WO2016003180A1

WO2016003180A1 - Composite preparation comprising 5-α-reductase inhibitor-containing film coating layer, and method for producing the composite preparation

Info

Publication number: WO2016003180A1
Application number: PCT/KR2015/006742
Authority: WO
Inventors: 김형서; 조정현; 김진철; 김용일; 박재현; 우종수
Original assignee: 한미약품 주식회사
Priority date: 2014-06-30
Filing date: 2015-06-30
Publication date: 2016-01-07
Also published as: MY181172A

Abstract

Provided are a composite preparation and a method for producing same, the composite preparation comprising: a core containing a first active ingredient; and a film coating layer containing a 5-α-reductase inhibitor, wherein the film coating layer is coated with a film coating solution which is a mixed solvent of water and organic solvent with a ratio of 30-80 wt% of the latter, and in which film coating material dissolved.

Description

A composite formulation comprising a 5-α-reductase inhibitor-containing film coating layer and a preparation method thereof

The present invention relates to a composite formulation comprising a 5-α-reductase inhibitor-containing film coating layer and a method for preparing the same, and more specifically, has a uniform content of the active ingredient and excellent dissolution rate, and against external normal impact. The present invention relates to a composite formulation comprising a 5-α-reductase inhibitor-containing film coating layer having stable properties of a coating layer and a method of manufacturing the same.

Men's prostate is about the size of a walnut egg in young and grows larger with age. 'Prostatic hyperplasia' is a disease in which the prostate enlarges with increasing age and the urethra passes inside the prostate, causing various symptoms. Means.

The cause of enlarged prostate is not yet clear, and as with other chronic diseases, several complex factors are known to work. The cause of the pathology that has been recognized to date is due to the aging of normal functioning testicles. Since the prostate is a testosterone-dependent organ, it needs a constant male hormone to maintain its growth and function, and if male hormone is not produced by castration, the prostate contracts.

Symptoms of enlarged prostate include urinating urine at least 8 times a day, night urination, strong and sudden urine (feeling urinary) and urinary urges, urinary urge, urge incontinence, night urination, urination pain, etc. Bladder storage disorders and delayed urination (when urine occurs when urine is seen), sedation (breaking up of urine), abdominal urination (when urinating), urinary weakness, feeling of urination, Lower Urinary Tract Symptoms (LUTS) commonly referred to as bladder discharge disorders.

5-α-reductase inhibitors are representative drugs used to treat prostatic hyperplasia and may be used alone, but may be tamsulosin or phosphodiesterase 5 inhibitors (e.g., Tadalafil, Vardenafil, Eudenafil, Sildenafil, etc.) is known to be used in the treatment of effective prostatic hyperplasia.

5-α-reductase inhibitors inhibit the conversion of testosterone to dihydrotestosterone, which further enhances prostate size-increasing activity, consequently inhibiting and thus increasing prostate size Relieves physical pressure on the urinary tract.

Tamsulosin is a drug that selectively inhibits α-adrenoceptor and acts selectively on the genitourinary system.It relaxes the smooth muscles and prostate gland surrounding the bladder, improving urinary excretion rate and improving the symptoms of benign prostatic hypertrophy. It is known to improve.

Tadalafil (Calis, Lilly ICOS) and Vardenafil (Levitra, GSK), both phosphodiesterase 5 inhibitors, were originally developed as treatments for erectile dysfunction, but are now adding indications for the treatment of prostatic hyperplasia and overactive bladder. (Euro Urol 2008; 1236-44; J Uro 2007; 1401-7).

Combinations of such 5-α-reductase inhibitors and tamsulosin; In addition, the combination of 5-α-reductase inhibitor and phosphodiesterase 5 inhibitor is very advantageous in terms of increased drug efficacy due to the difference in mechanism of action (EP 1 501 517; BJU Int. 2006 Apr. 97 Suppl 2 : 39-43; discussion 44-5).

However, as in the case of the concomitant medication, when the preparation of a combination formulation containing two or more active ingredients, there may be a problem in the stability of the active ingredient due to the interaction of two or more different active ingredients . As a way to secure the stability of such a composite preparation, a composite preparation in which the active ingredients are separated into separate layers by introducing a film coating layer containing another active ingredient into the active ingredient-containing core has been developed (EP 1 830 820). US 6,682,759).

In the case of a combination preparation comprising such a 5-α-reductase inhibitor-containing film coating layer, in order to ensure sufficient bioavailability and rapid effect upon oral administration, the 5-α-reductase inhibitor contained in the film coating layer in the combination preparation. High dissolution rate is required and content uniformity should be high. In addition, if the tensile strength of the film coating layer is not strong enough, the film coating layer may be peeled off or broken by the usual impact during the storage period of the product, it is not possible to ensure sufficient efficacy of the composite formulation, the product properties are poor due to the deformation of the external properties Commercialization may not be possible.

The present invention provides a co-formulation comprising a 5-α-reductase inhibitor-containing film coating layer which not only has a high dissolution rate and content uniformity of the active ingredient, but also stabilizes the coating layer against external impacts.

The present invention provides a method for producing a composite formulation comprising the 5-α-reductase inhibitor-containing film coating layer.

One aspect of the invention

A core containing the first active ingredient; And

A composite formulation comprising a film coating layer containing a 5-α-reductase inhibitor,

The film coating layer provides a composite agent is coated with a film coating solution containing a 5-α-reductase inhibitor and a film coating base in a mixed solvent of water and the organic solvent of 30 to 80% by weight of the organic solvent.

Another aspect of the invention

Preparing a core containing the first active ingredient;

Preparing a 5-α-reductase inhibitor-containing coating solution in which a 5-α-reductase inhibitor and a film coating base are dissolved in a mixed solvent of water and an organic solvent having a ratio of 30 to 80% by weight of an organic solvent; And

It provides a method for producing a composite preparation according to the present invention comprising the step of coating the coating solution on the core.

Co-formulation according to an aspect of the present invention can not only ensure a high dissolution rate and content uniformity of the active ingredient contained in the 5-α-reductase inhibitor-containing film coating layer, the film coating layer is a conventional external impact It may have a tensile strength to withstand.

