WO2016003180A1 - Preparation composite comprenant une couche de revêtement pelliculaire contenant un inhibiteur de la 5-alpha-réductase, et procédé pour produire la préparation composite - Google Patents

Preparation composite comprenant une couche de revêtement pelliculaire contenant un inhibiteur de la 5-alpha-réductase, et procédé pour produire la préparation composite Download PDF

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Publication number
WO2016003180A1
WO2016003180A1 PCT/KR2015/006742 KR2015006742W WO2016003180A1 WO 2016003180 A1 WO2016003180 A1 WO 2016003180A1 KR 2015006742 W KR2015006742 W KR 2015006742W WO 2016003180 A1 WO2016003180 A1 WO 2016003180A1
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Prior art keywords
polyvinyl alcohol
film coating
reductase inhibitor
formulation
coating layer
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PCT/KR2015/006742
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English (en)
Korean (ko)
Inventor
김형서
조정현
김진철
김용일
박재현
우종수
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한미약품 주식회사
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Application filed by 한미약품 주식회사 filed Critical 한미약품 주식회사
Priority to EP15815459.1A priority Critical patent/EP3150201B1/fr
Priority to ES15815459T priority patent/ES2781110T3/es
Priority to CN201580035935.6A priority patent/CN106659692B/zh
Priority to PL15815459T priority patent/PL3150201T3/pl
Priority claimed from KR1020150093777A external-priority patent/KR20160002411A/ko
Publication of WO2016003180A1 publication Critical patent/WO2016003180A1/fr
Priority to PH12016502536A priority patent/PH12016502536A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a composite formulation comprising a 5- ⁇ -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- ⁇ -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- ⁇ -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.
  • tamsulosin or phosphodiesterase 5 inhibitors e.g., Tadalafil, Vardenafil, Eudenafil, Sildenafil, etc.
  • 5- ⁇ -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 ⁇ -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
  • Vardenafil Levitra, GSK
  • the 5- ⁇ -reductase inhibitor contained in the film coating layer in the combination preparation in order to ensure sufficient bioavailability and rapid effect upon oral administration, the 5- ⁇ -reductase inhibitor contained in the film coating layer in the combination preparation.
  • High dissolution rate is required and content uniformity should be high.
  • 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- ⁇ -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- ⁇ -reductase inhibitor-containing film coating layer.
  • a composite formulation comprising a film coating layer containing a 5- ⁇ -reductase inhibitor
  • the film coating layer provides a composite agent is coated with a film coating solution containing a 5- ⁇ -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.
  • 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- ⁇ -reductase inhibitor-containing film coating layer, the film coating layer is a conventional external impact It may have a tensile strength to withstand.
  • 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.
  • 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.
  • finasteride which is a representative drug of 5- ⁇ -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.
  • the co-formulation enables a high-efficiency, commercial, and economical co-formulation containing two or more active ingredients including a 5- ⁇ -reductase inhibitor, thereby using a combination of drugs containing a 5- ⁇ -reductase inhibitor.
  • the patient's compliance with the medication can be improved.
  • FIG. 1 shows a composite formulation (a) coated with a 5- ⁇ -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.
  • 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.
  • FIG. 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. 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.
  • Example 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.
  • 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.
  • 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.
  • the present inventors have a high dissolution rate and content uniformity to prepare a stable and effective co-formulation comprising a 5- ⁇ -reductase inhibitor, but also a 5- ⁇ having a tensile strength that can withstand conventional external impact -
  • the redox enzyme-containing film coating layer was intensively studied.
  • 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- ⁇ -reductase inhibitor and the film coating base used to form the film coating layer.
  • a film coating layer having high dissolution rate and content uniformity can be formed.
  • a composite formulation comprising a film coating layer containing a 5- ⁇ -reductase inhibitor
  • the film coating layer provides a composite agent is coated with a film coating solution containing a 5- ⁇ -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.
  • the core containing the first active ingredient may be any solid pharmaceutical formulation commonly used in the pharmaceutical arts.
  • 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- ⁇ -reductase inhibitor may be formed on the surface of the core.
  • the film coating solution is a solution comprising any coating base and 5- ⁇ -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- ⁇ -reductase inhibitor.
  • the amount of the organic solvent may be used as a volume capable of dissolving both the coating base and the 5- ⁇ -reductase inhibitor, and may vary depending on the specific components of the 5- ⁇ -reductase inhibitor. In one embodiment, when the 5- ⁇ -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.
  • the organic solvent is ethanol.
  • the present inventors are a film coating liquid prepared by mixing a 5- ⁇ -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.
  • the dissolution test of the 5- ⁇ -reductase inhibitors was performed over time.
  • 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).
  • 5- ⁇ -reductase inhibitors such as finasteride or dutasteride
  • 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- ⁇ -reductase inhibitor significantly higher with a low dissolution deviation, it can be provided as a stable effective combination formulation.
  • the film coating base is polyvinyl alcohol- polyethylene glycol graft copolymer; And polyvinyl alcohol or polyvinylpyrrolidone.
  • 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.
  • the present inventors prepared a composite formulation in which a film coating layer including a 5- ⁇ -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- ⁇ -reductase inhibitor over time was performed.
  • 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).
  • 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.
  • the film coating layer is formed from the core.
  • 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.
