WO2016003181A1 - Composite preparation comprising active ingredient-containing film coating layer - Google Patents

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 second active ingredient, wherein the film coating layer comprises a polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol.

Description

Composite formulations comprising the active ingredient-containing film coating layer

The present invention relates to a composite formulation comprising an active ingredient-containing film coating layer and a method for producing the same, and more particularly, to an active ingredient-containing composition having a stable dissolution of the coating layer against external impacts and having an excellent dissolution rate of the active ingredient. It relates to a composite formulation comprising a film 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, 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 combination of the drug, in the preparation of a combination preparation containing two or more active ingredients, problems with the stability of the active ingredient may occur 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 ingredient is separated into a separate layer by introducing a film coating layer containing another active ingredient into the active ingredient-containing core has been developed (EP 1830820; US; 6,682,759).

In the case of a composite formulation comprising such an active ingredient-containing film coating layer, if the tensile strength of the film coating layer is not strong enough, the film coating layer may be peeled or broken by a normal impact during the storage period of the product, thereby ensuring sufficient efficacy of the composite formulation. It may not be possible, and the product may be impossible to commercialize due to the deterioration of external properties. In addition, in order to ensure sufficient bioavailability and rapid effect during oral administration, very high dissolution rate of the active ingredient contained in the film coating layer in the combination may be required.

The present invention provides a composite formulation comprising an active ingredient-containing film coating layer having a high dissolution rate of the active ingredient while the properties of the coating layer are stable against external normal impacts.

The present invention provides a method for producing a composite formulation comprising the active ingredient-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 second active ingredient,

The film coating layer provides a composite formulation comprising a polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol.

Another aspect of the invention

Preparing a core containing the first active ingredient;

Preparing a second active ingredient-containing coating solution in which a second active ingredient, a polyvinyl alcohol-polyethylene glycol graft copolymer, and a polyvinyl alcohol are dissolved in a 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.

The composite formulation according to one aspect of the present invention may not only have a tensile strength capable of withstanding the external impact of the active ingredient-containing film coating layer, but also ensure a high dissolution rate of the active ingredient contained in the film coating layer. Therefore, the combination preparation does not have a change in external properties even when the external impact is not only high marketability, there is no loss of drug efficacy, it is possible to secure sufficient bioavailability and rapid efficacy. As a result, the co-formulation may enable a good and effective co-formulation containing two or more active ingredients, thereby improving patient compliance with the co-administration of the drug. Moreover, by introducing a film coating layer in the preparation of the co-formulation, it is possible to significantly reduce the volume of the co-formulation, thus significantly reducing the size of the tablets or capsules produced in combination of simple single-agent formulations, thereby taking the patient's dose. It can increase the convenience.

1 shows a second active agent on the surface of a composite formulation (a) coated with a film coating layer containing a second active ingredient on the surface of a tablet core containing the first active ingredient and a hard capsule core containing the first active ingredient. It is a schematic diagram which shows the composite agent (b) coated with the film coating layer containing a component.

Figure 2 is a photograph of an example of a composite agent determined as a good product (a) and a bad product (b) in the defect test of the present specification.

Figure 3 shows the defective rate when removing the package after PTP packaging the composite formulation of Comparative Examples 1 to 8.

Figure 4 shows the defective rate when removing the package after PTP packaging the composite formulation of Examples 1 to 10.

FIG. 5 shows the defective rate of each coating base material when PTP packaging the composite formulations of Comparative Examples 1 to 4 was stored for 1 week at 60 ° C. and 0% RH, and then the packaging was removed.

Figure 6 shows the dissolution rate of finasteride from the complex formulation of Comparative Examples 1 to 4.

Figure 7 shows the dissolution rate of finasteride from the combination formulation of Examples 2-5.

FIG. 8 shows 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 3, 11 and 12.

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 intensively studied coating bases that enable the active ingredient-containing film coating layer of a composite formulation comprising the active ingredient-containing film coating layer to ensure a high dissolution rate of the drug contained in the film coating layer while having sufficient tensile strength. It was. As a result, when a polyvinyl alcohol-polyethylene glycol graft copolymer and a polyvinyl alcohol are combined among many film coating bases, the tensile strength of the film coating layer is sufficiently strong, so that the film coating layer is peeled off or broken by a normal impact during the product storage period. Not only that, it was found that it is possible to ensure a high dissolution rate of the drug contained in the film coating layer.

Thus, one aspect of the present invention

A core containing the first active ingredient; And

A composite formulation comprising a film coating layer containing a second active ingredient,

The film coating layer provides a composite formulation comprising a polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol.