Therefore, the combination preparation can secure sufficient bioavailability and fastness stably, and there is no change in external properties even in the external impact, so that the product quality is high and there is no loss of drug efficacy.

Furthermore, by introducing a 5-α-reductase inhibitor-containing film coating layer, the volume of the co-formulation can be significantly reduced, thus significantly reducing the size of the tablets or capsules produced in combination of simple single agent compositions, and as such This can increase the ease of taking the patient.

In addition, finasteride, which is a representative drug of 5-α-reductase inhibitor, is a drug having a teratogenicity even in a trace amount, so when manufacturing a solid preparation of finasteride, a manufacturer separates from the existing production line to block the incorporation into other medicines. The production line is required, the composite formulation can be manufactured by the finasteride coating layer only by coating, there is an advantage that it can be manufactured by providing only a separate coating machine. Therefore, the combination preparation has an advantage that it can be manufactured economically.

As a result, the co-formulation enables a high-efficiency, commercial, and economical co-formulation containing two or more active ingredients including a 5-α-reductase inhibitor, thereby using a combination of drugs containing a 5-α-reductase inhibitor. The patient's compliance with the medication can be improved.

FIG. 1 shows a composite formulation (a) coated with a 5-α-reductase inhibitor-containing film coating layer on the surface of a tablet core containing a first active ingredient and a surface of the hard capsule core containing a first active ingredient. It is a schematic diagram which shows the composite agent (b) coated with the -alpha-reductase inhibitor-containing film coating layer.

Figure 2 is a result and a graph showing the results of the dissolution test using the paddle method of the ten pharmacopoeia revised, 'dissolution test method' of the 'General Test Method' for the composite formulation of Example 1-11.

3 is a result and a graph showing the results of the dissolution test using the paddle method of the ten pharmacopoeia, the 'dissolution test method' of the 'General Test Method' for the Comparative Example 1-8 composite formulation.

Figure 4 shows the results of measuring the dissolution deviation during the dissolution test for the composite formulation of Example 1-11 and Comparative Example 1-8.

5 is an X-ray diffraction pattern measurement result of a finasteride powder as a raw material and a dry film of film coating liquids of Examples 2, 7 and Comparative Example 2. FIG.

6 is a SEM (Scanning Electron Microscope) image of the dry film of the film coating solution of Example 2 and Comparative Examples 2, 3.

Figure 7 is a photograph of an example of a composite preparation determined as a good product (a) and a bad product (b) in the defect test of the present specification.

8 is a graph showing a defective rate when the composite preparation of Comparative Example 9-16 is removed after PTP packaging.

Figure 9 is a graph showing the defective rate when removing the package after PTP packaging the composite formulation of Examples 12-21.

10 is a graph showing the defective rate of each coating base when removing the package after PTP packaging the composite formulations of Comparative Examples 9 to 12 and stored for 1 week at 60 ° C. and 0% RH.

11 is a graph showing the dissolution rate of finasteride from the co-formulations of Comparative Examples 9 to 12.

12 is a graph showing the dissolution rate of finasteride from the co-formulations of Examples 13 to 16.

FIG. 13 is a graph showing the defective rate when removing the package after PTP packaging in order to observe the difference in the defective rate between the formulations of the core of the composite formulations of Examples 14, 22 and 23.

All technical terms used in the present invention are used as the meaning generally understood by those skilled in the art unless otherwise defined. In addition, although a preferred method or sample is described herein, similar or equivalent things are included in the scope of the present invention. The contents of all publications that are incorporated herein by reference are incorporated by reference in their entirety.

The present inventors have a high dissolution rate and content uniformity to prepare a stable and effective co-formulation comprising a 5-α-reductase inhibitor, but also a 5-α having a tensile strength that can withstand conventional external impact -The redox enzyme-containing film coating layer was intensively studied. As a result, a mixed solvent of water and an organic solvent in which the ratio of the organic solvent is 30 to 80% by weight is used as a solvent in the preparation of the film coating solution containing the 5-α-reductase inhibitor and the film coating base used to form the film coating layer. In the case, it has been found that a film coating layer having high dissolution rate and content uniformity can be formed.

Thus, one aspect of the present invention

A core containing the first active ingredient; And

The core containing the first active ingredient may be any solid pharmaceutical formulation commonly used in the pharmaceutical arts. For example, the core may be in the form of tablets, hard capsules or soft capsules, but is not limited thereto. Filling portion filled in the hard capsule or soft capsule is typically any pharmaceutical formulation used in the pharmaceutical field may be granules, pellets, powders, tablets, solutions, or combinations thereof.

The core may be present at a rate of about 20 to 99.5 weight percent of the total coformulation.

The film coating layer containing the 5-α-reductase inhibitor may be formed on the surface of the core.

The film coating solution is a solution comprising any coating base and 5-α-reductase inhibitor used in the art to form a drug-containing film coating layer. The solvent for preparing the film coating solution is a mixed solvent of water and an organic solvent having a ratio of the organic solvent of 30 to 80% by weight. This mixed solvent can dissolve both the coating base and the 5-α-reductase inhibitor.

The amount of the organic solvent may be used as a volume capable of dissolving both the coating base and the 5-α-reductase inhibitor, and may vary depending on the specific components of the 5-α-reductase inhibitor. In one embodiment, when the 5-α-reductase inhibitor is finasteride, the amount of the organic solvent is about 120-576 mg per 5 mg of finasteride (see Examples 1-11 and Test Example 1).

The organic solvent may be any organic solvent that can be used in the preparation of the film coating liquid, for example methanol, ethanol, acetone, chloroform, dimethyl sulfoxide (DMSO), or any combination thereof. In one embodiment the organic solvent is ethanol.