  • 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.
  • 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.
  • FIG. 1 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- ⁇ -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- ⁇ -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.
  • 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- ⁇ -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.
  • 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.
  • 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.
  • the "first active ingredient” is intended to distinguish and distinguish other active ingredients of the co-formulation including the 5- ⁇ -reductase inhibitor from the 5- ⁇ -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- ⁇ -reductase inhibitor, for example tamsulosin or phosphodiesterase 5 inhibitors (eg tadalafil, sildenafil, vardenafil , Eudenafil, etc.).
  • a 5- ⁇ -reductase inhibitor for example tamsulosin or phosphodiesterase 5 inhibitors (eg tadalafil, sildenafil, vardenafil , Eudenafil, etc.).
  • the combination formulation is for oral administration.
  • the first active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof, and the second active ingredient is a 5- ⁇ -reductase inhibitor.
  • the 5- ⁇ -reductase inhibitor may be selected from the group consisting of finasteride, dutasteride, alphatradiol, and combinations thereof.
  • the dissolution rate of the 5- ⁇ -reductase inhibitor may be about 75% or more in 15 minutes.
  • 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.
  • 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.
  • the first active ingredient is a phosphodiesterase 5 inhibitor
  • the second active ingredient is a 5- ⁇ -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.
  • 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- ⁇ -reductase inhibitor may be selected from the group consisting of finasteride, dutasteride, alphatradiol, and combinations thereof.
  • the dissolution rate of the 5- ⁇ -reductase inhibitor may be about 75% or more in 15 minutes.
  • 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.
  • 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.
  • 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.
  • 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- ⁇ -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- ⁇ -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.
  • the co-formulation according to the present invention for the preparation of a co-formulation including a 5- ⁇ -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 - ⁇ -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.
  • 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 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.
  • 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- ⁇ -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- ⁇ -reductase inhibitor-containing co-agent can be produced more economically.
  • 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.
  • Test Example 1 Confirming dissolution of finasteride and coating base
  • t max is 1 to 2 hours, which requires rapid absorption through high dissolution rate. It is a drug.
  • t max is 1 to 2 hours, which requires rapid absorption through high dissolution rate. It is a drug.
  • 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 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.
  • 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.
  • Example 12-21 Preparation of a Co-Formulation with a 5- ⁇ -Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin Hydrochloride Capsule Core
  • the prepared capsules were dried at 35 ° C. for 30 minutes to prepare a composite formulation in which a film coating layer containing 5- ⁇ -reductase inhibitor was coated on the tamsulosin capsule core.
  • Comparative Example 9-16 Preparation of a Co-Formulation with a 5- ⁇ -Reductase Inhibitor-Containing Film Coating Layer Coated on Tamsulosin Hydrochloride Capsule Core
  • a film coating layer containing 5- ⁇ -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.
  • 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- ⁇ -reductase inhibitor was coated on tamsulosin ® odyssey core.
  • 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.
  • 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.
  • FIG. 7 shows photographs photographing an example of a composite agent determined as a good product (a) and a defective product (b).
  • 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.
  • Test 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
  • 16 to 16 and Examples 18 to 21 have been shown to be more preferred in terms of reducing defective rates.
  • Test Example 7 Defective testing by coating base under severe conditions
  • Comparative Example 10 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.
  • 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.
  • 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.
  • Test 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.
  • Example 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.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne une préparation composite et un procédé de fabrication de celle-ci, la préparation composite comprenant : un noyau contenant un premier principe actif ; et une couche de revêtement pelliculaire contenant un inhibiteur de la 5-α-réductase, la couche de revêtement pelliculaire étant mise en place en utilisant une solution de revêtement pelliculaire, laquelle est un solvant mixte constitué d'eau et de solvant organique dans un rapport de 30 à 80 % en poids pour ce dernier, et dans lequel le matériau de revêtement pelliculaire est dissous.
PCT/KR2015/006742 2014-06-30 2015-06-30 Preparation composite comprenant une couche de revêtement pelliculaire contenant un inhibiteur de la 5-alpha-réductase, et procédé pour produire la préparation composite WO2016003180A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP15815459.1A EP3150201B1 (fr) 2014-06-30 2015-06-30 Preparation composite comprenant une couche de revêtement pelliculaire contenant un inhibiteur de la 5-alpha-réductase, et procédé pour produire la préparation composite
ES15815459T ES2781110T3 (es) 2014-06-30 2015-06-30 Preparación de material compuesto que comprende una capa de recubrimiento de película, que contiene un inhibidor de la 5-alfa-reductasa, y método para la producción de la preparación de material compuesto
CN201580035935.6A CN106659692B (zh) 2014-06-30 2015-06-30 包括含有活性成分的膜包衣层的复合制剂
PL15815459T PL3150201T3 (pl) 2014-06-30 2015-06-30 Preparat kompozytowy zawierający błonową warstwę powlekającą zawierającą inhibitor 5-reduktazy i sposób wytwarzania preparatu kompozytowego
PH12016502536A PH12016502536A1 (en) 2014-06-30 2016-12-19 Composite preparation comprising 5-a-reductase inhibitor-containing film coating layer, and method for producing the composite preparation