The core containing the first active ingredient may be any 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 second active ingredient may be formed on the surface of the core. The film coating layer contains a combination of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol as a coating base.

The inventors have prepared a composite formulation in which a film coating layer comprising the second active ingredient and various coating bases is formed on a tablet or capsule core containing the first active ingredient, and then the poor test for each coating base and the preparation over time. 2 drug dissolution test 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 Examples 1 and 3). However, when polyvinyl alcohol was used as the coating base, a dissolution rate of less than 75% after 15 minutes was shown in the dissolution test according to the Korean Pharmacopoeia General Test Method (see Test Example 4). 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 combination of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol was used as the coating base, not only was the defect rate at which the film coating layer peeled or broken from the core significantly lower than about 10% (test Example 2 and 6), the elution test was found to have a sufficiently high dissolution rate of 75% or more after 15 minutes (see Test Example 5), showing a breakthrough result that can secure both a low film coating failure rate and a high dissolution rate .

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

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 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 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 second active ingredient 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 second active ingredient 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 select a coating base appropriately 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 comprise a pharmaceutically acceptable additive to the core and the active ingredient-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.

In the present specification, the "first active ingredient" and "second active ingredient" are intended to distinguish two or more active ingredients included in a combination preparation, and indicate the active ingredient contained in the core of the composite preparation in the first active ingredient and the film coating layer. The active ingredient contained in is referred to as a second active ingredient for convenience.

The first active ingredient and the second active ingredient may be applied to any drug requiring combination administration, for example metformin and rosuvastatin, fenofibric acid and rosuvastatin, omega-3 and rosuvastatin, amlodipine and Lozatan, clopidogrel and aspirin, metformin and glyphlenamide, naloxone and oxycodone, fexofenadine and montelukast, brinzolamide and timolol, lercanidipine and enalapril, tamsulosin and 5-alpha-reductase inhibitors, phospho Diesterase 5 inhibitors and 5-alpha-reductase inhibitors, naproxen and esomeprazole, metformin and glypenclamide, and the like can be used. Each of the first active ingredient and the second active ingredient may include a single ingredient, or may include a plurality of ingredients, if necessary.

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

In one embodiment, the second active ingredient is a 5-α-reductase inhibitor, and the first active ingredient may be any drug that requires coadministration with the 5-α-reductase inhibitor, for example tamsulosin (Tamsulosin) or phosphodiesterase 5 inhibitors (eg tadalafil, vardenafil, eudenafil, sildenafil, 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 preparation according to the present invention comprises a tamsulosin or phosphodiesterase 5 inhibitor as the first active ingredient and a 5-α-reductase inhibitor as the second active ingredient, it is an effective prostate treatment agent. Can be used.

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, vardenafil, udenafil, sildenafil or any combination thereof, in one embodiment 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.

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 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-formulation comprises tamsulosin or a pharmaceutically acceptable salt thereof as a first active ingredient, a 5-α-reductase inhibitor as a second active ingredient, a film coating layer The polyvinyl alcohol-polyethylene glycol graft copolymer of about 65-85% of polyvinyl alcohol units and about 15-35% of polyethylene glycol units comprises about 0.01-0.5% by weight of colloidal silica, and the weight average molecular weight is It is about 35,000-55,000 Daltons, the polyvinyl alcohol of the film coating layer has a molecular weight of about 20,000-200,000 Daltons, and the weight ratio of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol is about 7: 3-4: 6.

One embodiment of the present invention comprising tamsulosin or a pharmaceutically acceptable salt thereof, or a phosphodiesterase 5 inhibitor as a first active ingredient, and a 5-α-reductase inhibitor as a second active ingredient The combination preparation according to the present invention is excellent in tensile strength of the coating layer, and has excellent properties and stability, and obtains immediate release of the 5-α-reductase inhibitor, as well as two different prostatic hypertrophy drugs. All of the formulations can provide a synergistic effect in the treatment and alleviation of prostatic hyperplasia, thereby increasing patient compliance.

Another aspect of the invention

Preparing a core containing the first active ingredient;

Preparing a second active ingredient-containing coating solution in which a second active ingredient, a polyvinyl alcohol-polyethylene glycol graft copolymer, and a polyvinyl alcohol are dissolved in a 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.

Details of the manufacturing method may be applied as it is the description of the oral cosmetic formulation 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.