The present inventors are a film coating liquid prepared by mixing a 5-α-reductase inhibitor and a coating base in a mixed solvent having a weight ratio of various organic solvents, wherein a film coating layer is formed on a tablet or capsule core containing a first active ingredient. After preparing the combination formulation, the dissolution test of the 5-α-reductase inhibitors was performed over time. As a result, when the ratio of the organic solvent is coated with a film coating solution in which the film coating base is dissolved in a mixed solvent of water and the organic solvent of 30 to 80% by weight, the dissolution rate is higher than when the mixed solvent outside the ratio of the organic solvent is used. It was found to increase significantly and the dissolution deviation was significantly lowered (see Test Examples 2 and 3). This is because the film coating base and the 5-α-reductase inhibitor are dissolved when using a mixed solvent of water and an organic solvent in which the ratio of the organic solvent is 30 to 80% by weight, whereas a mixed solvent outside the ratio of the organic solvent can be used. In this case, it seems that the film coating base and / or 5-α-reductase inhibitor are not completely dissolved (see Test Example 1), and that the 5-crystalline-α-reductase inhibitor, which was originally in crystalline form, is completely dissolved in the mixed solvent and the film is coated. It appears to be due to a change in amorphous form upon formation solubility (see Test Example 4).

5-α-reductase inhibitors, such as finasteride or dutasteride, are immediate release, general tablets, and usually have a t _max of 1 to 2 hours, and are known to be drugs that require rapid absorption through high dissolution rates. Since the complex preparation according to the present invention has a dissolution rate of the 5-α-reductase inhibitor significantly higher with a low dissolution deviation, it can be provided as a stable effective combination formulation.

In one embodiment, the film coating base is polyvinyl alcohol- polyethylene glycol graft copolymer; And polyvinyl alcohol or polyvinylpyrrolidone. As a result of the experiment, when polyvinyl alcohol-polyethylene glycol graft copolymer is combined with polyvinyl alcohol or polyvinylpyrrole among numerous film coating bases, the tensile strength of the film coating layer is sufficiently strong, which is caused by the normal impact during the product storage period. Not only does the film coating layer peel off or breakage, but also the high dissolution rate of the drug contained in the film coating layer.

Specifically, the present inventors prepared a composite formulation in which a film coating layer including a 5-α-reductase inhibitor and various coating bases was formed on a tablet or capsule core containing the first active ingredient, and then the poor test for each coating base and A dissolution test of the 5-α-reductase inhibitor over time was performed. As a result, when the polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, povidone, and hypromellose alone are used as the coating base, the defective rate at which the film coating layer of the composite agent is peeled or broken from the core is 20 to 20. It was very high at 40%, and only polyvinyl alcohol was very low at less than 2% (see Test Example 5). However, when polyvinyl alcohol was used as the coating base, the dissolution rate was lower than 75% after 15 minutes in accordance with the general test method of the Korean Pharmacopoeia (see Test Example 8). Therefore, it is difficult to obtain a film coating layer that can secure a sufficiently high dissolution rate while having a high tensile strength of the film coating layer. In contrast, when a polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol or a combination of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinylpyrrolidone is used as the coating base, the film coating layer is formed from the core. Not only was the defect rate that peeled or broken down significantly lower than about 10% (see Test Examples 6 and 7), but also appeared to have a sufficiently high dissolution rate of 75% or more after 15 minutes in the dissolution test (see Test Examples 2 and 9), The results showed breakthrough results that could secure both low film coating defect rate and high dissolution rate.

In one embodiment of the present invention, the combination of the polyvinyl alcohol-polyethylene glycol graft copolymer with polyvinyl alcohol or polyvinylpyrrolidone may be used in a weight ratio of about 8: 2 to 4: 6. More specifically, the combination of polyvinyl alcohol-polyethylene glycol graft copolymer with polyvinyl alcohol may be used in a weight ratio of about 7: 3 to 4: 6, and more specifically in a weight ratio of about 6: 4. Can be.

The polyvinyl alcohol-polyethylene glycol graft copolymer may be composed of about 65 to 85% polyvinyl alcohol units and about 15 to 35% polyethylene glycol units, and may include about 0.01 to 0.5% colloidal silica. The weight average molecular weight may be about 35,000 to 55,000 daltons. Polyvinyl alcohol-polyethylene glycol graft copolymer, for example, as Kollicoat ^® ahyial (Kollicoat IR; BASF) is commercially available, and the Collicoat ^® IAL consists of about 75% polyvinyl alcohol units and about 25% polyethylene glycol units, contains about 0.3% colloidal silica, and has a weight average molecular weight of about 45,000 Daltons .

The polyvinylpyrrolidone may have a molecular weight of about 2,500 to 2,500,000 Daltons as a water-soluble polymer, the higher the molecular weight, the higher the viscosity.

The polyvinyl alcohol may have a molecular weight of about 20,000 to 200,000 Daltons as a water-soluble polymer, the higher the molecular weight, the higher the viscosity.

The film coating layer may be present in a ratio of about 0.5 to 80 parts by weight based on 100 parts by weight of the core.

In one embodiment of the invention, the co-formulation of the polyvinyl alcohol-polyethylene glycol graft copolymer is composed of about 65-85% polyvinyl alcohol units and 15-35% polyethylene glycol units, colloidal silica about 0.01- 0.5 weight percent, a weight average molecular weight is about 35,000-55,000 Daltons, the polyvinylpyrrolidone has a molecular weight of about 2,500 to 2,500,000 Daltons, polyvinyl alcohol- polyethylene glycol graft copolymer and polyvinylpyrrolidone The weight ratio of is about 8: 2-4: 6.

In one embodiment of the invention, the co-formulation of the polyvinyl alcohol-polyethylene glycol graft copolymer is composed of about 65-85% polyvinyl alcohol units and 15-35% polyethylene glycol units, colloidal silica about 0.01- 0.5 wt%, the weight average molecular weight is about 35,000-55,000 Daltons, the polyvinyl alcohol has a molecular weight of about 20,000-200,000 Daltons, the weight ratio of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol is about 7: 3-4: 6.

A schematic diagram of a combination preparation according to one embodiment of the present invention is shown in FIG. 1.

Figure 1 (a) is a schematic diagram showing a composite formulation coated with a film coating layer containing a 5-α-reductase inhibitor on the surface of the tablet core containing the first active ingredient.

