mixture thereof. The binder may be used in the amount of from about <NUM> to <NUM> wt% relative to the total weight of each independent part, and preferably from about <NUM> to <NUM> wt%.

Examples of the lubricant may include metal stearates such as stearic acid, calcium stearate, or magnesium stearate; talc; colloidal silica; sucrose fatty acid ester; hydrogenated vegetable oil; high melting point wax; glyceryl fatty acid esters; glycerol dibehenate; and a mixture thereof. The lubricant may be used in the amount of from about <NUM> to <NUM> wt% relative to the total weight of each independent part, and preferably from about <NUM> to <NUM> wt%.

In the present invention, the independent part of tadalafil and the independent part of tamsulosin may be each coated with a pharmaceutically acceptable coating material. The coating material to be used may include any polymer conventionally used in the related art. For example, the independent part of tadalafil may be coated by the commercial Opadry® manufactured by Colorcon Ltd. or the like as the coating material. The coating material for the independent part of tamsulosin is selected from the group consisting of polyvinyl acetate, povidone, methacrylate-ethyl acrylate copolymer, triacetin, propylene glycol, and a mixture thereof.

Preferably, the amount of the coating material should be maintained at the minimal level for the preparation of optimal-sized formulations and their efficient manufacture. For example, the coating material may be used in the amount of from about <NUM> to <NUM> wt% relative to the total weight of each independent part, and preferably from about <NUM> to <NUM> wt%. In the invention, the coating material on the independent part of the tamsulosin is used in the amount of <NUM> to <NUM> wt% relative to the total weight of the independent part of tamsulosin.

The capsules to be used in manufacturing the capsule composite formulation of the present invention are not particularly limited, but any conventional hard capsules used in medicinal products may be used. For example, any hard capsule containing hypromellose, pullulan, gelatin, polyvinyl alcohol, or a mixture thereof may be used.

Capsules used in medicinal products have a varying amount of an internal capacity depending on the size number, for example, size No. <NUM> has about <NUM>, size No. <NUM> about <NUM>, size No. <NUM> about <NUM>, size No. <NUM> about <NUM>, size No. <NUM> about <NUM>, etc..

The capsule composite formulation of the present invention employs tadalafil, a PDE <NUM> inhibitor, as the first active ingredient, thereby having therapeutic effects of preventing and treating erectile dysfunction and benign prostatic hyperplasia, whereas it employs tamsulosin, an α1a blocker, as the second active ingredient, thereby having continuous therapeutic effects for preventing and treating dysuresia diseases, such as benign prostatic hyperplasia, chronic prostatitis, chronic abdominal pain, urolithiasis, etc..

Suitable routes for administration of the capsule composite formulation of the present invention may include oral, buccal, and sublingual routes.

In the capsule composite formulation of the present invention, a pharmaceutical composition is efficiently filled into a capsule having a limited internal capacity, and thus it is possible to fill high-dose active ingredients into a small-sized capsule. Accordingly, the capsule composite formulation of the present invention can be manufactured with high productivity, and it also provides patients with improved convenience in taking medicines. Additionally, the two active ingredients, tadalafil and tamsulosin, are included within a hard capsule in a separate state, and thus the two ingredients can be completely separated. Therefore, the two active ingredients have little mutual impact on their dissolution rate, thus enabling an overall excellent dissolution rate.

Furthermore, the minimized reactivity between the active ingredients contributes to product stability over time thereby maximizing the therapeutic effect, and also an existing analysis method for the evaluation of stability over time of a single formulation can be used, without necessities for developing additional methods.

The capsule composite formulation of the present invention may be manufactured by a method including: a) mixing tadalafil or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive, and tableting the mixture; b) mixing tamsulosin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive, and granulating the mixture; and c) filling the tadalafil tablet prepared in step a), and the tamsulosin granules prepared in step b) into a hard capsule, in a separate state.

In step a), tablets may be manufactured by tableting the granules obtained by granulation. More specifically, tablets may be manufactured using a tableting machine according to a conventional method. Preferably, the tablets thus manufactured may have a suitable hardness, for example, an average hardness in the range of from <NUM> to <NUM> kp after tableting.

Step a) includes tableting, and thus, tadalafil is filled into a capsule in the form of a tablet. For example, the capsule composite formulation may be manufactured by performing tableting in step a), performing granulation in step b) and filling a tadalafil tablet and a tamsulosin granule, in a separate state, into a hard capsule.