In preparing the drug-containing coating solution, the solvent may be any solvent that is pharmaceutically acceptable while dissolving the second active ingredient, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinyl alcohol. As the solvent, water, ethanol, methanol, chloroform, dimethyl sulfoxide (DMSO) or a mixture thereof may be used. In one embodiment, water, ethanol, or a mixture thereof may be used, but is not limited thereto.

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.

In the case of including the 5-α-reductase inhibitor as the second active ingredient, finasteride typically has teratogenicity, and therefore, a manufacturer must have a separate and independent production line so as not to be incorporated into other medicines when manufacturing the finasteride-containing preparation. For example, when manufacturing as a solid preparation, all processes such as mixing, granulating, tableting and coating must 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.

Example 1-10: Preparation of a Co-Formulation with a 5-α-Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin Hydrochloride Capsule Core (1)

To prepare a coating solution by mixing the coating base of the various components and contents of Example 1-10 shown in Table 1 in an ethanol-water mixed solution (ethanol: water = 1: 1 (v / v)), and then a pan 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.

Comparative Example 1-8: Preparation of a Co-Formulation with a 5-α-Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin Hydrochloride Capsule Core (2)

Except for using the components of Comparative Examples 1-8 shown in Table 1, the film coating layer containing 5-α-reductase inhibitor in the same manner as in Example 1-10 is coated on the tamsulosin capsule core Prepared complex formulations were prepared.

TABLE 1

Examples 11 and 12 Preparation of a Co-Formulation with a 5-α-Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin OD Tablet Core

To prepare a coating solution by mixing the coating base is a combination of various components and contents shown in Table 2 in the ethanol-water mixed solution (ethanol: water = 1: 1 (v / v)), 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. And a purified compound produced was dried at 35 ℃ for 30 minutes to prepare a combined preparation for coating, who ^® Audio Information Core 5-α- reductase film coating layer is a ride channel containing eokjejeeul.

TABLE 2

Test Example 1: Defective Test by Coating Base

In order to evaluate the film tensile force and the breakage rate of the composite preparations of Comparative Examples 1 to 8, 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. 2, the film coating layer was peeled off from the core or damaged by itself. For reference, FIG. 2 shows a photograph of 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 3 and FIG.

TABLE 3

The formulations of Comparative Examples 1, 3, 4, 5, 7, and 8 using Colicoat ^® IAL, povidone and hypromellose as the sole coating base materials from the results of Table 3 and FIG. 3 are all about 20 to 20, respectively. It was found that the film coating layer was damaged at a high defective rate of 40%. On the other hand, Comparative Examples 2 and 6 using polyvinyl alcohol as the sole coating base material showed a low defective rate of about 2% or less.

Test Example 2: Poor Test of a Composite Preparation Comprising 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 1 for the composite preparations of Examples 1 to 10 are shown in Table 4 and FIG. 4.

TABLE 4

According to the results of Table 3 and Table 4, in Examples 1 to 10 using a combination of Collicoat ^® eye and polyvinyl alcohol as the coating base, compared to Comparative Example 1 and Comparative Example 5 using only Collicoat ^® eye alone It can be seen that the defective rate is dramatically reduced.

However, Example 2 using Colicoat ^® IAL and polyvinyl alcohol in a ratio of 7: 3 to 4: 6 compared to Examples 1 and 6 using Colicoat ^® eye and polyvinyl alcohol at a ratio of 8: 2. 5 to 5 and Examples 7 to 10 were found to be more preferred in terms of reducing the defective rate.

Test Example 3: Defective Testing by Coating Base Under Harsh Conditions

In order to confirm the stability according to the storage time of the composite formulation of Comparative Examples 1 to 4, 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 5 and FIG. 5.

TABLE 5

As shown in Table 5 and Figure 5, as a result of the defect test, Comparative Examples 1, 3 and 4 using only Colicoat ^® IAL, povidone and hypromellose as a coating base all showed a high failure rate of more than 80%. On the other hand, Comparative Example 2 using the polyvinyl alcohol as a coating base exhibited a defective rate of 17.4%, showing excellent properties and stability compared to Comparative Example 1, Comparative Example 3 and Comparative Example 4.

Test Example 4 Dissolution Test by Coating Base

In order to evaluate the dissolution rate of finasteride, the dissolution test was performed for the co-formulations of Comparative Examples 1 to 4 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 6 and FIG. 6.

TABLE 6

According to the results of Table 6 and Figure 6, Kollicoat ^® ahyial, compared with melo agarose each with povidone and Bottom Examples 1, 3 and 4 of the formulation is relatively high compared to the formulation of Comparative Example 2 with polyvinyl alcohol 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 2 using polyvinyl alcohol is likely to cause a problem of lower bioavailability compared to Comparative Examples 1, 3 and 4.