Figure 1 (b) is a schematic diagram showing a composite formulation coated with a film coating layer containing a 5-α-reductase inhibitor on the surface of the hard capsule core containing the first active ingredient.

The composite preparation according to the present invention may further include an inner skin that selectively separates the core and the film coating layer in order to more effectively prevent the interaction of the active ingredient. The inner skin may be present in a ratio of about 0.01 to 60 parts by weight relative to 100 parts by weight of the core. Film forming materials (film formers and / or coating agents) that can be used on the inner skin include hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, ethylcellulose, methylcellulose, polymethacrylate, Polyethyleneglycol, talc, titanium dioxide or mixtures thereof may be exemplified. In addition, any of those generally used in the pharmaceutical field may be used in formulating oral or parenteral solid preparations.

The combination according to the present invention may optionally further include an outer skin on the outer side of the active ingredient-containing film coating layer to further protect the combination from the outside. The outer skin portion may be any coating layer that does not significantly affect the high tensile strength of the active ingredient-containing film coating layer and the high dissolution rate of the active ingredient. Examples of such a coating may be a moisture proof coating, a light coating, or the like, and a person skilled in the art may appropriately select a coating base based on a known technique according to the type of coating.

The skin portion may be present in a ratio of about 0.01 to 60 parts by weight relative to 100 parts by weight of the core.

The complex formulation of the present invention may further include a pharmaceutically acceptable additive in the core and the 5-α-reductase inhibitor-containing film coating layer, in addition to the components. The additive may be selected from the group consisting of diluents, disintegrants, binders, stabilizers, lubricants, and any combination thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, rudipress, mannitol, calcium dihydrogen phosphate, starch, low-substituted hydroxypropyl cellulose, and any combination thereof, but is not limited thereto.

The disintegrant may be selected from the group consisting of crospovidone, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid, sodium alginate, and any combination thereof, but is not limited thereto. It doesn't happen.

The binder is a silicate such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copovidone, macrogol, hard anhydrous silicic acid, synthetic aluminum silicate, calcium silicate metasilicate aluminate, magnesium metasilicate aluminate It may be selected from the group consisting of derivatives, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and any combination thereof, but is not limited thereto.

The stabilizer may be selected from the group consisting of magnesium carbonate, sodium bicarbonate, sodium carbonate, calcium carbonate and any combination thereof, which is a basic stabilizer, but is not limited thereto.

The glidants include stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, glycerol dibehe Nate and any combination thereof, but is not limited thereto.

As used herein, the term "active ingredient" may include not only pharmacologically active agents for therapeutic purposes, but also all reagents and other medical preparations that can be administered to the human body for the purpose of diagnosis, prevention, and the like. The term also broadly refers to health functional food preparations as raw materials, ingredients or processed formulations thereof which are ingested for the purpose of obtaining useful effects for health purposes such as regulating nutrients or performing physiological actions on the structure and function of the human body. It may include.

As used herein, the "first active ingredient" is intended to distinguish and distinguish other active ingredients of the co-formulation including the 5-α-reductase inhibitor from the 5-α-reductase inhibitor, and the active ingredient contained in the core of the co-formulation. Is referred to as the first active ingredient for convenience.

The first active ingredient may be any drug that requires coadministration with a 5-α-reductase inhibitor, for example tamsulosin or phosphodiesterase 5 inhibitors (eg tadalafil, sildenafil, vardenafil , Eudenafil, etc.).

Combination of 5-α-reductase inhibitor and tamsulosin; In addition, the combination of 5-α-reductase inhibitor and phosphodiesterase 5 inhibitor is known to be effective in the treatment of prostate hypertrophy by individual drugs. It is known to be very advantageous (EP 1 501 517; BJU Int. 2006 Apr. 97 Suppl 2: 39-43; discussion 44-5). Therefore, when the combination according to the present invention includes tamsulosin or phosphodiesterase 5 inhibitor as the first active ingredient, it can be used as an effective prostate treatment.

In one embodiment of the invention, the combination formulation is for oral administration.

In one embodiment of the invention, the first active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof, and the second active ingredient is a 5-α-reductase inhibitor.

The 5-α-reductase inhibitor may be selected from the group consisting of finasteride, dutasteride, alphatradiol, and combinations thereof. In the dissolution test according to the general test method of the Korean Pharmacopoeia, the dissolution rate of the 5-α-reductase inhibitor may be about 75% or more in 15 minutes.

In one embodiment of the invention, the co-formulations are about 0.1 to 0.8 mg of tamsulosin or a pharmaceutically acceptable salt thereof as tamsulosin free base, considering the known daily dosage. More specifically, 0.2 mg to 0.6 mg, and may contain about 1 to 10 mg of finasteride as the second active ingredient.

In one embodiment of the present invention, the co-formulation of the present invention, considering the known daily dosage, 0.1 to Tamsulosin or a pharmaceutically acceptable salt thereof as the first active ingredient as a tamsulosin free base 0.8 mg, more specifically about 0.2 mg to 0.6 mg, and may include about 0.2 to 0.6 mg of dutasteride as the second active ingredient.

In one embodiment of the invention, the first active ingredient is a phosphodiesterase 5 inhibitor, and the second active ingredient is a 5-α-reductase inhibitor. The phosphodiesterase 5 inhibitor may be tadalafil, sildenafil, vardenafil, udenafil, or any combination thereof, and one embodiment is tadalafil. The tadalafil may be used in the form of the free base of the tadalafil, but may also be used as a pharmaceutically acceptable salt, for example, hydrobromide, phosphate, sulfate, hydrochloride, malate, fumarate, lactate, tartrate , Citrate, besylate, camsylate, gluconate, and the like, and preferably, tadalafil glass, but is not limited thereto.

In one embodiment of the present invention, the co-formulations are about 5 to 20 mg of tadalafil or a pharmaceutically acceptable salt thereof as tadalafil free base, more specifically, given a known daily dosage, more specifically May comprise 5 mg to 10 mg, and may comprise about 1 to 10 mg of finasteride as the second active ingredient.