Additionally, the method of manufacturing a capsule composite formulation may further include coating the tablet, obtained by the tableting in step a), with a pharmaceutically acceptable coating material. For example, the capsule composite formulation may be manufactured by performing coating after tableting of tadalafil in step a), performing coating after granulation of tamsulosin in step b), and filling a coated tadalafil tablet and a coated tamsulosin granule, in a separate state, into a hard capsule. Examples of the coating material suitable for tadalafil and tamsulosin are the same as described above.

The present invention is further described and illustrated in examples provided below, which are, however, not intended to limit the scope of the present invention.

The ingredients in powder form, corresponding to the independent part of tadalafil, were mixed, and the mixture was tableted by a circular punch having a diameter of <NUM>. The resulting tadalafil tablets were coated with a coating solution, i.e., a solution of Opadry® yellow (Colorcon Ltd. ) in purified water.

Additionally, the ingredients corresponding to the independent part of tamsulosin were mixed in powder form, and the mixture was prepared into granules. The resulting tamsulosin granules were coated with an inner coating solution, i.e., a solution of povidone, propylene glycol and polyvinyl acetate in water, and then coated further with an external coating solution, i.e., a solution of methacrylate-ethyl acrylate copolymer and triacetin in water.

The tadalafil tablets and the tamsulosin granules thus coated were filled into hard capsules No. <NUM> having hypromellose as a capsule material, and manufactured into a capsule composite formulation containing <NUM> of tadalafil and <NUM> of tamsulosin hydrochloride.

A capsule composite formulation containing <NUM> of tadalafil and <NUM> of tamsulosin hydrochloride was manufactured in the same manner as in Example <NUM>, except that the hard capsule used had pullulan as a capsule material.

A capsule composite formulation containing <NUM> of tadalafil and <NUM> of tamsulosin hydrochloride was manufactured in the same manner as in Example <NUM>, except that the hard capsule used had gelatin as a capsule material.

A mixture of the above ingredients was subjected to wet granulation using a binder, i.e., a solution of hydroxypropylcellulose and sodium lauryl sulfate in water, and then sieved with a <NUM> mesh sieve and dried.

The dried resultant was added with mannitol, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate, and then tableted by a tableting machine.

The tablet thus obtained which contains tadalafil and tamsulosin was then coated with a coating solution, i.e., a solution of Opadry® yellow in purified water. As a result, a simple mixed tablet composite formulation containing <NUM> of tadalafil and <NUM> of tamsulosin hydrochloride was obtained.

First, in order to prepare a tadalafil-containing layer, tadalafil was subjected to wet granulation using a binder, i.e., a solution of hydroxypropylcellulose and sodium lauryl sulfate in water, and then sieved with a <NUM> mesh sieve and dried. The dried resultant was added with mannitol, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate, and then tableted by a tableting machine.

Additionally, the ingredients for the tamsulosin-containing layer were mixed and then tableted along with the tadalafil tablet prepared in advance to manufacture a double-layered tablet.

The double-layered tablet thus obtained was then coated with a coating solution, i.e., a solution of Opadry® yellow in purified water. As a result, a double-layered tablet composite formulation containing <NUM> of tadalafil and <NUM> of tamsulosin hydrochloride was obtained.

The tadalafil and tamsulosin hydrochloride composite formulations prepared in Examples <NUM> - <NUM> and Comparative Examples <NUM> and <NUM> were evaluated for their dissolution according to the conditions described below.

A dissolution test was performed according to the Paddle method of the U. Pharmacopeia (USP) dissolution test using <NUM> of <NUM>% sodium lauryl sulfate (SLS). Samples for the dissolution test were collected at the initial stage, and after <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, respectively, and the tadalafil dissolution rate was measured via liquid chromatography under the conditions described below.

A dissolution test was performed according to the Paddle method of the USP dissolution test with a sinker at <NUM> rpm using <NUM> of the second fluid for disintegration test, i.e., pH <NUM> buffer. Samples for the dissolution test were collected in the amount of <NUM> at the initial stage, and after <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>, respectively. The tamsulosin dissolution rate of the samples thus collected was measured via liquid chromatography under the conditions described below.

The result of tadalafil dissolution is shown in Table <NUM> and <FIG>, and the result of tamsulosin dissolution is shown in Table <NUM> and <FIG>.

As shown in Table <NUM> and <FIG>, the capsule composite formulations prepared in Examples <NUM> to <NUM> and the simple mixed tablet composite formulations prepared in Comparative Example <NUM> revealed excellent tadalafil dissolution rates. However, in the case of the double-layered tablet composite formulation prepared in Comparative Example <NUM>, the tadalafil dissolution rate was decreased by about <NUM>% or more because part of tadalafil was in contact with a sustained release agent needed for tamsulosin.