Test Example 5: Dissolution test of a composite formulation containing a combination of a polyvinyl alcohol-polyethylene glycol graft copolymer and a polyvinyl alcohol as a coating base

The results of the dissolution test conducted under the same conditions and methods as in Test Example 4 with respect to the composite preparations of Examples 2 to 5 are shown in Table 7 and FIG. 7.

TABLE 7

From the results of Table 7 and Figure 7, it can be seen that the dissolution rate of 75% or more within 15 minutes in Examples 2 to 5 using Colicoat ^® eye and polyvinyl alcohol in a weight ratio of 7: 3 to 4: 6.

Test Example 6: 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 3, 11 and 12 of the composite preparations are shown in Table 8 and Figure 8 the results of the poor test in the same conditions and methods as in Test Example 1.

TABLE 8

As a result of poor tests on Examples 11 and 12, in which the core was tamsulosin tablets using the same coating base as in Example 3, which had excellent coating properties, stability, and dissolution rate, Example 11 and Example 12 were also 1%. It was confirmed that a low failure rate appeared below. 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 (15)

A core containing the first active ingredient; And A composite formulation comprising a film coating layer containing a second active ingredient, The film coating layer is a composite formulation comprising a polyvinyl alcohol- polyethylene glycol graft copolymer and polyvinyl alcohol. The combination formulation of claim 1, wherein the core is a tablet, hard capsule, or soft capsule. The polyvinyl alcohol-polyethylene glycol graft copolymer according to claim 1, comprising about 65-85% polyvinyl alcohol units and about 15-35% polyethylene glycol units, and comprises about 0.01-0.5% by weight colloidal silica. And a weight average molecular weight of about 35,000 to 55,000 Daltons. The combination preparation according to claim 1, wherein the polyvinyl alcohol has a molecular weight of 20,000-200,000 Daltons. The combination preparation according to claim 1, wherein the weight ratio of the polyvinyl alcohol-polyethylene glycol graft copolymer and the polyvinyl alcohol is about 7: 3-4: 6. The polyvinyl alcohol-polyethylene glycol graft copolymer according to claim 1, comprising about 65-85% polyvinyl alcohol units and about 15-35% polyethylene glycol units, and comprises 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 combination formulation of claim 1, wherein the first active ingredient comprises tamsulosin or a pharmaceutically acceptable salt thereof, and the second active ingredient comprises a 5-α-reductase inhibitor. 8. The combination formulation of claim 7, wherein the 5-α-reductase inhibitor is selected from the group consisting of finasteride, dutasteride, alphatradiol, and any combination thereof. 8. The method of claim 7, wherein the first active ingredient comprises about 0.1-0.6 mg of tamsulosin or a pharmaceutically acceptable salt thereof based on tamsulosin, and the second active ingredient is about 1-10 mg or duta of finasteride. A co-formulation comprising about 0.2 to 0.8 mg of steride. The combination formulation of claim 1, wherein the first active ingredient comprises a phosphodiesterase-5 inhibitor and the second active ingredient comprises a 5-α-reductase inhibitor. The group of claim 10, wherein the first active ingredient comprises tadalafil or a pharmaceutically acceptable salt thereof, and wherein the second active ingredient consists of finasteride, dutasteride, alphatradiol, and any combination thereof A combination formulation comprising a 5-α-reductase inhibitor selected from. The method of claim 10, wherein the first active ingredient comprises about 5-20 mg of tadalafil or a pharmaceutically acceptable salt thereof based on tadalafil, and the second active ingredient is about 1-10 mg or dutasteride about A combination formulation comprising 0.2 to 0.8 mg. The complex according to any one of claims 7 to 12, wherein the complex preparation exhibits a dissolution rate of at least about 75% of the 5-α-reductase inhibitor at 15 minutes when the dissolution test is performed according to the Korean Pharmacopoeia General Test Method. Formulation. Preparing a core containing the first active ingredient; Preparing a second active ingredient-containing coating solution in which a second active ingredient, a polyvinyl alcohol-polyethylene glycol graft copolymer, and a polyvinyl alcohol are dissolved in a solvent; And Coating the coating solution on the core; A method for producing a composite formulation according to any one of claims 1 to 12. The method of claim 14, wherein the solvent is water, ethanol, methanol, chloroform, dimethyl sulfoxide (DMSO), or a mixture thereof.

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