In one embodiment of the invention, the co-formulation of the present invention, considering the known daily dosage, about 5 to 20 mg of tadalafil or a pharmaceutically acceptable salt thereof as tadalafil free base, as a first active ingredient, More specifically, it may include 5 mg to 10 mg, and may include about 0.2 to 0.6 mg of dutasteride as the second active ingredient.

In one embodiment of the present invention, the co-formulations include tadalafil or a pharmaceutically acceptable salt thereof as a first active ingredient, finasteride as a second active ingredient, and the polyvinyl alcohol-polyethylene glycol graft copolymer. Is comprised of about 65-85% polyvinyl alcohol units and 15-35% polyethylene glycol units, comprising about 0.01-0.5% by weight colloidal silica, a weight average molecular weight of about 35,000-55,000 Daltons, wherein the polyvinylpyrroly The donor has a molecular weight of about 2,500 to 2,500,000 Daltons and the weight ratio of polyvinylalcohol-polyethyleneglycol graft copolymer and polyvinylpyrrolidone is about 8: 2-4: 6.

In one embodiment of the present invention, the combination preparation comprises tamsulosin or a pharmaceutically acceptable salt thereof as the first active ingredient, and contains finasteride as the second active ingredient, and the polyvinyl alcohol- The polyethyleneglycol graft copolymer consists of about 65-85% polyvinyl alcohol units and 15-35% polyethylene glycol units, comprises about 0.01-0.5% by weight colloidal silica, and has a weight average molecular weight of about 35,000-55,000 Daltons The polyvinyl alcohol has a molecular weight of about 20,000-200,000 Daltons, and the weight ratio of the polyvinyl alcohol-polyethylene glycol graft copolymer and the polyvinyl alcohol is about 7: 3-4: 6.

1 embodiment of the present invention comprising a phosphodiesterase 5 inhibitor, tamsulosin, or a pharmaceutically acceptable salt thereof as a first active ingredient and a 5-α-reductase inhibitor as a second active ingredient Combination formulation according to the example can not only obtain the immediate release and uniformity of the content of the 5-α-reductase inhibitor, but also excellent tensile properties of the coating layer and excellent properties and stability, two different prostatic hyperplasia All of the therapeutic drugs may be included in one formulation to provide a synergistic effect in the treatment and alleviation of prostatic hyperplasia, thereby increasing patient compliance.

In addition, the co-formulation according to the present invention, for the preparation of a co-formulation including a 5-α-reductase inhibitor, 5 to the core of the drug to be co-administered without simply mixing the composition of the single agent of each component that existed By introducing the -α-reductase inhibitor-containing film coating layer, the volume of the co-formulation can be significantly reduced. Therefore, the combination according to the present invention can significantly reduce the size of the tablet or capsule, thereby increasing the ease of taking the patient. For example, when formulated with a simple mixture of Tadalafil single product Cialis ^® 183.75 mg and Pinasteride monolithic Prosca ^® 153.87 mg, the mass is 337.62 mg to reduce the ease of taking, whereas the embodiment of the present invention (Examples 1 to 1) Combination formulation according to 8) has a mass of 175.5 mg, which has a significantly small size, so the dose can be significantly convenient.

Another aspect of the invention

Preparing a core containing the first active ingredient;

It provides a method for producing a composite preparation according to the present invention, comprising the step of coating the coating solution on the core.

Details of the preparation method can be applied as it is the description of the oral combination preparation according to all aspects of the present invention.

In preparing the core, the core may use any core that may be used as a core in the pharmaceutical field, and may be, for example, in the form of a tablet, a hard capsule, or a soft capsule, but is not limited thereto. Preparation of such a core may use any preparation available as a commercially available core, and may manufacture it directly. The core may be manufactured by a person skilled in the art according to the type of core using a technique known in the pharmaceutical field.

The coating method in the coating step may be any film coating technique commonly used in the pharmaceutical field. For example, a pan-coating method, a fluidized-bed coating method, a press-coating method, and the like are not limited thereto.

Finasteride typically has teratogenicity among the 5-α-reductase inhibitors, and therefore, a manufacturer must have a separate independent production line so as not to be incorporated into other medicines when manufacturing the finasteride-containing preparation, for example, when preparing as a solid preparation. All processes, such as granulation, tableting and coating, should be carried out in a separate workshop. Since the preparation method of the composite preparation according to the present invention is applied by coating the finasteride with the coating solution containing finasteride, it is possible to prepare the finasteride formulation relatively simply since it is necessary to secure a coating facility for coating the finasteride separately in the existing manufacturing facility. . Therefore, according to the method for preparing a co-formulation according to the present invention, there is an advantage that the 5-α-reductase inhibitor-containing co-agent can be produced more economically.

EXAMPLE

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

실시예 1-10 및 비교예 1-8: 피나스테라이드-함유 필름코팅층이 코팅된 복합제제의 제조 Examples 1-10 and Comparative Examples 1-8: Preparation of Composite Preparations Coated with Finasteride-Containing Film Coating Layer

As shown in Tables 1 to 3 below, the coating base was mixed with various ratios of an organic solvent-water mixed solvent to prepare a film coating solution, and then a tadalafil-containing tablet core using a pan coater (SFC-30, SEJONG). (160 mg per unit mass). The tadalafil-containing tablet core was tableted by tableting the granules obtained by mixing and granulating tadalafil with mannitol, pregelatinized starch, hydroxypropylcellulose, sodium lauryl sulfate, sodium starch glycolate. Tablets coated in a pan coater were dried at 35 ° C. for 30 minutes to prepare a composite formulation in which a film coating layer containing finasteride was coated on the tadalafil-containing tablet core. As a result of the preparation, it was found that the masses per unit formulation of the tablets prepared in Examples 1-8 were all 175.5 mg. In addition, as shown in Table 4, the coated base material by the same method ride number New hydrochloride and preparation of the composite agent-coated capsule in ^® (Co. Hanmi, South Korea), who is a capsule containing the navigation channel. The coated capsules were dried at 35 ° C. for 30 minutes to prepare a composite formulation in which a film coating layer containing finistide was coated on the tamsulosin-containing capsule core.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

시험예 1: 피나스테라이드 및 코팅 기제의 용해여부 확인Test Example 1: Confirming dissolution of finasteride and coating base

Finasteride, Colicoat ^® eye, povidone and polyvinyl alcohol were respectively added to the organic solvent-water mixed solvents of various ratios described in Tables 1 to 4, respectively, and visually confirmed dissolution.