As shown in Table <NUM> and <FIG>, the capsule composite formulations prepared in Examples <NUM> to <NUM> and the double-layered composite formulation prepared in Comparative Example <NUM> revealed excellent tamsulosin dissolution rates. However, in the case of the simple mixed tablet composite formulation prepared in Comparative Example <NUM>, tamsulosin was dissolved quickly due to the absence of a sustained release agent, but the formulation was not suitable for therapeutic treatment because of the short half-life of tamsulosin.

In light of the dissolution test results above, the capsule composite formulations of the present invention can provide excellent dissolution of both tadalafil and tamsulosin for lack of interaction between them because the two active ingredients, tadalafil and tamsulosin, are filled into the capsule in a separate state. On the contrary, in the case of the simple mixed tablet composite formulation and the double-layered composite formulation, the dissolution of tadalafil or tamsulosin was poor due to the interaction between the ingredients or the problems in the manufacture of the composite formulations.

Composite formulations containing tadalafil and tamsulosin hydrochloride prepared in Examples <NUM> - <NUM> and Comparative Examples <NUM> and <NUM> were tested for their impurities according to the conditions described below.

accelerated storage condition: at <NUM> with <NUM>% of relative humidity test timing: initial stage, after <NUM> month, <NUM> months, and <NUM> months.

Tests were performed according to the USP impurity test. The formulation corresponding to <NUM> of tadalafil was added to a <NUM> flask, which was then filled to half with a mobile phase and shaken for <NUM> minutes. The resultant was dissolved by ultrasonic vibration for about <NUM> minutes, mixed with a mobile phase to adjust its volume, and then filtered. The resultant in the amount of <NUM> was mixed again with <NUM> of the mobile phase to prepare a sample liquid having a final concentration of <NUM>/mL, and tadalafil impurities were measured by liquid chromatography according to the conditions described below.

Tests were performed according to the USP impurity test. The formulation corresponding to <NUM> of tamsulosin was added to a <NUM> flask, which was then diluted with a mobile phase. Exactly <NUM> of the resulting solution was taken and added into a <NUM> flask, to obtain a diluted sample. Tamsulosin impurities were measured by liquid chromatography under the conditions described below.

The amount of tadalafil impurities are shown in Tables <NUM> and <NUM> and <FIG>. The amount of tamsulosin impurities are shown in Tables <NUM> and <NUM> and <FIG>.

As shown in Tables <NUM> and <NUM> and <FIG>, the capsule composite formulations prepared in Examples <NUM> to <NUM> exhibited excellent tadalafil impurity levels and satisfied the USP standards for individual impurities and total impurities, i.e., <NUM>% or below and <NUM>% or below, respectively. However, in the case of the simple mixed tablet composite formulations prepared in Comparative Example <NUM>, and the double-layered tablet composite formulations prepared in Comparative Example <NUM>, the amount of impurities increased because part of tadalafil was in contact with tamsulosin or its excipients.

As shown in Tables <NUM> and <NUM> and <FIG>, the capsule composite formulations prepared in Examples <NUM> to <NUM> exhibited excellent tamsulosin impurity levels and satisfied the USP standards for individual impurities and total impurities, i.e., <NUM>% or below and <NUM>% or below, respectively. However, in the case of the simple mixed tablet composite formulations prepared in Comparative Example <NUM>, and the double-layered tablet composite formulations prepared in Comparative Example <NUM>, the amount of impurities increased because part of tamsulosin was in contact with tadalafil or its excipients.

Claim 1:
A capsule composite formulation comprising:
i) an independent part of tadalafil containing tadalafil or a pharmaceutically acceptable salt thereof; and
ii) an independent part of tamsulosin containing tamsulosin or a pharmaceutically acceptable salt thereof,
in a separate state,
wherein the independent part of tadalafil is in the form of a tablet, and the independent part of tamsulosin is in the form of granules,
wherein the independent part of tamsulosin is coated with a coating material selected from the group consisting of povidone, propylene glycol, polyvinyl acetate, methacrylate-ethyl acrylate copolymer, triacetin, and a mixture thereof, wherein the capsule composite formulation is filled into a hard capsule that has an internal capacity of <NUM>, and wherein the coating material is used in the amount of <NUM> to <NUM> wt% relative to the total weight of the independent part of tamsulosin.