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20140081223 2014-06-30
KR10-2014-0081223 2014-06-30
KR1020150093777A KR20160002411A (ko) 2014-06-30 2015-06-30 5-α-환원효소 억제제-함유 필름 코팅층을 포함하는 복합제제 및 그 제조방법
KR10-2015-0093777 2015-06-30

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Cited By (1)

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WO2019224840A1 (fr) * 2018-05-19 2019-11-28 Zim Laboratories Limited Nouvelle composition pharmaceutique de tamsulosine et de dutastéride

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KR20080007252A (ko) * 2005-04-13 2008-01-17 바이엘 헬스케어 아게 양성 전립선 과다형성증용 치료 조합물
WO2012127495A2 (fr) * 2011-02-28 2012-09-27 Titan Laboratories Pvt. Ltd. Composition pharmaceutique et son procédé de préparation
US20130171199A1 (en) * 2009-12-22 2013-07-04 Abbott Healthcare Private Limited Controlled release pharmaceutical composition
US20140010872A1 (en) * 2011-03-23 2014-01-09 Hanmi Pharm. Co., Ltd. Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor
KR20140013436A (ko) * 2012-07-24 2014-02-05 한미약품 주식회사 메트포르민 및 로수바스타틴을 포함하는 경구용 복합 제제

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KR20080007252A (ko) * 2005-04-13 2008-01-17 바이엘 헬스케어 아게 양성 전립선 과다형성증용 치료 조합물
US20130171199A1 (en) * 2009-12-22 2013-07-04 Abbott Healthcare Private Limited Controlled release pharmaceutical composition
WO2012127495A2 (fr) * 2011-02-28 2012-09-27 Titan Laboratories Pvt. Ltd. Composition pharmaceutique et son procédé de préparation
US20140010872A1 (en) * 2011-03-23 2014-01-09 Hanmi Pharm. Co., Ltd. Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor
KR20140013436A (ko) * 2012-07-24 2014-02-05 한미약품 주식회사 메트포르민 및 로수바스타틴을 포함하는 경구용 복합 제제

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BASF , PHARMA INGREDIENTS & SERVICES: "Kollicoat Protect, 03_040903e-08", TECHNICAL INFORMATION, February 2012 (2012-02-01), pages 1 - 10, XP055380857, Retrieved from the Internet <URL:http://www.pharma-ingredients.basf.com/Statements/Technical%20Informations/EN/Pharma%20Solutions/03_040903e_Kollicoa2%20Protect.pdf> *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019224840A1 (fr) * 2018-05-19 2019-11-28 Zim Laboratories Limited Nouvelle composition pharmaceutique de tamsulosine et de dutastéride
US11771691B2 (en) 2018-05-19 2023-10-03 Zim Laboratories Limited Pharmaceutical composition of Tamsulosin and Dutasteride

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