The results are shown in Table 5 below.

TABLE 5

As a result of confirming the dissolution of the finasteride and the coating base in the organic solvent-water mixed solution of various ratios described in Tables 1 to 4, povidone was dissolved in all the organic solvent-water mixed solution, polyvinyl alcohol was Comparative Example 8 It was dissolved in all proportions of the organic solvent-water mixed solvent except the organic solvent-water mixed solution. Finasteride in an organic solvent in Comparative Examples 1, 2, 5, 6 and 7 from the water mixture, Kollicoat ^® ahyial is an organic solvent of Comparative Examples 3, 4 and 8 were insoluble in water mixtures.

시험예 2: 용출률 확인Test Example 2: Dissolution Rate Confirmation

In order to evaluate the dissolution rate of finasteride in the composite formulations of Examples 1 to 11 and Comparative Examples 1 to 8, the dissolution test was performed as follows.

For the dissolution test, paddle method, which was the second method among the dissolution test methods of the 10 KPs and the General Test Method, was used. The test solution was revised by KEPCO 10, using 900 mL of distilled water and proceeded at a speed of 50 rpm according to the operation of the general release formulation. The test solution was collected at 0, 5, 10, 15, 30, and 45 minutes after the start of the test, and the standard solution prepared in advance by analyzing according to the 'liquid chromatograph method' in the 10 amendments of the Korean Pharmacopoeia Through the comparison, the dissolution rate was obtained at that time. Prosca tablet 5 mg (MSD) was used as a control.

The results are shown in FIGS. 2 (Examples 1-11) and 3 (Comparative Examples 1-8). And the result of the elution deviation is shown in FIG.

In Examples 1 to 11 coated with 30 to 80% (w / w) organic solvent from the results of FIGS. 2 to 4, the 5 minute dissolution rate was 70% and the 10 minute dissolution rate was maintained at 90%. On the other hand, in Comparative Examples 1 to 8, the 5 minute dissolution rate was maintained at 40 to 60%, and the 10 minute dissolution rate was maintained at 70 to 80%. In addition, finasteride elution variation is also significantly reduced. Therefore, it was confirmed from the results of FIGS. 2 to 4 that the dissolution rate of the finasteride of the composite formulation increases and the dissolution deviation is lowered during the preparation under the condition of the mixed solvent in which both the finasteride and the coating base are dissolved.

As described above, commercially available 5-α-reductase inhibitors such as finasteride or dutasteride are immediate release, general type tablets, and usually t _max is 1 to 2 hours, which requires rapid absorption through high dissolution rate. It is a drug. As can be seen from the experimental results of FIGS. 2 to 4, when using a ratio other than 30 to 80% organic solvent, stable fast absorption does not seem to be possible.

시험예 3: 함량 균일성 확인Test Example 3: Confirming Content Uniformity

In order to evaluate the content uniformity of finasteride in the composite formulations of Examples 1 to 11 and Comparative Examples 1 to 8, the content uniformity test was performed as follows.

The content uniformity test is conducted in accordance with the 'Contents Uniformity Test' section of the 'Formulation Uniformity Test Method' in the 'Dissolution Test Method' of the 10 KP and the General Test Method, and according to the `` Calculation of Judgment Values ''. The judgment value was calculated. The test solution was collected and analyzed according to the 'liquid chromatograph method' in the revised Korean Pharmacopoeia 10, 'General Test Method', and the content uniformity was calculated by comparison with the prepared standard solution.

The results are shown in Table 6 below.

TABLE 6

As a result of the content uniformity test as shown in Table 6, in Examples 1 to 11 coated with 30 to 80% (w / w) organic solvent, the determination value was excellent within 5, whereas Comparative Examples 1 to In the case of 8, the judgment value was found to be 8 or more, so that the content uniformity was remarkably inferior to Examples 1 to 11. In addition, many of Comparative Examples 1 to 8 were found to exceed the content uniformity determination criteria.

These results indicate that the composite formulation of Example uses a film coating solution in which both finasteride and a coating base are dissolved, whereas the composite formulation of Comparative Example uses a film coating solution in a state where the finasteride and the coating base are not dissolved but dispersed in large particles. It seems to be because of this.

시험예 4: 피나스테라이드 코팅층의 결정형 분석Test Example 4 Crystalline Analysis of the Finasteride Coating Layer

After spraying the film coating solution prepared in Examples 2, 7 and Comparative Example 2 in a separate petri dish and dried to form a film, and then recovered Crystal forms were analyzed under conditions of Cu X-ray, 40 kV, 100 mA, scan rate 3 deg / min using an X-ray diffraction analyzer (D8 Advance, Bruker).

The X-ray diffraction pattern of the raw material finasteride powder and the film coating liquid dried films of Examples 2, 7 and Comparative Example 2 formed above are shown in FIG. 5. In addition, the results of confirming the SEM (Scanning Electron Microscope) image for the film formed by spraying and drying the film coating liquid of Example 2 and Comparative Examples 2, 3 in a Petri dish and dried.

According to Figure 5, the raw material finasteride powder and the dry film of Comparative Example 2 showed a crystalline form, but Examples 2 and 7 appeared to be amorphous, the original crystalline form was changed to amorphous in the film coating layer according to the present invention Could know. In addition, according to FIG. 6, the pinasteride in the film coating layer according to the present invention is also transformed into an amorphous form, while the pinasteride in the film coating layer according to the comparative example maintains the crystalline form.

실시예 12-21: 탐수로신 염산염 캡슐 코어에 5-α-환원효소 억제제-함유 필름코팅층이 코팅된 복합제제의 제조Example 12-21 Preparation of a Co-Formulation with a 5-α-Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin Hydrochloride Capsule Core

To prepare a coating solution by mixing the coating base combined the various components and contents of Examples 12-21 described in Table 7 in ethanol-water mixed solution (ethanol: water = 1: 1 (v / v)), and then was coated on a coating machine using a (SFC-30, SEJONG) ride number new hydrochloride ride number who ^® capsules containing (Co. Hanmi, South Korea). The prepared capsules were dried at 35 ° C. for 30 minutes to prepare a composite formulation in which a film coating layer containing 5-α-reductase inhibitor was coated on the tamsulosin capsule core.

비교예 9-16: 탐수로신 염산염 캡슐 코어에 5-α-환원효소 억제제-함유 필름코팅층이 코팅된 복합제제의 제조Comparative Example 9-16: Preparation of a Co-Formulation with a 5-α-Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin Hydrochloride Capsule Core

A film coating layer containing 5-α-reductase inhibitor was coated on the tamsulosin capsule core in the same manner as in Example 12-21, except that only the components of Comparative Example 9-16 described in Table 7 were used. Prepared complex formulations were prepared.

TABLE 7

실시예 22 및 23: 탐수로신 OD 정 코어에 5-α-환원효소 억제제-함유 필름코팅층이 코팅된 복합제제의 제조Examples 22 and 23 Preparation of a Co-Formulation with a 5-α-Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin OD Tablet Core

After mixing the coating base, which is a combination of the various components and contents shown in Table 8 to the ethanol-water mixed solution (ethanol: water = 1: 1 (v / v)) to prepare a coating solution, and then a pan coater (SFC-30, using SEJONG) it was coated on the number who ride ^® audio information (Co., Hanmi) containing a number of new ride hydrochloride. The prepared composite tablets were dried at 35 ° C. for 30 minutes to prepare a composite formulation in which a film coating layer containing 5-α-reductase inhibitor was coated on tamsulosin ^® odyssey core.

TABLE 8

시험예 5: 코팅 기제별 불량 시험Test Example 5: Defective Test by Coating Base

In order to evaluate the film tensile force and the breakage rate of the composite formulations of Comparative Examples 9 to 16, a defect test was performed as follows.

First, each formulation was packaged with PTP by sealing with an aluminum film in an aluminum mold using a PTP packaging machine (Lab-Blister machine, OMAR FANTASY PLUS). Ten randomly selected public testers using the packaged formulations were tested to destroy 100 PTP packages for each formulation to release the packaged drug. In the test, as shown in FIG. 7, the film coating layer peeled off from the core or damaged by itself was regarded as a defect, and the state in which the defect was occupied was regarded as a normal coating state as before the packaging was examined. For reference, FIG. 7 shows photographs photographing an example of a composite agent determined as a good product (a) and a defective product (b).

The result of examining the ratio which the defect occupies is shown in following Table 9 and FIG.

TABLE 9

Table 9 and Comparative Examples 9, 11, 12, 13, 15, and combinations of 16 are all about 20 to 40 with a mellow agarose From the results of Figure 8 as Kollicoat ^® ahyial, povidone and hips each alone coating base It was found that the film coating layer was damaged at a high defective rate of%. On the other hand, Comparative Examples 10 and 14 using polyvinyl alcohol as the sole coating base showed low defect rates of about 2% or less.

시험예 6: 코팅 기제로서 폴리비닐알콜-폴리에틸렌글리콜 그라프트 공중합체와 폴리비닐알콜의 조합을 포함하는 복합제제의 불량시험Test Example 6: Poor test of a composite formulation containing a combination of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol as a coating base

The results of the poor test under the same conditions and methods as in Test Example 5 for the composite preparations of Examples 12 to 21 are shown in Table 10 and FIG. 9.

TABLE 10

According to the results of Table 9 and Table 10, in Examples 12 to 21 using a combination of Collicoat ^® eye and polyvinyl alcohol as a coating base, compared to Comparative Example 9 and Comparative Example 13 using only Collicoat ^® eye alone It can be seen that the defective rate is dramatically reduced.

However, Example 13 using Colicoat ^® Eye and polyvinyl alcohol in a ratio of 7: 3 to 4: 6 compared to Examples 12 and 17 using Colicoat ^® eye and polyvinyl alcohol in a ratio of 8: 2. 16 to 16 and Examples 18 to 21 have been shown to be more preferred in terms of reducing defective rates.

시험예 7: 가혹한 조건에서 코팅 기제별 불량시험Test Example 7: Defective testing by coating base under severe conditions

In order to confirm the stability according to the storage time of the composite formulation of Comparative Examples 9 to 12, the samples were stored in a constant temperature chamber at 60 ° C. and 0% RH for 1 week, and then a bad test was conducted in the same manner as in Test Example 1. . The test results are shown in Table 11 and FIG. 10.

TABLE 11

As shown in Table 11 and 10, Comparative Example As a result the coating mechanism of defect test as Kollicoat ^® ahyial, povidone and hips with the marshmallow agarose alone. 9, 11 and 12 exhibited both a high defect rate of 80% or more. On the other hand, Comparative Example 10 using the polyvinyl alcohol as a coating base exhibited a defective rate of 17.4%, showing excellent properties and stability compared to Comparative Examples 9, 11 and 12.

시험예 8: 코팅 기제별 용출 시험Test Example 8: Dissolution test for each coating base

In order to evaluate the dissolution rate of finasteride, the dissolution test was performed for the co-formulations of Comparative Examples 9 to 12 as follows.

For the dissolution test, paddle method, which was the second method among the dissolution test methods of the 10th Amendment of the Korean Pharmacopoeia and the General Test Method, was used. The test solution was prepared by using 900 mL of distilled water according to the 10th amendment of Korea Pharmacopoeia and proceeded at a speed of 50 rpm in accordance with the general release formulation. The test solution is collected at 0, 5, 10, 15, 30, 45 and 60 minutes after the start of the test and analyzed according to the 'liquid chromatograph method' in the 10 amendments of the Korean Pharmacopoeia and the General Test Method. The dissolution rate at that time was obtained by comparison with the prepared standard solution.

The results are shown in Table 12 and FIG. 11.

TABLE 12

According to the results of Table 12 and 11, Kollicoat ^® ahyial, compared with melo agarose each with povidone and Bottom Examples 9, 11, and the formulation of 12 compared to the formulation of Comparative Example 10 using the polyvinyl alcohol is relatively high It can be seen that it shows the dissolution rate.

Finasteride is a drug that requires rapid dissolution to secure a high bioavailability, so Comparative Example 10 using polyvinyl alcohol is likely to cause a problem of lower bioavailability compared to Comparative Examples 9, 11 and 12.

시험예 9: 코팅 기제로서 폴리비닐알콜-폴리에틸렌글리콜 그라프트 공중합체와 폴리비닐알콜의 조합을 포함하는 복합제제의의 용출 시험Test Example 9 Elution Test of a Composite Formulation Combining a Polyvinyl Alcohol-Polyethylene Glycol Graft Copolymer and a Polyvinyl Alcohol as a Coating Base

The dissolution test was carried out in the same conditions and methods as in Test Example 8 for the composite preparations of Examples 13 to 16 are shown in Table 13 and FIG. 12.

TABLE 13

From the results of Table 13 and Figure 12, it can be seen that the dissolution rate of 75% or more within 15 minutes in Examples 13 to 16 using Colicoat ^® eye and polyvinyl alcohol in a weight ratio of 7: 3 to 4: 6.

시험예 10: 코팅 기제로서 폴리비닐알콜-폴리에틸렌글리콜 그라프트 공중합체와 폴리비닐알콜의 조합을 포함하는 복합제제의 코어 형태별 불량시험Test Example 10: Defective test by core type of a composite formulation containing a combination of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol as a coating base

Examples 14, 22 and 23 of the composite preparations are shown in Table 14 and Figure 13 to the results of the poor test in the same conditions and methods as in Test Example 5.

TABLE 14

Using the same coating base as in Example 14, which ensures excellent coating properties, stability, and dissolution rate, a poor test was performed on Examples 22 and 23 whose cores were tamsulosin tablets. It was confirmed that a low defect rate appeared. Therefore, the co-formulation of the present invention was confirmed that the second drug-containing film coating layer can be applied to various types of cores as well as hard capsule cores.

Claims

A core containing the first active ingredient; And

A composite formulation comprising a film coating layer containing a 5-α-reductase inhibitor,

Wherein the film coating layer is coated with a film coating solution comprising a 5-α-reductase inhibitor and a film coating base in a mixed solvent of water and an organic solvent having a ratio of about 30 to 80% by weight of an organic solvent.
The combination formulation of claim 1, wherein the core is a tablet, hard capsule, or soft capsule.
The combination preparation according to claim 1, wherein the organic solvent is methanol, ethanol, acetone, chloroform, dimethyl sulfoxide (DMSO), or any combination thereof.
The method of claim 1, wherein the film coating base is polyvinyl alcohol- polyethylene glycol graft copolymer; And a combination of polyvinylpyrrolidone or polyvinyl alcohol.
The composite formulation of claim 1, wherein the polyvinylpyrrolidone has a molecular weight of about 2,500 to 2,500,000 Daltons.
The combination formulation of claim 1, wherein the polyvinyl alcohol has a molecular weight of about 20,000-200,000 Daltons.
The method of claim 1, wherein the polyvinyl alcohol- polyethylene glycol graft copolymer; And a combination formulation wherein the weight ratio of polyvinyl alcohol or polyvinylpyrrolidone is about 8: 2-4: 6.
The polyvinyl alcohol-polyethylene glycol graft copolymer according to claim 4, comprising about 65-85% polyvinyl alcohol units and about 15-35% polyethylene glycol units, comprising about 0.01-0.5% by weight colloidal silica. The weight average molecular weight is about 35,000-55,000 daltons; The polyvinylpyrrolidone has a molecular weight of about 2,500 to 2,500,000 daltons; Wherein the weight ratio of polyvinylalcohol-polyethyleneglycol graft copolymer and polyvinylpyrrolidone is about 8: 2-4: 6.
The polyvinyl alcohol-polyethylene glycol graft copolymer according to claim 4, comprising about 65-85% polyvinyl alcohol units and about 15-35% polyethylene glycol units, comprising about 0.01-0.5% by weight colloidal silica. The weight average molecular weight is about 35,000-55,000 daltons; The polyvinyl alcohol has a molecular weight of about 20,000-200,000 daltons; Wherein the weight ratio of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol is about 7: 3-4: 6.
The co-formulation according to claim 1, wherein the first active ingredient comprises tamsulosin, phosphodiesterase-5-inhibitor, or a pharmaceutically acceptable salt thereof.
The combination formulation of claim 1, wherein the 5-α-reductase inhibitor is selected from the group consisting of finasteride, dutasteride, alphatradiol, and combinations thereof.
The method according to claim 1, wherein the first active ingredient comprises about 5-20 mg of tadalafil or a pharmaceutically acceptable salt thereof based on tadalafil, and the 5-α-reductase inhibitor comprises about 1-10 mg of finasteride. The combination formulation containing.
13. The co-formulation according to claim 12, wherein the organic solvent is used in an amount of about 120 to 576 mg per about 5 mg of finasteride.
The combination preparation according to claim 1, wherein the combination preparation exhibits a dissolution rate of at least about 75% of a 5-α-reductase inhibitor at 15 minutes when tested in the dissolution test according to the Korean Pharmacopoeia General Test Method.
Preparing a core containing the first active ingredient;

Preparing a 5-α-reductase inhibitor-containing coating solution in which a 5-α-reductase inhibitor and a film coating base are dissolved in a mixed solvent of water and an organic solvent having a ratio of about 30 to 80% by weight of an organic solvent; And

Coating the coating solution on the core;

A method for producing a composite formulation according to any one of claims 1 to 14.